FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chen, HL Burton, EA Ross, GW Huang, XM Savica, R Abbott, RD Ascherio, A Caviness, JN Gao, X Gray, KA Hong, JS Kamel, F Jennings, D Kirshner, A Lawler, C Liu, R Miller, GW Nussbaum, R Peddada, SD Rick, AC Ritz, B Siderowf, AD Tanner, CM Troster, AI Zhang, J AF Chen, Honglei Burton, Edward A. Ross, G. Webster Huang, Xuemei Savica, Rodolfo Abbott, Robert D. Ascherio, Alberto Caviness, John N. Gao, Xiang Gray, Kimberly A. Hong, Jau-Shyong Kamel, Freya Jennings, Danna Kirshner, Annette Lawler, Cindy Liu, Rui Miller, Gary W. Nussbaum, Robert Peddada, Shyamal D. Rick, Amy Comstock Ritz, Beate Siderowf, Andrew D. Tanner, Caroline M. Troester, Alexander I. Zhang, Jing TI Research on the Premotor Symptoms of Parkinson's Disease: Clinical and Etiological Implications SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review ID SLEEP BEHAVIOR DISORDER; HUMAN ALPHA-SYNUCLEIN; BOWEL MOVEMENT FREQUENCY; INCIDENTAL LEWY BODIES; CENTRAL-NERVOUS-SYSTEM; LRRK2 G2019S MUTATION; H5N1 INFLUENZA-VIRUS; OLFACTORY DYSFUNCTION; RISK-FACTORS; MOUSE MODEL AB BACKGROUND: The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. OBJECTIVES: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. METHODS: This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. DISCUSSION: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. CONCLUSION: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. C1 [Chen, Honglei; Gray, Kimberly A.; Hong, Jau-Shyong; Kamel, Freya; Kirshner, Annette; Lawler, Cindy; Liu, Rui; Peddada, Shyamal D.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Burton, Edward A.] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Huang, Xuemei] Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. [Savica, Rodolfo] Mayo Clin, Rochester, MN USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Ascherio, Alberto; Gao, Xiang] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Caviness, John N.] Mayo Clin Arizona, Scottsdale, AZ USA. [Jennings, Danna] Inst Neurodegenerat Disorders, New Haven, CT USA. [Miller, Gary W.] Emory Univ, Atlanta, GA 30322 USA. [Nussbaum, Robert] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Rick, Amy Comstock] Parkinsons Act Network, Washington, DC USA. [Ritz, Beate] Univ Calif Los Angeles, Los Angeles, CA USA. [Siderowf, Andrew D.] Avid Radiopharmaceut, Philadelphia, PA USA. [Tanner, Caroline M.] Parkinson Inst, Sunnyvale, CA USA. [Tanner, Caroline M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Troester, Alexander I.] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Zhang, Jing] Univ Washington, Seattle, WA 98195 USA. RP Chen, HL (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov RI Gray, Kimberly/B-6989-2009; Ritz, Beate/E-3043-2015; OI Kamel, Freya/0000-0001-5052-6615; Chen, Honglei/0000-0003-3446-7779 FU National Institute of Environmental Health Sciences; Complete Genomics Inc.; Michael J. Fox Foundation; Brin Foundation; Parkinson's Institute and Clinical Center; Parkinson's Disease Foundation; U.S. Army Medical Research Acquisition Activity (the Telemedicine & Advanced Technology Research Center-managed Neurotoxin Exposure Treatment Research Program); National Institutes of Health, National Institute of Neurological Disorders and Stroke FX The Parkinson's Disease Premotor Symptom Symposium was jointly supported by the intramural and extramural research programs of the National Institute of Environmental Health Sciences. We thank M. Watson and K. Gillig for their help in organizing the meeting and E. J. Zhao and E. Hood for their help in preparing this manuscript.; X. G. has a consultancy relationship with Teva; R.N. was a paid consultant for Complete Genomics Inc.; A. C. R is an employee of the Parkinson Action Network; and A. D. S. is an employee of Avid Radiopharmaceuticals Inc. C. M. T. is an employee of the Parkinson's Institute. She serves on the Scientific Advisory Boards of the Michael J. Fox Foundation and the National Spasmodic Dystonia Association and has provided consulting services to Impax Pharmaceuticals, Adamas Pharmaceuticals, and Abbvie Pharmaceuticals. She also receives grant support from the Michael J. Fox Foundation, the Brin Foundation, James and Sharron Clark, the Parkinson's Institute and Clinical Center, the Parkinson's Disease Foundation, the U.S. Army Medical Research Acquisition Activity (the Telemedicine & Advanced Technology Research Center-managed Neurotoxin Exposure Treatment Research Program), and the National Institutes of Health, National Institute of Neurological Disorders and Stroke. A. I. T is a consultant and/or speaker for Medtronic, St. Jude Medical, and Boston Scientific. The other authors declare they have no actual or - potential competing financial interests. NR 99 TC 21 Z9 23 U1 0 U2 19 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 NOV-DEC PY 2013 VL 121 IS 11-12 BP 1245 EP 1252 DI 10.1289/ehp.1306967 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 266ZA UT WOS:000328061900012 PM 23933572 ER PT J AU Lam, T Williams, PL Burns, JS Sergeyev, O Korrick, SA Lee, MM Birnbaum, LS Revich, B Altshul, LM Patterson, DG Turner, WE Hauser, R AF Lam, Thuy Williams, Paige L. Burns, Jane S. Sergeyev, Oleg Korrick, Susan A. Lee, Mary M. Birnbaum, Linda S. Revich, Boris Altshul, Larisa M. Patterson, Donald G., Jr. Turner, Wayman E. Hauser, Russ TI Predictors of Serum Chlorinated Pesticide Concentrations among Prepubertal Russian Boys SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID PERSISTENT ORGANIC POLLUTANTS; SCHOOL-AGED CHILDREN; POLYCHLORINATED-BIPHENYLS; ORGANOCHLORINE PESTICIDES; DIOXIN EXPOSURE; ADIPOSE-TISSUE; DIETARY-INTAKE; LIFE-STYLE; HEXACHLOROBENZENE; HEXACHLOROCYCLOHEXANE AB BACKGROUND: Few studies have evaluated predictors of childhood exposure to organochlorine pesticides (OCPs), a class of lipophilic persistent chemicals. Objectives: Our goal was to identify predictors of serum OCP concentrations-hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), and p,p-dichlorodiphenyldichloroethylene (p,p'-DDE)-among boys in Chapaevsk, Russia. METHODS: Between 2003 and 2005, 499 boys 8-9 years of age were recruited in a prospective cohort. The initial study visit included a physical examination; blood collection; health, lifestyle, and food-frequency questionnaires; and determination of residential distance from a local factory complex that produced HCB and beta-HCH. Fasting serum samples were analyzed for OCPs at the U.S. Centers for Disease Control and Prevention. General linear regression models were used to identify predictors of the boys' serum HCB, beta-HCH, and p,p'-DDE concentrations. RESULTS: Among 355 boys with OCP measurements, median serum HCB, beta-HCH, and p,p'-DDE concentrations were 158, 167, and 284 ng/g lipid, respectively. Lower body mass index, longer breastfeeding duration, and local dairy consumption were associated with higher concentrations of OCPs. Boys who lived < 2 km from the factory complex had 64% (95% CI: 37, 96) and 57% (95% CI: 32, 87) higher mean HCB and beta-HCH concentrations, respectively, than boys who lived >= 5 km away. Living > 3 years in Chapaevsk predicted higher beta-HCH concentrations, and having parents who lacked a high school education predicted higher p,p'-DDE concentrations. CONCLUSIONS: Among this cohort of prepubertal Russian boys, predictors of serum OCPs included consumption of local dairy products, longer local residence, and residential proximity to the local factory complex. C1 [Lam, Thuy; Burns, Jane S.; Korrick, Susan A.; Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Williams, Paige L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Sergeyev, Oleg] Samara State Med Univ, Dept Phys Educ & Hlth, Samara, Russia. [Sergeyev, Oleg] Chapaevsk Med Assoc, Chapaevsk, Samara Region, Russia. [Korrick, Susan A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Lee, Mary M.] Univ Massachusetts, Sch Med, Dept Pediat & Cell Biol, Pediat Endocrine Div, Worcester, MA USA. [Birnbaum, Linda S.] NCI, Res Triangle Pk, NC USA. [Birnbaum, Linda S.] NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Revich, Boris] Russian Acad Sci, Inst Forecasting, Moscow, Russia. [Altshul, Larisa M.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. [Altshul, Larisa M.] Environm Hlth & Engn Inc, Needham, MA USA. [Patterson, Donald G., Jr.] EnviroSolut Consulting Inc, Auburn, GA USA. [Patterson, Donald G., Jr.] Axys Analyt Solut, Sidney, BC, Canada. [Patterson, Donald G., Jr.] Exponent Inc, Maynard, MA USA. [Turner, Wayman E.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Lam, T (reprint author), Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg 1,Room 1406N, Boston, MA 02115 USA. EM tlam@mail.harvard.edu; rhauser@hsph.harvard.edu RI Sergeyev, Oleg/H-8854-2013 OI Sergeyev, Oleg/0000-0002-5745-3348 FU U.S. Environmental Protection Agency [R82943701]; National Institute of Environmental Health Sciences [ES014370, ES000002, ES017117]; National Institute for Occupational Safety and Health [T42-OH008416-04] FX This work was funded by the U.S. Environmental Protection Agency (R82943701) and the National Institute of Environmental Health Sciences (ES014370, ES000002, and ES017117). T. L. is supported by National Institute for Occupational Safety and Health training grant T42-OH008416-04. NR 45 TC 6 Z9 6 U1 3 U2 12 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 NOV-DEC PY 2013 VL 121 IS 11-12 BP 1372 EP 1377 DI 10.1289/ehp.1306480 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 266ZA UT WOS:000328061900028 PM 23955839 ER PT J AU Piao, YS Wiesenfeld, P Sprando, R Arnold, JT AF Piao, Yun-shang Wiesenfeld, Paddy Sprando, Robert Arnold, Julia T. TI TGF beta 1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment? SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE TGF beta 1; Reactive prostate stroma; Androstenedione; Testosterone; DHEA; Steroid metabolism ID TRANSFORMING-GROWTH-FACTOR; 3-BETA-HYDROXYSTEROID DEHYDROGENASE; 5 17-BETA-HYDROXYSTEROID-DEHYDROGENASE; FACTOR-BETA; ESTROGEN METABOLISM; EPITHELIAL-CELLS; CANCER; TYPE-2; DHEA; GROWTH-FACTOR-BETA-1 AB The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGF beta 1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGF beta 1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGF beta 1 produced time-and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGF beta 1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3 beta hydroxysteroid dehydrogenase (HSD), and down-regulation of 17 beta HSD5, and 17 beta HSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens. Published by Elsevier Ltd. C1 [Piao, Yun-shang; Arnold, Julia T.] NIH, Div Intramural Res, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Wiesenfeld, Paddy; Sprando, Robert] US FDA, Div Toxicol, Off Appl Res & Safety Assessment, Ctr Food Safety & Appl Nutr, Laurel, MD 20708 USA. RP Arnold, JT (reprint author), NCI, NIH, 9609 Med Ctr Dr,Rm 3W206, Rockville, MD 20850 USA. EM jarnold@mail.nih.gov FU National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD [Z01 AT000006-09] FX The authors thank Dr. Guenter Vollmer (Technical University, Dresden, Germany) for constructive comments in reviewing this manuscript. This work was supported by the Intramural Research Program, (Z01 AT000006-09) National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD. NR 45 TC 6 Z9 6 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD NOV PY 2013 VL 138 BP 206 EP 213 DI 10.1016/j.jsbmb.2013.05.016 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 264UK UT WOS:000327906300022 PM 23770322 ER PT J AU Abeliovich, H Zarei, M Rigbolt, KTG Youle, RJ Dengjel, J AF Abeliovich, Hagai Zarei, Mostafa Rigbolt, Kristoffer T. G. Youle, Richard J. Dengjel, Joern TI Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy SO NATURE COMMUNICATIONS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; MONITORING AUTOPHAGY; OXIDATIVE STRESS; YEAST; DEGRADATION; FISSION; GTPASE; FUSION; MUTANTS; COMPLEX AB Mitophagy, the autophagic degradation of mitochondria, is an important housekeeping function in eukaryotic cells, and defects in mitophagy correlate with ageing phenomena and with several neurodegenerative disorders. A central mechanistic question regarding mitophagy is whether mitochondria are consumed en masse, or whether an active process segregates defective molecules from functional ones within the mitochondrial network, thus allowing a more efficient culling mechanism. Here we combine a proteomic study with a molecular genetics and cell biology approach to determine whether such a segregation process occurs in yeast mitochondria. We find that different mitochondrial matrix proteins undergo mitophagic degradation at distinctly different rates, supporting the active segregation hypothesis. These differential degradation rates depend on mitochondrial dynamics, suggesting a mechanism coupling weak physical segregation with mitochondrial dynamics to achieve a distillation-like effect. In agreement, the rates of mitophagic degradation strongly correlate with the degree of physical segregation of specific matrix proteins. C1 [Abeliovich, Hagai] Hebrew Univ Jerusalem, Robert H Smith Fac Agr Food & Environm, Inst Biochem Food Sci & Nutr, IL-76100 Rehovot, Israel. [Abeliovich, Hagai; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Zarei, Mostafa; Rigbolt, Kristoffer T. G.; Dengjel, Joern] Univ Freiburg, Ctr Biol Signaling Studies, FRIAS, D-79104 Freiburg, Germany. [Zarei, Mostafa; Rigbolt, Kristoffer T. G.; Dengjel, Joern] Univ Freiburg, Ctr Biol Signaling Studies, BIOSS, D-79104 Freiburg, Germany. [Zarei, Mostafa; Rigbolt, Kristoffer T. G.; Dengjel, Joern] Univ Freiburg, ZBSA Ctr Biol Syst Anal, D-79104 Freiburg, Germany. [Zarei, Mostafa; Rigbolt, Kristoffer T. G.; Dengjel, Joern] Univ Freiburg, Dept Dermatol, Med Ctr, D-79104 Freiburg, Germany. RP Abeliovich, H (reprint author), Hebrew Univ Jerusalem, Robert H Smith Fac Agr Food & Environm, Inst Biochem Food Sci & Nutr, POB 12, IL-76100 Rehovot, Israel. EM hagai.abeliovich@mail.huji.ac.il FU Israel Science Foundation [1016/07, 422/12]; intramural programme of NINDS; Excellence Initiative of the German Federal and State Governments through Freiburg Institute for Advanced Studies (FRIAS); School of Life Sciences - LifeNet; Center for Biological Signaling Studies; German Research Foundation, DFG [DE 1757/2-1]; German Ministry for Education and Research, BMBF [NephAge (031 5896A)]; Danish Natural Sciences Research Council FX We thank Orian Shirihai, Leslie Kane, Ian Holt and J.-C. Martinou for stimulating and fruitful discussions, members of the Youle lab for support and encouragement, and Dikla Journo-Eckstien for technical assistance. We also thank J.-C. Martinou and Zvulun Elazar for critical reading of the manuscript. This work was funded by Israel Science Foundation grants 1016/07 and 422/12 to H. A., by the intramural programme of NINDS, and by the Excellence Initiative of the German Federal and State Governments through Freiburg Institute for Advanced Studies (FRIAS), School of Life Sciences - LifeNet (JD) and the Center for Biological Signaling Studies (BIOSS, JD), by grants DE 1757/2-1 from the German Research Foundation, DFG, and through GerontoSys II - NephAge (031 5896A) from the German Ministry for Education and Research, BMBF (JD), and by a grant from the Danish Natural Sciences Research Council (KTGR). NR 54 TC 21 Z9 21 U1 0 U2 19 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 NOV PY 2013 VL 4 AR 2789 DI 10.1038/ncomms3789 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266LJ UT WOS:000328025000004 PM 24240771 ER PT J AU Lencz, T Guha, S Liu, CY Rosenfeld, J Mukherjee, S DeRosse, P John, M Cheng, LJ Zhang, CL Badner, JA Ikeda, M Iwata, N Cichon, S Rietschel, M Nothen, MM Cheng, ATA Hodgkinson, C Yuan, QP Kane, JM Lee, AT Pisante, A Gregersen, PK Pe'er, I Malhotra, AK Goldman, D Darvasi, A AF Lencz, Todd Guha, Saurav Liu, Chunyu Rosenfeld, Jeffrey Mukherjee, Semanti DeRosse, Pamela John, Majnu Cheng, Lijun Zhang, Chunling Badner, Judith A. Ikeda, Masashi Iwata, Nakao Cichon, Sven Rietschel, Marcella Noethen, Markus M. Cheng, A. T. A. Hodgkinson, Colin Yuan, Qiaoping Kane, John M. Lee, Annette T. Pisante, Anne Gregersen, Peter K. Pe'er, Itsik Malhotra, Anil K. Goldman, David Darvasi, Ariel TI Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder SO NATURE COMMUNICATIONS LA English DT Article ID TRADITIONAL DIAGNOSTIC BOUNDARIES; ASHKENAZI JEWISH POPULATION; HEPARAN-SULFATE; LINKAGE DISEQUILIBRIUM; COMMON VARIANTS; GENE; SUSCEPTIBILITY; RISK; EXPRESSION; DISEASE AB Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in P-meta = 9.49 x 10(-12) (odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and P-meta = 2.67 x 10(-8) (OR = 1.15, 95% CI: 1.08-1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders. C1 [Lencz, Todd; Guha, Saurav; Rosenfeld, Jeffrey; Mukherjee, Semanti; DeRosse, Pamela; John, Majnu; Kane, John M.; Malhotra, Anil K.] North Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp Div, Dept Psychiat, Div Res, Glen Oaks, NY 11004 USA. [Lencz, Todd; Kane, John M.; Malhotra, Anil K.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY 11030 USA. [Lencz, Todd; Kane, John M.; Malhotra, Anil K.] Yeshiva Univ Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10461 USA. [Lencz, Todd; Kane, John M.; Malhotra, Anil K.] Hofstra Univ, Sch Med, Dept Psychiat, Hempstead, NY 11550 USA. [Lencz, Todd; Kane, John M.; Malhotra, Anil K.] Hofstra Univ, Sch Med, Dept Mol Med, Hempstead, NY 11550 USA. [Liu, Chunyu] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Cheng, Lijun; Zhang, Chunling; Badner, Judith A.] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Ikeda, Masashi; Iwata, Nakao] Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan. [Cichon, Sven; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany. [Rietschel, Marcella] Univ Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-68159 Mannheim, Germany. [Cheng, A. T. A.] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Hodgkinson, Colin; Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. [Lee, Annette T.; Gregersen, Peter K.] Feinstein Inst Med Res, Robert S Boas Ctr Human Genet & Genom, Manhasset, NY 11030 USA. [Pisante, Anne; Darvasi, Ariel] Hebrew Univ Jerusalem, Inst Life Sci, Dept Genet, IL-91904 Jerusalem, Israel. [Gregersen, Peter K.] Hofstra Univ, Dept Med, Sch Med, Hempstead, NY 11550 USA. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. RP Lencz, T (reprint author), North Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp Div, Dept Psychiat, Div Res, Glen Oaks, NY 11004 USA. EM lencz@lij.edu; ariel@hebrew.edu RI Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X; Guha, Saurav/0000-0002-0620-5408; Nothen, Markus/0000-0002-8770-2464 FU North Shore-LIJ Health System Foundation; National Institutes of Health [RC2 MH089964, R01 MH095458, R01 MH084098, P50 MH080173, P30 MH090590, R01 MH080425] FX We thank Michael Ryan of the Feinstein Institute Biorepository for assistance with sample handling and preparation. This work was supported by the North Shore-LIJ Health System Foundation and the National Institutes of Health (RC2 MH089964, R01 MH095458 and R01 MH084098 to T. L.; P50 MH080173 to A. K. M.; P30 MH090590 to J.M.K.; and R01 MH080425 to C. L.). We thank David B. Goldstein for providing summary data from the Aberdeen and Munich cohorts. We are extremely grateful to investigators, including Pablo Gejman, John Kelsoe and Nick Craddock, who have made their genotype data publicly available through dbGAP and the Wellcome Trust Case-Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of these data sets is available from www.wtccc.org.uk as well as the following studies within dbGAP (http://www.ncbi.nlm.nih.gov/projects/gap):; /cgi-bin/study.cgi?study_id = phs000167.v1.p1;; /cgi-bin/study.cgi?study_id = phs000021.v2.p1;; /cgi-bin/study.cgi?study_id = phs000017.v3.p1. NR 48 TC 30 Z9 30 U1 3 U2 13 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 NOV PY 2013 VL 4 AR 2739 DI 10.1038/ncomms3739 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266KQ UT WOS:000328023000010 PM 24253340 ER PT J AU Singh, N Ma, B Leonardo, CC Ahmad, AS Narumiya, S Dore, S AF Singh, Nilendra Ma, Bo Leonardo, Christopher Charles Ahmad, Abdullah Shafique Narumiya, Shuh Dore, Sylvain TI Role of PGE(2) EP1 Receptor in Intracerebral Hemorrhage-Induced Brain Injury SO NEUROTOXICITY RESEARCH LA English DT Article DE Collagenase; Hematoma; Microglia; Neurodegeneration; Prostaglandin ID AMERICAN-HEART-ASSOCIATION; WIDE THERAPEUTIC WINDOW; FOCAL CEREBRAL-ISCHEMIA; FUNCTIONAL RECOVERY; CELL-DEATH; MICE; INFLAMMATION; RAT; EXPRESSION; STROKE AB Prostaglandin E-2 (PGE(2)) has been described to exert beneficial and detrimental effects in various neurologic disorders. These conflicting roles of PGE(2) could be attributed to its diverse receptor subtypes, EP1-EP4. At present, the precise role of EP1 in intracerebral hemorrhage (ICH) is unknown. Therefore, to elucidate its possible role in ICH, intrastriatal injection of collagenase was given in randomized groups of adult male wildtype (WT) and EP1 receptor knockout (EP1(-/-)) C57BL/6 mice. Functional outcomes including neurologic deficits, rotarod performance, open field activity, and adhesive removal performance were evaluated at 24, 48, and 72 h post-ICH. Lesion volume, cell survival and death, were assessed using Cresyl Violet, and Fluoro-Jade staining, respectively. Microglial activation and phagocytosis were estimated using Iba1 immunoreactivity and fluorescently-labeled microspheres. Following 72 h post-ICH, EP1(-/-) mice showed deteriorated outcomes compared to the WT control mice. These outcomes were demonstrated by elevated neurological deficits, exacerbated lesion volume, and significantly worsened sensorimotor functions. Fluoro-Jade staining showed significantly increased numbers of degenerating neurons and reduced neuronal survival in EP1(-/-) compared to WT mice. To assess in vivo phagocytosis, the number of microspheres phagocytosed by Iba1-positive cells was 145.4 +/- 15.4 % greater in WT compared to EP1(-/-) mice. These data demonstrate that EP1 deletion exacerbates neuro-behavioral impairments following ICH, potentially by slowing down/impairing microglial phagocytosis. A better understanding of this EP1 mechanism could lead to improved intervention strategies for hemorrhagic stroke. C1 [Singh, Nilendra; Leonardo, Christopher Charles; Ahmad, Abdullah Shafique; Dore, Sylvain] Univ Florida, Dept Anesthesiol, Ctr Translat Res Neurodegenerat Dis, Gainesville, FL 32610 USA. [Ma, Bo] NIA, Div Neurogenet, Bethesda, MD 21225 USA. [Narumiya, Shuh] Kyoto Univ, Dept Pharmacol, Kyoto 6068315, Japan. [Dore, Sylvain] Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. [Dore, Sylvain] Univ Florida, Dept Neurol, Gainesville, FL 32610 USA. [Dore, Sylvain] Univ Florida, Dept Psychiat, Gainesville, FL 32610 USA. RP Dore, S (reprint author), Univ Florida, Dept Neurosci, Gainesville, FL 32610 USA. EM sdore@ufl.edu RI MA, BO/L-6502-2015 OI MA, BO/0000-0001-5922-666X FU National Institutes of Health [NS046400, AG022971]; American Heart Association [09POST2080364] FX We thank all Dore lab team members for their active participation. National Institutes of Health (NS046400, AG022971) to SD, and the American Heart Association (09POST2080364) to BM. NR 62 TC 10 Z9 10 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 EI 1476-3524 J9 NEUROTOX RES JI Neurotox. Res. PD NOV PY 2013 VL 24 IS 4 BP 549 EP 559 DI 10.1007/s12640-013-9410-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 268CJ UT WOS:000328145300009 PM 23824501 ER PT J AU Apkarian, AV Neugebauer, V Koob, G Edwards, S Levine, JD Ferrari, L Egli, M Regunathan, S AF Apkarian, A. Vania Neugebauer, Volker Koob, George Edwards, Scott Levine, Jon D. Ferrari, Luiz Egli, Mark Regunathan, Soundar TI Neural mechanisms of pain and alcohol dependence SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the Society-for-Neuroscience CY OCT 13-17, 2012 CL New Orleans, LA SP Soc Neuroscience DE Chronic pain; Drug addiction; Alcohol; Reward; Emotion ID CORTICOTROPIN-RELEASING-FACTOR; MEDIAL PREFRONTAL CORTEX; CHRONIC BACK-PAIN; PROTEIN-KINASE-C; CENTRAL AMYGDALA NEURONS; SYNAPTIC PLASTICITY; DECISION-MAKING; CONDITIONED FEAR; CENTRAL NUCLEUS; ARTHRITIC PAIN AB An association between chronic pain conditions and alcohol dependence has been revealed in numerous studies with episodes of alcohol abuse antedating chronic pain in some people and alcohol dependence emerging after the onset of chronic pain in others. Alcohol dependence and chronic pain share common neural circuits giving rise to the possibility that chronic pain states could significantly affect alcohol use patterns and that alcohol dependence could influence pain sensitivity. The reward and emotional pathways that regulate drug/alcohol addiction also mediate chronic pain. For example, pain-evoked activation of brain learning and brain reward circuitry may modulate cortical processing of pain and central sensitization mediated by mesocorticolimbic circuitry. Imbalance and reorganization of amygdala-mPFC interactions may not only be important for persistent pain, but also for disorders characterized by the abnormal persistence of emotional-affective states such as drug and alcohol addiction. Further studies are necessary to understand how these neural circuits are regulated in comorbid conditions of alcoholism and chronic pain. In addition, long term alcohol use could induce pain symptoms and may exacerbate chronic pain arising from other sources. While prior studies have established a role of neuroendocrine stress axis mediators in alcohol abuse and neurotoxic effects, these studies have not explored the distinction between the individual impact of alcohol and stress hormones. Future studies should explore the mechanisms mediating the contribution of alcohol and stress axis hormones on pain, an important question in our understanding of the neurobiology of alcohol abuse and chronic pain. Published by Elsevier Inc. C1 [Apkarian, A. Vania] Northwestern Univ, Sch Med, Dept Neurosci, Chicago, IL USA. [Neugebauer, Volker] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX 77555 USA. [Koob, George; Edwards, Scott] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Levine, Jon D.; Ferrari, Luiz] Univ Calif San Francisco, Div Neurosci NIH Pain Ctr, San Francisco, CA 94143 USA. [Egli, Mark; Regunathan, Soundar] NIAAA, Div Neurosci & Behav, NIH, Bethesda, MD 20892 USA. RP Regunathan, S (reprint author), NIAAA, Div Neurosci & Behav, NIH, Bethesda, MD 20892 USA. EM regunathans@mail.nih.gov RI koob, george/P-8791-2016; OI Apkarian, A. Vania/0000-0002-9788-7458 FU NINDS NIH HHS [R01 NS035115, R01 NS038261, R01 NS081121] NR 120 TC 17 Z9 17 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD NOV 1 PY 2013 VL 112 BP 34 EP 41 DI 10.1016/j.pbb.2013.09.008 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 265AY UT WOS:000327923300006 PM 24095683 ER PT J AU Mensah, GA AF Mensah, George A. TI Introduction: Progress in Cardiovascular Diseases and Diabetes in Africa SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 6 TC 0 Z9 0 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 232 EP 233 DI 10.1016/j.pcad.2013.10.013 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200002 PM 24267429 ER PT J AU Moran, A Forouzanfar, M Sampson, U Chugh, S Feigin, V Mensah, G AF Moran, Andrew Forouzanfar, Mohammad Sampson, Uchechukwu Chugh, Sumeet Feigin, Valery Mensah, George TI The Epidemiology of Cardiovascular Diseases in Sub-Saharan Africa: The Global Burden of Diseases, Injuries and Risk Factors 2010 Study SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Cardiovascular disease; Sub-Saharan Africa; Mortality; Burden of disease; Global health ID ISCHEMIC-HEART-DISEASE; SYSTEMATIC ANALYSIS; POPULATION; FAILURE; COMMON AB The epidemiology of cardiovascular diseases in sub-Saharan Africa is unique among world regions, with about half of cardiovascular diseases (CVDs) due to causes other than atherosclerosis. CVD epidemiology data are sparse and of uneven quality in sub-Saharan Africa. Using the available data, the Global Burden of Diseases, Risk Factors, and Injuries (GBD) 2010 Study estimated CVD mortality and burden of disease in sub-Saharan Africa in 1990 and 2010. The leading CVD cause of death and disability in 2010 in sub-Saharan Africa was stroke; the largest relative increases in CVD burden between 1990 and 2010 were in atrial fibrillation and peripheral arterial disease. CVD deaths constituted only 8.8% of all deaths and 3.5% of all disability-adjusted life years (DALYs) in sub-Sahara Africa, less than a quarter of the proportion of deaths and burden attributed to CVD in high income regions. However, CVD deaths in sub-Saharan Africa occur at younger ages on average than in the rest of the world. It remains uncertain if increased urbanization and life expectancy in some parts of sub-Saharan African nations will transition the region to higher CVD burden in future years. (C) 2013 Elsevier Inc. All rights reserved. C1 [Moran, Andrew] Columbia Univ, Div Gen Med, Med Ctr, New York, NY 10032 USA. [Forouzanfar, Mohammad] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Sampson, Uchechukwu] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. [Chugh, Sumeet] Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. [Feigin, Valery] Auckland Univ Technol, Auckland, New Zealand. [Mensah, George] NHLBI, NIH, Bethesda, MD 20892 USA. RP Moran, A (reprint author), Columbia Univ, Div Gen Med, Presbyterian Hosp, 9th Floor East Room 105,622 West 168th St, New York, NY 10032 USA. EM aem35@columbia.edu FU NHLBI NIH HHS [K08 HL089675] NR 25 TC 32 Z9 32 U1 6 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 234 EP 239 DI 10.1016/j.pcad.2013.09.019 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200003 PM 24267430 ER PT J AU Mensah, GA AF Mensah, George A. TI Descriptive Epidemiology of Cardiovascular Risk Factors and Diabetes in Sub-Saharan Africa SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Cardiovascular diseases; Sub-Saharan Africa; Cardiovascular risk factors ID SYSTEMATIC ANALYSIS; GLOBAL BURDEN; HEART-DISEASE; MYOCARDIAL-INFARCTION; SOUTH-AFRICA; 21 REGIONS; URBANIZATION; TRANSITION; POPULATION; INTERHEART AB Reliable data on risk factor levels, exposure history, and population distribution can help inform policies and programs for disease prevention and control. With rare exception however, ideal local data on major risk factors and causes of death and disease burden have been scarce in sub-Saharan Africa (SSA). Basic community surveys in some countries and recent systematic analysis of disease burden attributable to 67 risk factors and risk factor clusters in 21 regions of the world provide an opportunity to examine and relate diabetes and cardiovascular risk factors to mortality and burden in SSA. Rising body mass index, especially in women in Southern Africa; and rising systolic blood pressure in East Africa for both sexes, and in West Africa for women are the major cardiometabolic risk factors. Harmful use of alcohol, especially in Southern SSA, tobacco use, and physical inactivity are also important. Improving vital registration and risk factor surveillance remain major challenges. Published by Elsevier Inc. C1 [Mensah, George A.] NHLBI, Off Director, NIH, Bethesda, MD 20892 USA. RP Mensah, GA (reprint author), NHLBI, NIH, IOD, 31 Ctr Dr MSC 2486, Bethesda, MD 20892 USA. EM george.mensah@nih.gov NR 45 TC 14 Z9 14 U1 3 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 240 EP 250 DI 10.1016/j.pcad.2013.10.014 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200004 PM 24267431 ER PT J AU Tekola-Ayele, F Adeyemo, AA Rotimi, CN AF Tekola-Ayele, Fasil Adeyemo, Adebowale A. Rotimi, Charles N. TI Genetic Epidemiology of Type 2 Diabetes and Cardiovascular Diseases in Africa SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Type 2 diabetes; Cardiovascular diseases; Genetics; Epidemiology; Africa ID CORONARY-ARTERY-DISEASE; QUANTITATIVE TRAIT LOCI; NITRIC-OXIDE SYNTHASE; GENOME-WIDE SEARCH; BLOOD-PRESSURE; WEST AFRICANS; SUSCEPTIBILITY GENES; FAMILY-HISTORY; MELLITUS AADM; HEART-DISEASE AB The burdens of type 2 diabetes (T2D) and cardiovascular diseases (CVD) are increasing in Africa. T2D and CVD are the result of the complex interaction between inherited characteristics, lifestyle, and environmental factors. The epidemic of obesity is largely behind the exploding global incidence of T2D. However, not all obese individuals develop diabetes and positive family history is a powerful risk factor for diabetes and CVD. Recent implementations of high throughput genotyping and sequencing approaches have advanced our understanding of the genetic basis of diabetes and CVD by identifying several genomic loci that were not previously linked to the pathobiology of these diseases. However, African populations have not been adequately represented in these global genomic efforts. Here, we summarize the state of knowledge of the genetic epidemiology of T2D and CVD in Africa and highlight new genomic initiatives that promise to inform disease etiology, public health and clinical medicine in Africa. Published by Elsevier Inc. C1 [Tekola-Ayele, Fasil; Adeyemo, Adebowale A.; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), Bldg 12A,Room 4047 12 South Dr,MSC 5635, Bethesda, MD 20892 USA. EM rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Intramural Research Program of the Center for Research on Genomics and Global Health; National Human Genome Research Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Center for Information Technology; Office of the Director at the National Institutes of Health [1ZIAHG200362-02] FX This work was supported by the Intramural Research Program of the Center for Research on Genomics and Global Health. The Center for Research on Genomics and Global Health is supported by the National Human Genome Research Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362-02). NR 78 TC 8 Z9 8 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 251 EP 260 DI 10.1016/j.pcad.2013.09.013 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200005 PM 24267432 ER PT J AU O'Connor, MY Thoreson, CK Ramsey, NLM Ricks, M Sumner, AE AF O'Connor, Michelle Y. Thoreson, Caroline K. Ramsey, Natalie L. M. Ricks, Madia Sumner, Anne E. TI The Uncertain Significance of Low Vitamin D Levels in African Descent Populations: A Review of the Bone and Cardiometabolic Literature SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Vitamin D; Melanin; Lactose Intolerance; Africans; African Diaspora; African-Americans ID SERUM 25-HYDROXYVITAMIN D; NUTRITION EXAMINATION SURVEY; RURAL GAMBIAN WOMEN; 3RD NATIONAL-HEALTH; D SUPPLEMENTATION; BLOOD-PRESSURE; LACTOSE-INTOLERANCE; MINERAL DENSITY; PARATHYROID-HORMONE; RACIAL-DIFFERENCES AB Vitamin D levels in people of African descent are often described as inadequate or deficient. Whether low vitamin D levels in people of African descent lead to compromised bone or cardiometabolic health is unknown. Clarity on this issue is essential because if clinically significant vitamin D deficiency is present, vitamin D supplementation is necessary. However, if vitamin D is metabolically sufficient, vitamin D supplementation could be wasteful of scarce resources and even harmful. In this review vitamin D physiology is described with a focus on issues specific to populations of African descent such as the influence of melanin on endogenous vitamin D production and lactose intolerance on the willingness of people to ingest vitamin D fortified foods. Then data on the relationship of vitamin D to bone and cardiometabolic health in people of African descent are evaluated. Published by Elsevier Inc. C1 [O'Connor, Michelle Y.; Thoreson, Caroline K.; Ramsey, Natalie L. M.; Ricks, Madia; Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), Bld 10-CRC,Rm 6-5940,MSC 1612,9000 Rockville Pike, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov FU Intramural Research Program of NIDDK FX All the authors were supported by the Intramural Research Program of NIDDK. NR 78 TC 8 Z9 8 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 261 EP 269 DI 10.1016/j.pcad.2013.10.015 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200006 PM 24267433 ER PT J AU Sampson, UKA Amuyunzu-Nyamongo, M Mensah, GA AF Sampson, Uchechukwu K. A. Amuyunzu-Nyamongo, Mary Mensah, George A. TI Health Promotion and Cardiovascular Disease Prevention in Sub-Saharan Africa SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review DE Cardiovascular disease; Sub-Saharan Africa; Non-communicable diseases; Health promotion; Prevention ID CORONARY RISK-FACTOR; SYSTEMATIC ANALYSIS; BLOOD-PRESSURE; HEART-DISEASE; GLOBAL BURDEN; 21 REGIONS; LITERACY; MORTALITY; COMMUNITY; OUTCOMES AB Recent population studies demonstrate an increasing burden of cardiovascular disease (CVD) and related risk factors in sub-Saharan Africa (SSA). The mitigation or reversal of this trend calls for effective health promotion and preventive interventions. In this article, we review the core principles, challenges, and progress in promoting cardiovascular health with special emphasis on interventions to address physical inactivity, poor diet, tobacco use, and adverse cardiometabolic risk factor trends in SSA. We focus on the five essential strategies of the Ottawa Charter for Health Promotion. Successes highlighted include community-based interventions in Ghana, Nigeria, South Africa, and Mauritius and school-based programs in Kenya, Namibia, and Swaziland. We address the major challenge of developing integrated interventions, and showcase partnerships opportunities. We conclude by calling for intersectoral partnerships for effective and sustainable intervention strategies to advance cardiovascular health promotion and close the implementation gap in accordance with the 2009 Nairobi Call to Action on Health Promotion. Published by Elsevier Inc. C1 [Sampson, Uchechukwu K. A.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Sampson, Uchechukwu K. A.] VUMC, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Sampson, Uchechukwu K. A.] VUMC, Dept Radiol & Radiol Sci, Nashville, TN USA. [Amuyunzu-Nyamongo, Mary] African Inst Hlth & Dev, Nairobi, Kenya. [Amuyunzu-Nyamongo, Mary] Consortium NCD Prevent & Control Sub Saharan Afri, Nairobi, Kenya. [Mensah, George A.] NHLBI, Off Director, NIH, Bethesda, MD 20892 USA. RP Sampson, UKA (reprint author), Vanderbilt Univ, Med Ctr, Sect Cardiovasc Dis Prevent, 315 Preston Res Bldg,2220 Pierce Ave, Nashville, TN 37232 USA. EM u.sampson@vanderbilt.edu FU Robert Wood Johnson Foundation FX The authors do not have any conflicts of interest to disclose. Dr. Sampson's effort was supported in part by Harold Amos Medical Faculty Award of the Robert Wood Johnson Foundation. NR 58 TC 2 Z9 2 U1 4 U2 22 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 EI 1873-1740 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD NOV-DEC PY 2013 VL 56 IS 3 BP 344 EP 355 DI 10.1016/j.pcad.2013.10.007 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 263TP UT WOS:000327831200015 PM 24267442 ER PT J AU Stover, AM Reeve, BB Piper, BF Alfano, CM Smith, AW Mitchell, SA Bernstein, L Baumgartner, KB McTiernan, A Ballard-Barbash, R AF Stover, Angela M. Reeve, Bryce B. Piper, Barbara F. Alfano, Catherine M. Smith, Ashley Wilder Mitchell, Sandra A. Bernstein, Leslie Baumgartner, Kathy B. McTiernan, Anne Ballard-Barbash, Rachel TI Deriving clinically meaningful cut-scores for fatigue in a cohort of breast cancer survivors: a Health, Eating, Activity, and Lifestyle (HEAL) Study SO QUALITY OF LIFE RESEARCH LA English DT Article DE Cancer-related fatigue; Breast cancer survivors; Measurement; Piper Fatigue Scale; Health-related quality of life ID QUALITY-OF-LIFE; PATIENT-REPORTED OUTCOMES; UNITED-STATES; WOMEN; DIAGNOSIS; CHEMOTHERAPY; EXPLORATION; PREVALENCE; RECURRENCE; DEPRESSION AB To empirically determine clinically meaningful cut-scores on the 0-10 response scale of the revised Piper Fatigue Scale (PFS-R) and its shorter version (PFS-12). Breast cancer survivors were classified (i.e., none, mild, moderate, or severe fatigue) based on the cut-scores, and relationships between these cut-scores and decrements in health-related quality of life (HRQOL) were examined. A total of 857 breast cancer survivors, stages in situ-IIIa, from the Health, Eating, Activity, and Lifestyle (HEAL) Study were eligible. Survivors completed the PFS-R, SF-36, and a sexual health scale approximately 3 years after diagnosis. Multivariate analysis of covariance was used to examine five fatigue severity cut-score models, controlling for demographics, clinical characteristics, comorbidity, and antidepressant use. Multivariate regression was used to examine HRQOL decrements by cut-score category. Analyses supported two similar fatigue severity cut-score models for the PFS-R and PFS-12: Model A.) none (0), mild (1-3), moderate (4-6), and severe (7-10); and Model D.) none (0), mild (1-2), moderate (3-5), and severe (6-10). For every threshold increase in fatigue severity, clinically meaningful decrements in physical, mental, and sexual health scores were observed, supporting construct validity of the fatigue cut-scores. Standardized fatigue cut-scores may enhance interpretability and comparability across studies and populations and guide treating planning. C1 [Stover, Angela M.] Univ N Carolina, Dept Hlth Behav, Chapel Hill, NC 27599 USA. [Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Piper, Barbara F.] Natl Univ, San Diego, CA USA. [Alfano, Catherine M.; Smith, Ashley Wilder; Mitchell, Sandra A.; Ballard-Barbash, Rachel] NCI, Frederick, MD 21701 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Baumgartner, Kathy B.] Univ Louisville, Louisville, KY 40292 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Reeve, BB (reprint author), Univ N Carolina, 1101-D McGavran Greenberg Hall,Campus Box 7411, Chapel Hill, NC 27599 USA. EM bbreeve@email.unc.edu FU NCI [N01-CN-75036-20, N01-CN-05228, N01-PC-67010]; UNC Lineberger Comprehensive Cancer Center Cancer Control and Education (CCEP) Predoctoral Fellowship [5R25-CA057726] FX The parent HEAL Study was supported by NCI contracts N01-CN-75036-20, N01-CN-05228, and N01-PC-67010. The first author is supported by a UNC Lineberger Comprehensive Cancer Center Cancer Control and Education (CCEP) Predoctoral Fellowship (5R25-CA057726). NR 60 TC 5 Z9 5 U1 0 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 NOV PY 2013 VL 22 IS 9 BP 2279 EP 2292 DI 10.1007/s11136-013-0360-6 PG 14 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 268ZB UT WOS:000328208300003 PM 23420495 ER PT J AU Paz, SH Slotkin, J McKean-Cowdin, R Lee, P Owsley, C Vitale, S Varma, R Gershon, R Hays, RD AF Paz, Sylvia H. Slotkin, Jerry McKean-Cowdin, Roberta Lee, Paul Owsley, Cynthia Vitale, Susan Varma, Rohit Gershon, Richard Hays, Ron D. TI Development of a vision-targeted health-related quality of life item measure SO QUALITY OF LIFE RESEARCH LA English DT Article DE Vision-related quality of life; NIH Toolbox; Instrument development; Instrument psychometric evaluation and calibration ID VISUAL FUNCTION QUESTIONNAIRE; GRAVES OPHTHALMOPATHY; GO-QOL; PSYCHOMETRIC PROPERTIES; OUTCOMES MEASUREMENT; REFRACTIVE STATUS; RASCH ANALYSIS; DRY EYE; VALIDITY; DISEASE AB To develop a vision-targeted health-related quality of life (HRQOL) measure for the NIH Toolbox for the Assessment of Neurological and Behavioral Function. We conducted a review of existing vision-targeted HRQOL surveys and identified color vision, low luminance vision, distance vision, general vision, near vision, ocular symptoms, psychosocial well-being, and role performance domains. Items in existing survey instruments were sorted into these domains. We selected non-redundant items and revised them to improve clarity and to limit the number of different response options. We conducted 10 cognitive interviews to evaluate the items. Finally, we revised the items and administered them to 819 individuals to calibrate the items and estimate the measure's reliability and validity. The field test provided support for the 53-item vision-targeted HRQOL measure encompassing 6 domains: color vision, distance vision, near vision, ocular symptoms, psychosocial well-being, and role performance. The domain scores had high levels of reliability (coefficient alphas ranged from 0.848 to 0.940). Validity was supported by high correlations between National Eye Institute Visual Function Questionnaire scales and the new-vision-targeted scales (highest values were 0.771 between psychosocial well-being and mental health, and 0.729 between role performance and role difficulties), and by lower mean scores in those groups self-reporting eye disease (F statistic with p < 0.01 for all comparisons except cataract with ocular symptoms, psychosocial well-being, and role performance scales). This vision-targeted HRQOL measure provides a basis for comprehensive assessment of the impact of eye diseases and treatments on daily functioning and well-being in adults. C1 [Paz, Sylvia H.; Hays, Ron D.] Univ Calif Los Angeles, Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Slotkin, Jerry; Gershon, Richard] Northwestern Univ Feinberg, Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [McKean-Cowdin, Roberta; Varma, Rohit] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Doheny Eye Inst, Los Angeles, CA 90033 USA. [Lee, Paul] Duke Univ, Dept Ophthalmol, Durham, NC 27710 USA. [Owsley, Cynthia] Univ Alabama Birmingham, Dept Ophthalmol, Sch Med, Birmingham, AL 35294 USA. [Vitale, Susan] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Paz, SH (reprint author), Univ Calif Los Angeles, Sch Med, Dept Med, Div Gen Internal Med & Hlth Serv Res, 911 Broxton Ave, Los Angeles, CA 90095 USA. EM shpaz@ucla.edu OI Lee, Paul/0000-0002-3338-136X FU Blueprint for Neuroscience Research, National Institutes of Health [HHS-N-260-2006-00007-C]; NIA [P30AG021684, P30-AG028748]; NCMHD [P20MD000182] FX This study was supported by the Blueprint for Neuroscience Research, National Institutes of Health under Contract No. HHS-N-260-2006-00007-C. Drs. Hays and Paz were also supported in part by NIA grant P30AG021684. Dr. Hays was additionally supported in part by NIA grant P30-AG028748 and the NCMHD P20MD000182. NR 36 TC 5 Z9 5 U1 1 U2 8 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 NOV PY 2013 VL 22 IS 9 BP 2477 EP 2487 DI 10.1007/s11136-013-0365-1 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 268ZB UT WOS:000328208300022 PM 23475688 ER PT J AU Ren, JQ Stroncek, DF Zhao, YD Jin, P Castiello, L Civini, S Wang, H Feng, J Tran, K Kuznetsov, SA Robey, PG Sabatino, M AF Ren, Jiaqiang Stroncek, David F. Zhao, Yingdong Jin, Ping Castiello, Luciano Civini, Sara Wang, Huan Feng, Ji Tran, Katherine Kuznetsov, Sergei A. Robey, Pamela G. Sabatino, Marianna TI Intra-subject variability in human bone marrow stromal cell (BMSC) replicative senescence: Molecular changes associated with BMSC senescence SO STEM CELL RESEARCH LA English DT Article ID MESENCHYMAL STEM-CELLS; AMYOTROPHIC-LATERAL-SCLEROSIS; GENE; CULTURE; DIFFERENTIATION; OSTEOGENESIS; TRANSPLANTATION; IDENTIFICATION; PROLIFERATION; THERAPY AB The outcomes of clinical trials using bone marrow stromal cell (BMSC) are variable; the degree of the expansion of BMSCs during clinical manufacturing may contribute to this variability since cell expansion is limited by senescence. Human BMSCs from aspirates of healthy subjects were subcultured serially until cell growth stopped. Phenotype and functional measurements of BMSCs from two subjects including senescence-associated beta-galactosidase staining and colony formation efficiency changed from an early to a senescence pattern at passage 6 or 7. Transcriptome analysis of 10 early and 15 late passage BMSC samples from 5 subjects revealed 2122 differentially expressed genes, which were associated with immune response, development, and cell proliferation pathways. Analysis of 57 serial BMSC samples from 7 donors revealed that the change from an early to senescent profile was variable among subjects and occurred prior to changes in phenotypes. BMSC age expressed as a percentage of maximum population doublings (PDs) was a good indicator for an early or senescence transcription signature but this measure of BMSC life span can only be calculated after expanding BMSCs to senescence. In order to find a more useful surrogate measure of BMSC age, we used a computational biology approach to identify a set of genes whose expression at each passage would predict elapsed age of BMSCs. A total of 155 genes were highly correlated with BMSC age. A least angle regression algorithm identified a set of 24 BMSC age-predictive genes. In conclusion, the onset of senescence-associated molecular changes was variable and preceded changes in other indicators of BMSC quality and senescence. The 24 BMSC age predictive genes will be useful in assessing the quality of clinical BMSC products. Published by Elsevier B.V. C1 [Ren, Jiaqiang; Stroncek, David F.; Jin, Ping; Castiello, Luciano; Civini, Sara; Wang, Huan; Feng, Ji; Tran, Katherine; Sabatino, Marianna] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Kuznetsov, Sergei A.; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM renj@mail.nih.gov; DStroncek@cc.nih.gov; zhaoy@ctep.nci.nih.gov; Pjin@cc.nih.gov; castiellol@cc.nih.gov; civinis@cc.nih.gov; Heidi.wang@nih.gov; fenj2@cc.nih.gov; katherine.tran@nih.gov; skuznetsov@dir.nidcr.nih.gov; probey@dir.nidcr.nih.gov; sabatinom@cc.nih.gov RI Robey, Pamela/H-1429-2011; Castiello, Luciano/K-8616-2016 OI Robey, Pamela/0000-0002-5316-5576; Castiello, Luciano/0000-0001-7146-3158 FU NIH Bone Marrow Stromal Cell Transplantation Center (BMSCTC); Department of Transfusion Medicine, Clinical Center NIH FX The authors thank the staff of the Cell Processing Laboratory, Department of Transfusion Medicine, Clinical Center, NIH for their support of these studies. We also thank Dr. Francesco Marincola and Dr. Ena Wang (Department of Transfusion Medicine, Clinical. Center; NIH) for useful discussions and comments on the manuscript. This work was funded by NIH Bone Marrow Stromal Cell Transplantation Center (BMSCTC) and the Department of Transfusion Medicine, Clinical Center NIH. The authors declared no conflict of interest. NR 51 TC 19 Z9 20 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 NOV PY 2013 VL 11 IS 3 BP 1060 EP 1073 DI 10.1016/j.scr.2013.07.005 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 264UA UT WOS:000327905300009 PM 23959330 ER PT J AU Tsang, WH Wang, B Wong, WK Shi, S Chen, X He, XJ Gu, S Hu, JB Wang, CD Liu, PC Lu, G Chen, XF Zhao, H Poon, WS Chan, WY Feng, B AF Tsang, Wan-Hong Wang, Bin Wong, Wing Ki Shi, Shuo Chen, Xiao He, Xiangjun Gu, Shen Hu, Jiabiao Wang, Chengdong Liu, Pi-Chu Lu, Gang Chen, Xiongfong Zhao, Hui Poon, Wai-Sang Chan, Wai-Yee Feng, Bo TI LIF-dependent primitive neural stem cells derived from mouse ES cells represent a reversible stage of neural commitment SO STEM CELL RESEARCH LA English DT Article ID IN-VITRO; DEFAULT MECHANISM; SELF-RENEWAL; DIFFERENTIATION; INDUCTION; PLURIPOTENCY; PRECURSORS; FATE; FGF; NEUROGENESIS AB Primitive neural stem cells (NSCs) define an early stage of neural induction, thus provide a model to understand the mechanism that controls initial neural commitment. In this study, we investigated primitive NSCs derived from mouse embryonic stem cells (ESCs). By genome-wide transcriptional profiling, we revealed their unique signature and depicted the molecular changes underlying critical cell fate transitions during early neural induction at a global level. Together with qRT-PCR analysis, our data illustrated that primitive NSCs retained expression of key pluripotency genes Oct4 and Nanog, while exhibiting repression of other pluripotency-related genes Zscan4, Foxp1 and Dusp9 and up-regulation of neural markers Sox1 and Hes1. The early differentiation feature in primitive NSCs was also supported by their intermediate characters on cell cycle profiles. Moreover, re-plating primitive NSCs back to ESC culture condition could reverse them back to ESC stage, as shown by reversible regulation of marker genes, cell cycle profile changes and enhanced embryoid body formation. In addition, our microarray analysis also identified genes differentially expressed in primitive NSCs, and loss-of-function analysis demonstrated that Hes1 and Ccdc141 play important function at this stage, opening up an opportunity to further understand the regulation of early neural commitment. (C) 2013 Elsevier B.V. All rights reserved. C1 [Tsang, Wan-Hong; Wang, Bin; Wong, Wing Ki; Shi, Shuo; Chen, Xiao; He, Xiangjun; Gu, Shen; Hu, Jiabiao; Wang, Chengdong; Lu, Gang; Zhao, Hui; Chan, Wai-Yee; Feng, Bo] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Key Lab Regenerat Med,Minist Educ, Shatin, Hong Kong, Peoples R China. [Wang, Bin; Shi, Shuo; Lu, Gang; Zhao, Hui; Poon, Wai-Sang; Chan, Wai-Yee; Feng, Bo] CUHK Shenzhen Res Inst, Shenzhen, Peoples R China. [Chen, Xiao] Zhejiang Univ, Sch Med, Ctr Stem Cell & Tissue Engn, Hangzhou 310003, Zhejiang, Peoples R China. [Liu, Pi-Chu; Lu, Gang; Poon, Wai-Sang] Chinese Univ Hong Kong, Dept Surg, Shatin, Hong Kong, Peoples R China. [Chen, Xiongfong] NCI, Adv Biomed Comp Ctr, NIH, Frederick, MD 21702 USA. RP Chan, WY (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Area 39, Room G03,Lo Kwee Seong Integrated Biomed Sci Bldg, Shatin, Hong Kong, Peoples R China. EM chanwy@cuhk.edu.hk; fengbo@cuhk.edu.hk RI Chen, Xiao/A-4384-2009; Poon, Wai Sang/F-1558-2011; Zhao, Hui/B-8429-2016; Feng, Bo/D-7831-2014 OI Chen, Xiao/0000-0002-4438-5286; FU Research Grants Council of Hong Kong [CUHK 464411, HKUST T13-607/12R]; National Natural Science Foundation of China [A.03.12.00601] FX This work was supported by grants from the Research Grants Council of Hong Kong (CUHK 464411 to B.F.) (HKUST T13-607/12R to Y.I. et al.); and in part by funds from the National Natural Science Foundation of China (A.03.12.00601 to B.F.). We are grateful to Huck-Hui Ng for ESC and EpiSC lines. We thank Jianwei Ren and William K. F. Tse for their critical comments on the manuscript. NR 52 TC 3 Z9 3 U1 0 U2 7 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 NOV PY 2013 VL 11 IS 3 BP 1091 EP 1102 DI 10.1016/j.scr.2013.07.007 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 264UA UT WOS:000327905300011 PM 23973799 ER PT J AU Abe, Y Sakairi, T Beeson, C Kopp, JB AF Abe, Yoshifusa Sakairi, Toru Beeson, Craig Kopp, Jeffrey B. TI TGF-beta 1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE podocyte; mitochondria; bioenergetics; TGF-beta 1; oxygen consumption rate; extracellular acidification rate ID GROWTH-FACTOR-BETA; MAMMALIAN TARGET; TGF-BETA; NAD(P)H OXIDASE; GENE-EXPRESSION; TRANSGENIC MICE; RENAL-DISEASE; RAPAMYCIN; APOPTOSIS; KIDNEY AB TGF-beta 1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Am J Physiol Renal Physiol 305: F1477-F1490, 2013. First published September 18, 2013; doi:10.1152/ajprenal.00182.2013.-Transforming growth factor (TGF)-beta has been associated with podocyte injury; we have examined its effect on podocyte bioenergetics. We studied transformed mouse podocytes, exposed to TGF-beta 1, using a label-free assay system, Seahorse XF24, which measures oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Both basal OCR and ATP generation-coupled OCR were significantly higher in podocytes exposed to 0.3-10 ng/ml of TGF-beta 1 for 24, 48, and 72 h. TGF-beta 1 (3 ng/ml) increased oxidative capacity 75%, and 96% relative to control after 48 and 72 h, respectively. ATP content was increased 19% and 30% relative to control after a 48- and 72-h exposure, respectively. Under conditions of maximal mitochondrial function, TGF-beta 1 increased palmitate-driven OCR by 49%. Thus, TGF-beta 1 increases mitochondrial oxygen consumption and ATP generation in the presence of diverse energy substrates. TGF-beta 1 did not increase cell number or mitochondrial DNA copy number but did increase mitochondrial membrane potential (MMP), which could explain the OCR increase. Reactive oxygen species (ROS) increased by 32% after TGF-beta 1 exposure for 48 h. TGF-beta activated the mammalian target of rapamycin (mTOR) pathway, and rapamycin reduced the TGF-beta 1-stimulated increases in OCR, ECAR, ATP generation, cellular metabolic activity, and protein generation. Our data suggest that TGF-beta 1, acting, in part, via mTOR, increases mitochondrial MMP and OCR, resulting in increased ROS generation and that this may contribute to podocyte injury. C1 [Abe, Yoshifusa] Showa Univ Sch Med, Dept Pediat, Tokyo, Japan. [Abe, Yoshifusa; Kopp, Jeffrey B.] Natl Inst Diabet & Digest & Kidney Dis, Kidney Dis Sect, NIH, Bethesda, MD USA. [Sakairi, Toru] Gunma Univ Grad Sch Med, Dept Med & Clin Sci, Maebashi, Gumma, Japan. [Beeson, Craig] Med Univ S Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA. RP Kopp, JB (reprint author), NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program [ZO1-DK043308] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program, under project ZO1-DK043308. We are grateful to Hideko Takahashi and Huiyan Lu for technical assistance with animal care, Satoshi Watanabe for technical assistance with electron microscopy, Dr. Hisashi Hasumi and Dr. Masaya Baba for valuable advice, and Dr. Kevin Bittman and Dr. Min Wu, both of Seahorse Bioscience, for valuable advice in the design and interpretation of particular experiments. We wish to thank Dr. Tom Leto for a critical review of the manuscript. NR 40 TC 15 Z9 16 U1 1 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD NOV PY 2013 VL 305 IS 10 BP F1477 EP F1490 DI 10.1152/ajprenal.00182.2013 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 257YU UT WOS:000327424600011 PM 24049142 ER PT J AU Murphy, SC Shott, JP Parikh, S Etter, P Prescott, WR Stewart, VA AF Murphy, Sean C. Shott, Joseph P. Parikh, Sunil Etter, Paige Prescott, William R. Stewart, V. Ann TI Review Article: Malaria Diagnostics in Clinical Trials SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Review ID POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; PLASMODIUM-FALCIPARUM MALARIA; HISTIDINE-RICH PROTEIN-2; MEDIATED ISOTHERMAL AMPLIFICATION; SEQUENCE-BASED AMPLIFICATION; REVERSE TRANSCRIPTION PCR; PREGNANT-WOMEN; ENDEMIC AREA; OPERATIONAL ACCURACY AB Malaria diagnostics are widely used in epidemiologic studies to investigate natural history of disease and in drug and vaccine clinical trials to exclude participants or evaluate efficacy. The Malaria Laboratory Network (MLN), managed by the Office of HIV/AIDS Network Coordination, is an international working group with mutual interests in malaria disease and diagnosis and in human immunodeficiency virus/acquired immunodeficiency syndrome clinical trials. The MLN considered and studied the wide array of available malaria diagnostic tests for their suitability for screening trial participants and/or obtaining study endpoints for malaria clinical trials, including studies of HIV/malaria co-infection and other malaria natural history studies. The MLN provides recommendations on microscopy, rapid diagnostic tests, serologic tests, and molecular assays to guide selection of the most appropriate test(s) for specific research objectives. In addition, this report provides recommendations regarding quality management to ensure reproducibility across sites in clinical trials. Performance evaluation, quality control, and external quality assessment are critical processes that must be implemented in all clinical trials using malaria tests. C1 [Murphy, Sean C.] Univ Washington, Dept Lab Med, Med Ctr, Seattle, WA 98195 USA. [Shott, Joseph P.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Etter, Paige] Fred Hutchinson Canc Res Ctr, Off HIV AIDS Network Coordinat, Seattle, WA 98104 USA. [Prescott, William R.] Hydas World Hlth, Hershey, PA USA. [Stewart, V. Ann] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Murphy, SC (reprint author), Univ Washington, Dept Lab Med, Med Ctr, Seattle, WA 98195 USA. EM murphysc@uw.edu; shottj@mail.nih.gov; sunil.parikh@yale.edu; petter@fhcrc.org; william.prescott@hydasworldhealth.org; astewart@usuhs.edu FU Office of HIV/AIDS Network Coordination Malaria Laboratory Network [U01A1068614]; Division of Intramural Research, NIAID, NIH; [1K08AI097238]; [R01HD068174]; [NO1-AI-85355] FX The Office of HIV/AIDS Network Coordination Malaria Laboratory Network is supported by grant U01A1068614. The authors are also supported by grants 1K08AI097238 (Sean C. Murphy), R01HD068174 (Sunil Parikh), and NO1-AI-85355 (William R. Prescott). Joseph P. Shott is supported by the Division of Intramural Research, NIAID, NIH. NR 134 TC 10 Z9 10 U1 0 U2 16 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2013 VL 89 IS 5 BP 824 EP 839 DI 10.4269/ajtmh.12-0675 PG 16 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 251BZ UT WOS:000326904100003 PM 24062484 ER PT J AU Mejia, R Nash, TE AF Mejia, Rojelio Nash, Theodore E. TI Corticosteroid Withdrawal Precipitates Perilesional Edema around Calcified Taenia solium Cysts SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID NEUROCYSTICERCOSIS LESIONS; STATUS-EPILEPTICUS; MRI ABNORMALITIES; EPILEPTOGENESIS; FREQUENCY AB Calcified Taenia solium granulomas are the focus of repeated episodes of perilesional edema and seizures in 50% of persons with calcifications, history of seizures, and a positive serology for cysticercosis. The pathophysiology is unclear but recent studies suggest the edema is caused by inflammation. We report two new cases and four other published cases where cessation of corticosteroids appeared to result in recurrence or new appearance of perilesional edema around calcifications. This suggests that perilesional edema is an immune-mediated phenomenon. C1 NIAID, Helminth Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mejia, Rojelio] Baylor Coll Med, Natl Sch Trop Med, Houston, TX 77030 USA. [Nash, Theodore E.] NIAID, Gastrointestinal Parasites Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Mejia, Rojelio; Nash, Theodore E.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nash, TE (reprint author), NIAID, Gastrointestinal Parasites Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rojelio.mejia@bcm.edu; tnash@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; U.S. National Institutes of Health FX This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases; U.S. National Institutes of Health. NR 24 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD NOV PY 2013 VL 89 IS 5 BP 919 EP 923 DI 10.4269/ajtmh.13-0350 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 251BZ UT WOS:000326904100016 PM 24002482 ER PT J AU Duncan, K Rosean, TR Tompkins, VS Olivier, A Sompallae, R Zhan, F Tricot, G Acevedo, MR Ponto, LLB Walsh, SA Tygrett, LT Berger, AJ Waldschmidt, T Morse, HC Sunderland, JJ Janz, S AF Duncan, K. Rosean, T. R. Tompkins, V. S. Olivier, A. Sompallae, R. Zhan, F. Tricot, G. Acevedo, M. R. Ponto, L. L. B. Walsh, S. A. Tygrett, L. T. Berger, A. J. Waldschmidt, T. Morse, H. C., III Sunderland, J. J. Janz, S. TI F-18-FDG-PET/CT imaging in an IL-6-and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib SO BLOOD CANCER JOURNAL LA English DT Article DE GEMM (genetically engineered mouse model) of human cancer; preclinical cancer drug testing; plasma cell neoplasia ID POSITRON-EMISSION-TOMOGRAPHY; CONTRAST-ENHANCED MRI; B-CELL; C-MYC; ANTITUMOR-ACTIVITY; TRANSGENIC MICE; BONE-DISEASE; FDG PET/CT; MALIGNANCIES; EXPRESSION AB F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(Delta E mu) gene insertion and the widely expressed H2-L-d-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage-and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma. C1 [Duncan, K.; Rosean, T. R.; Tompkins, V. S.; Olivier, A.; Sompallae, R.; Tygrett, L. T.; Waldschmidt, T.; Janz, S.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. [Rosean, T. R.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Interdisciplinary Immunol Grad Program, Iowa City, IA 52242 USA. [Sompallae, R.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Bioinformat Core Facil, Iowa City, IA 52242 USA. [Zhan, F.; Tricot, G.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Acevedo, M. R.; Ponto, L. L. B.; Walsh, S. A.; Sunderland, J. J.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Radiol, Iowa City, IA 52242 USA. [Berger, A. J.] Takeda Pharmaceut Co Ltd, Cambridge, MA USA. [Morse, H. C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD USA. RP Sunderland, JJ (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Radiol, 3881 JPP, Iowa City, IA 52242 USA. EM john-sunderland@uiowa.edu; siegfried-janz@uiowa.edu OI Morse, Herbert/0000-0002-9331-3705; Tompkins, Van/0000-0003-1279-8075 FU Intramural Research Program of the NIAID; NCI core Grant of The University of Iowa Holden Comprehensive Cancer Center (HCCC) [P30CA086862]; Oberley Research Grant from HCCC; Multiple Myeloma Research Foundation; International Waldenstrom's Macroglobulinemia Foundation; NCI [R01CA151354] FX This research was performed by KD in partial fulfillment of the requirements for the Degree Master of Sciences in the Graduate Program of the University of Iowa Department of Pathology. We thank Ling Hu for expert mouse husbandry. This work was supported in part by the Intramural Research Program of the NIAID (to HCM), by NCI core Grant P30CA086862 in support of The University of Iowa Holden Comprehensive Cancer Center (HCCC), by an Oberley Research Grant from HCCC (to JJS), by research awards from the Multiple Myeloma Research and International Waldenstrom's Macroglobulinemia Foundations (to SJ) and by R01CA151354 from the NCI (to SJ). NR 52 TC 14 Z9 14 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2044-5385 J9 BLOOD CANCER J JI Blood Cancer J. PD NOV PY 2013 VL 3 AR UNSP e165 DI 10.1038/bcj.2013.61 PG 12 WC Oncology SC Oncology GA 267BO UT WOS:000328069400011 PM 24292417 ER PT J AU Makarova, KS Koonin, EV AF Makarova, Kira S. Koonin, Eugene V. TI Archaeology of Eukaryotic DNA Replication SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID OKAZAKI FRAGMENT MATURATION; GINS COMPLEX; POLYMERASE-ALPHA; STRUCTURAL BASIS; CELL-CYCLE; SULFOLOBUS-SOLFATARICUS; EVOLUTIONARY HISTORY; FUNCTIONAL-ANALYSIS; CATALYTIC SUBUNIT; CONSERVED DOMAINS AB Recent advances in the characterization of the archaeal DNA replication system together with comparative genomic analysis have led to the identification of several previously un-characterized archaeal proteins involved in replication and currently reveal a nearly complete correspondence between the components of the archaeal and eukaryotic replication machineries. It can be inferred that the archaeal ancestor of eukaryotes and even the last common ancestor of all extant archaea possessed replication machineries that were comparable in complexity to the eukaryotic replication system. The eukaryotic replication system encompasses multiple paralogs of ancestral components such that heteromeric complexes in eukaryotes replace archaeal homomeric complexes, apparently along with subfunctionalization of the eukaryotic complex subunits. In the archaea, parallel, lineage-specific duplications of many genes encoding replication machinery components are detectable as well; most of these archaeal paralogs remain to be functionally characterized. The archaeal replication system shows remarkable plasticity whereby even some essential components such as DNA polymerase and single-stranded DNA-binding protein are displaced by unrelated proteins with analogous activities in some lineages. C1 [Makarova, Kira S.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU U.S. Department of Health and Human Services FX The authors' research is supported by the intramural funds of the U.S. Department of Health and Human Services (to the National Library of Medicine). NR 116 TC 16 Z9 17 U1 1 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD NOV PY 2013 VL 5 IS 11 AR a012963 DI 10.1101/cshperspect.a012963 PG 25 WC Cell Biology SC Cell Biology GA 262NN UT WOS:000327742400006 PM 23881942 ER PT J AU Traub, LM Bonifacino, JS AF Traub, Linton M. Bonifacino, Juan S. TI Cargo Recognition in Clathrin-Mediated Endocytosis SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; AP-3 ADAPTER COMPLEX; VIRUS TYPE-1 NEF; DI-LEUCINE MOTIF; PHOSPHOTYROSINE-BINDING DOMAIN; POLARIZED EPITHELIAL-CELLS; SENSORY ORGAN PRECURSOR; ADP-RIBOSYLATION FACTOR; GROWTH-FACTOR RECEPTOR; FATE DETERMINANT NUMB AB The endosomal system is expansive and complex, characterized by swift morphological transitions, dynamic remodeling of membrane constituents, and intracellular positioning changes. To properly navigate this ever-altering membrane labyrinth, transmembrane protein cargoes typically require specific sorting signals that are decoded by components of protein coats. The best-characterized sorting process within the endosomal system is the rapid internalization of select transmembrane proteins within clathrin-coated vesicles. Endocytic signals consist of linear motifs, conformational determinants, or covalent modifications in the cytosolic domains of transmembrane cargo. These signals are interpreted by a diverse set of clathrin-associated sorting proteins (CLASPs) that translocate from the cytosol to the inner face of the plasma membrane. Signal recognition by CLASPs is highly cooperative, involving additional interactions with phospholipids, Arf GTPases, other CLASPs, and clathrin, and is regulated by large conformational changes and covalent modifications. Related sorting events occur at other endosomal sorting stations. C1 [Traub, Linton M.] Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15261 USA. [Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Traub, LM (reprint author), Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15261 USA. EM traub@pitt.edu OI Bonifacino, Juan S./0000-0002-5673-6370 FU National Institutes of Health (NIH) [R01 DK53249]; NICHD, NIH FX L.M.T. is supported by the extramural program of National Institutes of Health (NIH) (R01 DK53249). J.S.B. is supported by the intramural program of NICHD, NIH. We are grateful to Bertram Canagarajah, John Guatelli, Jim Hurley, David Owen, Xuefeng Ren, and Yong Xiong for providing atomic coordinate files. NR 196 TC 47 Z9 47 U1 3 U2 20 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD NOV PY 2013 VL 5 IS 11 AR a016790 DI 10.1101/cshperspect.a016790 PG 23 WC Cell Biology SC Cell Biology GA 262NN UT WOS:000327742400007 PM 24186068 ER PT J AU Chan, K Resnick, MA Gordenin, DA AF Chan, Kin Resnick, Michael A. Gordenin, Dmitry A. TI The choice of nucleotide inserted opposite abasic sites formed within chromosomal DNA reveals the polymerase activities participating in translesion DNA synthesis SO DNA REPAIR LA English DT Article DE Abasic site; Translesion DNA synthesis; APOBEC; Single-strand DNA; Deoxycytidyltransferase ID THYMINE-THYMINE DIMER; YEAST REV1 PROTEIN; SACCHAROMYCES-CEREVISIAE; INDUCED MUTAGENESIS; POL-ETA; TRANSFERASE-ACTIVITY; ACCESSORY SUBUNITS; ESCHERICHIA-COLI; DCMP TRANSFERASE; IN-VIVO AB Abasic sites in genomic DNA can be a significant source of mutagenesis in biological systems, including human cancers. Such mutagenesis requires translesion DNA synthesis (TLS) bypass of the abasic site by specialized DNA polymerases. The abasic site bypass specificity of TLS proteins had been studied by multiple means in vivo and in vitro, although the generality of the conclusions reached have been uncertain. Here, we introduce a set of yeast reporter strains for investigating the in vivo specificity of abasic site bypass at numerous random positions within chromosomal DNA. When shifted to 37 degrees C, these strains underwent telomere uncapping and resection that exposed reporter genes within a long 3' ssDNA overhang. Human APOBEC3G cytosine deaminase was expressed to create uracils in ssDNA, which were excised by uracil-DNA N-glycosylase. During repair synthesis, error-prone TLS bypassed the resulting abasic sites. Because of APOBEC3G's strict motif specificity and the restriction of abasic site formation to only one DNA strand, this system provides complete information about the location of abasic sites that led to mutations. We recapitulated previous findings on the roles of REV1 and REV3. Further, we found that sequence context can strongly influence the relative frequency of A or C insertion. We also found that deletion of Pol32, a non-essential common subunit of Pols delta and zeta, resulted in residual low-frequency C insertion dependent on Rev1 catalysis. We summarize our results in a detailed model of the interplay between TLS components leading to error-prone bypass of abasic sites. Our results underscore the utility of this system for studying TLS bypass of many types of lesions within genomic DNA. Published by Elsevier B.V. C1 [Chan, Kin; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Gordenin, DA (reprint author), 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM chank2@niehs.nih.gov; resnick@niehs.nih.gov; gordenin@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU National Institute of Environmental Health Sciences (NIH, DHHS) [E5065073] FX We thank Drs. T.A. Kunkel, D.R. Menendez, T.T. Nguyen, and S.A. Roberts for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIH, DHHS) project E5065073 to MAR. NR 71 TC 20 Z9 20 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 EI 1568-7856 J9 DNA REPAIR JI DNA Repair PD NOV PY 2013 VL 12 IS 11 BP 878 EP 889 DI 10.1016/j.dnarep.2013.07.008 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 260FA UT WOS:000327579200004 PM 23988736 ER PT J AU Kodama, S Negishi, M AF Kodama, Susumu Negishi, Masahiko TI Sulfotransferase genes: Regulation by nuclear receptors in response to xeno/endo-biotics SO DRUG METABOLISM REVIEWS LA English DT Review DE Constitutive active/androstane receptor; gene regulation; pregnane X receptor; sulfotransferase; xeno-sensing nuclear receptor ID PREGNANE-X-RECEPTOR; CONSTITUTIVE-ANDROSTANE RECEPTOR; THYROID-HORMONE METABOLISM; BILE-ACID METABOLISM; VITAMIN-D-RECEPTOR; DEHYDROEPIANDROSTERONE SULFOTRANSFERASE; ESTROGEN SULFOTRANSFERASE; CYTOSOLIC SULFOTRANSFERASES; STEROID SULFATASE; MOUSE-LIVER AB Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription factors. They can be activated by a broad range of lipophilic xenobiotics including therapeutics drugs. In addition to xenobiotics, endogenous compounds such as steroid hormones and bile acids can also activate PXR and/or CAR. These nuclear receptors regulate genes that encode enzymes and transporters that metabolize and excrete both xenobiotics and endobiotics. Sulfotransferases (SULTs) are a group of these enzymes and sulfate xenobiotics for detoxification. In general, inactivation by sulfation constitutes the mechanism to maintain homeostasis of endobiotics. Thus, deciphering the molecular mechanism by which PXR and CAR regulate SULT genes is critical for understanding the roles of SULTs in the alterations of physiological and pathophysiological processes caused by drug treatment or environmental exposures. C1 [Kodama, Susumu] Tohoku Univ, Grad Sch Pharmaceut Sci, Div Drug Metab & Mol Toxicol, Sendai, Miyagi 980, Japan. [Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Japan Society for the Promotion of Science [24790142]; National Institutes of Health, and National Institute of Environmental Health Sciences [Z01ES1005-01] FX This work was supported by Grant-in-Aid for Young Scientists from Japan Society for the Promotion of Science: 24790142 (S.K.) and by the Intramural Research Program of the National Institutes of Health, and National Institute of Environmental Health Sciences: Z01ES1005-01 (M.N.). NR 119 TC 5 Z9 5 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0360-2532 EI 1097-9883 J9 DRUG METAB REV JI Drug Metab. Rev. PD NOV PY 2013 VL 45 IS 4 BP 441 EP 449 DI 10.3109/03602532.2013.835630 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 266FQ UT WOS:000328009200007 PM 24025090 ER PT J AU Gage, JC Joste, N Ronnett, BM Stoler, M Hunt, WC Schiffman, M Wheeler, CM AF Gage, Julia C. Joste, Nancy Ronnett, Brigette M. Stoler, Mark Hunt, William C. Schiffman, Mark Wheeler, Cosette M. CA New Mexico HPV Pap Registry Steeri TI A comparison of cervical histopathology variability using whole slide digitized images versus glass slides: experience with a statewide registry SO HUMAN PATHOLOGY LA English DT Article DE Cervical intraepithelial neoplasia; Whole slide imaging; Clinical pathology; Reliability; Registries ID INTEROBSERVER VARIATION; INTRAEPITHELIAL NEOPLASIA; SURGICAL PATHOLOGY; VIRTUAL MICROSCOPY; BIOPSY SPECIMENS; DIAGNOSIS; DYSPLASIA; AGREEMENT AB Whole slide imaging is increasingly used for primary and consultative diagnoses, teaching, telepathology, slide sharing, and archiving. We compared pathologist evaluations of glass slides and corresponding digitized images within the context of a statewide surveillance effort. Cervical specimens collected by the New Mexico HPV Pap Registry research program targeted cases diagnosed between 2006 and 2010. Two samples of 250 slides each were digitized with the ScanScope XT (Aperio, Vista, CA) microscope and reviewed with Aperio ImageScope reader. (1) A "random set" had a distribution of community diagnoses: 70% from cases of cervical intraepithelial neoplasia grade 2 or higher, 20% from cases of cervical intraepithelial neoplasia grade 1 and 10% from negative cases. (2) A "discrepant set" was represented by difficult cases where 2 study pathologists initially disagreed. Within the regular workflow of the New Mexico HPV Pap Registry, 3 pathologists read the slides 2 to 3 times each without knowledge of clinical history, previous readings or sampling scheme. Pathologists also read each corresponding image twice. For within- and between-reader comparisons we calculated unweighted kappa statistics and asymmetry chi(2) tests. Across all comparisons, slides and images yielded similar results. For the random set, almost all within-reader and between-reader Kappa values ranged between 0.7 and 0.8 and 0.6 and 0.7, respectively. For the discrepant set, most within- and between-reader kappa values were 0.4 to 0.6. As cervical intraepithelial neoplasia diagnostic terminology changes, pathologists may need to reread histopathology slides to compare disease trends over time, eg, before/after introduction of human papillomavirus vaccination. Diagnosis of cervical intraepithelial neoplasia differed little between slides and corresponding digitized images. (C) 2013 Elsevier Inc. All rights reserved. C1 [Gage, Julia C.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20850 USA. [Joste, Nancy; Hunt, William C.; Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Ctr HPV Prevent, Albuquerque, NM 87131 USA. [Ronnett, Brigette M.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Ronnett, Brigette M.] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. [Stoler, Mark] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. RP Wheeler, CM (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Pathol, House Prevent Epidemiol HOPE, Albuquerque, NM 87131 USA. EM cwheeler@salud.unm.edu FU Merck and Co, Inc; Glaxo SmithKline FX C.M.W. has received funding through the University of New Mexico from (1) Merck and Co, Inc, and Glaxo SmithKline for HPV vaccine studies and travel reimbursements related to publication activities and (2) equipment and reagents from Roche Molecular Systems for HPV genotyping. Dr Schiffman and Dr Gage report working with Qiagen, Inc, on an independent evaluation of non-commercial uses of CareHPV (a low-cost HPV test for low-resource regions) for which they have received research reagents and technical aid from Qiagen at no cost. They have received HPV testing for research at no cost from Roche. The other authors report no conflicts of interest. NR 24 TC 8 Z9 8 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 EI 1532-8392 J9 HUM PATHOL JI Hum. Pathol. PD NOV PY 2013 VL 44 IS 11 BP 2542 EP 2548 DI 10.1016/j.humpath.2013.06.015 PG 7 WC Pathology SC Pathology GA 261SB UT WOS:000327683800021 PM 24075599 ER PT J AU Nugent, LF Shi, GP Vistica, BP Ogbeifun, O Hinshaw, SJH Gery, I AF Nugent, Lindsey F. Shi, Guangpu Vistica, Barbara P. Ogbeifun, Osato Hinshaw, Samuel J. H. Gery, Igal TI ITE, A Novel Endogenous Nontoxic Aryl Hydrocarbon Receptor Ligand, Efficiently Suppresses EAU and T-Cell-Mediated Immunity SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE aryl hydrocarbon receptor ligand; experimental autoimmune uveitis; T-cell mediated immunity ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; CYTOKINE GM-CSF; INFLAMMATION; DIFFERENTIATION; ACTIVATION; MECHANISMS; UVEITIS AB PURPOSE. Ligands for aryl hydrocarbon receptor (AHR), such as dioxins, are highly toxic. One such ligand, TCDD, was found to exert potent immunosuppressive capacities in mice developing pathogenic autoimmune processes, including EAU, but its toxicity makes it unusable for humans. A recently identified endogenous AHR ligand, ITE, is also immunosuppressive, but is nontoxic and could therefore be useful for therapy in humans. Here, we tested ITE for its capacity to inhibit EAU and related immune responses. METHODS. EAU was induced in B10. A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP; 40 mu g) in CFA. Treatment with ITE was by daily intraperitoneal injection of 0.2 mg. Disease severity was assessed by both fundoscopy and histological examination. Draining lymph node cells were tested for proliferation by thymidine uptake and for cytokine production and release by ELISA. In addition, the intracellular expression of cytokines and Foxp3 was determined by flow cytometry. Serum antibodies were measured by ELISA. RESULTS. Treatment with ITE efficiently inhibited the development of EAU in mice, as well as the cellular immune responses against IRBP and PPD. ITE treatment inhibited the expansion of both Th1 and Th17 subpopulations, as well as their release of the signature cytokines, IFNgamma and IL-17. The treatment moderately increased, however, the proportion of Foxp3 expressing T-regulatory cells. Antibody production was not affected by the treatment. CONCLUSIONS. ITE, an endogenous AHR ligand, efficiently inhibits EAU development and related cellular immune responses. Being nontoxic, ITE may be considered for treatment of pathogenic immunity in humans. C1 [Nugent, Lindsey F.; Shi, Guangpu; Vistica, Barbara P.; Ogbeifun, Osato; Hinshaw, Samuel J. H.; Gery, Igal] NEI, Expt Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Gery, I (reprint author), NEI, Lab Immunol, NIH, Bldg 10,Room 10N208, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov 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 25 TC 5 Z9 6 U1 0 U2 8 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 NOV PY 2013 VL 54 IS 12 BP 7463 EP 7469 DI 10.1167/iovs.12-11479 PG 7 WC Ophthalmology SC Ophthalmology GA 265KH UT WOS:000327949700037 PM 24150760 ER PT J AU Sadowsky, CL Hammond, ER Strohl, AB Commean, PK Eby, SA Damiano, DL Wingert, JR Bae, KT McDonald, JW AF Sadowsky, Cristina L. Hammond, Edward R. Strohl, Adam B. Commean, Paul K. Eby, Sarah A. Damiano, Diane L. Wingert, Jason R. Bae, Kyongtae T. McDonald, John W., III TI Lower extremity functional electrical stimulation cycling promotes physical and functional recovery in chronic spinal cord injury SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Spinal cord injury; Activity-based restorative therapy; Functional electrical stimulation; Rehabilitation; Cycle ergometry; Assistive technology; Paraplegia; Tetraplegia; Rehabilitation; Physical muscle strength; Spasticity; Quality of life ID RESTORING FUNCTION; PROGENITOR CELLS; BODY-COMPOSITION; STEM-CELLS; INDIVIDUALS; REGENERATION; THERAPY; REHABILITATION AB Objective: To examine the effect of long-termlower extremity functional electrical stimulation (FES) cycling on the physical integrity and functional recovery in people with chronic spinal cord injury (SCI). Design: Retrospective cohort, mean follow-up 29.1 months, and cross-sectional evaluation. Setting: Washington University Spinal Cord Injury Neurorehabilitation Center, referral center. Participants: Twenty-five people with chronic SCI who received FES during cycling were matched by age, gender, injury level, and severity, and duration of injury to 20 people with SCI who received range of motion and stretching. Intervention: Lower extremity FES during cycling as part of an activity-based restorative treatment regimen. Main outcome measure: Change in neurological function: motor, sensory, and combined motor-sensory scores (CMSS) assessed by the American Spinal Injury Association Impairment scale. Response was defined as >= 1 point improvement. Results: FES was associated with an 80% CMSS responder rate compared to 40% in controls. An average 9.6 CMSS point loss among controls was offset by an average 20-point gain among FES subjects. Quadriceps muscle mass was on average 36% higher and intra/inter-muscular fat 44% lower, in the FES group. Hamstring and quadriceps muscle strength was 30 and 35% greater, respectively, in the FES group. Quality of life and daily function measures were significantly higher in FES group. Conclusion: FES during cycling in chronic SCI may provide substantial physical integrity benefits, including enhanced neurological and functional performance, increased muscle size and force-generation potential, reduced spasticity, and improved quality of life. C1 [Sadowsky, Cristina L.; Hammond, Edward R.; McDonald, John W., III] Int Ctr Spinal Cord Injury, Baltimore, MD USA. [Sadowsky, Cristina L.; Hammond, Edward R.; McDonald, John W., III] Kennedy Krieger, Hugo W Moser Res Inst, Baltimore, MD USA. [Sadowsky, Cristina L.] Dept Neurol JWM, Dept Phys Med & Rehabil, Baltimore, MD USA. [Strohl, Adam B.] Mt Sinai Med Ctr, Div Plast & Reconstruct Surg, New York, NY USA. [Commean, Paul K.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Eby, Sarah A.] Sinai Hosp, Dept Phys Med & Rehabil, Baltimore, MD 21215 USA. [Damiano, Diane L.] NIH, Bethesda, MD 20892 USA. [Wingert, Jason R.] Univ N Carolina, Dept Hlth & Wellness, Asheville, NC 28804 USA. [Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [McDonald, John W., III] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. RP McDonald, JW (reprint author), Kennedy Krieger Inst, Int Ctr Spinal Cord Injury, 716 North Broadway,4th Floor, Baltimore, MD 21205 USA. EM mcdonaldj@kennedykrieger.org RI Damiano, Diane/B-3338-2010 OI Damiano, Diane/0000-0002-2770-5356 FU Deans Fund at Washington University School of Medicine; Barnes-Jewish Hospital Foundation; Barnes-Jewish Hospital Auxiliary Foundation; Christopher Reeve Paralysis Foundation (C.S.); Nextsteps Foundation (St. Louis, MO); Sam Schmidt Foundation (Las Vegas, NV; C.S.); Gateway to a Cure Foundation (St. Louis, MO); Eric Westacott Foundation (St. Louis, MO); Intramural Research Program at the NIH Clinical Center FX This work was supported by funding from the Deans Fund at Washington University School of Medicine (J.W.M.), Barnes-Jewish Hospital Foundation (J.W.M.), the Barnes-Jewish Hospital Auxiliary Foundation (J.W.M.), Christopher Reeve Paralysis Foundation (C.S., J.W.M.), the Nextsteps Foundation (St. Louis, MO; J.W.M.), the Sam Schmidt Foundation (Las Vegas, NV; C.S., J.W.M.), Gateway to a Cure Foundation (St. Louis, MO; J.W.M.), and the Eric Westacott Foundation (St. Louis, MO; J.W.M.) and, in part, by the Intramural Research Program at the NIH Clinical Center. Our appreciation to Anna Schneider for technical assistance. Author J.W.M. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 40 TC 9 Z9 10 U1 1 U2 24 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 EI 2045-7723 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD NOV PY 2013 VL 36 IS 6 BP 623 EP 631 DI 10.1179/2045772313Y.0000000101 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 264JC UT WOS:000327871900007 PM 24094120 ER PT J AU Merino, JG Luby, M Benson, RT Davis, LA Hsia, AW Latour, LL Lynch, JK Warach, S AF Merino, Jose G. Luby, Marie Benson, Richard T. Davis, Lisa A. Hsia, Amie W. Latour, Lawrence L. Lynch, John K. Warach, Steven TI Predictors of Acute Stroke Mimics in 8187 Patients Referred to a Stroke Service SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Acute stroke; emergency medicine; stroke mimics; diagnosis ID EMERGENCY; CARE; OUTCOMES; TRIALS; SAFETY AB Background: Some patients seen by a stroke team do not have cerebrovascular disease but a condition that mimics stroke. The purpose of this study was to determine the rate and predictors of stroke mimics in a large sample. Methods: This is an analysis of data from consecutive patients seen by the National Institutes of Health Stroke Program over 10 years. Data were collected prospectively as a quality improvement initiative. Patients with a cerebrovascular event or a stroke mimic were compared with the Student t or Pearson chi-square test as appropriate, and logistic regression was done to identify independent predictors. Results: The analysis included 8187 patients: 30% had a stroke mimic. Patients with a stroke mimic were younger, and the proportion of patients with a stroke mimic was higher among women, patients without any risk factors, those seen as a code stroke or who arrived to the emergency department via personal vehicle, and those who had the onset of symptoms while inpatients. The proportion of patients with a stroke mimic was marginally higher among African-Americans than Caucasians. Factors associated with the greatest odds of having a stroke mimic in the logistic regression were lack of a history of hypertension, atrial fibrillation or hyperlipidemia. Conclusions: One third of the patients seen by a stroke team over 10 years had a stroke mimic. Factors associated with a stroke mimic may be ascertained by an emergency physician before calling the stroke team. C1 [Merino, Jose G.; Luby, Marie; Benson, Richard T.; Davis, Lisa A.; Hsia, Amie W.; Latour, Lawrence L.; Lynch, John K.; Warach, Steven] NINDS, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. [Merino, Jose G.] Johns Hopkins Community Phys, Bethesda, MD 20814 USA. [Merino, Jose G.] Suburban Hosp Stroke Ctr, Bethesda, MD USA. [Benson, Richard T.; Hsia, Amie W.] Medstar Washington Hosp Ctr, Stroke Ctr, Washington, DC USA. [Warach, Steven] Seton UT Southwestern Clin Res Inst, Austin, TX USA. RP Merino, JG (reprint author), Johns Hopkins Community Phys, 7315 Wisconsin Ave,Suite 700, Bethesda, MD 20814 USA. EM jmerino3@jhmi.edu OI Merino, Jose/0000-0002-6676-0008 FU Division of Intramural Research of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health FX The Division of Intramural Research of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health supported this research. NR 16 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 EI 1532-8511 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD NOV PY 2013 VL 22 IS 8 BP E397 EP E403 DI 10.1016/j.jstrokecerebrovasdis.2013.04.018 PG 7 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 262FF UT WOS:000327719000021 PM 23680681 ER PT J AU Crooks, DR Natarajan, TG Chen, CM Huang, HZ Ghosh, MC Tong, WH Haller, RG Wu, C Rouault, TA AF Crooks, Daniel R. Natarajan, Thanemozhi G. Chen, Chuming Huang, Hongzhan Ghosh, Manik C. Tong, Wing-Hang Haller, Ronald G. Wu, Cathy Rouault, Tracey A. TI FGF-21 secretion and ketogenic enzyme expression are hallmarks of chronic energy deficiency in human skeletal muscles depleted of iron sulfur clusters SO MITOCHONDRION LA English DT Meeting Abstract C1 [Crooks, Daniel R.; Natarajan, Thanemozhi G.; Wu, Cathy] Georgetown Univ, Med Ctr, Dept Biochem Mol & Cellular Biol, Washington, DC 20057 USA. [Crooks, Daniel R.; Ghosh, Manik C.; Tong, Wing-Hang; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Med Program, Bethesda, MD 20892 USA. [Chen, Chuming; Huang, Hongzhan; Wu, Cathy] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Haller, Ronald G.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75231 USA. [Haller, Ronald G.] VA North Texas Med Ctr, Dallas, TX 75231 USA. [Haller, Ronald G.] Neuromuscular Ctr, Inst Exercise & Environm Med, Dallas, TX 75231 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 MA 18 BP 904 EP 904 DI 10.1016/j.mito.2013.07.018 PG 1 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500058 ER PT J AU Young, MJ Sun, KY Humble, MM Copeland, WC AF Young, Matthew J. Sun, Kathie Y. Humble, Maggie M. Copeland, William C. TI The complexity of heterozygous POLG2 mutations associated with human mitochondrial disease SO MITOCHONDRION LA English DT Meeting Abstract C1 [Young, Matthew J.; Humble, Maggie M.; Copeland, William C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Sun, Kathie Y.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 MA 91 BP 930 EP 930 DI 10.1016/j.mito.2013.07.084 PG 1 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500124 ER PT J AU Milena, P Pickrell, AM Youle, RJ Moraes, CT AF Milena, Pinto Pickrell, Alicia M. Youle, Richard J. Moraes, Carlos T. TI The role of Parkin in the clearance of defective mitochondria with deleted mtDNA in the CNS SO MITOCHONDRION LA English DT Meeting Abstract C1 [Milena, Pinto; Moraes, Carlos T.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Pickrell, Alicia M.; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Moraes, Carlos T.] Univ Miami, Miller Sch Med, Neurosci Grad Program, Miami, FL 33136 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 MA 103 BP 935 EP 935 DI 10.1016/j.mito.2013.07.095 PG 1 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500135 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 MITOCHONDRION LA English DT Meeting Abstract C1 [Wolfe, Lynne A.; Regier, Debra; Boerkorl, Neal] NHGRI, Undiag 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, Div Pediat Neurol, Dept Pediat, Childrens Hosp, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 MA 102 BP 935 EP 935 DI 10.1016/j.mito.2013.07.094 PG 1 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500134 ER PT J AU Pickrell, AM Huang, CH Pinto, M Moraes, CT Youle, RJ AF Pickrell, Alicia M. Huang, Chiu-Hui Pinto, Milena Moraes, Carlos T. Youle, Richard J. TI Therapy for mitochondrial diseases: An investigation into the potential to stimulate Parkin-mediated mitophagy SO MITOCHONDRION LA English DT Meeting Abstract C1 [Pickrell, Alicia M.; Huang, Chiu-Hui; Pinto, Milena; Moraes, Carlos T.; Youle, Richard J.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 MA 123 BP 943 EP 943 DI 10.1016/j.mito.2013.07.111 PG 1 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500151 ER PT J AU Moraes, CT Anderson, V Mohan, C AF Moraes, Carlos T. Anderson, Vernon Mohan, Charles TI Translational research in primary mitochondrial diseases: Challenges and opportunities SO MITOCHONDRION LA English DT Article DE Workshop; Mitochondrial diseases; Animal models; NIH AB On March 8-9, 2012, the NIH intramural and extramural research communities as well as representatives from industries and foundations with a common interest in primary mitochondrial diseases met in Bethesda to identify the major barriers to the development of better treatment for mitochondrial diseases. Besides the importance to the patient population, it has become clear in the last decade that advances in understanding and treating primary mitochondrial diseases will impact research into a large number of degenerative conditions known to have a significant mitochondrial dysfunction component in their pathogenic mechanisms (secondary mitochondrial diseases) that affect millions of people, including Alzheimer's disease, Parkinson's disease, diabetes, ALS, autism spectrum disorders, and many others. We would like to make this discussion available to the scientific community, as it provides a framework on how patient advocacy groups, individual academic units, pharmaceutical companies, and the NIH can interact to address problems related to mitochondrial diseases. The main goals of this workshop were as follows: (1) to share information related to primary mitochondrial disease among the NIH Intramural and Extramural Research Program Investigators, (2) to develop and/or enhance systems to facilitate future collaboration and sharing of information, (3) to survey obstacles, needs and priorities of primary mitochondrial diseases research, and (4) to develop mechanisms to enhance translation of basic science discoveries to diagnostics and therapeutics. C1 [Moraes, Carlos T.] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Anderson, Vernon] NIGMS, Div Pharmacol Physiol & Biol Chem, Bethesda, MD USA. [Mohan, Charles] United Mitochondrial Dis Fdn, Pittsburgh, PA USA. RP Moraes, CT (reprint author), Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. EM cmoraes@med.miami.edu FU UMDF/NIH FX A UMDF/NIH sponsored workshop to identify barriers to treatments to mitochondrial diseases. NR 0 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 EI 1872-8278 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2013 VL 13 IS 6 BP 945 EP 952 DI 10.1016/j.mito.2013.08.002 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 255ZY UT WOS:000327280500155 PM 23962609 ER PT J AU Moody, AD Batchelor, E AF Moody, Amie D. Batchelor, Eric TI Promoter decoding of transcription factor dynamics SO MOLECULAR SYSTEMS BIOLOGY LA English DT Editorial Material ID GENE-EXPRESSION; SINGLE-CELL; NOISE; P53 C1 [Moody, Amie D.; Batchelor, Eric] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Batchelor, E (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room B1B42,10 Ctr Dr, Bethesda, MD 20892 USA. EM batchelore@mail.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD NOV PY 2013 VL 9 AR 703 DI 10.1038/msb.2013.63 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267GK UT WOS:000328084500001 PM 24189398 ER PT J AU Song, C Chiasson, MA Nursimulu, N Hung, SS Wasmuth, J Grigg, ME Parkinson, J AF Song, Carl Chiasson, Melissa A. Nursimulu, Nirvana Hung, Stacy S. Wasmuth, James Grigg, Michael E. Parkinson, John TI Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE flux balance analysis; metabolic reconstruction; strain differences; Toxoplasma gondii ID FLUX BALANCE ANALYSIS; PLASMODIUM-FALCIPARUM; BIOCHEMICAL-CHARACTERIZATION; MYCOBACTERIUM-TUBERCULOSIS; COPROPORPHYRINOGEN OXIDASE; ESCHERICHIA-COLI; BIOSYNTHESIS; EVOLUTION; MODELS; HOST AB Increasingly, metabolic potential is proving to be a critical determinant governing a pathogen's virulence as well as its capacity to expand its host range. To understand the potential contribution of metabolism to strain-specific infectivity differences, we present a constraint-based metabolic model of the opportunistic parasite, Toxoplasma gondii. Dominated by three clonal strains (Type I, II, and III demonstrating distinct virulence profiles), T. gondii exhibits a remarkably broad host range. Integrating functional genomic data, our model (which we term as iCS382) reveals that observed strain-specific differences in growth rates are driven by altered capacities for energy production. We further predict strain-specific differences in drug susceptibilities and validate one of these predictions in a drug-based assay, with a Type I strain demonstrating resistance to inhibitors that are effective against a Type II strain. We propose that these observed differences reflect an evolutionary strategy that allows the parasite to extend its host range, as well as result in a subsequent partitioning into discrete strains that display altered virulence profiles across different hosts, different organs, and even cell types. C1 [Song, Carl; Nursimulu, Nirvana; Hung, Stacy S.; Wasmuth, James; Parkinson, John] Hosp Sick Children, Program Mol Struct & Funct, Toronto, ON M5G 0A4, Canada. [Song, Carl; Hung, Stacy S.; Parkinson, John] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Chiasson, Melissa A.; Grigg, Michael E.] NIAID, NIH, Parasit Dis Lab, Mol Parasitol Sect, Bethesda, MD 20892 USA. [Nursimulu, Nirvana] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada. [Parkinson, John] Univ Toronto, Dept Biochem, Toronto, ON, Canada. RP Parkinson, J (reprint author), Hosp Sick Children, Program Mol Struct & Funct, 21-9709 Peter Gilgan Ctr Res & Learning,686 Bay S, Toronto, ON M5G 0A4, Canada. EM john.parkinson@utoronto.ca RI Parkinson, John/A-4424-2008 OI Parkinson, John/0000-0001-9815-1189 FU Canadian Institutes for Health Research (CIHR-MOP) [84556]; Natural Sciences and Engineering Research Council (NSERC) [188266-04]; Ontario Ministry of Research and Innovation; Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID) FX This study was funded by the Canadian Institutes for Health Research (CIHR-MOP #84556 to JP and MEG) and the Natural Sciences and Engineering Research Council (NSERC #188266-04 to JP). JP also acknowledges support from the Ontario Ministry of Research and Innovation. MEG and MAC also acknowledge support from the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID). JP is a member of the Center for the analysis of genome evolution and function (CAGEF). MEG is a Scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity. Computing resources were provided by the SciNet HPC Consortium. NR 81 TC 14 Z9 14 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD NOV PY 2013 VL 9 AR 708 DI 10.1038/msb.2013.62 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 267GK UT WOS:000328084500006 PM 24247825 ER PT J AU Wen, H Gomella, AA Patel, A Lynch, SK Morgan, NY Anderson, SA Bennett, EE Xiao, XH Liu, C Wolfe, DE AF Wen, Han Gomella, Andrew A. Patel, Ajay Lynch, Susanna K. Morgan, Nicole Y. Anderson, Stasia A. Bennett, Eric E. Xiao, Xianghui Liu, Chian Wolfe, Douglas E. TI Subnanoradian X-ray phase-contrast imaging using a far-field interferometer of nanometric phase gratings SO NATURE COMMUNICATIONS LA English DT Article ID FOURIER-TRANSFORM METHOD; UNWRAPPING ALGORITHM; DIFFRACTION; TOMOGRAPHY; RETRIEVAL; MICROTOMOGRAPHY; RADIOGRAPHY; MICROSCOPY; RADIATION; RATIO AB Hard X-ray phase-contrast imaging characterizes the electron density distribution in an object without the need for radiation absorption. The power of phase contrast to resolve subtle changes, such as those in soft tissue structures, lies in its ability to detect minute refractive bending of X-rays. Here we report a far-field, two-arm interferometer based on the new nanometric phase gratings, which can detect X-ray refraction with subnanoradian sensitivity, and at the same time overcomes the fundamental limitation of ultra-narrow bandwidths (Delta lambda/lambda similar to 10(-4)) of the current, most sensitive methods based on crystal interferometers. On a 1.5% bandwidth synchrotron source, we demonstrate clear visualization of blood vessels in unstained mouse organs in simple projection views, with over an order-of-magnitude higher phase contrast than current near-field grating interferometers. C1 [Wen, Han; Gomella, Andrew A.; Patel, Ajay; Lynch, Susanna K.; Morgan, Nicole Y.; Anderson, Stasia A.; Bennett, Eric E.] NIH, Bethesda, MD 20892 USA. [Xiao, Xianghui; Liu, Chian] Argonne Natl Lab, Adv Photon Source, Lemont, IL 60439 USA. [Wolfe, Douglas E.] Penn State Univ, State Coll, PA 16804 USA. RP Wen, H (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM han.wen@nih.gov FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX We thank the staff of the NanoFab facility of National Institute of Standards and Technology, Gaithersburg, Maryland, for their assistance with fabrication of the gratings; the Animal Surgery and Resources Core and Dr. Alan Michelson of NHLBI, NIH, for their help with biological specimens; Dr. Dumitru Mazilu for his help with mechanical design and fabrication. 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 56 TC 11 Z9 11 U1 2 U2 19 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 NOV PY 2013 VL 4 AR 2659 DI 10.1038/ncomms3659 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266IU UT WOS:000328018100001 PM 24189696 ER PT J AU Burotto, M Fojo, AT AF Burotto, Mauricio Fojo, Antonio Tito TI Acetyl-L-Carnitine and Prevention of Chemotherapy-Induced Peripheral Neuropathy: Can Anything Work? SO ONCOLOGIST LA English DT Editorial Material C1 [Burotto, Mauricio; Fojo, Antonio Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, AT (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD NOV PY 2013 VL 18 IS 11 BP 1151 EP 1152 DI 10.1634/theoncologist.2013-0385 PG 2 WC Oncology SC Oncology GA 262ZN UT WOS:000327776500001 PM 24217999 ER PT J AU Gerber, LH Sikdar, S Armstrong, K Diao, GQ Heimur, J Kopecky, J Turo, D Otto, P Gebreab, T Shah, J AF Gerber, Lynn H. Sikdar, Siddhartha Armstrong, Katee Diao, Guoqing Heimur, Juliana Kopecky, John Turo, Diego Otto, Paul Gebreab, Tadesse Shah, Jay TI A Systematic Comparison Between Subjects With No Pain and Pain Associated With Active Myofascial Trigger Points SO PM&R LA English DT Article ID MUSCLE; NECK; PREVALENCE AB Objective: To determine whether standard evaluations of pain distinguish subjects with no pain from those with myofascial pain syndromes (MPS) and active myofascial trigger points (MTrPs) and to assess whether self-reports of mood, function, and health-related quality of life differ between these groups. Design: A prospective, descriptive study. Setting: University. Patients: Adults with and without neck pain. Methods: We evaluated adults with MPS and active (painful) MTrPs and those without pain. Subjects in the "active" (A) group had at least one active MTrP with spontaneous pain that was persistent, lasted longer than 3 months, and had characteristic pain on palpation. Subjects in the "no pain" (NP) group had no spontaneous pain. However, some of these subjects had discomfort upon MTrP palpation (latent MTrP), whereas others in the NP group had no discomfort upon palpation of nodules or had no nodules. Outcome Measures: Each participant underwent range of motion measurement, a 10-point manual muscle test, and manual and algometric palpation. The latter determined the pain/pressure threshold using an algometer of 4 predetermined anatomic sites along the upper trapezius. Participants rated pain using a verbal analog scale (0-10) and completed the Brief Pain Inventory and Oswestry Disability Scale (which included a sleep subscale), the Short -Form 36 Health Survey, and the Profile of Mood States. Results: The A group included 24 subjects (mean age 36 years; 16 women), and the NP group included 26 subjects (mean age 26 years; 12 women). Group A subjects differed from NP subjects in the number of latent MTrPs (P = .0062), asymmetrical cervical range of motion (P = .01 for side bending and P = .002 for rotation), and in all pain reports (P < .0001), algometry (P < .03), Profile of Mood States (P < .038), Short Form 36 Health Survey (P < .01), and Oswestry Disability Scale (P < .0001). Conclusion: A systematic musculoskeletal evaluation of people with MPS reliably distinguishes them from subjects with no pain. The 2 groups are significantly different in their physical findings and self-reports of pain, sleep disturbance, disability, health status, and mood. These findings support the view that a "local" pain syndrome has significant associations with mood, health-related quality of life, and function. C1 [Gerber, Lynn H.; Armstrong, Katee] George Mason Univ, Coll Hlth & Human Serv, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Sikdar, Siddhartha; Otto, Paul] George Mason Univ, Volgenau Sch Engn, Dept Elect & Comp Engn, Fairfax, VA 22030 USA. [Sikdar, Siddhartha; Turo, Diego; Otto, Paul] George Mason Univ, Volgenau Sch Engn, Dept Bioengn, Fairfax, VA 22030 USA. [Diao, Guoqing] George Mason Univ, Volgenau Sch Engn, Dept Stat, Fairfax, VA 22030 USA. [Heimur, Juliana; Gebreab, Tadesse; Shah, Jay] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Kopecky, John] George Mason Univ, Coll Sci, Fairfax, VA 22030 USA. RP Gerber, LH (reprint author), George Mason Univ, Coll Hlth & Human Serv, Ctr Study Chron Illness & Disabil, 4400 Univ Cr, Fairfax, VA 22030 USA. EM nger-ber1@gmu.edu OI Sikdar, Siddhartha/0000-0002-6426-2320 FU National Institutes of Health; NIH (NIAMS) [R01AR057348]; NSF; VHA FX Disclosure related to this publication: grant, National Institutes of Health; Disclosures related to this publication: grant, NIH (NIAMS grant R01AR057348 provided funding for this study); support for travel to meetings for the study or other purposes, AAPM&R, CAPMR, ISURA, GSPN (travel support for invited talks and/or workshops); Disclosures outside this publication: grants/grants pending, NIH, NSF, VHA NR 29 TC 18 Z9 18 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD NOV PY 2013 VL 5 IS 11 BP 931 EP 938 DI 10.1016/j.pmrj.2013.06.006 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 260FE UT WOS:000327579600004 PM 23810811 ER PT J AU Ardeljan, D Chan, CC AF Ardeljan, Daniel Chan, Chi-Chao TI Aging is not a disease: Distinguishing age-related macular degeneration from aging SO PROGRESS IN RETINAL AND EYE RESEARCH LA English DT Article DE Age-related macular degeneration; Aging; Homeostasis; Para-inflammation; Oxidative stress; Retina ID RETINAL-PIGMENT EPITHELIUM; GLYCATION END-PRODUCTS; COMPLEMENT FACTOR-H; HUMAN BRUCHS MEMBRANE; ENDOPLASMIC-RETICULUM STRESS; MITOCHONDRIAL-DNA DAMAGE; HUMAN RPE CELLS; SUBRETINAL DRUSENOID DEPOSITS; KAPPA-B ACTIVATION; C-REACTIVE PROTEIN AB Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD. Published by Elsevier Ltd. C1 [Ardeljan, Daniel; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Ardeljan, Daniel] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. RP Chan, CC (reprint author), NEI, NIH, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM dardelj1@jhu.edu; chanc@nei.nih.gov OI Chan, Chi-Chao/0000-0001-9460-8049 FU NEI FX The authors state no conflicts of interest. We appreciate Dr. Janet Sparrow's critical review of the manuscript. This work was supported by the NEI Intramural Fund. NR 319 TC 51 Z9 54 U1 4 U2 32 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1350-9462 J9 PROG RETIN EYE RES JI Prog. Retin. Eye Res. PD NOV PY 2013 VL 37 BP 68 EP 89 DI 10.1016/j.preteyeres.2013.07.003 PG 22 WC Ophthalmology SC Ophthalmology GA 264VI UT WOS:000327908700004 PM 23933169 ER PT J AU Horowitz, LM Snyder, DJ Pao, M Rosenstein, DL AF Horowitz, Lisa M. Snyder, Deborah J. Pao, Maryland Rosenstein, Donald L. TI Response-Suicide Screening in General Hospitals SO PSYCHOSOMATICS LA English DT Letter C1 [Horowitz, Lisa M.; Snyder, Deborah J.; Pao, Maryland] NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Rosenstein, Donald L.] Univ N Carolina, Comprehens Canc Support Program, Chapel Hill, NC USA. RP Horowitz, LM (reprint author), NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. NR 4 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 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD NOV-DEC PY 2013 VL 54 IS 6 BP 605 EP 606 PG 3 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 258XM UT WOS:000327492000016 PM 23932536 ER PT J AU Bluemke, DA AF Bluemke, David A. TI Invited Commentary SO RADIOGRAPHICS LA English DT Editorial Material C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 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 NOV-DEC PY 2013 VL 33 IS 7 AR 7 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 262TG UT WOS:000327759900014 ER PT J AU Thomas, RS Philbert, MA Auerbach, SS Wetmore, BA Devito, MJ Cote, I Rowlands, JC Whelan, MP Hays, SM Andersen, ME Meek, ME Reiter, LW Lambert, JC Clewell, HJ Stephens, ML Zhao, QJ Wesselkamper, SC Flowers, L Carney, EW Pastoor, TP Petersen, DD Yauk, CL Nong, A AF Thomas, Russell S. Philbert, Martin A. Auerbach, Scott S. Wetmore, Barbara A. Devito, Michael J. Cote, Ila Rowlands, J. Craig Whelan, Maurice P. Hays, Sean M. Andersen, Melvin E. Meek, M. E. (Bette) Reiter, Lawrence W. Lambert, Jason C. Clewell, Harvey J., III Stephens, Martin L. Zhao, Q. Jay Wesselkamper, Scott C. Flowers, Lynn Carney, Edward W. Pastoor, Timothy P. Petersen, Dan D. Yauk, Carole L. Nong, Andy TI Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework SO TOXICOLOGICAL SCIENCES LA English DT Article DE in vitro and altenatives; biotransformation and toxicokinetics; predictive toxicology; risk assessment; safety evaluation; exposure ID EPAS TOXCAST PROGRAM; ENVIRONMENTAL CHEMICALS; IN-VIVO; TISSUE DISTRIBUTION; BIOMONITORING DATA; DRUG DISCOVERY; POOLED SAMPLES; IPCS FRAMEWORK; EXPOSURE; DOSIMETRY AB Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency. C1 [Thomas, Russell S.; Wetmore, Barbara A.; Andersen, Melvin E.; Clewell, Harvey J., III] Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. [Philbert, Martin A.] Univ Michigan, Sch Publ Hlth, Toxicol Program, Ann Arbor, MI 48019 USA. [Auerbach, Scott S.; Devito, Michael J.] NIEHS, Div Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Cote, Ila; Flowers, Lynn] US EPA, Natl Ctr Environm Assessment, Arlington, VA 22202 USA. [Rowlands, J. Craig; Carney, Edward W.] Dow Chem Co USA, Toxicol & Environm Res & Consulting, Midland, MI 48674 USA. [Whelan, Maurice P.] European Commiss DG Joint Res Ctr, Inst Hlth & Consumer Protect, Syst Toxicol Unit, Ispra, Italy. [Hays, Sean M.] Summit Toxicol LLP, Allenspark, CO 80510 USA. [Meek, M. E. (Bette)] Univ Ottawa, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON K1N 6N5, Canada. [Reiter, Lawrence W.] US EPA, Raleigh, NC 27606 USA. [Lambert, Jason C.; Zhao, Q. Jay; Wesselkamper, Scott C.; Petersen, Dan D.] US EPA, Natl Ctr Environm Assessment, Cincinnati, OH 45268 USA. [Stephens, Martin L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Pastoor, Timothy P.] Syngenta Crop Protect, Toxicol & Hlth Sci Dept, Greensboro, NC 27419 USA. [Yauk, Carole L.; Nong, Andy] Hlth Canada, Hlth Environm & Consumer Safety Branch, Environm Hlth Sci & Res Bur, Ottawa, ON K1A 0K9, Canada. RP Thomas, RS (reprint author), Hamner Inst Hlth Sci, 6 Davis Dr,POB 12137, Res Triangle Pk, NC 27709 USA. EM rthomas@thehamner.org OI Andersen, Melvin/0000-0002-3894-4811; Thomas, Russell/0000-0002-2340-0301; Yauk, Carole/0000-0003-4919-876X FU American Chemistry Council's Long-Range Research Initiative FX The work by R.S.T., M.E.A., H.J.C. III, and B.A.W. on this manuscript was supported by the American Chemistry Council's Long-Range Research Initiative. The views expressed by authors affiliated with the U. S. Environmental Protection Agency are those of the authors and do not necessarily reflect the views or policies of the U. S. Environmental Protection Agency. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the U. S. government. The authors wish to thank Chad Blystone and Alex Merrick for reviewing the manuscript. NR 68 TC 68 Z9 69 U1 5 U2 56 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2013 VL 136 IS 1 BP 4 EP 18 DI 10.1093/toxsci/kft178 PG 15 WC Toxicology SC Toxicology GA 258KQ UT WOS:000327458600002 PM 23958734 ER PT J AU Gribble, MO Voruganti, VS Cropp, CD Francesconi, KA Goessler, W Umans, JG Silbergeld, EK Laston, SL Haack, K Kao, WHL Fallin, MD MacCluer, JW Cole, SA Navas-Acien, A AF Gribble, Matthew O. Voruganti, Venkata Saroja Cropp, Cheryl D. Francesconi, Kevin A. Goessler, Walter Umans, Jason G. Silbergeld, Ellen K. Laston, Sandra L. Haack, Karin Kao, Wen Hong Linda Fallin, Margaret Daniele MacCluer, Jean W. Cole, Shelley A. Navas-Acien, Ana TI SLCO1B1 Variants and Urine Arsenic Metabolites in the Strong Heart Family Study SO TOXICOLOGICAL SCIENCES LA English DT Article DE American Indians; arsenic metabolism; arsenic species; SLCO1B1; OATPC; Strong Heart Study ID METHYLTRANSFERASE AS3MT GENE; DRUG-DRUG INTERACTIONS; CARDIOVASCULAR-DISEASE; INTESTINAL-ABSORPTION; SOUTHWESTERN TAIWAN; AMERICAN-INDIANS; LINKAGE ANALYSIS; CANCER RISK; CELL-LINE; EXPOSURE AB Arsenic species patterns in urine are associated with risk for cancer and cardiovascular diseases. The organic anion transporter coded by the gene SLCO1B1 may transport arsenic species, but its association with arsenic metabolites in human urine has not yet been studied. The objective of this study is to evaluate associations of urine arsenic metabolites with variants in the candidate gene SLCO1B1 in adults from the Strong Heart Family Study. We estimated associations between % arsenic species biomarker traits and 5 single-nucleotide polymorphisms (SNPs) in the SLCO1B1 gene in 157 participants, assuming additive genetics. Linear regression models for each SNP accounted for kinships and were adjusted for sex, body mass index, and study center. The minor allele of rs1564370 was associated with lower %MMA (p .0003) and higher %DMA (p .0002), accounting for 8% of the variance for %MMA and 9% for %DMA. The rs1564370 minor allele homozygote frequency was 17% and the heterozygote frequency was 43%. The minor allele of rs2291075 was associated with lower %MMA (p .0006) and higher %DMA (p .0014), accounting for 7% of the variance for %MMA and 5% for %DMA. The frequency of rs2291075 minor allele homozygotes was 1% and of heterozygotes was 15%. Common variants in SLCO1B1 were associated with differences in arsenic metabolites in a preliminary candidate gene study. Replication of this finding in other populations and analyses with respect to disease outcomes are needed to determine whether this novel candidate gene is important for arsenic-associated disease risks. C1 [Gribble, Matthew O.; Kao, Wen Hong Linda; Fallin, Margaret Daniele; Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Voruganti, Venkata Saroja; Laston, Sandra L.; Haack, Karin; MacCluer, Jean W.; Cole, Shelley A.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78227 USA. [Cropp, Cheryl D.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [Goessler, Walter] Karl Franzens Univ Graz, Inst Chem Analyt Chem, Graz, Austria. [Umans, Jason G.] MedStar Hlth Res Inst, Hyattsville, MD 20782 USA. [Umans, Jason G.] Georgetown Howard Univ Ctr Clin & Translat Sci, Washington, DC 20007 USA. [Silbergeld, Ellen K.; Navas-Acien, Ana] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Gribble, Matthew O.; Navas-Acien, Ana] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP Gribble, MO (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St Off W7513D, Baltimore, MD 21205 USA. EM mgribble@jhsph.edu OI Goessler, Walter/0000-0002-0142-9373; Gribble, Matthew/0000-0002-1614-2981 FU National Heart Lung and Blood Institute [R01HL090863]; National Heart Lung and Blood Institute (SHS) [HL41642, HL41652, HL41654, HL065520, HL65521]; National Institute of Environmental Health Sciences [R01ES021367, P30ES03819]; National Institute of Diabetes and Digestive and Kidney Diseases [5T32DK062707-10]; National Center for Research Resources [C06 RR13556, C06 RR017515] FX National Heart Lung and Blood Institute (R01HL090863, SHS grants HL41642, HL41652, HL41654, HL065520, HL65521); National Institute of Environmental Health Sciences (R01ES021367, P30ES03819); National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK062707-10); National Center for Research Resources (C06 RR13556, C06 RR017515). NR 68 TC 4 Z9 4 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2013 VL 136 IS 1 BP 19 EP 25 DI 10.1093/toxsci/kft181 PG 7 WC Toxicology SC Toxicology GA 258KQ UT WOS:000327458600003 PM 23970802 ER PT J AU Nussinov, R Tsai, CJ Mattos, C AF Nussinov, Ruth Tsai, Chung-Jung Mattos, Carla TI 'Pathway drug cocktail': targeting Ras signaling based on structural pathways SO TRENDS IN MOLECULAR MEDICINE LA English DT Review DE cancer; drug discovery; parallel pathways; classification; structures; oncogenic mutations ID ACQUIRED-RESISTANCE; MEK INHIBITORS; PROTEOME SCALE; MAPK-PATHWAY; CANCER-CELLS; H-RAS; PROTEINS; SWITCH; BRAF; BINDING AB Tumors bearing Ras mutations are notoriously difficult to treat. Drug combinations targeting the Ras protein or its pathway have also not met with success. 'Pathway drug cocktails', which are combinations aiming at parallel pathways, appear more promising; however, to be usefully exploited, a repertoire of classified pathway combinations is desirable. This challenge would be facilitated by the availability of the structural network of signaling pathways. When integrated with functional and systems level clinical data, they can be powerful in advancing novel therapeutic platforms. Based on structural knowledge, drug cocktails may tear into multiple cellular processes that drive tumorigenesis, and help in deciphering the interrelationship between Ras mutations and the rewired Ras network. The pathway drug cocktail paradigm can be applied to other signaling protein targets. C1 [Nussinov, Ruth; Tsai, Chung-Jung] NCI, Basic Res Program, SAIC Frederick Inc, Canc & Inflammat Program,Ctr Canc Res, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Mattos, Carla] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Canc & Inflammat Program,Ctr Canc Res, Ft Detrick, MD 21702 USA. EM NussinoR@helix.nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; extramural program [R56 CA096867] FX We would like to thank Christian W. Johnson for making Figures 3 and 4. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (R.N.) and by the extramural program under grant number R56 CA096867 (C.M.). NR 71 TC 29 Z9 29 U1 1 U2 13 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 NOV PY 2013 VL 19 IS 11 BP 695 EP 704 DI 10.1016/j.molmed.2013.07.009 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 265BA UT WOS:000327923500006 PM 23953481 ER PT J AU Molina-Cruz, A Lehmann, T Knockel, J AF Molina-Cruz, Alvaro Lehmann, Tovi Knoeckel, Julia TI Could culicine mosquitoes transmit human malaria? SO TRENDS IN PARASITOLOGY LA English DT Review DE malaria; transmission; mosquito; Culex; Anopheles ID COMPLEMENT-LIKE PROTEIN; SUB-SAHARAN AFRICA; ANOPHELES-GAMBIAE; CHIKUNGUNYA VIRUS; PLASMODIUM-FALCIPARUM; LOCAL ADAPTATION; XANTHURENIC ACID; AEDES-AEGYPTI; ONYONG-NYONG; WEST-NILE AB Human malaria is known to be transmitted strictly by anopheline mosquitoes. Culicine mosquitoes such as Aedes spp. and Culex spp. are important vectors of other human pathogens including viruses and filarial worms, but have never been observed to transmit mammalian malarias. Culicines do transmit avian malarias and, interestingly, allow partial development of mammalian-infectious Plasmodium parasites, implying that physiological barriers in the mosquitoes prevent parasite transmission. Although the mechanism(s) are not known, the mosquito immune system is probably involved in eliminating Plasmodium. However, Plasmodium has shown substantial capacity to adapt to new vectors, and current ecological changes caused by humans could promote adaptation of human-infectious Plasmodium parasites to culicines. Such an event could have widespread epidemiological implications and therefore merits attention. C1 [Molina-Cruz, Alvaro; Lehmann, Tovi; Knoeckel, Julia] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. RP Knockel, J (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM julia.knoeckel@gmail.com OI Knoeckel, Julia/0000-0001-6688-7714 FU National Institutes of Health Intramural Research Program FX We would like to thank Louis H. Miller and Jose Ribeiro (Laboratory for Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health), Scott Weaver (University of Texas Medical Branch, Galveston, TX), Peter Armbruster (Georgetown University, Washington DC), and Louis Lambrechts (Institut Pasteur, Paris, France) for helpful suggestions and insightful comments on the manuscript, and Jose Luis Ramirez for assistance in image processing. This work was supported by the National Institutes of Health Intramural Research Program. NR 73 TC 5 Z9 5 U1 1 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 EI 1471-5007 J9 TRENDS PARASITOL JI Trends Parasitol. PD NOV PY 2013 VL 29 IS 11 BP 530 EP 537 DI 10.1016/j.pt.2013.09.003 PG 8 WC Parasitology SC Parasitology GA 261UN UT WOS:000327690200004 PM 24140295 ER PT J AU Gunduz-Cinar, O Hill, MN McEwen, BS Holmes, A AF Gunduz-Cinar, Ozge Hill, Matthew N. McEwen, Bruce S. Holmes, Andrew TI Amygdala FAAH and anandamide: mediating protection and recovery from stress SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review DE endocannabinoid; post-traumatic stress disorder; anxiety; fear; depression; 2-AG ID ACID AMIDE HYDROLASE; CB1 CANNABINOID RECEPTORS; RAT BASOLATERAL AMYGDALA; CONTEXTUAL FEAR MEMORY; ENDOCANNABINOID SYSTEM; CONDITIONED FEAR; MONOACYLGLYCEROL LIPASE; PREFRONTAL CORTEX; NERVOUS-SYSTEM; FUNCTIONAL INTERACTIONS AB A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA CBI (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress. C1 [Gunduz-Cinar, Ozge; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. [Hill, Matthew N.] Univ Calgary, Hotchkiss Brain Inst, Dept Cell Biol, Calgary, AB, Canada. [Hill, Matthew N.] Univ Calgary, Hotchkiss Brain Inst, Dept Psychiat & Anat, Calgary, AB, Canada. [McEwen, Bruce S.] Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10021 USA. RP Gunduz-Cinar, O (reprint author), NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20892 USA. EM ozge.gunduzcinar@nih.gov; mnhill@ucalgary.ca FU NIAAA Intramural Research Program; Department of Defense in the Center for Neuroscience and Regenerative Medicine; Canadian Institutes of Health Research; Tier II Canada Research Chair FX O.G-C. and A.H. are supported by the NIAAA Intramural Research Program and Department of Defense in the Center for Neuroscience and Regenerative Medicine. M.N.H. is the recipient of a Tier II Canada Research Chair and operating funds from the Canadian Institutes of Health Research. NR 120 TC 50 Z9 51 U1 0 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD NOV PY 2013 VL 34 IS 11 BP 637 EP 644 DI 10.1016/j.tips.2013.08.008 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260FS UT WOS:000327581000009 PM 24325918 ER PT J AU Bosserman, MA Downey, T Noinaj, N Buchanan, SK Rohr, J AF Bosserman, Mary A. Downey, Theresa Noinaj, Nicholas Buchanan, Susan K. Rohr, Juergen TI Molecular Insight into Substrate Recognition and Catalysis of Baeyer-Villiger Monooxygenase MtmOIV, the Key Frame-Modifying Enzyme in the Biosynthesis of Anticancer Agent Mithramycin SO ACS CHEMICAL BIOLOGY LA English DT Article ID ANTITUMOR ANTIBIOTIC MITHRAMYCIN; X-RAY-DIFFRACTION; PRODUCER STREPTOMYCES-ARGILLACEUS; COMBINATORIAL BIOSYNTHESIS; PSEUDOMONAS-PUTIDA; CRYSTAL-STRUCTURE; DIKETOCAMPHANE MONOOXYGENASE; ENANTIOSELECTIVE OXIDATIONS; PAGETS-DISEASE; CANCER-CELLS AB Baeyer-Villiger monooxygenases (BVMOs) have been shown to play key roles for the biosynthesis of important natural products. MtmOIV, a homodimeric FAD- and NADPH-dependent BVMO, catalyzes the key frame-modifying steps of the mithramycin biosynthetic pathway, including an oxidative C-C bond cleavage, by converting its natural substrate premithramycin B into mithramycin DK, the immediate precursor of mithramycin. The drastically improved protein structure of MtmOIV along with the high-resolution structure of MtmOIV in complex with its natural substrate premithramycin B are reported here, revealing previously undetected key residues that are important for substrate recognition and catalysis. Kinetic analyses of selected mutants allowed us to probe the substrate binding pocket of MtmOIV and also to discover the putative NADPH binding site. This is the first substrate-bound structure of MtmOIV providing new insights into substrate recognition and catalysis, which paves the way for the future design of a tailored enzyme for the chemo-enzymatic preparation of novel mithramycin analogues. C1 [Bosserman, Mary A.; Downey, Theresa; Rohr, Juergen] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA. [Bosserman, Mary A.; Noinaj, Nicholas; Buchanan, Susan K.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rohr, J (reprint author), Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, 789 South Limestone St, Lexington, KY 40536 USA. EM jrohr2@email.uky.edu RI Rohr, Jurgen/G-5375-2014 OI Rohr, Jurgen/0000-0001-6447-5951 FU NIH [CA 091901]; NIH, National Institute of Diabetes and Digestive and Kidney Diseases; U.S. Department of Energy FX This work was supported by NIH grant CA 091901 to J.R. N.N. and S.K.B. were supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. Data were collected at Southeast Regional Collaborative Access Team (SER-CAT) beamline 22-ID at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U.S. Department of Energy. We also wish to acknowledge S. G. Van Lanen and J. S. Thorson for sharing lab instrumentation with us. NR 60 TC 8 Z9 8 U1 3 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD NOV PY 2013 VL 8 IS 11 BP 2466 EP 2477 DI 10.1021/cb400399b PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 254OP UT WOS:000327175300015 PM 23992662 ER PT J AU Bertola, A Park, O Gao, B AF Bertola, A. Park, O. Gao, B. TI Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury: A critical role for E-selectin SO ALCOHOL LA English DT Meeting Abstract CT Alcohol-and-Immunology-Research-Interest-Group (AIRIG) Meeting on Alcohol and Inflammatory Responses CY NOV 22, 2013 CL Loyola Univ Chicago, Hlth Sci Campus, Dept Surg, Maywood, IL SP Alcohol & Immunol Res Interest Grp HO Loyola Univ Chicago, Hlth Sci Campus, Dept Surg C1 [Bertola, A.; Park, O.; Gao, B.] NIAAA, Lab Liver Dis, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD NOV PY 2013 VL 47 IS 7 MA 3 BP 568 EP 568 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 260FX UT WOS:000327581500012 ER PT J AU Mathews, SA Feng, D Gao, B AF Mathews, S. A. Feng, D. Gao, B. TI Natural killer T cells play an important role in chronic plus binge ethanol-induced liver injury SO ALCOHOL LA English DT Meeting Abstract CT Alcohol-and-Immunology-Research-Interest-Group (AIRIG) Meeting on Alcohol and Inflammatory Responses CY NOV 22, 2013 CL Loyola Univ Chicago, Hlth Sci Campus, Dept Surg, Maywood, IL SP Alcohol & Immunol Res Interest Grp HO Loyola Univ Chicago, Hlth Sci Campus, Dept Surg C1 [Mathews, S. A.; Feng, D.; Gao, B.] NIAAA, NIH, Bethesda, 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 NOV PY 2013 VL 47 IS 7 BP 572 EP 572 PG 1 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 260FX UT WOS:000327581500028 ER PT J AU Scoffone, HM Krajewski, M Zorca, S Bereal-Williams, C Littel, P Seamon, C Mendelsohn, L Footman, E Abi-Jaoudeh, N Sachdev, V Machado, RF Cuttica, M Shamburek, R Cannon, RO Remaley, A Minniti, CP Kato, GJ AF Scoffone, Heather M. Krajewski, Megan Zorca, Suzana Bereal-Williams, Candice Littel, Patricia Seamon, Catherine Mendelsohn, Laurel Footman, Eleni Abi-Jaoudeh, Nadine Sachdev, Vandana Machado, Roberto F. Cuttica, Michael Shamburek, Robert Cannon, Richard O., III Remaley, Alan Minniti, Caterina P. Kato, Gregory J. TI Effect of Extended-Release Niacin on Serum Lipids and on Endothelial Function in Adults With Sickle Cell Anemia and Low High-Density Lipoprotein Cholesterol Levels SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VASCULAR REACTIVITY; METABOLIC SYNDROME; DISEASE; DYSFUNCTION; ATHEROSCLEROSIS; HYPERTENSION; MECHANISM; MARKERS AB Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C <39 mg/dl or apoA-I <99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 +/- 7.7 vs 0.9 +/- 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C. Published by Elsevier Inc. C1 [Scoffone, Heather M.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Bethesda, MD USA. [Scoffone, Heather M.; Krajewski, Megan; Zorca, Suzana; Bereal-Williams, Candice; Littel, Patricia; Seamon, Catherine; Mendelsohn, Laurel; Footman, Eleni; Machado, Roberto F.; Minniti, Caterina P.; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Sachdev, Vandana; Shamburek, Robert; Cannon, Richard O., III; Remaley, Alan] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Abi-Jaoudeh, Nadine] NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Machado, Roberto F.; Cuttica, Michael] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM katogj@upmc.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU NIH Clinical Research Training Program; Case Western Reserve University Clinical Research Scholars Program FX The authors are grateful to the patients with sickle cell disease who enrolled on this study. They also thank additional clinical research staff who assisted in the recruitment and follow-up of these patients, including James Nichols, RN. The authors thank Mary K. Hall, CIP, and Stephanie Housel, MS, for protocol management. Dr. Scoffone acknowledges the support of the NIH Clinical Research Training Program and the Case Western Reserve University Clinical Research Scholars Program. NR 26 TC 4 Z9 4 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD NOV 1 PY 2013 VL 112 IS 9 BP 1499 EP 1504 DI 10.1016/j.amjcard.2013.06.035 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 253QJ UT WOS:000327104100039 PM 24035168 ER PT J AU Klein, R Li, XH Kuo, JZ Klein, BEK Cotch, MF Wong, TY Taylor, KD Rotter, JI AF Klein, Ronald Li, Xiaohui Kuo, Jane Z. Klein, Barbara E. K. Cotch, Mary Frances Wong, Tien Y. Taylor, Kent D. Rotter, Jerome I. TI Associations of Candidate Genes to Age-Related Macular Degeneration Among Racial/Ethnic Groups in the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID COMPLEMENT-FACTOR-H; CARDIOVASCULAR-DISEASE; CHINESE POPULATION; RACIAL-DIFFERENCES; UNITED-STATES; PREVALENCE; MACULOPATHY; POLYMORPHISMS; EYE; LOC387715 AB PURPOSE: To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans. DESIGN: Cross-sectional study. METHODS: SETTING: Multicenter study. STUDY POPULATION: A total of 2456 persons aged 45-84 years with genotype information and fundus photographs. PROCEDURES: Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples. MAIN OUTCOME MEASURE: Prevalence of early AlVID. RESULTS: Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for 1 to 10.0 for 4 risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend = 4.2x 10(-7)). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent "across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency's approaching that of whites. CONCLUSIONS: The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them. ((C) 2013 by Elsevier Inc. All rights reserved.) C1 [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI 53726 USA. [Li, Xiaohui; Kuo, Jane Z.; Taylor, Kent D.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic 3010, Australia. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, 610 N Walnut St,4th Floor WARF, Madison, WI 53726 USA. EM kleinr@epi.ophth.wisc.edu OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; MESA [R01-HL071051, R01-HL071205, R01-HL071250, R01-HL071251, R01-HL071252, R01-HL071258, R01-HL071259]; NIH Intramural Research Award [ZIAEY000403]; NIH [HL69979] FX The authors have no proprietary or commercial interest in any materials discussed in this article. The Multi-Ethnic Study of Atherosclerosis (MESA) was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, MESA Family was conducted and supported in collaboration with MESA investigators by grants and contracts R01-HL071051, R01-HL071205, R01-HL071250, R01-HL071251, R01-HL071252, R01-HL071258, R01-HL071259, and NIH Intramural Research Award ZIAEY000403. Additional support was provided by NIH grant HL69979 (R.K. and.T.Y.W.) and in part by the Cedars-Sinai Board of Governors' Chair in Medical Genetics (J.I.R.). None of the above named sponsors or funding organizations had any role in the design or conduct of this research. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Heart, Lung, and Blood Institute; the National Eye Institute; or the National Institutes of Health. Contributions of authors: design of the study (R.K.); conduct of the study (R.K.); collection of data (R.K., M.F.C., PR.); analysis of data (X.L., J.Z.K., K.D.T.); interpretation of the data (J.I.R., X.L., J.Z.K., B.E.K.K., R.K.); manuscript preparation (R.K., B.E.K.K., J:I.R.); manuscript review (XL., J.Z.K., B.E.K.K., M.F.C., T.Y.W., K.D.T., J.I.R.); and manuscript approval (XL., J.Z.K., B.E.K.K., M.F.C., T.Y.W., K.D.T., J.I.R.). NR 49 TC 8 Z9 8 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 NOV PY 2013 VL 156 IS 5 BP 1010 EP 1020 DI 10.1016/j.ajo.2013.06.004 PG 11 WC Ophthalmology SC Ophthalmology GA 250NJ UT WOS:000326859200021 PM 23938121 ER PT J AU Jin, SM Youle, RJ AF Jin, Seok Min Youle, Richard J. TI The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria SO AUTOPHAGY LA English DT Article DE unfolded protein response; mitochondria; PINK1; PARK2; Parkin; mitophagy; LONP ID MAMMALIAN-CELLS; PARKIN; IMPORT; ACTIVATION; MUTATIONS; PROTEASE; TRANSLOCATION; REQUIREMENT; RECRUITMENT; CHAPERONES AB Defective mitochondria exert deleterious effects on host cells. To manage this risk, mitochondria display several lines of quality control mechanisms: mitochondria-specific chaperones and proteases protect against misfolded proteins at the molecular level, and fission/fusion and mitophagy segregate and eliminate damage at the organelle level. An increase in unfolded proteins in mitochondria activates a mitochondrial unfolded protein response (UPRmt) to increase chaperone production, while the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin, whose mutations cause familial Parkinson disease, remove depolarized mitochondria through mitophagy. It is unclear, however, if there is a connection between those different levels of quality control (QC). Here, we show that the expression of unfolded proteins in the matrix causes the accumulation of PINK1 on energetically healthy mitochondria, resulting in mitochondrial translocation of PARK2, mitophagy and subsequent reduction of unfolded protein load. Also, PINK1 accumulation is greatly enhanced by the knockdown of the LONP1 protease. We suggest that the accumulation of unfolded proteins in mitochondria is a physiological trigger of mitophagy. C1 [Jin, Seok Min; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke FX We thank Dr Nick J Hoogenraad for kindly providing the OTC constructs. This work is supported by the National Institute of Neurological Disorders and Stroke intramural program. NR 32 TC 80 Z9 83 U1 0 U2 13 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD NOV 1 PY 2013 VL 9 IS 11 BP 1750 EP 1757 DI 10.4161/auto.26122 PG 8 WC Cell Biology SC Cell Biology GA 257XM UT WOS:000327421100011 PM 24149988 ER PT J AU Yamano, K Youle, RJ AF Yamano, Koji Youle, Richard J. TI PINK1 is degraded through the N-end rule pathway SO AUTOPHAGY LA English DT Article DE mitochondrial import; PARKIN; ubiquitin; PARL; mitophagy ID UBIQUITIN LIGASE; MITOCHONDRIAL-MEMBRANE; PARKINSONS-DISEASE; PROTEASE PARL; IMPORT; LOCALIZATION; CLEAVAGE; MUTANTS; KINASE; DROSOPHILA-PINK1 AB PINK1, a mitochondrial serine/threonine kinase, is the product of a gene mutated in an autosomal recessive form of Parkinson disease. PINK1 is constitutively degraded by an unknown mechanism and stabilized selectively on damaged mitochondria where it can recruit the E3 ligase PARK2/PARKIN to induce mitophagy. Here, we show that, under steady-state conditions, endogenous PINK1 is constitutively and rapidly degraded by E3 ubiquitin ligases UBR1, UBR2 and UBR4 through the N-end rule pathway. Following precursor import into mitochondria, PINK1 is cleaved in the transmembrane segment by a mitochondrial intramembrane protease PARL generating an N-terminal destabilizing amino acid and then retrotranslocates from mitochondria to the cytosol for N-end recognition and proteasomal degradation. Thus, sequential actions of mitochondrial import, PARL-processing, retrotranslocation and recognition by N-end rule E3 enzymes for the ubiquitin proteosomal degradation defines the rapid PINK1 turnover. PINK1 steady-state elimination by the N-end rule identifies a novel organelle to cytoplasm turnover pathway that yields a mechanism to flag damaged mitochondria for autophagic elimination. C1 [Yamano, Koji; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov FU Japan Society for the Promotion of Science; National Institute of Neurological Disorders and Stroke FX We thank C Wang for construction of the pink1 KO HeLa cell line, DP Sideris and the other members of the Youle laboratory for valuable discussions and comments, Y Li for help with mass spectrometry, YT Kwon for the kind gift of ubr1-/-ubr2-/-LucRNAi and ubr1-/-ubr2-/-Ubr4RNAi MEF cells and of anti-UBR1 and anti-UBR2 antibodies, B De Strooper for parl-/- MEFs and Z Zang for pink1-/- MEFs. This research is supported by Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad (to KY) and by the National Institute of Neurological Disorders and Stroke intramural program. NR 39 TC 101 Z9 104 U1 0 U2 15 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD NOV 1 PY 2013 VL 9 IS 11 BP 1758 EP 1769 DI 10.4161/auto.24633 PG 12 WC Cell Biology SC Cell Biology GA 257XM UT WOS:000327421100012 PM 24121706 ER PT J AU Lu, Y You, M Ghazoui, Z Liu, PY Vedell, PT Wen, WD Bode, AM Grubbs, CJ Lubet, RA AF Lu, Yan You, Ming Ghazoui, Zara Liu, Pengyuan Vedell, Peter T. Wen, Weidong Bode, Ann M. Grubbs, Clinton J. Lubet, Ronald A. TI Concordant Effects of Aromatase Inhibitors on Gene Expression in ER+ Rat and Human Mammary Cancers and Modulation of the Proteins Coded by These Genes SO CANCER PREVENTION RESEARCH LA English DT Article ID HUMAN BREAST-CANCER; SPRAGUE-DAWLEY RATS; POSTMENOPAUSAL WOMEN; CELL-PROLIFERATION; VOROZOLE; TAMOXIFEN; LETROZOLE; THERAPY; TUMORS; MODEL AB Aromatase inhibitors are effective in therapy/prevention of estrogen receptor-positive (ER+) breast cancers. Rats bearing methylnitrosourea (MNU)-induced ER+ mammary cancers were treated with the aromatase inhibitor vorozole (1.25 mg/kg BW/day) for five days. RNA expression showed 162 down-regulated and 180 upregulated (P < 0.05 and fold change >1.5) genes. Genes modulated by vorozole were compared with published data from four clinical neoadjuvant trials using aromatase inhibitors (anastrozole or letrozole). More than 30 genes and multiple pathways exhibited synchronous changes in animal and human datasets. Cell-cycle genes related to chromosome condensation in prometaphase [anaphase-prometaphase complex (APC) pathway, including Aurora-A kinase, BUBR1B, TOP2, cyclin A, cyclin B CDC2, and TPX-2)] were downregulated in animal and human studies reflecting the strong antiproliferative effects of aromatase inhibitors. Comparisons of rat arrays with a cell culture study where estrogen was removed from MCF-7 cells showed decreased expression of E2F1-modulated genes as a major altered pathway. Alterations of the cell cycle and E2F-related genes were confirmed in a large independent set of human samples (81 pairs baseline and two weeks anastrozole treatment). Decreases in proliferation-related genes were confirmed at the protein level for cyclin A2, BuRB1, cdc2, Pttg, and TPX-2. Interestingly, the proteins downregulated in tumors were similarly downregulated in vorozole-treated normal rat mammary epithelium. Finally, decreased expression of known estrogen-responsive genes (including TFF, 1,3, progesterone receptor, etc.) were decreased in the animal model. These studies demonstrate that gene expression changes (pathways and individual genes) are similar in humans and the rat model. C1 [Lu, Yan; You, Ming; Liu, Pengyuan; Vedell, Peter T.] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Lu, Yan; You, Ming; Liu, Pengyuan; Vedell, Peter T.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. [Lu, Yan; You, Ming; Liu, Pengyuan; Vedell, Peter T.] Med Coll Wisconsin, Ctr Canc, Milwaukee, WI 53226 USA. [Ghazoui, Zara] Inst Canc Res, Breakthrough Breast Canc Res, London SW3 6JB, England. [Wen, Weidong] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Bode, Ann M.] Hormel Inst, Austin, MN USA. [Grubbs, Clinton J.] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Lubet, Ronald A.] NCI, Chemoprevent Agent Dev Res Grp, Rockville, MD USA. RP Grubbs, CJ (reprint author), Univ Alabama Birmingham, 1670 Univ Blvd,Volker Hall G-78-D Box 800, Birmingham, AL 35294 USA. EM clintongrubbs@uabmc.edu FU National Cancer Institute [HHSN261200433001C, HHSN261200433008C] FX This study was supported by National Cancer Institute, contract number HHSN261200433001C and HHSN261200433008C. NR 33 TC 5 Z9 5 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2013 VL 6 IS 11 BP 1151 EP 1161 DI 10.1158/1940-6207.CAPR-13-0126 PG 11 WC Oncology SC Oncology GA 259IB UT WOS:000327519500001 PM 24067424 ER PT J AU Safaeian, M Porras, C Pan, YJ Kreimer, A Schiller, JT Gonzalez, P Lowy, DR Wacholder, S Schiffman, M Rodriguez, AC Herrero, R Kemp, T Shelton, G Quint, W van Doorn, LJ Hildesheim, A Pinto, LA AF Safaeian, Mahboobeh Porras, Carolina Pan, Yuanji Kreimer, Aimee Schiller, John T. Gonzalez, Paula Lowy, Douglas R. Wacholder, Sholom Schiffman, Mark Rodriguez, Ana C. Herrero, Rolando Kemp, Troy Shelton, Gloriana Quint, Wim van Doorn, Leen-Jan Hildesheim, Allan Pinto, Ligia A. CA CVT Grp TI Durable Antibody Responses Following One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle Vaccine in the Costa Rica Vaccine Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID HUMORAL IMMUNITY; IMMUNOGENICITY; SAFETY; HUMAN-PAPILLOMAVIRUS-16; PROTECTION; DURATION; AVIDITY; CELLS; ASSAY; PCR AB The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPVVLPs will induce long-term protection. C1 [Safaeian, Mahboobeh; Pan, Yuanji; Kreimer, Aimee; Schiller, John T.; Lowy, Douglas R.; Wacholder, Sholom; Schiffman, Mark; Kemp, Troy; Shelton, Gloriana; Hildesheim, Allan; Pinto, Ligia A.] NCI, NIH, Bethesda, MD 20892 USA. [Quint, Wim; van Doorn, Leen-Jan] DDL Diagnost Lab, Voorburg, Netherlands. [Gonzalez, Paula; Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, 9609 Med Ctr Dr,Rm 6-E224,MSC 9767, Bethesda, MD 20892 USA. EM safaeianm@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; National Institutes of Health Office of Research on Women's Health; Ministry of Health of Costa Rica FX 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 the 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 U.S. Food and Drug Administration BB-IND 7920. NR 30 TC 87 Z9 88 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD NOV PY 2013 VL 6 IS 11 BP 1242 EP 1250 DI 10.1158/1940-6207.CAPR-13-0203 PG 9 WC Oncology SC Oncology GA 259IB UT WOS:000327519500009 PM 24189371 ER PT J AU Ambudkar, IS AF Ambudkar, Indu S. TI TRPC1: Getting physical in space SO CELL CYCLE LA English DT Editorial Material ID SKELETAL-MUSCLE; CELL-CYCLE; MICROGRAVITY C1 Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM indu.ambudkar@nih.gov NR 8 TC 0 Z9 0 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD NOV 1 PY 2013 VL 12 IS 21 BP 3355 EP 3356 DI 10.4161/cc.26637 PG 2 WC Cell Biology SC Cell Biology GA 257JZ UT WOS:000327381000006 PM 24091530 ER PT J AU Templeton, JP Wang, XD Freeman, NE Ma, ZW Lu, A Hejtmancik, F Geisert, EE AF Templeton, Justin P. Wang, XiangDi Freeman, Natalie E. Ma, Zhiwei Lu, Anna Hejtmancik, Fielding Geisert, Eldon E. TI A crystallin gene network in the mouse retina SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE crystallin; BXD strains; promoter analysis; quantitative trait loci; transcription factor ID BZIP TRANSCRIPTION FACTOR; ALPHA-B-CRYSTALLIN; LENS DEVELOPMENT; L-MAF; MICROARRAY ANALYSIS; OXIDATIVE STRESS; DELTA-CRYSTALLIN; A-CRYSTALLIN; RAT RETINA; EXPRESSION AB The present study was designed to examine the regulation of crystallin genes and protein in the mouse retina using the BXD recombinant inbred (RI) strains. Illumina Sentrix BeadChip Arrays (MouseWG-6v2) were used to analyze mRNA levels in 75 BXD RI strains along with the parental strains (C57Bl/6J and DBA/2J), and the reciprocal crosses in the Hamilton Eye Institute (HEI) Retina Dataset (www.genenetwork.org). Protein levels were investigated using immunoblots to quantify levels of proteins and indirect immunohistochemistry to define the distribution of protein. Algorithms in the Genomatix program were used to identify transcription factor binding sites common to the regulatory sequences in the 5' regions of co-regulated set of crystallin and other genes as compared to a set of control genes. As subset of genes, including many encoding lens crystallins is part of a tightly co-regulated network that is active in the retina. Expression of this crystallin network appears to be binary in nature, being expressed either at relatively low levels or being highly upregulated. Relative to a control set of genes, the 5' regulatory sequences of the crystallin network genes show an increased frequency of a set of common transcription factor-binding sites, the most common being those of the Maf family. Chromatin immunoprecipitation of human lens epithelial cells (HLEC) and rat retinal ganglion cells (RGC) confirmed the functionality of these sites, showing that MafA binds the predicted sites of CRYGA and CRYGD in HLE and CRYAB, CRYGA, CRYBA1, and CRYBB3 in RGC cells. In the retina there is a highly correlated group of genes containing many members of the alpha- beta- and gamma-crystallin families. These genes can be dramatically upregulated in the retina. One transcription factor that appears to be involved in this coordinated expression is the MAF family transcription of factors associated with both lens and extralenticular expression of crystallin genes. (C) 2013 Published by Elsevier Ltd. C1 [Templeton, Justin P.; Wang, XiangDi; Freeman, Natalie E.; Geisert, Eldon E.] Univ Tennessee, Dept Ophthalmol, Hlth Sci Ctr, Memphis, TN 38163 USA. [Ma, Zhiwei; Lu, Anna; Hejtmancik, Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Geisert, EE (reprint author), Univ Tennessee, Dept Ophthalmol, Hlth Sci Ctr, 930 Madison Av,Suite 731, Memphis, TN 38163 USA. EM egeisert@uthsc.edu FU NEI [RO1017841]; Research to Prevent Blindness (UTHSC) FX This work is supported by NEI grant RO1017841 and an Unrestricted Grant from Research to Prevent Blindness (UTHSC). NR 43 TC 12 Z9 12 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 EI 1096-0007 J9 EXP EYE RES JI Exp. Eye Res. PD NOV PY 2013 VL 116 BP 129 EP 140 DI 10.1016/j.exer.2013.08.001 PG 12 WC Ophthalmology SC Ophthalmology GA 259YP UT WOS:000327562500015 PM 23978599 ER PT J AU Crown, KN Savytskyy, OP Malik, SB Logsdon, J Williams, RS Tainer, JA Zolan, ME AF Crown, K. Nicole Savytskyy, Oleksandr P. Malik, Shehre-Banoo Logsdon, John Williams, R. Scott Tainer, John A. Zolan, Miriam E. TI A Mutation in the FHA Domain of Coprinus cinereus Nbs1 Leads to Spo11-Independent Meiotic Recombination and Chromosome Segregation SO G3-GENES GENOMES GENETICS LA English DT Article DE MRN complex; Coprinus cinereus; recombination; DNA replication; meiosis ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; MULTIPLE SEQUENCE ALIGNMENT; HOLLIDAY JUNCTIONS; MRE11 COMPLEX; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; CROSSING-OVER; MRE11/RAD50/NBS1 COMPLEX AB Nbs1, a core component of the Mre11-Rad50-Nbs1 complex, plays an essential role in the cellular response to DNA double-strand breaks (DSBs) and poorly understood roles in meiosis. We used the basidiomycete Coprinus cinereus to examine the meiotic roles of Nbs1. We identified the C. cinereus nbs1 gene and demonstrated that it corresponds to a complementation group previously known as rad3. One allele, nbs1-2, harbors a point mutation in the Nbs1 FHA domain and has a mild spore viability defect, increased frequency of meiosis I nondisjunction, and an altered crossover distribution. The nbs1-2 strain enters meiosis with increased levels of phosphorylated H2AX, which we hypothesize represent unrepaired DSBs formed during premeiotic replication. In nbs1-2, there is no apparent induction of Spo11-dependent DSBs during prophase. We propose that replication-dependent DSBs, resulting from defective replication fork protection and processing by the Mre11-Rad50-Nbs1 complex, are competent to form meiotic crossovers in C. cinereus, and that these crossovers lead to high levels of faithful chromosome segregation. In addition, although crossover distribution is altered in nbs1-2, the majority of crossovers were found in subtelomeric regions, as in wild-type. Therefore, the location of crossovers in C. cinereus is maintained when DSBs are induced via a Spo11-independent mechanism. C1 [Crown, K. Nicole; Savytskyy, Oleksandr P.; Zolan, Miriam E.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Malik, Shehre-Banoo; Logsdon, John] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA. [Williams, R. Scott] NIEHS, Res Triangle Pk, NC 27709 USA. [Tainer, John A.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Zolan, ME (reprint author), Indiana Univ, Dept Biol, 1001 East 3rd St, Bloomington, IN 47405 USA. EM mzolan@indiana.edu RI Williams, Robert/A-6059-2015 FU National Institutes of Health (NIH); NIH [GM43930]; Indiana MetaCyt Initiative of Indiana University; Lilly Endowment, Inc.; NSF [MCB-0216702]; Canadian Institute for Advanced Research Integrated Microbial Biodiversity Program; National Cancer Institute [CA117638, CA92584]; United States NIH, National Institute of Environmental Health Sciences (NIEHS) [1Z01ES102765-01] FX We thank Pat Pukkila, Soni Lacefield, and Claire Burns for critical reading of the manuscript, and Elizabeth Housworth for help and advice early in the course of these experiments. K.N.C. was supported in part by the National Institutes of Health (NIH) Genetics Training Grant to Indiana University. M.Z. provided laboratory support with NIH grant GM43930 and the Indiana MetaCyt Initiative of Indiana University, which is funded in part by a major grant from the Lilly Endowment, Inc. J.M.L. and S. B. M. were supported by the NSF grant MCB-0216702 (to J.M.L.). S. B. M. was supported by a Junior Fellowship from the Canadian Institute for Advanced Research Integrated Microbial Biodiversity Program. J.A.T. was supported by National Cancer Institute grants CA117638 and CA92584. This research was supported in part by the intramural research program of the United States NIH, National Institute of Environmental Health Sciences (NIEHS) (1Z01ES102765-01 to R.S.W.). NR 104 TC 5 Z9 5 U1 2 U2 11 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 NOV PY 2013 VL 3 IS 11 BP 1927 EP 1943 DI 10.1534/g3.113.007906 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 255LY UT WOS:000327241900004 PM 24062528 ER PT J AU Hong, FX Simon, R AF Hong, Fangxin Simon, Richard TI Run-In Phase III Trial Design With Pharmacodynamics Predictive Biomarkers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID RANDOMIZED CLINICAL-TRIALS; DISCONTINUATION DESIGN; PHYSICIANS HEALTH; CARCINOMA CELLS; DENDRITIC CELLS; EFFICIENCY; PLACEBO; FUSIONS; BREAST AB Developments in biotechnology have stimulated the use of predictive biomarkers to identify patients who are likely to benefit from a targeted therapy. Several randomized phase III designs have been introduced for development of a targeted therapy using a diagnostic test. Most such designs require biomarkers measured before treatment. In many cases, it has been very difficult to identify such biomarkers. Promising candidate biomarkers can sometimes be effectively measured after a short run-in period on the new treatment. We introduce a new design for phase III trials with a candidate predictive pharmacodynamic biomarker measured after a short run-in period. Depending on the therapy and the biomarker performance, the trial would either randomize all patients but perform a separate analysis on the biomarker-positive patients or only randomize marker-positive patients after the run-in period. We evaluate the proposed design compared with the conventional phase III design and discuss how to design a run-in trial based on phase II studies. The proposed design achieves a major sample size reduction compared with the conventional randomized phase III design in many cases when the biomarker has good sensitivity (0.7) and specificity (0.7). This requires that the biomarker be measured accurately and be indicative of drug activity. However, the proposed design loses some of its advantage when the proportion of potential responders is large (> 50%) or the effect on survival from run-in period is substantial. Incorporating a pharmacodynamic biomarker requires careful consideration but can expand the capacity of clinical trials to personalize treatment decisions and enhance therapeutics development. C1 [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Simon, Richard] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov FU Department of Biostatistics and Computational Biology Research Scientist Fund FX This work was supported by the Department of Biostatistics and Computational Biology Research Scientist Fund (to FH). NR 20 TC 2 Z9 2 U1 0 U2 1 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 NOV PY 2013 VL 105 IS 21 BP 1628 EP 1633 DI 10.1093/jnci/djt265 PG 6 WC Oncology SC Oncology GA 251ZL UT WOS:000326973900009 PM 24096624 ER PT J AU Polley, MYC Freidlin, B Korn, EL Conley, BA Abrams, JS McShane, LM AF Polley, Mei-Yin C. Freidlin, Boris Korn, Edward L. Conley, Barbara A. Abrams, Jeffrey S. McShane, Lisa M. TI Statistical and Practical Considerations for Clinical Evaluation of Predictive Biomarkers SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CELL LUNG-CANCER; RANDOMIZED PHASE-III; ADJUVANT TEMOZOLOMIDE; MAINTENANCE THERAPY; BREAST-CANCER; GLIOBLASTOMA; DESIGN; CETUXIMAB; EGFR; CHEMOTHERAPY AB Predictive biomarkers to guide therapy for cancer patients are a cornerstone of precision medicine. Discussed herein are considerations regarding the design and interpretation of such predictive biomarker studies. These considerations are important for both planning and interpreting prospective studies and for using specimens collected from completed randomized clinical trials. Specific issues addressed are differentiation between qualitative and quantitative predictive effects, challenges due to sample size requirements for predictive biomarker assessment, and consideration of additional factors relevant to clinical utility assessment, such as toxicity and cost of new therapies as well as costs and potential morbidities associated with routine use of biomarker-based tests. C1 [Polley, Mei-Yin C.; Freidlin, Boris; Korn, Edward L.; McShane, Lisa M.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Conley, Barbara A.] NCI, Canc Diag Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Abrams, Jeffrey S.] NCI, Canc Treatment & Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Polley, MYC (reprint author), NCI, Biometr Res Branch, NIH, 9609 Med Ctr Dr,Rm 5W638,MSC 9735, Bethesda, MD 20892 USA. EM polleymc@mail.nih.gov NR 28 TC 29 Z9 29 U1 0 U2 6 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 NOV PY 2013 VL 105 IS 22 BP 1677 EP 1683 DI 10.1093/jnci/djt282 PG 7 WC Oncology SC Oncology GA 259PO UT WOS:000327539000004 PM 24136891 ER PT J AU Zhu, CS Pinsky, PF Kramer, BS Prorok, PC Purdue, MP Berg, CD Gohagan, JK AF Zhu, Claire S. Pinsky, Paul F. Kramer, Barnett S. Prorok, Philip C. Purdue, Mark P. Berg, Christine D. Gohagan, John K. TI The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and Its Associated Research Resource SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID FORCE RECOMMENDATION STATEMENT; NURSES HEALTH; MORTALITY; COSTS AB The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is a large-scale research effort conducted by the National Cancer Institute. PLCO offers an example of coordinated research by both the extramural and intramural communities of the National Institutes of Health. The purpose of this article is to describe the PLCO research resource and how it is managed and to assess the productivity and the costs associated with this resource. Such an in-depth analysis of a single large-scale project can shed light on questions such as how large-scale projects should be managed, what metrics should be used to assess productivity, and how costs can be compared with productivity metrics. A comprehensive publication analysis identified 335 primary research publications resulting from research using PLCO data and biospecimens from 2000 to 2012. By the end of 2012, a total of 9679 citations (excluding self-citations) have resulted from this body of research publications, with an average of 29.7 citations per article, and an h index of 45, which is comparable with other large-scale studies, such as the Nurses Health Study. In terms of impact on public health, PLCO trial results have been used by the US Preventive Services Task Force in making recommendations concerning prostate and ovarian cancer screening. The overall cost of PLCO was $454 million over 20 years, adjusted to 2011 dollars, with approximately $37 million for the collection, processing, and storage of biospecimens, including blood samples, buccal cells, and pathology tissues. C1 [Zhu, Claire S.; Pinsky, Paul F.; Kramer, Barnett S.; Prorok, Philip C.; Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Purdue, Mark P.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gohagan, John K.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Pinsky, PF (reprint author), NCI, Early Detect Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. EM pinskyp@mail.nih.gov RI Berg , Christine/K-1047-2014; Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 NR 18 TC 8 Z9 8 U1 0 U2 8 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 NOV PY 2013 VL 105 IS 22 BP 1684 EP 1693 DI 10.1093/jnci/djt281 PG 10 WC Oncology SC Oncology GA 259PO UT WOS:000327539000005 PM 24115361 ER PT J AU Tarasova, VD Trepp-Carrasco, AG Thompson, R Recker, RR Chong, WH Collins, MT Armas, LAG AF Tarasova, Valentina D. Trepp-Carrasco, Alejandro G. Thompson, Robert Recker, Robert R. Chong, William H. Collins, Michael T. Armas, Laura A. G. TI Successful Treatment of Tumor-Induced Osteomalacia due to an Intracranial Tumor by Fractionated Stereotactic Radiotherapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PHOSPHATURIC MESENCHYMAL TUMORS; ONCOGENIC OSTEOMALACIA; LOCALIZATION; VARIANT AB Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, characterized by tumor secretion of fibroblast growth factor-23 (FGF23) causing hypophosphatemia due to renal phosphate wasting. TIO is usually caused by small, benign, difficult-to-localize, mesenchymal tumors. Although surgery with wide excision of tumor borders is considered the "gold standard" for definitive therapy, it can be associated with considerable morbidity depending on the location. To date, radiation therapy has not been considered as an effective treatment modality in TIO. Objective: A 67-year-old female presented with multiple nontraumatic fractures, progressive bone pain, and muscle weakness for 4 years. She was found to have biochemical evidence of urinary phosphate wasting with low serum phosphorus, low-normal serum calcium, normal 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and high serum FGF23 levels. TIO was diagnosed. Selective venous sampling for FGF23 confirmed that a 1.7-cm left frontal mass, radiographically similar to a meningioma, was the causative tumor. She declined surgery due to fear of complications and instead underwent fractionated stereotactic radiotherapy for 6 weeks. Results: In less than 4 years after radiation therapy, she was successfully weaned off phosphorus and calcitriol, starting from 2 g of oral phosphorus daily and 1 mu g of calcitriol daily. Her symptoms have resolved, and she has not had any new fractures. Conclusions: Stereotactic radiotherapy was an effective treatment modality for TIO in our patient. Fractionated stereotactic radiation therapy represents an alternative to surgery for patients with TIO who are not surgical candidates or who decline surgery. C1 [Tarasova, Valentina D.; Trepp-Carrasco, Alejandro G.; Recker, Robert R.; Armas, Laura A. G.] Creighton Univ, Omaha, NE 68131 USA. [Thompson, Robert] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Chong, William H.; Collins, Michael T.] NIH, Bethesda, MD 20892 USA. RP Tarasova, VD (reprint author), Creighton Univ, 601 North 30th St,Suite 5766, Omaha, NE 68131 USA. EM tarasova.md@gmail.com; larmas@creighton.edu FU Intramural NIH HHS [ZIA DE000649-19] NR 16 TC 3 Z9 3 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2013 VL 98 IS 11 BP 4267 EP 4272 DI 10.1210/jc.2013-2528 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 254QP UT WOS:000327180700032 PM 24014621 ER PT J AU Brown, RJ Cochran, E Gorden, P AF Brown, Rebecca J. Cochran, Elaine Gorden, Phillip TI Metreleptin Improves Blood Glucose in Patients With Insulin Receptor Mutations SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RABSON-MENDENHALL-SYNDROME; DEPENDENT DIABETES-MELLITUS; LEPTIN-REPLACEMENT THERAPY; CALORIC RESTRICTION; HEPATIC STEATOSIS; WEIGHT-LOSS; RESISTANCE; LIPODYSTROPHY; DYSFUNCTION; MECHANISMS AB Context: Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. Objective: Our objective was to study 1-year effects of recombinant human methionyl leptin (metreleptin) in 5 patients with RMS and 10-year effects in 2 of these patients. Design and Setting: We conducted an open-label nonrandomized study at the National Institutes of Health. Patients: Patients were adolescents with RMS and poorly controlled diabetes. Intervention: Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/d) of metreleptin for 10 years, including 3 cycles of metreleptin withdrawal and reinitiation. In all 5 patients, 1-year effects of metreleptin (0.22 mg/kg/d) were studied. Outcome Measures: Hemoglobin A1c (HbA1c) and body mass index (BMI) z-scores were evaluated every 6 months. Results: HbA1c decreased from 11.4% +/- 1.1% at baseline to 9.3% +/- 1.9% after 6 months and 9.7% +/- 1.6% after 12 months of metreleptin (P = .007). In patients treated for 10 years, HbA1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 +/- 1.8 at baseline, to -2.6 +/- 1.6 after 12 months of metreleptin (P = .0006). Changes in BMI z-score correlated with changes in HbA1c (P < .0001). Conclusions: Metreleptin treatment for 12 months was associated with a 1.7% reduction in HbA1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve HbA1c targets. C1 [Brown, Rebecca J.; Cochran, Elaine; Gorden, Phillip] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Brown, RJ (reprint author), Bldg 10 CRC,Room 6-5942,10 Ctr Dr, Bethesda, MD 20892 USA. EM brownrebecca@mail.nih.gov FU intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 40 TC 6 Z9 7 U1 2 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2013 VL 98 IS 11 BP E1749 EP E1756 DI 10.1210/jc.2013-2317 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 254QP UT WOS:000327180700007 PM 23969187 ER PT J AU Muniyappa, R Warren, MA Zhao, XC Aney, SC Courville, AB Chen, KY Brychta, RJ Germain-Lee, EL Weinstein, LS Skarulis, MC AF Muniyappa, Ranganath Warren, Mary A. Zhao, Xiongce Aney, Sara C. Courville, Amber B. Chen, Kong Y. Brychta, Robert J. Germain-Lee, Emily L. Weinstein, Lee S. Skarulis, Monica C. TI Reduced Insulin Sensitivity in Adults With Pseudohypoparathyroidism Type 1a SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RESISTANCE; DEFICIENCY; ALPHA; G(S)ALPHA; OBESITY; GENE; MASS AB Context: Disruption of theGs beta maternal allele leads to severe obesityandinsulin resistance in miceand early-onset obesity in patients with pseudohypoparathyroidism (PHP) type 1a. However, insulin resistance and glucose metabolism have not been systematically characterized in patients with PHP1a. Objective, Design, and Setting: In a cross-sectional, case-control study, we examined insulin sensitivity, beta-cell function, energy expenditure (EE), and sympathetic nervous system activity in adults with PHP1a. Study Participants: PHP1a patients (n = 8) and healthy control subjects (n = 24) matched for age (41 +/- 7 vs 41 +/- 7 years [mean +/- SD]), gender, and percent body fat. Methods: Insulin sensitivity (SI), acute insulin response to glucose, and disposition index were assessed during a frequently sampled iv glucose tolerance test. Oral glucose insulin sensitivity (OGIS) was measured during a mixed meal. EE was measured using whole-room indirect calorimetry. Body composition was assessed via dual-energy x-ray absorptiometry and sympathetic nervous system activity by measuring 24-hour urinary catecholamine concentrations. Results: PHP1a patients were less insulin-sensitive than their matched controls based uon SI and OGIS. Nondiabetic PHP1a patients tended to have a lower SI (P=.09) and reduced OGIS (P =.03). Disposition index, a composite measure of beta-cell function, also tended to be lower in patients (P =.07). Total caloric intake, resting EE, total EE, meal-induced thermogenesis, and 24-hour urinary catecholamine concentrations were not significantly different between the groups. Conclusions: Adults with PHP-1a have reduced insulin sensitivity compared with their matched controls that may contribute to the pathogenesis of glucose intolerance and diabetes in these patients. C1 [Muniyappa, Ranganath; Warren, Mary A.; Zhao, Xiongce; Aney, Sara C.; Chen, Kong Y.; Brychta, Robert J.; Skarulis, Monica C.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Courville, Amber B.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Germain-Lee, Emily L.] Johns Hopkins Univ, Sch Med, Albright Clin, Kennedy Krieger Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Skarulis, MC (reprint author), NIDDK, Clin Endocrine Sect, Diabet Endocrinol & Obes Branch, NIH,CRC, 10 Ctr Dr MSC 1613,Bldg 10,Room 6-3940, Bethesda, MD 20892 USA. EM monicas@intra.niddk.nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; U.S. Food and Drug Administration Orphan Products Development [R01 FD-R-002568] FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and U. S. Food and Drug Administration Orphan Products Development Grant R01 FD-R-002568 (to E. L. G.-L.). NR 19 TC 10 Z9 10 U1 0 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2013 VL 98 IS 11 BP E1796 EP E1801 DI 10.1210/jc.2013-1594 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 254QP UT WOS:000327180700014 PM 24030943 ER PT J AU Joiner, WM Cavanaugh, J FitzGibbon, EJ Wurtz, RH AF Joiner, Wilsaan M. Cavanaugh, James FitzGibbon, Edmond J. Wurtz, Robert H. TI Corollary discharge contributes to perceived eye location in monkeys SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE saccade; vision; stability; monkey ID BRAIN-STEM TELLS; VISUAL-STABILITY; FRONTAL-CORTEX; SUPERIOR COLLICULUS; PARIETAL CORTEX; SIGNALS SENT; MOVEMENTS; FIELD; REPRESENTATION; POSITION AB Despite saccades changing the image on the retina several times per second, we still perceive a stable visual world. A possible mechanism underlying this stability is that an internal retinotopic map is updated with each saccade, with the location of objects being compared before and after the saccade. Psychophysical experiments have shown that humans derive such location information from a corollary discharge (CD) accompanying saccades. Such a CD has been identified in the monkey brain in a circuit extending from superior colliculus to frontal cortex. There is a missing piece, however. Perceptual localization is established only in humans and the CD circuit only in monkeys. We therefore extended measurement of perceptual localization to the monkey by adapting the target displacement detection task developed in humans. During saccades to targets, the target disappeared and then reappeared, sometimes at a different location. The monkeys reported the displacement direction. Detections of displacement were similar in monkeys and humans, but enhanced detection of displacement from blanking the target at the end of the saccade was observed only in humans, not in monkeys. Saccade amplitude varied across trials, but the monkey's estimates of target location did not follow that variation, indicating that eye location depended on an internal CD rather than external visual information. We conclude that monkeys use a CD to determine their new eye location after each saccade, just as humans do. C1 [Joiner, Wilsaan M.; Cavanaugh, James; FitzGibbon, Edmond J.; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. [Joiner, Wilsaan M.] George Mason Univ, Dept Bioengn, Fairfax, VA 22030 USA. RP Joiner, WM (reprint author), George Mason Univ, Dept Bioengn, Nguyen Engn Bldg,1G5,4400 Univ Dr,Rm 3800, Fairfax, VA 22030 USA. EM wjoiner2@gmu.edu FU National Eye Institute Intramural Research Program at the National Institutes of Health FX This work was supported by the National Eye Institute Intramural Research Program at the National Institutes of Health. NR 25 TC 8 Z9 8 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2013 VL 110 IS 10 BP 2402 EP 2413 DI 10.1152/jn.00362.2013 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 257YL UT WOS:000327423600014 PM 23986562 ER PT J AU Van Ryzin, C AF Van Ryzin, Carol TI Adrenal Insufficiency: Causes and Prevention of Adrenal Crisis SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Van Ryzin, C (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM Carol.Vanryzin@nih.gov NR 9 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD NOV-DEC PY 2013 VL 28 IS 6 BP 620 EP 621 DI 10.1016/j.pedn.2013.08.003 PG 2 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 251NX UT WOS:000326937600027 PM 23994548 ER PT J AU Hocking, WG Tammemagi, MC Commins, J Oken, MM Kvale, PA Hu, P Ragard, LR Riley, TL Pinsky, P Beck, TM Prorok, PC AF Hocking, William G. Tammemagi, Martin C. Commins, John Oken, Martin M. Kvale, Paul A. Hu, Ping Ragard, Lawrence R. Riley, Tom L. Pinsky, Paul Beck, Thomas M. Prorok, Philip C. TI Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial SO LUNG CANCER LA English DT Article DE Lung neoplasms; Mortality; Radiography; Screening; Methods; Risk factors ID SOLITARY PULMONARY NODULES; CLINICAL-PREDICTION MODEL; RANDOMIZED-TRIAL; PROGNOSIS; MORTALITY; DELAY AB Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55-74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Hocking, William G.] Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, WI USA. [Tammemagi, Martin C.] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Commins, John; Riley, Tom L.] Informat Management Serv Inc, Rockville, MD USA. [Oken, Martin M.] Univ Minnesota, Virginia Piper Canc Inst, Minneapolis, MN USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Dept Pulm Dis, Detroit, MI USA. [Hu, Ping; Pinsky, Paul] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Ragard, Lawrence R.] Westat Corp, Rockville, MD USA. [Beck, Thomas M.] St Lukes Reg Med Ctr, Mt States Tumor Inst, Boise, ID USA. [Prorok, Philip C.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Hocking, WG (reprint author), Dept Oncol Hematol, 1000N Oak Ave, Marshfield, WI 54449 USA. EM hocking.william@marshfieldclinic.org OI Hocking, William/0000-0002-0690-3759 FU Division of Cancer Prevention, National Cancer Institute; NIH; DHHS [NO1-CN-25518] FX This research was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, and DHHS, Contract #NO1-CN-25518. The NCI participated in trial design and provided oversight during conduct of the study. Trial Registration: clinicaltrials.gov identifier: NCT00002540. NR 24 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD NOV PY 2013 VL 82 IS 2 BP 238 EP 244 DI 10.1016/j.lungcan.2013.07.017 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 257ED UT WOS:000327365500008 PM 23993734 ER PT J AU Xu, ZY Bagci, U Kubler, A Luna, B Jain, S Bishai, WR Mollura, DJ AF Xu, Ziyue Bagci, Ulas Kubler, Andre Luna, Brian Jain, Sanjay Bishai, William R. Mollura, Daniel J. TI Computer-aided detection and quantification of cavitary tuberculosis from CT scans SO MEDICAL PHYSICS LA English DT Article DE cavitary tuberculosis; airway tree; computer aided detection; segmentation; fuzzy connectedness ID PULMONARY TUBERCULOSIS; ANTITUBERCULOUS THERAPY; LUNG; SEGMENTATION; DISEASE; IMAGES; TOMOGRAPHY; DEFINITION; DIAGNOSIS; TREE AB Purpose: To present a computer-aided detection tool for identifying, quantifying, and evaluating tuberculosis (TB) cavities in the infected lungs from computed tomography (CT) scans. Methods: The authors' proposed method is based on a novel shape-based automated detection algorithm on CT scans followed by a fuzzy connectedness (PC) delineation procedure. In order to assess interaction between cavities and airways, the authors first roughly identified air-filled structures (airway, cavities, esophagus, etc.) by thresholding over Hounsfield unit of CT image. Then, airway and cavity structure detection was conducted within the support vector machine classification algorithm. Once airway and cavities were detected automatically, the authors extracted airway tree using a hybrid multiscale approach based on novel affinity relations within the FC framework and segmented cavities using intensity-based FC algorithm. At final step, the authors refined airway structures within the local regions of PC with finer control. Cavity segmentation results were compared to the reference truths provided by expert radiologists and cavity formation was tracked longitudinally from serial CT scans through shape and volume information automatically determined through the authors' proposed system. Morphological evolution of the cavitary TB were analyzed accordingly with this process. Finally, the authors computed the minimum distance between cavity surface and nearby airway structures by using the linear time distance transform algorithm to explore potential role of airways in cavity formation and morphological evolution. Results: The proposed methodology was qualitatively and quantitatively evaluated on pulmonary CT images of rabbits experimentally infected with TB, and multiple markers such as cavity volume, cavity surface area, minimum distance from cavity surface to the nearest bronchial-tree, and longitudinal change of these markers (namely, morphological evolution of cavities) were determined precisely. While accuracy of the authors' cavity detection algorithm was 94.61%, airway detection part of the proposed methodology showed even higher performance by 99.8%. Dice similarity coefficients for cavitary segmentation experiments were found to be approximately 99.0% with respect to the reference truths provided by two expert radiologists (blinded to their evaluations). Moreover, the authors noted that volume derived from the authors' segmentation method was highly correlated with those provided by the expert radiologists (R-2 = 0.99757 and R-2 = 0.99496, p <0.001, with respect to the observer 1 and observer 2) with an interobserver agreement of 98%. The authors quantitatively confirmed that cavity formation was positioned by the nearby bronchial-tree after exploring the respective spatial positions based on the minimum distance measurement. In terms of efficiency, the core algorithms take less than 2 min on a linux machine with 3.47 GHz CPU and 24 GB memory. Conclusion: The authors presented a fully automatic method for cavitary TB detection, quantification, and evaluation. The performance of every step of the algorithm was qualitatively and quantitatively assessed. With the proposed method, airways and cavities were automatically detected and subsequently delineated in high accuracy with heightened efficiency. Furthermore, not only morphological information of cavities were obtained through the authors' proposed framework, but their spatial relation to airways, and longitudinal analysis was also provided to get further insight on cavity formation in tuberculosis disease. To the authors' best of knowledge, this is the first study in computerized analysis of cavitary tuberculosis from CT scans. (C) 2013 American Association of Physicists in Medicine. C1 [Xu, Ziyue; Bagci, Ulas; Mollura, Daniel J.] NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Kubler, Andre; Luna, Brian; Jain, Sanjay; Bishai, William R.] Johns Hopkins Univ, Ctr TB Res, Baltimore, MD 21287 USA. [Kubler, Andre] Univ London Imperial Coll Sci Technol & Med, Dept Med, London W12 0HS, England. [Jain, Sanjay] Johns Hopkins Univ, Ctr Infect & Inflammat Imaging Res, Baltimore, MD 21287 USA. [Bishai, William R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Xu, ZY (reprint author), NIH, Ctr Infect Dis Imaging CIDI Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. EM ziyue.xu@nih.gov RI Xy, Ziyue/K-9438-2014; OI Xy, Ziyue/0000-0002-5728-6869; Bagci, Ulas/0000-0001-7379-6829; Luna, PhD, Brian/0000-0001-6718-4551 FU CIDI, the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institute of Biomedical Imaging and Bioengineering (NIBIB) FX This research is supported by CIDI, the intramural research program of the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB). W. R. Bishai acknowledges R01 Al 079590 and the support of Howard Hughes Medical Institute (HHMI). S. JaM acknowledges the Grant No. DP2 0D006492-01. A. Kubler is funded by internal grant from Imperial College London, and acknowledges Dr. J. S. Friedland and Dr. P. T. G. Elkington. NR 39 TC 8 Z9 8 U1 2 U2 7 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 NOV PY 2013 VL 40 IS 11 AR 113701 DI 10.1118/1.4824979 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 252FZ UT WOS:000326991800069 PM 24320475 ER PT J AU Sobek, S Dalla Rosa, I Pommier, Y Bornholz, B Kalfalah, F Zhang, HL Wiesner, RJ von Kleist-Retzow, JC Hillebrand, F Schaal, H Mielke, C Christensen, MO Boege, F AF Sobek, Stefan Dalla Rosa, Ilaria Pommier, Yves Bornholz, Beatrice Kalfalah, Faiza Zhang, Hongliang Wiesner, Rudolf J. von Kleist-Retzow, Juergen-Christoph Hillebrand, Frank Schaal, Heiner Mielke, Christian Christensen, Morten O. Boege, Fritz TI Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I SO NUCLEIC ACIDS RESEARCH LA English DT Article ID N-TERMINAL DOMAIN; RNA-POLYMERASE-II; MAMMALIAN MITOCHONDRIA; DNA NUCLEOIDS; MTDNA; CELLS; ACTIVATION; NUCLEAR; TFAM; REPLICATION AB Mitochondrial topoisomerase I is a genetically distinct mitochondria-dedicated enzyme with a crucial but so far unknown role in the homeostasis of mitochondrial DNA metabolism. Here, we present data suggesting a negative regulatory function in mitochondrial transcription or transcript stability. Deficiency or depletion of mitochondrial topoisomerase I increased mitochondrial transcripts, whereas overexpression lowered mitochondrial transcripts, depleted respiratory complexes I, III and IV, decreased cell respiration and raised superoxide levels. Acute depletion of mitochondrial topoisomerase I triggered neither a nuclear mito-biogenic stress response nor compensatory topoisomerase II beta upregulation, suggesting the concomitant increase in mitochondrial transcripts was due to release of a local inhibitory effect. Mitochondrial topoisomerase I was co-immunoprecipitated with mitochondrial RNA polymerase. It selectively accumulated and rapidly exchanged at a subset of nucleoids distinguished by the presence of newly synthesized RNA and/or mitochondrial RNA polymerase. The inactive Y559F-mutant behaved similarly without affecting mitochondrial transcripts. In conclusion, mitochondrial topoisomerase I dampens mitochondrial transcription and thereby alters respiratory capacity. The mechanism involves selective association of the active enzyme with transcriptionally active nucleoids and a direct interaction with mitochondrial RNA polymerase. The inhibitory role of topoisomerase I in mitochondrial transcription is strikingly different from the stimulatory role of topoisomerase I in nuclear transcription. C1 [Sobek, Stefan; Bornholz, Beatrice; Kalfalah, Faiza; Mielke, Christian; Christensen, Morten O.; Boege, Fritz] Univ Dusseldorf, Fac Med, Inst Clin Chem, D-40225 Dusseldorf, Germany. [Sobek, Stefan; Bornholz, Beatrice; Kalfalah, Faiza; Mielke, Christian; Christensen, Morten O.; Boege, Fritz] Univ Dusseldorf, Fac Med, Diagnost Lab, D-40225 Dusseldorf, Germany. [Dalla Rosa, Ilaria; Pommier, Yves; Zhang, Hongliang] NCI, Natl Inst Hlth, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Wiesner, Rudolf J.] Univ Cologne, Ctr Physiol & Pathophysiol, Inst Vegetat Physiol, D-50931 Cologne, Germany. [Wiesner, Rudolf J.; von Kleist-Retzow, Juergen-Christoph] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. [Wiesner, Rudolf J.] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany. [von Kleist-Retzow, Juergen-Christoph] Univ Cologne, Fac Med, Dept Pediat, D-50931 Cologne, Germany. [Hillebrand, Frank; Schaal, Heiner] Univ Dusseldorf, Fac Med, Ctr Microbiol & Virol, Inst Virol, D-40225 Dusseldorf, Germany. RP Boege, F (reprint author), Univ Dusseldorf, Fac Med, Inst Clin Chem, D-40225 Dusseldorf, Germany. EM boege@med.uni-duesseldorf.de FU Deutsche Forschungsgemeinschaft [SFB 728, GRK 1033, DFG Wi 889/6-2]; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Deutsche Forschungsgemeinschaft [SFB 728 and GRK 1033 to F. B., DFG Wi 889/6-2 to R.J.W.] and the National Institutes of Health, National Cancer Institute, Center for Cancer Research [Intramural Research Program to Y.P.]. Funding for open access charge: Research budget of the Institute of Clin. Chemistry and Lab. Diagnostics, Univ. Dusseldorf, of which the corresponding author is the director. NR 44 TC 11 Z9 11 U1 2 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2013 VL 41 IS 21 BP 9848 EP 9857 DI 10.1093/nar/gkt768 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 259QQ UT WOS:000327541800027 PM 23982517 ER PT J AU Sugiman-Marangos, SN Peel, JK Weiss, YM Ghirlando, R Junop, MS AF Sugiman-Marangos, Seiji N. Peel, John K. Weiss, Yoni M. Ghirlando, Rodolfo Junop, Murray S. TI Crystal structure of the DdrB/ssDNA complex from Deinococcus radiodurans reveals a DNA binding surface involving higher-order oligomeric states SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION-VELOCITY; IONIZING-RADIATION; DDRB PROTEIN; REPAIR; RADIORESISTANCE; RESISTANCE; DOMAIN; FORM AB The ability of Deinococcus radiodurans to recover from extensive DNA damage is due in part to its ability to efficiently repair its genome, even following severe fragmentation by hundreds of double-strand breaks. The single-strand annealing pathway plays an important role early during the recovery process, making use of a protein, DdrB, shown to greatly stimulate ssDNA annealing. Here, we report the structure of DdrB bound to ssDNA to 2.3 A. Pentameric DdrB was found to assemble into higher-order structures that coat ssDNA. To gain further mechanistic insight into the protein's function, a number of point mutants were generated altering both DNA binding and higher order oligomerization. This work not only identifies higher-order DdrB associations but also suggests the presence of an extended DNA binding surface running along the 'top' surface of a DdrB pentamer and continuing down between two individual subunits of the ring structure. Together this work sheds new insight into possible mechanisms for DdrB function in which higher-order assemblies of DdrB pentamers assist in the pairing of complementary ssDNA using an extended DNA binding surface. C1 [Sugiman-Marangos, Seiji N.; Peel, John K.; Weiss, Yoni M.; Junop, Murray S.] McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. [Sugiman-Marangos, Seiji N.; Peel, John K.; Weiss, Yoni M.; Junop, Murray S.] McMaster Univ, MG DeGroote Inst Infect Dis Res, Hamilton, ON L8N 3Z5, Canada. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Junop, MS (reprint author), McMaster Univ, Dept Biochem & Biomed Sci, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM junopm@mcmaster.ca RI Junop, Murray/E-4160-2015 OI Junop, Murray/0000-0001-6676-5717 FU Natural Sciences and Engineering Research Council of Canada [2008R00075]; Offices of Biological and Environmental Research and Basic Energy Sciences of the US Department of Energy; National Center for Research Resources [P41RR012408]; National Institute of General Medical Sciences of the National Institutes of Health; Intramural Research Program of the National Institutes Health [P41GM103473]; National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK; National Science and Engineering Research Council of Canada FX Natural Sciences and Engineering Research Council of Canada through grant [2008R00075 to M.S.J.] and studentship (to S.N.S.M. and Y.M.W.); Offices of Biological and Environmental Research and Basic Energy Sciences of the US Department of Energy; National Center for Research Resources [P41RR012408] and National Institute of General Medical Sciences [P41GM103473] of the National Institutes of Health; Intramural Research Program of the National Institutes Health, the National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK (in part) (to R.G.). Funding for open access charge: National Science and Engineering Research Council of Canada. NR 32 TC 6 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD NOV PY 2013 VL 41 IS 21 BP 9934 EP 9944 DI 10.1093/nar/gkt759 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 259QQ UT WOS:000327541800035 PM 23975200 ER PT J AU Marcum, ZA Zheng, Y Perera, S Strotmeyer, E Newman, AB Simonsick, EM Shorr, RI Bauer, DC Donohue, JM Hanlon, JT AF Marcum, Zachary A. Zheng, Yan Perera, Subashan Strotmeyer, Elsa Newman, Anne B. Simonsick, Eleanor M. Shorr, Ronald I. Bauer, Douglas C. Donohue, Julie M. Hanlon, Joseph T. CA Hlth ABC Study TI Prevalence and correlates of self-reported medication non-adherence among older adults with coronary heart disease, diabetes mellitus, and/or hypertension SO RESEARCH IN SOCIAL & ADMINISTRATIVE PHARMACY LA English DT Article DE Medication adherence; Chronic disease; Aged ID CONCEPTUALLY BASED APPROACH; COST-RELATED NONADHERENCE; BODY-COMPOSITION; RACIAL-DIFFERENCES; LOGISTIC-REGRESSION; BLOOD-PRESSURE; HEALTH-CARE; PART-D; ADHERENCE; OUTCOMES AB Background: Information about the prevalence and correlates of self-reported medication nonadherence using multiple measures in older adults with chronic cardiovascular conditions is needed. Objective: To examine the prevalence and correlates of self-reported medication nonadherence among community-dwelling elders with chronic cardiovascular conditions. Methods: Participants (n = 897) included members from the Health, Aging and Body Composition Study with coronary heart disease, diabetes mellitus, and/or hypertension at Year 10. Self-reported nonadherence was measured by the 4-item Morisky Medication Adherence Scale (MMAS-4) and 2-item cost-related nonadherence (CRN-2) scale at Year 11. Factors (demographic, health status, and access to care) were examined for association with the MMAS-4 and then for association with the CRN-2 scale. Results: Nonadherence per the MMAS-4 and CRN-2 scale was reported by 40.7% and 7.7% of participants, respectively, with little overlap (3.7%). Multivariable logistic regression analyses found that black race was significantly associated with nonadherence per the MMAS-4 (P = 0.002) and the CRN-2 scale (P = 0.005). Other correlates of nonadherence per the MMAS-4 (with independent associations) included having cancer (P = 0.04), a history of falls (P = 0.02), sleep disturbances (P = 0.04) and having a hospitalization in the previous 6 months (P = 0.005). Conversely, being unmarried (P = 0.049), having worse self-reported health (P = 0.04) and needs being poorly met by income (P = 0.02) showed significant independent associations with nonadherence per the CRN-2 scale. Conclusions: Self-reported medication nonadherence was common in older adults with chronic cardiovascular conditions and only one factor - race - was associated with both types. The research implication of this finding is that it highlights the need to measure both types of self-reported nonadherence in older adults. Moreover, the administration of these quick measures in the clinical setting should help identify specific actions such as patient education or greater use of generic medications or pill boxes that may address barriers to medication nonadherence. (C) 2013 Elsevier Inc. All rights reserved. C1 [Marcum, Zachary A.; Zheng, Yan; Perera, Subashan; Newman, Anne B.; Hanlon, Joseph T.] Univ Pittsburgh, Sch Med, Dept Geriatr Med, Pittsburgh, PA 15213 USA. [Perera, Subashan; Strotmeyer, Elsa; Newman, Anne B.; Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Shorr, Ronald I.] Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Gainesville, FL 32608 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med Gen Internal Med, San Francisco, CA 94143 USA. [Donohue, Julie M.] Univ Pittsburgh, Dept Hlth Policy & Management, Pittsburgh, PA USA. RP Marcum, ZA (reprint author), Univ Pittsburgh, Sch Med, Dept Geriatr Med, Pittsburgh, PA 15213 USA. EM zam12@pitt.edu RI Perera, Subashan/D-7603-2014; Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; OI Strotmeyer, Elsa/0000-0002-4093-6036; Newman, Anne/0000-0002-0106-1150; Donohue, Julie/0000-0003-2418-6017 FU AHRQ HHS [K12 HS019461, R01 HS017695, R01 HS018721, R01HS018721]; NCATS NIH HHS [KL2 TR000146, UL1 TR000005]; NIA NIH HHS [N01-AG-6-2101, K07 AG033174, K07-AG-033174, N01 AG062101, N01-AG-6-2103, N01-AG-6-2106, P30 AG024827, P30-AG-024827, R01 AG027017, R01 AG028050, R01 AG034056, R01-AG-28050, R01AG034056, R56 AG027017, R56AG 027017]; NINR NIH HHS [R01 NR010135, R01 NR012459, R01-NR12459] NR 48 TC 21 Z9 21 U1 3 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7411 EI 1934-8150 J9 RES SOC ADMIN PHARM JI Res. Soc. Adm. Pharm. PD NOV-DEC PY 2013 VL 9 IS 6 BP 817 EP 827 DI 10.1016/j.sapharm.2012.12.002 PG 11 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 255PN UT WOS:000327252400016 PM 23291338 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Friclkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, DR Hill, NS Horan, T Kollef, M Levy, M Septimus, E Van Antwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Friclkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean R. Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward Van Antwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events: Executive Summary SO RESPIRATORY CARE LA English DT Article DE ventilator-associated pneumonia; ICU; epidemiology; public health; critical care; mechanicalventilation C1 [Magill, Shelley S.; Friclkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Hosp Epidemiol & Qual Improvement, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hess, Dean R.] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Div Pulm Crit Care & Sleep, Warren Alpert Med Sch, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [Van Antwerpen, Carole] New York State Dept Hlth, Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [Van Antwerpen, Carole] Council State & Terr Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov FU Centers for Disease Control and Prevention (CDC) FX The work described herein was supported by the Centers for Disease Control and Prevention (CDC). NR 2 TC 2 Z9 2 U1 0 U2 2 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD NOV PY 2013 VL 58 IS 11 BP 1985 EP 1989 DI 10.4187/respcare.02759 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 252JZ UT WOS:000327002300021 ER PT J AU Sanchez, GAM de Jesus, AA Goldbach-Mansky, R AF Sanchez, Gina A. Montealegre de Jesus, Adriana Almeida Goldbach-Mansky, Raphaela TI Monogenic Autoinflammatory Diseases: Disorders of Amplified Danger Sensing and Cytokine Dysregulation SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Cryopyrin-associated periodic syndrome (CAPS); Neonatal-onset multisystem inflammatory disease (NOMID); Proteasome-associated autoinflammatory syndrome (PRAAS); Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE); Deficiency of the IL-1 receptor antagonist (DIRA); Inflammasome; Autoinflammatory diseases; Intracellular pattern recognition receptors (PRR) ID FAMILIAL MEDITERRANEAN FEVER; MEVALONATE KINASE-DEFICIENCY; MUCKLE-WELLS-SYNDROME; CONGENITAL DYSERYTHROPOIETIC ANEMIA; RECURRENT MULTIFOCAL OSTEOMYELITIS; PEDIATRIC GRANULOMATOUS ARTHRITIS; GENERALIZED PUSTULAR PSORIASIS; RILONACEPT INTERLEUKIN-1 TRAP; INFLAMMATORY-BOWEL-DISEASE; PERIODIC SYNDROME TRAPS AB The pathogenesis of monogenic autoinflammatory diseases converges on the presence of exaggerated immune responses that are triggered through activation of altered pattern recognition receptor (PRR) pathways and result in cytokine/chemokine amplification loops and the inflammatory clinical phenotype seen in autoinflammatory patients. The PAR response can be triggered by accumulation of metabolites, by mutations in sensors leading to their constitutive overactivation, or by mutations in mediator cytokine pathways that lead to amplification and/or inability to downregulate an inflammatory response in hematopoietic and/or nonhematopoietic cells. The study of the pathogenesis of sterile inflammation in patients with autoinflammatory syndromes continues to uncover novel inflammatory pathways. C1 [Sanchez, Gina A. Montealegre; de Jesus, Adriana Almeida; Goldbach-Mansky, Raphaela] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. RP Goldbach-Mansky, R (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Translat Autoinflammatory Dis Sect, NIH, Bldg 10,Room 6D47-B,10 Ctr Dr, Bethesda, MD 20892 USA. EM goldbacr@mail.nih.gov FU Intramural NIH HHS [ZIA AR041138-07, Z01 AR041138-05, Z01 AR041138-06, Z99 AR999999, ZIA AR041138-08, ZIA AR041138-09, ZIA AR041138-10] NR 129 TC 15 Z9 16 U1 1 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD NOV PY 2013 VL 39 IS 4 BP 701 EP + DI 10.1016/j.rdc.2013.08.001 PG 35 WC Rheumatology SC Rheumatology GA 260BT UT WOS:000327570700004 PM 24182851 ER PT J AU Ramanathan, A Srinivasalu, H Colbert, RA AF Ramanathan, Anusha Srinivasalu, Hemalatha Colbert, Robert A. TI Update on Juvenile Spondyloarthritis SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Juvenile spondyloarthritis; Enthesitis-related arthritis; Juvenile psoriatic arthritis; HLA-B27; Axial spondyloarthritis ID ENTHESITIS-RELATED ARTHRITIS; ACTIVE ANKYLOSING-SPONDYLITIS; DISTAL INTERPHALANGEAL JOINT; ANTITUMOR NECROSIS FACTOR; SOCIETY CLASSIFICATION CRITERIA; UNFOLDED PROTEIN RESPONSE; MAJOR CLINICAL-RESPONSE; IDIOPATHIC ARTHRITIS; PSORIATIC-ARTHRITIS; RADIOGRAPHIC PROGRESSION AB Spondyloarthritis (SpA) encompasses a group of disorders linked by overlapping clinical manifestations and genetic predisposition. Newer classification systems developed for adults with SpA focus on identifying individuals with axial or predominantly peripheral involvement. All forms of SpA can begin during childhood, and can be considered on a continuum with adult disease. Nevertheless, there are important differences in presentation and outcome that depend on age at onset. This article highlights these differences, what has been learned about genetics and pathogenesis of SpA, and important unmet needs for future studies. C1 [Ramanathan, Anusha] Childrens Hosp Los Angeles, Keck Sch Med USC, Div Rheumatol, Los Angeles, CA 90027 USA. [Srinivasalu, Hemalatha] George Washington Univ, Childrens Natl Med Ctr, Div Rheumatol, Washington, DC 20010 USA. [Colbert, Robert A.] Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Pediat Translat Res Branch, NIH, Bethesda, MD 20892 USA. RP Colbert, RA (reprint author), Natl Inst Arthrit Musculoskeletal & Skin Dis NIAM, Pediat Translat Res Branch, NIH, Bldg 10 CRC Rm 1-5142,10 Ctr Dr, Bethesda, MD 20892 USA. EM colbertr@mail.nih.gov FU NIAMS Intramural Research Program [Z01 AR041184] FX R.A. Colbert was supported by the NIAMS Intramural Research Program, Z01 AR041184. NR 103 TC 6 Z9 7 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD NOV PY 2013 VL 39 IS 4 BP 767 EP + DI 10.1016/j.rdc.2013.06.002 PG 23 WC Rheumatology SC Rheumatology GA 260BT UT WOS:000327570700007 PM 24182854 ER PT J AU Rider, LG Katz, JD Jones, OY AF Rider, Lisa G. Katz, James D. Jones, Olcay Y. TI Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Juvenile myositis; Juvenile dermatomyositis; Juvenile polymyositis; Overlap myositis; Myositis-specific autoantibodies; Treatment; Biologic therapies ID CLINICALLY AMYOPATHIC DERMATOMYOSITIS; INCLUSION-BODY MYOSITIS; ALLIANCE CONSENSUS CONFERENCE; CONNECTIVE-TISSUE DISEASES; INTERSTITIAL LUNG-DISEASE; NECROSIS-FACTOR-ALPHA; GENE 5 ANTIBODY; MACROPHAGIC MYOFASCIITIS; ORBITAL MYOSITIS; INTRAVENOUS CYCLOPHOSPHAMIDE AB This review updates recent trends in the classification of the juvenile idiopathic inflammatory myopathies (JIIM) and the emerging standard of treatment of the most common form of JIIM, juvenile dermatomyositis. The JIIM are rare, heterogeneous autoimmune diseases that share chronic muscle inflammation and weakness. A growing spectrum of clinicopathologic groups and serologic phenotypes defined by the presence of myositis autoantibodies are now recognized, each with differing demographics, clinical manifestations, laboratory findings, and prognoses. Although daily oral corticosteroids remain the backbone of treatment, disease-modifying anti-rheumatic drugs are almost always used adjunctively and biologic therapies may benefit patients with recalcitrant disease. C1 [Rider, Lisa G.] Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, NIH, Bethesda, MD 20892 USA. [Rider, Lisa G.; Katz, James D.; Jones, Olcay Y.] George Washington Univ, Dept Med, Myositis Ctr, Div Rheumatol, Washington, DC 20037 USA. [Jones, Olcay Y.] Walter Reed Natl Mil Med Ctr, Div Pediat Rheumatol, Dept Pediat, Bethesda, MD 20889 USA. RP Rider, LG (reprint author), Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Program Clin Res, NIH, CRC 4-2352,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov RI hui, li/L-5008-2013; OI Rider, Lisa/0000-0002-6912-2458 FU Intramural Research Program of the NIH, National Institute of Environmental Health FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health. The authors have no conflicts of interest. NR 138 TC 18 Z9 19 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD NOV PY 2013 VL 39 IS 4 BP 877 EP + DI 10.1016/j.rdc.2013.06.001 PG 29 WC Rheumatology SC Rheumatology GA 260BT UT WOS:000327570700012 PM 24182859 ER PT J AU Burks, SR Ziadloo, A Kim, SJ Nguyen, BA Frank, JA AF Burks, Scott R. Ziadloo, Ali Kim, Saejeong J. Nguyen, Ben A. Frank, Joseph A. TI Noninvasive Pulsed Focused Ultrasound Allows Spatiotemporal Control of Targeted Homing for Multiple Stem Cell Types in Murine Skeletal Muscle and the Magnitude of Cell Homing Can Be Increased Through Repeated Applications SO STEM CELLS LA English DT Article DE Pulsed focused ultrasound; High intensity focused ultrasound; Stem cells; Mesenchymal stem cells; Endothelial precursor cells; Targeted delivery ID MARROW STROMAL CELLS; BONE-MARROW; CEREBRAL-ISCHEMIA; IN-VIVO; MICROBUBBLE DESTRUCTION; MYOCARDIAL-INFARCTION; PROGENITOR CELLS; SATELLITE CELLS; ADIPOSE-TISSUE; SOLID TUMORS AB Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient molecular zip codes of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. Stem Cells2013;31:2551-2560 C1 [Burks, Scott R.; Ziadloo, Ali; Kim, Saejeong J.; Nguyen, Ben A.; Frank, Joseph A.] NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Burks, Scott R.] NIH, Imaging Sci Training Program, Ctr Clin, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, Bethesda, MD USA. RP Burks, SR (reprint author), 10 Ctr Dr,Room B1N256, Bethesda, MD 20892 USA. EM scott.burks@nih.gov FU Intramural Research Program of the NIH Clinical Center; National Institute of Biomedical Imaging and Bioengineering FX This research was funded by the Intramural Research Program of the NIH Clinical Center and National Institute of Biomedical Imaging and Bioengineering. NR 49 TC 10 Z9 11 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD NOV PY 2013 VL 31 IS 11 BP 2551 EP 2560 DI 10.1002/stem.1495 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 252QY UT WOS:000327025600024 PM 23922277 ER PT J AU Albanese, E Taylor, C Siervo, M Stewart, R Prince, MJ Acosta, D AF Albanese, Emiliano Taylor, Clare Siervo, Mario Stewart, Robert Prince, Martin J. Acosta, Daisy TI Dementia severity and weight loss: A comparison across eight cohorts. The 10/66 study SO ALZHEIMERS & DEMENTIA LA English DT Article DE Dementia; Dementia severity; Weight loss; Developing countries; Epidemiology; Observational study; Older adults; Population-based sample; Cross-cohort; Meta-analysis; Aging ID BODY-MASS INDEX; CROSS-SECTIONAL SURVEYS; ALZHEIMERS-DISEASE; INCIDENT DEMENTIA; LATIN-AMERICA; MORTALITY; ASSOCIATION; COMMUNITY; METAANALYSIS; PREVALENCE AB Background: We aimed to investigate the association between dementia severity and weight loss in countries with low and middle incomes, where most prevalent cases reside. Methods: Cross-sectional catchment area surveys were performed in Cuba, Mexico, Venezuela, Peru, Dominican Republic, Puerto Rico, China, and India. In 16,538 older adults (>= 65 years of age), significant weight loss was self-reported and confirmed by an informant. We conducted neuropsychological testing and clinical and neurological assessments. Dementia severity was determined by applying a validated algorithm and was quantified by the Clinical Dementia Rating Scale. Results: The characteristics of those who reported weight loss varied across countries. In Poisson models, after controlling for relevant covariates and for waist and arm circumferences, dementia severity was associated with reported weight loss (pooled prevalence ratios [95% confidence intervals {CI]] 2.19 [1.98, 2.41]; 3.81 [3.35,4.33]; and 5.18 [4.41, 6.10] for CDR 0.5, 1, and 2/3, respectively, compared with CDR 0). The association increased linearly through stages of dementia severity in all countries (P for trend < .001), and between-country heterogeneity was minimal. Conclusions: We found a strong gradient effect in the direct association between dementia severity and reported weight loss, homogeneous across sites from eight countries, consistent with mechanistic data on the role of neurodegenerative processes on energy balance and with dietary changes due to disease severity. Considering the well-recognized effect of weight loss on morbidity and mortality and the large number affected by dementia in less resourced countries, amelioration of weight loss in dementia patients should be considered with priority in these settings. (C) 2013 The Alzheimer's Association. All rights reserved. C1 [Albanese, Emiliano] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Taylor, Clare; Stewart, Robert; Prince, Martin J.] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Siervo, Mario] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Acosta, Daisy] Univ Nacl Pedro Henriquez Urena, Dept Internal Med, Santo Domingo, Dominican Rep. RP Albanese, E (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. EM emiliano.albanese@gmail.com RI Prince, Martin/A-9170-2010; OI Prince, Martin/0000-0003-1379-7146; Stewart, Robert/0000-0002-4435-6397 FU Wellcome Trust (UK) [GR066133]; World Health Organization; U.S. Alzheimer's Association [IIRG-04-1286]; FondoNacional de Ciencia Y Tecnologia, Consejo de DesarolloCientifico Y Humanistic, Universidad Central de Venezuela (Venezuela); GlaxoSmithKline; Novartis; Lundbeck; Pfizer; Eisai; National Institute on Aging; National Institutes of Health; National Institute for Health Research (NIHR) Biomedical Research Centre; Dementia Biomedical Research Unit at South London; Maudsley NHS Foundation Trust; King's College London FX The 10/66 Dementia Research Group population-based surveys were funded by the Wellcome Trust (UK) (GR066133); the World Health Organization; the U.S. Alzheimer's Association (IIRG-04-1286); and the FondoNacional de Ciencia Y Tecnologia, Consejo de DesarolloCientifico Y Humanistic, Universidad Central de Venezuela (Venezuela). The Rockefeller Foundation supported a dissemination meeting in their Bellagio Centre. Alzheimer's Disease International (ADI) has provided support for networking and infrastructure. The 10/66 Dementia Research Group works closely with ADI, which is a nonprofit federation of 77 Alzheimer associations around the world. ADI is committed to strengthening Alzheimer associations worldwide, raising awareness regarding dementia and Alzheimer's disease, and advocating for more and better services for people with dementia and their caregivers. ADI is supported in part by grants from GlaxoSmithKline, Novartis, Lundbeck, Pfizer, and Eisai. Emiliano Albanese is supported by the Intramural Research Program of the National Institute on Aging and the National Institutes of Health. Robert Stewart is partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre, the Dementia Biomedical Research Unit at South London, the Maudsley NHS Foundation Trust, and King's College London. None of the funders had any role in the design, data collection, manuscript writing, or decision to submit for publication. NR 40 TC 16 Z9 16 U1 1 U2 10 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 NOV PY 2013 VL 9 IS 6 BP 649 EP 656 DI 10.1016/j.jalz.2012.11.014 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 254NP UT WOS:000327172700005 PM 23474042 ER PT J AU Breitner, J Baker, L Drye, L Evans, D Lyketsos, C Ryan, L Zandi, P Baker, L Breitner, J Saucedo, HH Anau, J Cholerton, B Kramer, K Zandi, P Drye, L Casper, AS Meinert, C Martin, B Jenkins, G McCaffrey, L Meinert, J Vaidya, V Ahuja, A May, P Ryan, L Lyketsos, CG Steinberg, M Brandt, J Pedroso, JJ Bergey, A Gogel, C Smith, L Kraus, J Stern, RA Green, RC Gavett, B Mwicigi, J Baldwin, L McGowan, T Johnson, P Qiu, W Frederick, J Raghavan, S Rossi, C Mandell, A Dinizo, D Roth, MT Porsteinsson, A Ismail, MS Weber, M Brand, C Richard, J Stear, K Schepp, S Cosman, K Martin, K Craft, S Baker, L Dahl, D Garrett, G Tidwell, J Thielke, S Smith, L Arbuckle, M Strong, W Ladenberg, J Callaghan, M Watson, S Skinner, J Bowton, K Sabbagh, M Belden, C Liebsack, C Davis, K Arnieri, L Malek-Ahmadi, M Nicholson, L Jacobson, S Schwartz, E Mullan, M Luis, C Parrish, J Faircloth, M Ervin, T Girard, J Burke, D Keegan, A Evans, D AF Breitner, John Baker, Laura Drye, Lea Evans, Denis Lyketsos, Constantine Ryan, Laurie Zandi, Peter Baker, Laura Breitner, John Saucedo, Hector Hernandez Anau, Jane Cholerton, Brenna Kramer, Kirise Zandi, Peter Drye, Lea Casper, Anne Shanklin Meinert, Curtis Martin, Barbara Jenkins, Gabrielle McCaffrey, Lee Meinert, Jill Vaidya, Vijay Ahuja, Alka May, Pat Ryan, Laurie Lyketsos, Constantine G. Steinberg, Martin Brandt, Jason Pedroso, Julia J. Bergey, Alyssa Gogel, Carol Smith, Lynn Kraus, Jennifer Stern, Robert A. Green, Robert C. Gavett, Brandon Mwicigi, Jane Baldwin, Lorraine McGowan, Theresa Johnson, Patricia Qiu, Wendy Frederick, Jamie Raghavan, Sumati Rossi, Carol Mandell, Alan Dinizo, Daniella Roth, Mary Tara Porsteinsson, Anton Ismail, M. Saleem Weber, Miriam Brand, Connie Richard, Jennifer Stear, Kelly Schepp, Sue Cosman, Kelly Martin, Kimberly Craft, Suzanne Baker, Laura Dahl, Deborah Garrett, Grace Tidwell, Jamie Thielke, Stephen Smith, Lauren Arbuckle, Matthew Strong, William Ladenberg, Juliet Callaghan, Maureen Watson, Stennis Skinner, Jeannine Bowton, Kaysha Sabbagh, Marwan Belden, Christine Liebsack, Carolyn Davis, Kathryn Arnieri, Lauren Malek-Ahmadi, Michael Nicholson, Lisa Jacobson, Sandra Schwartz, Elliot Mullan, Michael Luis, Cheryl Parrish, Julia Faircloth, Marlee Ervin, Terry Girard, Janette Burke, Deborah Keegan, Andrew Evans, Denis CA Alzheimer's Dis Antiinflammatory TI Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) The Alzheimer's Disease Anti-inflammatory Prevention Trial Research Group SO ALZHEIMERS & DEMENTIA LA English DT Article DE Prevention; Clinical trial; Alzheimer's disease; Nonsteroidal anti-inflammatory drug; Naproxen; Celecoxib ID DOUBLE-BLIND; DRUGS; ROFECOXIB; NAPROXEN; PLACEBO; INHIBITION; CELECOXIB; ASPIRIN; DESIGN; NSAIDS AB Objectives: The Alzheimer's Disease Anti-inflammatory Prevention Trial Follow-up Study (ADAPT-FS) was designed to evaluate the efficacy of naproxen and celecoxib for the primary prevention of Alzheimer's disease (AD) several years after cessation of treatment in ADAPT. Methods: ADAPT was a randomized, double-masked, multicenter clinical trial of naproxen or celecoxib vs placebo (1:1:1.5 assignment ratio) at six U.S.-based clinics. The trial enrolled 2528 people between 2001 and 2004. Treatments were discontinued in December 2004 and participants were monitored regularly until 2007. In 2010 and 2011, ADAPT-FS screened 1537 participants by telephone and, if indicated, examined them in person using standardized clinical assessments. The primary outcome was time to diagnosis of AD. Death index searches were performed for participants not located. Results: Eighty-nine additional AD events were identified (24 celecoxib, 25 naproxen, and 40 placebo) yielding a total of 161 events (48 [6.6% of randomized participants] celecoxib, 43 [6.0%] naproxen, and 70 [6.5%] placebo) across ADAPT and ADAPT-FS. Adjusted hazard ratios (HRs) comparing each treatment with placebo showed no overall reduction in risk of AD: HR celecoxib vs placebo, 1.03 (95% confidence interval [CI], 0.72-1.50; P = .86); HR naproxen vs placebo, 0.92 (95% CI, 0.62-1.35; P = .66). There were 349 deaths (110 [15.2%] celecoxib, 96 [13.4%] naproxen, and 143 [13.2%] placebo). Risk of death was similar for the naproxen- and placebo-assigned groups (HR, 0.99; 95% CI, 0.76-1.28; P = .93) and slightly higher for celecoxib compared with the placebo-assigned group (HR, 1.15; 95% CI, 0.90-1.48; P = .27). Conclusions: These results acquired during a follow-up of approximately 7 years (which included a median of less than 1.5 years of treatment) do not support the hypothesis that celecoxib or naproxen prevent AD in adults with a family history of dementia. 2013 The Alzheimer's Association. All rights reserved. C1 [Breitner, John; Baker, Laura; Breitner, John] Douglas Mental Hlth Univ Inst, Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada. [Breitner, John; Baker, Laura; Breitner, John] McGill Univ, Montreal, PQ, Canada. [Baker, Laura; Porsteinsson, Anton; Ismail, M. Saleem; Weber, Miriam; Brand, Connie; Richard, Jennifer; Stear, Kelly; Schepp, Sue; Cosman, Kelly; Martin, Kimberly] Veteran Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Baker, Laura; Zandi, Peter; Porsteinsson, Anton; Ismail, M. Saleem; Weber, Miriam; Brand, Connie; Richard, Jennifer; Stear, Kelly; Schepp, Sue; Cosman, Kelly; Martin, Kimberly] Univ Washington, Sch Med, Seattle, WA USA. [Drye, Lea; Zandi, Peter; Saucedo, Hector Hernandez; Anau, Jane; Cholerton, Brenna; Kramer, Kirise] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Evans, Denis; Mullan, Michael; Luis, Cheryl; Parrish, Julia; Faircloth, Marlee; Ervin, Terry; Girard, Janette; Burke, Deborah; Keegan, Andrew; Evans, Denis] Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. [Lyketsos, Constantine; Ryan, Laurie] Johns Hopkins Sch Med, Baltimore, MD 60612 USA. [Ryan, Laurie] NIA, Bethesda, MD 20892 USA. [Zandi, Peter] Vet Affairs Puget Sound Hlth Care Syst, Res Grp Resource Ctr Chairmans Off, Seattle, WA USA. [Zandi, Peter; Drye, Lea; Casper, Anne Shanklin; Meinert, Curtis; Martin, Barbara; Jenkins, Gabrielle; McCaffrey, Lee; Meinert, Jill; Vaidya, Vijay; Ahuja, Alka; May, Pat] NIA, Project Off, Bethesda, MD 20892 USA. [Lyketsos, Constantine G.; Steinberg, Martin; Brandt, Jason; Pedroso, Julia J.; Bergey, Alyssa; Gogel, Carol; Smith, Lynn; Kraus, Jennifer] Boston Univ, Sch Med, Boston, MA 02118 USA. [Stern, Robert A.; Green, Robert C.; Gavett, Brandon; Mwicigi, Jane; Baldwin, Lorraine; McGowan, Theresa; Johnson, Patricia; Qiu, Wendy; Frederick, Jamie; Raghavan, Sumati; Rossi, Carol; Mandell, Alan; Dinizo, Daniella; Roth, Mary Tara] Univ Rochester, Sch Med, Rochester, NY USA. [Craft, Suzanne; Baker, Laura; Dahl, Deborah; Garrett, Grace; Tidwell, Jamie; Thielke, Stephen; Smith, Lauren; Arbuckle, Matthew; Strong, William; Ladenberg, Juliet; Callaghan, Maureen; Watson, Stennis; Skinner, Jeannine; Bowton, Kaysha] Sun Hlth Res Inst, Sun City, AZ USA. [Sabbagh, Marwan; Belden, Christine; Liebsack, Carolyn; Davis, Kathryn; Arnieri, Lauren; Malek-Ahmadi, Michael; Nicholson, Lisa; Jacobson, Sandra; Schwartz, Elliot] Roskamp Inst Memory Clin, Tampa, FL USA. RP Breitner, J (reprint author), Douglas Mental Hlth Univ Inst, Ctr Studies Prevent Alzheimers Dis, Montreal, PQ, Canada. EM ldrye@jhsph.edu FU National Institute on Aging (NIA) [U01 AG15477, 2U01 AG015477-06A2]; N. Bud Grossman Center for Memory Research and Care; Minnesota Medical Foundation FX Funding for this study was provided by the National Institute on Aging (NIA) U01 AG15477 and 2U01 AG015477-06A2, the N. Bud Grossman Center for Memory Research and Care, and the Minnesota Medical Foundation. NR 28 TC 25 Z9 25 U1 1 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 NOV PY 2013 VL 9 IS 6 BP 714 EP 723 DI 10.1016/j.jalz.2012.11.012 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 254NP UT WOS:000327172700012 ER PT J AU McHugh, MJ Demers, CH Braud, J Briggs, R Adinoff, B Stein, EA AF McHugh, Meredith J. Demers, Catherine H. Braud, Jacquelyn Briggs, Richard Adinoff, Bryon Stein, Elliot A. TI Striatal-insula circuits in cocaine addiction: implications for impulsivity and relapse risk SO AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE LA English DT Article DE Addiction; cocaine; connectivity; impulsivity; insula; neuroimaging; relapse; striatum ID MEDIAL PREFRONTAL CORTEX; FUNCTIONAL CONNECTIVITY; NEURAL SYSTEMS; DECISION-MAKING; DRUG-ADDICTION; DEPENDENT INDIVIDUALS; INDUCED REINSTATEMENT; OUTCOME PREDICTORS; DOPAMINE-RECEPTORS; TRAIT IMPULSIVITY AB Background: Dysregulated striatal functioning coupled with executive control deficits arising from abnormal frontal cortical function are considered key mechanisms in the development and maintenance of cocaine addiction. The same features are thought to underlie high trait impulsivity observed in cocaine-addicted populations. Objectives: Employing resting state functional connectivity, the current study sought to identify cortico-striatal circuit alterations in cocaine addiction and examine the degree to which circuit connectivity contributes to relapse risk and impulsivity among cocaine-addicted individuals. Methods: Whole-brain resting-state functional magnetic resonance imaging connectivity was assessed in 45 cocaine-addicted individuals relative to 22 healthy controls using seed volumes in the left and right caudate, putamen and nucleus accumbens. Cocaine-addicted individuals completed scans in the final week of a 2-4 weeks residential treatment episode. Relapse by day 30 post-discharge served to separate cocaine-addicted individuals into relapse and non-relapse groups. All participants completed the Barratt Impulsivity Scale (BIS-11a). Results: Cocaine-addicted individuals exhibited reduced positive connectivity between the bilateral putamen and posterior insula and right postcentral gyrus. Group differences were primarily driven by reduced connectivity in relapse individuals relative to controls. No relapse versus non-relapse differences emerged. Impulsivity (BIS-11a) was higher in cocaine-addicted participants, an effect that was partially mediated by reduced putamen-posterior insula connectivity in this group. Conclusion: Cocaine addiction, relapse risk and impulsivity were associated with reduced connectivity in putamen-posterior insula/postcentral gyrus circuits implicated in temporal discounting and habitual responding. Findings provide new insight into the neurobiological mechanisms underlying impulsivity and relapse in cocaine addiction. C1 [McHugh, Meredith J.; Demers, Catherine H.; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Braud, Jacquelyn; Adinoff, Bryon] UT Southwestern Med Ctr, Dept Psychiat, Dallas, TX USA. [Briggs, Richard] UT Southwestern Med Ctr, Dept Radiol, Dallas, TX USA. [Adinoff, Bryon] VA North Texas Hlth Care Syst, Dallas, TX USA. RP McHugh, MJ (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM meredith.mchugh@nih.gov; EStein@intra.nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [DA023203] NR 79 TC 30 Z9 30 U1 2 U2 21 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0095-2990 EI 1097-9891 J9 AM J DRUG ALCOHOL AB JI Am. J. Drug Alcohol Abuse PD NOV PY 2013 VL 39 IS 6 SI SI BP 424 EP 432 DI 10.3109/00952990.2013.847446 PG 9 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 251YE UT WOS:000326969600011 PM 24200212 ER PT J AU Malekzadeh, MM Khademi, H Pourshams, A Etemadi, A Poustchi, H Bagheri, M Khoshnia, M Sohrabpour, AA Aliasgari, A Jafari, E Islami, F Semnani, S Abnet, CC Pharoah, PDP Brennan, P Boffetta, P Dawsey, SM Malekzadeh, R Kamangar, F AF Malekzadeh, Masoud M. Khademi, Hooman Pourshams, Akram Etemadi, Arash Poustchi, Hossein Bagheri, Mohammad Khoshnia, Masoud Sohrabpour, Amir Ali Aliasgari, Ali Jafari, Elham Islami, Farhad Semnani, Shahryar Abnet, Christian C. Pharoah, Paul D. P. Brennan, Paul Boffetta, Paolo Dawsey, Sanford M. Malekzadeh, Reza Kamangar, Farin TI Opium Use and Risk of Mortality from Digestive Diseases: A Prospective Cohort Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; FATTY LIVER-DISEASE; ESOPHAGEAL CANCER; GOLESTAN COHORT; BLADDER-CANCER; IRAN; ADDICTION; MORPHINE; OPIOIDS; METABOLISM AB OBJECTIVES: Opium use, particularly in low doses, is a common practice among adults in northeastern Iran. We aimed to investigate the association between opium use and subsequent mortality from disorders of the digestive tract. METHODS: We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50,045 adults were enrolled during a 4-year period (2004-2008) and followed annually until December 2012, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. RESULTS: In all, 8,487 (17%) participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 474 deaths from digestive diseases were reported (387 due to gastrointestinal cancers and 87 due to nonmalignant etiologies). Opium use was associated with an increased risk of death from any digestive disease (adjusted hazard ratio (HR)=1.55, 95% confidence interval (CI)=1.24-1.93). The association was dose dependent, with a HR of 2.21 (1.57-3.31) for the highest quintile of cumulative opium use vs. no use (P-trend=0.037). The HRs (95% CI) for the associations between opium use and malignant and nonmalignant causes of digestive mortality were 1.38 (1.07-1.76) and 2.60 (1.57-4.31), respectively. Increased risks were seen both for smoking opium and for ingestion of opium. CONCLUSIONS: Long-term opium use, even in low doses, is associated with increased risk of death from both malignant and nonmalignant digestive diseases. C1 [Malekzadeh, Masoud M.; Khademi, Hooman; Pourshams, Akram; Etemadi, Arash; Poustchi, Hossein; Bagheri, Mohammad; Sohrabpour, Amir Ali; Aliasgari, Ali; Jafari, Elham; Islami, Farhad; Malekzadeh, Reza; Kamangar, Farin] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Khademi, Hooman; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.; Kamangar, Farin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Khoshnia, Masoud; Semnani, Shahryar] Golestan Univ Med Sci, GRCGH, Gorgan, Iran. [Islami, Farhad] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Islami, Farhad] Inst Translat Epidemiol, New York, NY USA. [Pharoah, Paul D. P.; Boffetta, Paolo] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D. P.; Boffetta, Paolo] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21251 USA. RP Kamangar, F (reprint author), Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Portage Ave Campus,Room 302, Baltimore, MD 21251 USA. EM farin.kamangar@morgan.edu RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Semnani, Shahryar/N-2270-2016; Khoshnia, Masoud/P-5665-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Semnani, Shahryar/0000-0002-8768-6142; Khoshnia, Masoud/0000-0001-7352-8058; Malekzadeh, Reza/0000-0003-1043-3814 FU Tehran University of Medical Sciences [81/15]; Cancer Research UK [C20/A5860]; Intramural Research Program of the National Cancer Institute, National Institutes of Health; International Agency for Research on Cancer FX Financial support : The Golestan Cohort Study was funded by Tehran University of Medical Sciences (grant No: 81/15) for equipment, staff transport, and staff salary; by Cancer Research UK (grant No: C20/A5860) for staff salary; and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health for equipment, and through various collaborative research agreements with the International Agency for Research on Cancer. The study has also received special support from the Social Security Organization of Iran Golestan Branch. NR 64 TC 11 Z9 11 U1 2 U2 11 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 NOV PY 2013 VL 108 IS 11 BP 1757 EP 1765 DI 10.1038/ajg.2013.336 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 251IQ UT WOS:000326921800011 PM 24145676 ER PT J AU Geraghty, P Hardigan, AA Wallace, AM Mirochnitchenko, O Thankachen, J Arellanos, L Thompson, V D'Armiento, JM Foronjy, RF AF Geraghty, Patrick Hardigan, Andrew A. Wallace, Alison M. Mirochnitchenko, Oleg Thankachen, Jincy Arellanos, Leo Thompson, Victor D'Armiento, Jeanine M. Foronjy, Robert F. TI The Glutathione Peroxidase 1-Protein Tyrosine Phosphatase 1B-Protein Phosphatase 2A Axis A Key Determinant of Airway Inflammation and Alveolar Destruction SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE phosphorylation; inflammation; oxidation; kinase ID OBSTRUCTIVE PULMONARY-DISEASE; CIGARETTE-SMOKE; PROTEIN PHOSPHATASE; LUNG INFLAMMATION; INNATE IMMUNE; PHOSPHORYLATION; MICE; EXPRESSION; EMPHYSEMA; CERAMIDE AB Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure. C1 [Geraghty, Patrick; Hardigan, Andrew A.; Foronjy, Robert F.] St Lukes Roosevelt Hosp, New York, NY USA. [Wallace, Alison M.; Thankachen, Jincy; Arellanos, Leo; Thompson, Victor; D'Armiento, Jeanine M.] Columbia Univ, New York, NY USA. [Mirochnitchenko, Oleg] NIH, Bethesda, MD 20892 USA. RP Foronjy, RF (reprint author), St Lukes Hlth Sci Ctr, Dept Med, Antenucci Bldg,432 West 58th St, New York, NY 10019 USA. EM rforonjy@chpnet.org FU Flight Attendant Medical Research Institute [YCSA 113380, 24,039, 074,047]; National Institutes of Health [5R01HL098528-04, 5R01HL086936-04] FX This work was supported by Flight Attendant Medical Research Institute grant YCSA 113380 and 24,039, Clinical Innovator Award grant 074,047, and National Institutes of Health grant 5R01HL098528-04 (R. F. F.), and by National Institutes of Health grant 5R01HL086936-04 (J.M.D.). NR 44 TC 18 Z9 18 U1 1 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD NOV PY 2013 VL 49 IS 5 BP 721 EP 730 DI 10.1165/rcmb.2013-0026OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 251WV UT WOS:000326964800005 PM 23590304 ER PT J AU Concheiro, M Anizan, S Ellefsen, K Huestis, MA AF Concheiro, Marta Anizan, Sebastien Ellefsen, Kayla Huestis, Marilyn A. TI Simultaneous quantification of 28 synthetic cathinones and metabolites in urine by liquid chromatography-high resolution mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Synthetic cathinones; Urine; LC-HRMS; Stability ID ENCOUNTERED DESIGNER DRUG; IN-VITRO METABOLISM; RAT URINE; GC-MS; MEPHEDRONE; 3,4-METHYLENEDIOXYPYROVALERONE; 4-METHYLMETHCATHINONE; DETECTABILITY; TOXICOLOGY; STABILITY AB Synthetic cathinones are novel stimulants derived from cathinone, with amphetamines or cocaine-like effects, often labeled "not for human consumption" and considered "legal highs". Emergence of these new designer drugs complicate interpretation of forensic and clinical cases, with introduction of many new analogs designed to circumvent legislation and vary effects and potencies. We developed a method for the simultaneous quantification of 28 synthetic cathinones, including four metabolites, in urine by liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). These cathinones include cathinone, methcathinone, and synthetic cathinones position-3'-substituted, N-alkyl-substituted, ring-substituted, methylenedioxy-substituted, and pyrrolidinyl-substituted. One mL phosphate buffer pH 6 and 25 mu L IStd solution were combined with 0.25 mL urine, and subjected to solid phase cation exchange extraction (SOLA SCX). The chromatographic reverse-phase separation was achieved with a gradient mobile phase of 0.1 % formic acid in water and in acetonitrile in 20 min. We employed a Q Exactive high resolution mass spectrometer, with compounds identified and quantified by target-MSMS experiments. The assay was linear from 0.5-1 to 100 mu g/L, with limits of detection of 0.25-1 mu g/L. Imprecision (n = 20) was < 15.9 % and accuracy (n = 20) 85.2-118.1 %. Extraction efficiency was 78.9-116.7 % (CV 1.4-16.7 %, n = 5), process efficiency 57.7-104.9 %, and matrix effects from -29.5 % to 1.5 % (CV 1.9-13.1 %, n = 10). Most synthetic cathinones were stable at 4 A degrees C for 72 h (n = 27) and after 3 freeze-thaw cycles (n = 26), but many (n = 19) were not stable at room temperature for 24 h (losses up to -67.6 %). The method was applied to authentic urine specimens from synthetic cathinone users. This method provides a comprehensive confirmation method for 28 synthetic cathinones in urine, with good selectivity and specificity. C1 [Concheiro, Marta; Anizan, Sebastien; Ellefsen, Kayla; 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,Suite 200,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). NR 32 TC 32 Z9 33 U1 9 U2 71 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 NOV PY 2013 VL 405 IS 29 BP 9437 EP 9448 DI 10.1007/s00216-013-7386-z PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 254YN UT WOS:000327206100014 PM 24196122 ER PT J AU Hays, RD Spritzer, KL Amtmann, D Lai, JS DeWitt, EM Rothrock, N DeWalt, DA Riley, WT Fries, JF Krishnan, E AF Hays, Ron D. Spritzer, Karen L. Amtmann, Dagmar Lai, Jin-Shei DeWitt, Esi Morgan Rothrock, Nan DeWalt, Darren A. Riley, William T. Fries, James F. Krishnan, Eswar TI Upper-Extremity and Mobility Subdomains From the Patient-Reported Outcomes Measurement Information System (PROMIS) Adult Physical Functioning Item Bank SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Lower extremity; Psychometrics; Rehabilitation; Upper extremity ID RESPONSE THEORY AB Objective: To create upper-extremity and mobility subdomain scores from the Patient-Reported Outcomes Measurement Information System (PROM'S) physical functioning adult item bank. Design: Expert reviews were used to identify upper-extremity and mobility items from the PROM'S item bank. Psychometric analyses were conducted to assess empirical support for scoring upper-extremity and mobility subdomains. Setting: Data were collected from the U.S. general population and multiple disease groups via self-administered surveys. Participants: The sample (N=21,773) included 21,133 English-speaking adults who participated in the PROMIS wave 1 data collection and 640 Spanish-speaking Latino adults recruited separately. Interventions: Not applicable. Main Outcome Measures: We used English- and Spanish-language data and, existing PROM'S item parameters for the physical functioning item bank to estimate upper-extremity and mobility scores. In addition, we fit graded response models to calibrate the upper-extremity items and mobility items separately, compare separate to combined calibrations, and produce subdomain scores. Results: After eliminating items because of local dependency, 16 items remained to assess upper extremity and 17 items to assess mobility. The estimated correlation between upper extremity and mobility was .59 using existing PROMIS physical functioning item parameters (r=.60 using parameters calibrated separately for upper-extremity and mobility items). Conclusions: Upper-extremity and mobility subdomains shared about 35% of the variance in common, and produced comparable scores whether calibrated separately or together. The identification of the subset of items tapping these 2 aspects of physical functioning and scored using the existing PROMIS parameters provides the option of scoring these subdomains in addition to the overall physical functioning score. (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Hays, Ron D.; Spritzer, Karen L.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Dept Med, Los Angeles, CA 90095 USA. [Hays, Ron D.] RAND Corp, Santa Monica, CA USA. [Amtmann, Dagmar] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Lai, Jin-Shei; Rothrock, Nan] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [DeWitt, Esi Morgan] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA. [DeWalt, Darren A.] Univ N Carolina, Cecil G Sheps Ctr Hlth Serv Res, Div Gen Med & Clin Epidemiol, Chapel Hill, NC USA. [Riley, William T.] NCI, Sci Res & Technol Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fries, James F.; Krishnan, Eswar] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. RP Hays, RD (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Dept Med, 911 Broxton Ave, Los Angeles, CA 90095 USA. EM drhays@ucla.edu RI AOCID, AO Foundation/R-6455-2016; OI DeWalt, Darren/0000-0003-2270-751X FU Statistical Center (Northwestern University) [1U54AR057951]; Technology Center (Northwestern University) [1U54AR057943]; Network Center (American Institutes for Research) [1U54AR057926]; University of Washington, Seattle [1U01AR057954, 1U01AR052171]; University of North Carolina, Chapel Hill [2U01AR052181]; Children's Hospital of Philadelphia [1U01AR057956]; Stanford University [2U01AR052158]; Boston University [1U01AR057929]; University of California, Los Angeles [1U01AR057936]; University of Pittsburgh [2U01AR052155]; Georgetown University [U01AR057971]; Children's Hospital Medical Center, Cincinnati [1U01AR057940]; University of Maryland, Baltimore [1U01AR057967]; Duke University [2U01AR052186]; UCLA/DREW Project EXPORT, NIMHD [2P20MD000182]; AO Foundation; [1U01AR057948] FX PROM'S II was funded by cooperative agreements with a Statistical Center (Northwestern University, PI: David Cella, PhD, 1U54AR057951), a Technology Center (Northwestern University, PI: Richard C. Gershon, PhD, 1U54AR057943), a Network Center (American Institutes for Research, PI: Susan [San] D. Keller, PhD, 1U54AR057926), and 13 primary research sites that may include more than 1 institution (State University of New York, Stony Brook, PIs: Joan E. Broderick, PhD, and Arthur A. Stone, PhD, 1U01AR057948; University of Washington, Seattle, PIs: Heidi M. Crane, MD, MPH, Paul K. Crane, MD, MPH, and Donald L. Patrick, PhD, 1U01AR057954; University of Washington, Seattle, PIs: Dagmar Amtmann, PhD, and Karon Cook, PhD, 1U01AR052171; University of North Carolina, Chapel Hill, PI: Darren A. DeWalt, MD, MPH, 2U01AR052181; Children's Hospital of Philadelphia, PI: Christopher B. Format, MD, PhD, 1U01AR057956; Stanford University, PI: James F. Fries, MD, 2U01AR052158; Boston University, PIs: Stephen M. Haley, PhD, and David Scott Tulsky, PhD [University of Michigan, Ann Arbor], 1U01AR057929, University of California, Los Angeles, Pis: Dinesh Khanna, MD, and Brennan Spiegel, MD, MSHS, 1U01AR057936; University of Pittsburgh, PI: Paul A. Pilkonis, PhD, 2U01AR052155; Georgetown University, Pis: Carol. M. Moinpour, PhD [Fred Hutchinson Cancer Research Center, Seattle], and Arnold L. Potosky, PhD, U01AR057971; Children's Hospital Medical Center, Cincinnati, PI: Esi M. Morgan DeWitt, MD, MSCE, 1U01AR057940; University of Maryland, Baltimore, PI: Lisa M. Shuiman, MD, 1U01AR057967; and Duke University, PI: Kevin P. Weinfurt, PhD, 2U01AR052186). The study was also supported by UCLA/DREW Project EXPORT, NIMHD (grant no. 2P20MD000182) and in part by the AO Foundation. NR 17 TC 19 Z9 19 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD NOV PY 2013 VL 94 IS 11 BP 2291 EP 2296 DI 10.1016/j.apmr.2013.05.014 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 250KV UT WOS:000326852600035 PM 23751290 ER PT J AU Soe, KC Devaiah, BN Singer, DS AF Soe, Katherine C. Devaiah, Ballachanda N. Singer, Dinah S. TI Transcriptional coactivator CIITA, a functional homolog of TAF1, has kinase activity SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Article DE CIITA; MHC class II; MHC class I; TAF7; Transcription; Kinase ID II TRANSACTIVATOR CIITA; MHC CLASS-I; ACETYLTRANSFERASE ACTIVITY; HISTONE H2B; PHOSPHORYLATION; TAF(II)250; EXPRESSION; COMPLEX; PROMOTERS; REGULATOR AB The Major Histocompatibility Complex (MHC) class II transactivator (CIITA) mediates activated immune responses and its deficiency results in the Type II Bare Lymphocyte Syndrome. CIITA is a transcriptional coactivator that regulates gamma-interferon-activated transcription of MHC class land class II genes. It is also a functional homolog of TAF1, a component of the general transcription factor complex TFIID. TAF1 and CIITA both possess intrinsic acetyltransferase (AT) activity that is required for transcription initiation. In response to induction by gamma-interferon, CIITA and it's AT activity bypass the requirement for TAF1 AT activity. TAF1 also has kinase activity that is essential for its function. However, no similar activity has been identified for CIITA thus far. Here we report that CIITA, like TAF1, is a serine-threonine kinase. Its substrate specificity parallels, but does not duplicate, that of TAFI in phosphorylating the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF and histone H2B. Like TAFI, CIITA autophosphorylates, affecting its interaction with TAF7. Additionally, CIITA phosphorylates histone H2B at Ser36, a target of TAF1 that is required for transcription during cell cycle progression and stress response. However, unlike TAF1, CIITA also phosphorylates all the other histones. The identification of this novel kinase activity of CIITA further clarifies its role as a functional homolog of TAF1 which may operate during stress and gamma-IFN activated MHC gene transcription. Published by Elsevier B.V. C1 [Soe, Katherine C.; Devaiah, Ballachanda N.; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM Dinah.singer@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Jenny Ting for her generous gift of CIITA mutants, Dr. Paul Roche for technical advice and Dr. Ming Zhou for performing the mass spec. We thank members of the lab for helpful discussions. We also thank Drs. Keiko Ozato, Paul Roche and Stoney Simons Jr. for their critical review of this manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 26 TC 3 Z9 7 U1 1 U2 4 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 NOV PY 2013 VL 1829 IS 11 BP 1184 EP 1190 DI 10.1016/j.bbagrm.2013.09.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 253SD UT WOS:000327108700003 PM 24036077 ER PT J AU Lewis, BA AF Lewis, Brian A. TI O-GlcNAcylation at promoters, nutrient sensors, and transcriptional regulation SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Transcription; RNA polymerase II; O-GlcNAc; Nutrient sensor ID RNA-POLYMERASE-II; N-ACETYLGLUCOSAMINE TRANSFERASE; EMBRYONIC STEM-CELLS; CIRCADIAN CLOCK; GLCNAC TRANSFERASE; INSULIN-RESISTANCE; TERMINAL DOMAIN; CHRONIC DISEASE; HISTONE H3; IN-VIVO AB Post-translational modifications play important roles in transcriptional regulation. Among the less understood PTMs is O-GlcNAcylation. Nevertheless, O-GlcNAcylation in the nucleus is found on hundreds of transcription factors and coactivators and is often found in a mutually exclusive ying-yang relationship with phosphorylation. O-GlcNAcylation also links cellular metabolism directly to the proteome, serving as a conduit of metabolic information to the nucleus. This review serves as a brief introduction to O-GlcNAcylation, emphasizing its important thematic roles in transcriptional regulation, and highlights several recent and important additions to the literature that illustrate the connections between O-GlcNAc and transcription. Published by Elsevier B.V. C1 NCI, Metab Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Lewis, BA (reprint author), NCI, Metab Branch, CCR, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lewisbri@mail.nih.gov FU Intramural Program/CCR/NCI/NIH FX BAL would like to thank Drs. Alfonzo Fernandez and Melissa Resto for the suggestions and comments. BAL acknowledges the funding from the Intramural Program/CCR/NCI/NIH. NR 70 TC 14 Z9 14 U1 1 U2 15 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 NOV PY 2013 VL 1829 IS 11 BP 1202 EP 1206 DI 10.1016/j.bbagrm.2013.09.003 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 253SD UT WOS:000327108700005 PM 24076017 ER PT J AU Barrett, AJ AF Barrett, A. John TI Immune Recovery in Pediatric Transplantation: Can T Cell-Depleted Peripheral Blood Stem Cell Transplantation Beat Cord Blood Transplantation? SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Editorial Material C1 [Barrett, A. John] NHLBI, Allogene Stem Cell Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Hematol Branch, CRC, Room 3-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2013 VL 19 IS 11 BP 1531 EP 1532 DI 10.1016/j.bbmt.2013.09.002 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 250KL UT WOS:000326851600001 PM 24035781 ER PT J AU Gress, RE Miller, JS Battiwalla, M Bishop, MR Giralt, SA Hardy, NM Kroger, N Wayne, AS Landau, DA Wu, CJ AF Gress, Ronald E. Miller, Jeffrey S. Battiwalla, Minoo Bishop, Michael R. Giralt, Sergio A. Hardy, Nancy M. Kroeger, Nicolaus Wayne, Alan S. Landau, Dan A. Wu, Catherine J. TI Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part I. Biology of Relapse after Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Stem cell transplantation; Relapse; Allogeneic; Prevention; Biology; Treatment ID NATURAL-KILLER-CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; T-CELLS; INTENSIVE CHEMOTHERAPY; MULTIPLE-MYELOMA; CLONAL EVOLUTION; BREAST-CANCER; NK CELLS; CYTOMEGALOVIRUS; RECONSTITUTION AB In the National Cancer Institute's Second Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on the Biology of Relapse discussed recent advances in understanding some of the host-, disease-, and transplantation-related contributions to relapse, emphasizing concepts with potential therapeutic implications. Relapse after hematopoietic stem cell transplantation (HSCT) represents tumor escape, from the cytotoxic effects of the conditioning regimen and from immunologic control mediated by reconstituted lymphocyte populations. Factors influencing the biology of the therapeutic graft-versus-malignancy (GVM) effect-and relapse-include conditioning regimen effects on lymphocyte populations and homeostasis, immunologic niches, and the tumor microenvironment; reconstitution of lymphocyte populations and establishment of functional immune competence; and genetic heterogeneity within the malignancy defining potential for clonal escape. Recent developments in T cell and natural killer cell homeostasis and reconstitution are reviewed, with implications for prevention and treatment of relapse, as is the application of modern genome sequencing to defining the biologic basis of GVM, clonal escape, and relapse after HSCT. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Gress, Ronald E.; Hardy, Nancy M.] NCI, Expt Transplantat & Immunol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Miller, Jeffrey S.] Univ Minnesota, Ctr Canc, Minneapolis, MN USA. [Battiwalla, Minoo] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Bishop, Michael R.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Giralt, Sergio A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Kroeger, Nicolaus] Univ Med Ctr Hamburg Eppendorf, Dept Stem Cell Transplantat, Hamburg, Germany. [Wayne, Alan S.] NCI, Pediat Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Landau, Dan A.; Wu, Catherine J.] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Landau, Dan A.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hardy, NM (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, Hatfield Clin Res Ctr, 10 Ctr Dr,Room 3E-3330, Bethesda, MD 20892 USA. EM hardyn@mail.nih.gov OI Miller, Jeffrey S/0000-0002-0339-4944 FU National Institutes of Health: the National Cancer Institute/Center for Cancer Research; National Institutes of Health: National Heart, Lung and Blood Institute FX Supported in part by the Intramural Research Programs of the National Institutes of Health: the National Cancer Institute/Center for Cancer Research and the National Heart, Lung and Blood Institute. NR 48 TC 8 Z9 8 U1 0 U2 4 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 NOV PY 2013 VL 19 IS 11 BP 1537 EP 1545 DI 10.1016/j.bbmt.2013.08.010 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 250KL UT WOS:000326851600004 PM 24018395 ER PT J AU Wardell, JR Hodgkinson, KM Binder, AK Seymour, KA Korach, KS Vanderhyden, BC Freiman, RN AF Wardell, Jennifer R. Hodgkinson, Kendra M. Binder, April K. Seymour, Kimberly A. Korach, Kenneth S. Vanderhyden, Barbara C. Freiman, Richard N. TI Estrogen Responsiveness of the TFIID Subunit TAF4B in the Normal Mouse Ovary and in Ovarian Tumors SO BIOLOGY OF REPRODUCTION LA English DT Article DE estradiol/estradiol receptor; ovarian cancer; ovary; premature ovarian failure; TAF4B ID HORMONE REPLACEMENT THERAPY; TBP-ASSOCIATED FACTOR; GENE-EXPRESSION; RECEPTOR-BETA; TARGET GENES; IN-VIVO; RISK-FACTORS; CELL-GROWTH; CANCER; ALPHA AB Estrogen signaling in the ovary is a fundamental component of normal ovarian function, and evidence also indicates that excessive estrogen is a risk factor for ovarian cancer. We have previously demonstrated that the gonadally enriched TFIID subunit TAF4B, a paralog of the general transcription factor TAF4A, is required for fertility in mice and for the proliferation of ovarian granulosa cells following hormonal stimulation. However, the relationship between TAF4B and estrogen signaling in the normal ovary or during ovarian tumor initiation and progression has yet to be defined. Herein, we show that Taf4b mRNA and TAF4B protein, but not Taf4a mRNA or TAF4A protein, are increased in whole ovaries and granulosa cells of the ovary after exposure to 17beta-estradiol or the synthetic estrogen diethylstilbestrol and that this response occurs within hours after stimulation. Furthermore, this increase occurs via nuclear estrogen receptors both in vivo and in a mouse granulosa cancer cell line, NT-1. We observe a significant increase in Taf4b mRNA in estrogen-supplemented mouse ovarian tumors, which correlates with diminished survival of these mice. These data highlight the novel response of the general transcription factor TAF4B to estrogen in the normal ovary and during ovarian tumor progression in the mouse, suggesting its potential role in regulating actions downstream of estrogen stimulation. C1 [Wardell, Jennifer R.; Freiman, Richard N.] Brown Univ, Pathobiol Grad Program, Providence, RI 02912 USA. [Seymour, Kimberly A.; Freiman, Richard N.] Brown Univ, Dept Mol & Cellular Biol & Biochem, Providence, RI 02912 USA. [Hodgkinson, Kendra M.; Vanderhyden, Barbara C.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. [Hodgkinson, Kendra M.; Vanderhyden, Barbara C.] Ottawa Hosp Res Inst, Ctr Canc Therapeut, Ottawa, ON, Canada. [Binder, April K.; Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. RP Freiman, RN (reprint author), Brown Univ, Dept Mol & Cellular Biol & Biochem, 70 Ship St, Providence, RI 02912 USA. EM Richard_Freiman@Brown.edu OI Korach, Kenneth/0000-0002-7765-418X FU American Cancer Society Research Scholar [DMC-117629]; National Institutes of Health [R01 HD065445]; National Institutes of Health Center of Biomedical Research Excellence Center for Cancer Signaling Networks [RR031153]; Canadian Institutes of Health Research [MOP-111194]; National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program [Z01ES70065] FX Supported by American Cancer Society Research Scholar Grant DMC-117629 to R.N.F.; by National Institutes of Health grant R01 HD065445 to R.N.F.; by National Institutes of Health Center of Biomedical Research Excellence Center for Cancer Signaling Networks grant RR031153 to R.N.F.; by Canadian Institutes of Health Research Grant MOP-111194 to B. C. V.; and by National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program grant Z01ES70065 to K. S. K. Presented in part at a poster session during the 45th Annual Meeting of the Society for the Study of Reproduction and the 18th Ovarian Workshop, August 12-15, 2012, State College, Pennsylvania, and during the 46th Annual Meeting of the Society for the Study of Reproduction, July 22-26, 2013, Montreal, Quebec, Canada. NR 47 TC 2 Z9 2 U1 0 U2 2 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 NOV PY 2013 VL 89 IS 5 AR 116 DI 10.1095/biolreprod.113.111336 PG 9 WC Reproductive Biology SC Reproductive Biology GA 254CF UT WOS:000327139300010 PM 24068106 ER PT J AU Wood, WA Chai, X Weisdorf, D Martin, PJ Cutler, C Inamoto, Y Wolff, D Pavletic, SZ Pidala, J Palmer, JM Arora, M Arai, S Jagasia, M Storer, B Lee, SJ Mitchell, S AF Wood, W. A. Chai, X. Weisdorf, D. Martin, P. J. Cutler, C. Inamoto, Y. Wolff, D. Pavletic, S. Z. Pidala, J. Palmer, J. M. Arora, M. Arai, S. Jagasia, M. Storer, B. Lee, S. J. Mitchell, S. TI Comorbidity burden in patients with chronic GVHD SO BONE MARROW TRANSPLANTATION LA English DT Article DE chronic GVHD; comorbidities; outcomes; allogeneic hematopoietic cell transplantation ID HEMATOPOIETIC-CELL TRANSPLANTATION; VERSUS-HOST-DISEASE; REPORTED OUTCOMES; REDUCED-INTENSITY; PHYSICAL FUNCTION; INDEX; LYMPHOMA; MORTALITY; SEVERITY; LEUKEMIA AB Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n = 239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04-1.42, P = 0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was <= 100 000/mu L (HR: 2.01:1.20-3.35, P = 0.01), but not when it was >100 000/mu L (HR: 1.05:0.90-1.22, P = 0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed. C1 [Wood, W. A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Chai, X.; Martin, P. J.; Inamoto, Y.; Storer, B.; Lee, S. J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Weisdorf, D.; Arora, M.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Cutler, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolff, D.] Univ Regensburg, Dept Hematol & Clin Oncol, D-93053 Regensburg, Germany. [Pavletic, S. Z.; Mitchell, S.] NCI, NIH, Bethesda, MD 20892 USA. [Pidala, J.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Palmer, J. M.] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Arai, S.] Stanford Univ, Med Ctr, Div Blood & Marrow Transplantat, Stanford, CA 94305 USA. [Jagasia, M.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. RP Wood, WA (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Phys Off Bldg,170 Manning Dr, Chapel Hill, NC 27599 USA. EM wawood@med.unc.edu OI Wood, William/0000-0001-7439-2543 FU National Institutes of Health/National Cancer Institute [CA 118953, KL2TR000084] FX This work was supported by National Institutes of Health/National Cancer Institute grant CA 118953 as well as grant KL2TR000084. NR 22 TC 8 Z9 8 U1 1 U2 1 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 NOV PY 2013 VL 48 IS 11 BP 1429 EP 1436 DI 10.1038/bmt.2013.70 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 250WR UT WOS:000326887900010 PM 23665819 ER PT J AU Siziopikou, KP Anderson, SJ Cobleigh, MA Julian, TB Arthur, DW Zheng, P Mamounas, EP Pajon, ER Behrens, RJ Eakle, JF Leasure, NC Atkins, JN Polikoff, JA Seay, TE McCaskill-Stevens, WJ Rabinovitch, R Costantino, JP Wolmark, N AF Siziopikou, Kalliopi P. Anderson, Stewart J. Cobleigh, Melody A. Julian, Thomas B. Arthur, Douglas W. Zheng, Ping Mamounas, Eleftherios P. Pajon, Eduardo R. Behrens, Robert J. Eakle, Janice F. Leasure, Nick C. Atkins, James N. Polikoff, Jonathan A. Seay, Thomas E. McCaskill-Stevens, Worta J. Rabinovitch, Rachel Costantino, Joseph P. Wolmark, Norman TI Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE DCIS; Non-invasive breast cancer; HER2; Clinical trials ID INTRADUCTAL BREAST-CANCER; SURGICAL ADJUVANT BREAST; BIOLOGICAL MARKERS; PROTEIN OVEREXPRESSION; MORPHOLOGIC FEATURES; MONOCLONAL-ANTIBODY; MOLECULAR-FEATURES; CELL-PROLIFERATION; HORMONE-RECEPTORS; HISTOLOGICAL TYPE AB NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at > 50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust. C1 [Siziopikou, Kalliopi P.; Anderson, Stewart J.; Cobleigh, Melody A.; Julian, Thomas B.; Arthur, Douglas W.; Mamounas, Eleftherios P.; Pajon, Eduardo R.; Behrens, Robert J.; Eakle, Janice F.; Leasure, Nick C.; Atkins, James N.; Polikoff, Jonathan A.; Seay, Thomas E.; McCaskill-Stevens, Worta J.; Rabinovitch, Rachel; Costantino, Joseph P.; Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project NSABP, Pittsburgh, PA USA. [Siziopikou, Kalliopi P.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Anderson, Stewart J.; Zheng, Ping; Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, NSABP Biostat Ctr, Pittsburgh, PA 15261 USA. [Cobleigh, Melody A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Julian, Thomas B.; Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Arthur, Douglas W.] Virginia Commonwealth Univ, Richmond, VA USA. [Mamounas, Eleftherios P.] Aultman Hosp, Canton, OH USA. [Pajon, Eduardo R.] Colorado Canc Res Program, Denver, CO USA. [Behrens, Robert J.] Iowa Oncol Res Assoc, Des Moines, IA USA. [Eakle, Janice F.] Florida Canc Specialists, Sarasota, FL USA. [Leasure, Nick C.] Reading Reg Hosp, McGlinn Family Canc Ctr, W Reading, PA USA. [Atkins, James N.] Southeast Canc Control Consortium CCOP, Winston Salem, NC USA. [Polikoff, Jonathan A.] Kaiser Permanente So Calif, San Diego, CA USA. [Seay, Thomas E.] Atlanta Reg Community Clin Oncol Program, Atlanta, GA USA. [McCaskill-Stevens, Worta J.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rabinovitch, Rachel] Univ Colorado, Aurora, CO USA. RP Julian, TB (reprint author), Allegheny Gen Hosp, Allegheny Canc Ctr, 320 E N Ave, Pittsburgh, PA 15212 USA. EM tjulian@wpahs.org OI Anderson, Stewart/0000-0001-8948-0650 FU Genentech, Inc.; [NCI-U10-CA-12027]; [U10-CA-37377]; [U10-CA-69974]; [U10-CA-69651]; [U10-CA-21661] FX This work was supported by NCI-U10-CA-12027, U10-CA-37377, U10-CA-69974, U10-CA-69651, U10-CA-21661, and Genentech, Inc., a member of the Roche Group. The authors wish to acknowledge Dr. Luis Chu, and the following pathologists for interpreting HER2 tests: Drs. Pincas Bitterman, Paolo Gattuso, and Ritu Ghai, Rush University Medical Center. NR 43 TC 16 Z9 17 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2013 VL 142 IS 2 BP 415 EP 421 DI 10.1007/s10549-013-2755-z PG 7 WC Oncology SC Oncology GA 253JB UT WOS:000327079800016 PM 24202240 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, DR Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean R. Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events Executive Summary SO CHEST LA English DT Article C1 [Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Balk, Robert; Burns, Suzanne M.; Deutschman, Clifford S.; Gutterman, David; Hammer, Beth; Hill, Nicholas S.; Kollef, Marin; Levy, Mitchell; Lipsett, Pamela] Amer Thorac Soc, Soc Crit Care Med, Crit Care Soc Collaborat Amer Assoc Crit Care Nur, Amer Coll Chest Phys, Philadelphia, PA USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Surveillance Working Grp, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Professionals Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Hosp Epidemiol & Qual Improvement, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA USA. [Hess, Dean R.] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Territorial Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept Hlth & Human Serv, Off Dis Prevent & Hlth Promot, Washington, DC USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov OI Diekema, Daniel/0000-0003-1273-0724 NR 2 TC 6 Z9 6 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD NOV PY 2013 VL 144 IS 5 BP 1448 EP 1452 DI 10.1378/chest.13-1640 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 254DI UT WOS:000327143700010 PM 24189858 ER PT J AU Marx, GR Shirali, G Levine, JC Guey, LT Cnota, JF Baffa, JM Border, WL Colan, S Ensing, G Friedberg, MK Goldberg, DJ Idriss, SF John, JB Lai, WW Lu, MM Menon, SC Ohye, RG Saudek, D Wong, PC Pearson, GD AF Marx, Gerald R. Shirali, Girish Levine, Jami C. Guey, Lin T. Cnota, James F. Baffa, Jeanne M. Border, William L. Colan, Steve Ensing, Gregory Friedberg, Mark K. Goldberg, David J. Idriss, Salim F. John, J. Blaine Lai, Wyman W. Lu, Minmin Menon, Shaji C. Ohye, Richard G. Saudek, David Wong, Pierre C. Pearson, Gail D. CA Pediat Heart Network Investigators TI Multicenter Study Comparing Shunt Type in the Norwood Procedure for Single-Ventricle Lesions Three-Dimensional Echocardiographic Analysis SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE echocardiography; heart defects; congenital; pediatrics ID LEFT-HEART SYNDROME; BIDIRECTIONAL CAVOPULMONARY ANASTOMOSIS; CARDIAC MAGNETIC-RESONANCE; EJECTION FRACTION; 3D ECHOCARDIOGRAPHY; IN-VITRO; VOLUME; MASS; ADAPTATION; VALIDATION AB Background The Pediatric Heart Network's Single Ventricle Reconstruction (SVR) trial randomized infants with single right ventricles (RVs) undergoing a Norwood procedure to a modified Blalock-Taussig or RV-to-pulmonary artery shunt. This report compares RV parameters in the 2 groups using 3-dimensional echocardiography. Methods and Results Three-dimensional echocardiography studies were obtained at 10 of 15 SVR centers. Of the 549 subjects, 314 underwent 3-dimensional echocardiography studies at 1 to 4 time points (pre-Norwood, post-Norwood, pre-stage II, and 14 months) for a total of 757 3-dimensional echocardiography studies. Of these, 565 (75%) were acceptable for analysis. RV volume, mass, mass:volume ratio, ejection fraction, and severity of tricuspid regurgitation did not differ by shunt type. RV volumes and mass did not change after the Norwood, but increased from pre-Norwood to pre-stage II (end-diastolic volume [milliliters]/body surface area [BSA](1.3), end-systolic volume [milliliters]/BSA(1.3), and mass [grams]/BSA(1.3) mean difference [95% confidence interval]=25.0 [8.7-41.3], 19.3 [8.3-30.4], and 17.9 [7.3-28.5], then decreased by 14 months (end-diastolic volume/BSA(1.3), end-systolic volume/BSA(1.3), and mass/BSA(1.3) mean difference [95% confidence interval]=-24.4 [-35.0 to -13.7], -9.8 [-17.9 to -1.7], and -15.3 [-22.0 to -8.6]. Ejection fraction decreased from pre-Norwood to pre-stage II (mean difference [95% confidence interval]=-3.7 [-6.9 to -0.5]), but did not decrease further by 14 months. Conclusions We found no statistically significant differences between study groups in 3-dimensional echocardiography measures of RV size and function, or magnitude of tricuspid regurgitation. Volume unloading was seen after stage II, as expected, but ejection fraction did not improve. This study provides insights into the remodeling of the operated univentricular RV in infancy. C1 [Marx, Gerald R.; Levine, Jami C.; Colan, Steve] Boston Childrens Hosp, Boston, MA USA. [Shirali, Girish] Childrens Mercy Hosp & Clin, Kansas City, MO USA. [Guey, Lin T.; Lu, Minmin] New England Res Inst, Watertown, MA 02172 USA. [Cnota, James F.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Baffa, Jeanne M.] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Border, William L.] Emory Univ, Sch Med, Atlanta, GA USA. [Ensing, Gregory; Ohye, Richard G.] Univ Michigan, Ann Arbor, MI 48109 USA. [Friedberg, Mark K.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Friedberg, Mark K.] Univ Toronto, Toronto, ON, Canada. [Goldberg, David J.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA USA. [Idriss, Salim F.] Duke Univ, Med Ctr, Durham, NC USA. [John, J. Blaine] Congenital Heart Inst Florida Pediat, Tampa, FL USA. [Lai, Wyman W.] Columbia Univ, Med Ctr, New York, NY USA. [Menon, Shaji C.] Univ Utah, Salt Lake City, UT USA. [Saudek, David] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Wong, Pierre C.] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Pearson, GD (reprint author), NHLBI, 6701 Rockledge Dr,Room 8132, Bethesda, MD 20892 USA. EM pearsong@mail.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health [HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, HL085057] FX This study was supported by grants (HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, and HL085057) from the National Heart, Lung, and Blood Institute, National Institutes of Health. The views of the authors are their own and do not necessarily reflect an official position of the National Heart, Lung, and Blood Institute. NR 24 TC 5 Z9 5 U1 0 U2 0 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 NOV PY 2013 VL 6 IS 6 BP 934 EP 942 DI 10.1161/CIRCIMAGING.113.000304 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 253UI UT WOS:000327114400019 PM 24097422 ER PT J AU Olivieri, LJ Baba, RY Arai, AE Bandettini, WP Rosing, DR Bakalov, V Sachdev, V Bondy, CA AF Olivieri, Laura J. Baba, Ridhwan Y. Arai, Andrew E. Bandettini, W. Patricia Rosing, Douglas R. Bakalov, Vladimir Sachdev, Vandana Bondy, Carolyn A. TI Spectrum of Aortic Valve Abnormalities Associated With Aortic Dilation Across Age Groups in Turner Syndrome SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE abnormalities; aorta; echocardiography; magnetic resonance imaging; Turner syndrome ID CARDIOVASCULAR MALFORMATIONS; DILATATION; DISSECTION; PREVALENCE; ADULTS; MORPHOLOGY; ANOMALIES; CHILDREN; DISEASE; WOMEN AB Background Congenital aortic valve fusion is associated with aortic dilation, aneurysm, and rupture in girls and women with Turner syndrome. Our objective was to characterize aortic valve structure in subjects with Turner syndrome and to determine the prevalence of aortic dilation and valve dysfunction associated with different types of aortic valves. Methods and Results The aortic valve and thoracic aorta were characterized by cardiovascular MRI in 208 subjects with Turner syndrome in an institutional review board-approved natural history study. Echocardiography was used to measure peak velocities across the aortic valve and the degree of aortic regurgitation. Four distinct valve morphologies were identified: tricuspid aortic valve, 64% (n=133); partially fused aortic valve, 12% (n=25); bicuspid aortic valve, 23% (n=47); and unicuspid aortic valve, 1% (n=3). Age and body surface area were similar in the 4 valve morphology groups. There was a significant trend, independent of age, toward larger body surface area-indexed ascending aortic diameters with increasing valve fusion. Ascending aortic diameters were (meanSD) 16.9 +/- 3.3, 18.3 +/- 3.3, and 19.8 +/- 3.9 mm/m(2) (P<0.0001) for tricuspid aortic valve, partially fused aortic valve, and bicuspid aortic valve+unicuspid aortic valve, respectively. Partially fused aortic valve, bicuspid aortic valve, and unicuspid aortic valve were significantly associated with mild aortic regurgitation and elevated peak velocities across the aortic valve. Conclusions Aortic valve abnormalities in Turner syndrome occur with a spectrum of severity and are associated with aortic root dilation across age groups. Partial fusion of the aortic valve, traditionally regarded as an acquired valve problem, had an equal age distribution and was associated with an increased ascending aortic diameters. C1 [Baba, Ridhwan Y.; Bakalov, Vladimir; Bondy, Carolyn A.] NICHHD, Bethesda, MD USA. [Olivieri, Laura J.; Arai, Andrew E.; Bandettini, W. Patricia; Rosing, Douglas R.; Sachdev, Vandana] NHLBI, NIH, Bethesda, MD 20892 USA. RP Olivieri, LJ (reprint author), NHLBI, NIH, Ctr Clin, Bldg 10,Room B1D416,MSC 1061, Bethesda, MD 20892 USA. EM Laura.Olivieri@nih.gov FU National Institutes of Health Division of Intramural Research at the National Heart, Lung, and Blood Institute; Division of Intramural Research at the National Institute of Child Health and Human Development FX This work was supported by the National Institutes of Health Division of Intramural Research at the National Heart, Lung, and Blood Institute, as well as the Division of Intramural Research at the National Institute of Child Health and Human Development. NR 35 TC 14 Z9 15 U1 0 U2 2 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 NOV PY 2013 VL 6 IS 6 BP 1018 EP 1023 DI 10.1161/CIRCIMAGING.113.000526 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 253UI UT WOS:000327114400029 PM 24084490 ER PT J AU Hong, CW Xu, S Imbesi, KL Wood, BJ AF Hong, Cheng William Xu, Sheng Imbesi, Kimberly L. Wood, Bradford J. TI Integrated laser-guided CT biopsy SO CLINICAL IMAGING LA English DT Article DE Biopsy; Angle selection; CT guidance; Interventional; Laser guidance ID GUIDANCE-SYSTEM; NAVIGATION; DEVICE AB The diagnostic yield of computed tomography (CT)-guided biopsies is dependent on accurate needle insertion. A laser-assisted angle selection system was custom fabricated and used during a CT-guided lung biopsy. Off-target error was measured comparing standard methods to the laser method while pointing towards the target from the skin. The difference between the planned angle and selected angle using the laser-assisted system was 2, improved from 12 with the standard method. Although yet to be confirmed, laser-assisted angle selection systems may improve the accuracy of needle placement, which may translate into improved outcomes for certain needle based procedures. Published by Elsevier Inc. C1 [Hong, Cheng William; Xu, Sheng; Imbesi, Kimberly L.; Wood, Bradford J.] NIH, Ctr Intervent Oncol, Ctr Clin, Bethesda, MD 20892 USA. [Hong, Cheng William] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. [Imbesi, Kimberly L.] Duke Univ, Sch Med, Durham, NC 27705 USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol, Ctr Clin, 10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM bwood@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); Center for Interventional Oncology; Pfizer Inc; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX Thanks to Ankur Kapoor, PhD who assisted in software and hardware design and custom integration. This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) and the Center for Interventional Oncology. The opinions expressed herein do not necessarily represent the opinions of the U.S. Government or the NIH. This research was made possible through the 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. NIH and Philips Healthcare have a cooperative research and development agreement NR 10 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-7071 EI 1873-4499 J9 CLIN IMAG JI Clin. Imaging PD NOV-DEC PY 2013 VL 37 IS 6 BP 1135 EP 1137 DI 10.1016/j.clinimag.2013.08.006 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 250NE UT WOS:000326858700030 PM 24035262 ER PT J AU Zheng, W Thorne, N McKew, JC AF Zheng, Wei Thorne, Natasha McKew, John C. TI Phenotypic screens as a renewed approach for drug discovery SO DRUG DISCOVERY TODAY LA English DT Review ID PLURIPOTENT STEM-CELLS; CHOLESTEROL ABSORPTION INHIBITOR; CALCIUM-CHANNEL ANTAGONISTS; PARKINSONS-DISEASE; TARGETS; IDENTIFICATION; MODULATORS; MECHANISM; TOXICITY; ASSAYS AB The significant reduction in the number of newly approved drugs in the past decade has been partially attributed to failures in discovery and validation of new targets. Evaluation of recently approved new drugs has revealed that the number of approved drugs discovered through phenotypic screens, an original drug screening paradigm, has exceeded those discovered through the molecular target-based approach. Phenotypic screening is thus gaining new momentum in drug discovery with the hope that this approach may revitalize drug discovery and improve the success rate of drug approval through the discovery of viable lead compounds and identification of novel drug targets. C1 [Zheng, Wei; Thorne, Natasha; McKew, John C.] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. NR 82 TC 69 Z9 73 U1 7 U2 35 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 EI 1878-5832 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD NOV PY 2013 VL 18 IS 21-22 BP 1067 EP 1073 DI 10.1016/j.drudis.2013.07.001 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 252JO UT WOS:000327001200006 PM 23850704 ER PT J AU Jenkins, LMM Figeys, D AF Jenkins, Lisa M. Miller Figeys, Daniel TI Dynamic proteins: changes in structures, activities and networks SO FEBS JOURNAL LA English DT Article C1 [Jenkins, Lisa M. Miller] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Figeys, Daniel] Univ Ottawa, Ottawa Inst Syst Biol, Dept Biochem & Microbiol & Immunol, Ottawa, ON K1N 6N5, Canada. RP Jenkins, LMM (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD NOV PY 2013 VL 280 IS 22 BP 5569 EP 5569 DI 10.1111/febs.12548 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 254AA UT WOS:000327130900001 ER PT J AU Wlodawer, A Minor, W Dauter, Z Jaskolski, M AF Wlodawer, Alexander Minor, Wladek Dauter, Zbigniew Jaskolski, Mariusz TI Protein crystallography for aspiring crystallographers or how to avoid pitfalls and traps in macromolecular structure determination SO FEBS JOURNAL LA English DT Review DE data collection and processing; electron density maps; protein crystallography; structure refinement; structure solution; structure quality; structure validation ID HIGH-RESOLUTION STRUCTURE; X-RAY-STRUCTURE; NATIVE BIOLOGICAL MACROMOLECULES; PANCREATIC TRYPSIN-INHIBITOR; NERVE GROWTH-FACTOR; CRYSTAL-STRUCTURE; ANOMALOUS DIFFRACTION; MOLECULAR-REPLACEMENT; 3-DIMENSIONAL STRUCTURE; SYNCHROTRON-RADIATION AB The number of macromolecular structures deposited in the Protein Data Bank now approaches 100000, with the vast majority of them determined by crystallographic methods. Thousands of papers describing such structures have been published in the scientific literature, and 20 Nobel Prizes in chemistry or medicine have been awarded for discoveries based on macromolecular crystallography. New hardware and software tools have made crystallography appear to be an almost routine (but still far from being analytical) technique and many structures are now being determined by scientists with very limited experience in the practical aspects of the field. However, this apparent ease is sometimes illusory and proper procedures need to be followed to maintain high standards of structure quality. In addition, many noncrystallographers may have problems with the critical evaluation and interpretation of structural results published in the scientific literature. The present review provides an outline of the technical aspects of crystallography for less experienced practitioners, as well as information that might be useful for users of macromolecular structures, aiming to show them how to interpret (but not overinterpret) the information present in the coordinate files and in their description. A discussion of the extent of information that can be gleaned from the atomic coordinates of structures solved at different resolution is provided, as well as problems and pitfalls encountered in structure determination and interpretation. C1 [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Minor, Wladek] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA USA. [Minor, Wladek] Midwest Ctr Struct Genom, Lemont, IL USA. [Minor, Wladek] New York Struct Genom Consortium, New York, NY USA. [Minor, Wladek] Ctr Struct Genom Infect Dis, Bethesda, MD USA. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne Natl Lab, Chicago, IL USA. [Jaskolski, Mariusz] Adam Mickiewicz Univ, Fac Chem, Dept Crystallog, PL-60780 Poznan, Poland. [Jaskolski, Mariusz] Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, Poznan, Poland. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@nih.gov RI Minor, Wladek/F-3096-2014; OI Minor, Wladek/0000-0001-7075-7090 FU NIH, National Cancer Institute, Center for Cancer Research; Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201200026C]; [GM053163]; [GM094585]; [GM094662]; [GM093342] FX We thank Dr Jerry Alexandratos for assistance with the preparation of the figures and Milosz Ruszkowski for the photograph in Fig. 1A. Original work in the laboratories of A. W. and Z.D. was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. W. M. was supported by grants GM053163, GM094585, GM094662 and GM093342, and was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201200026C. NR 136 TC 27 Z9 27 U1 3 U2 49 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-464X EI 1742-4658 J9 FEBS J JI FEBS J. PD NOV PY 2013 VL 280 IS 22 BP 5705 EP 5736 DI 10.1111/febs.12495 PG 32 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 254AA UT WOS:000327130900013 PM 24034303 ER PT J AU Bilke, S Schwentner, R Yang, F Kauer, M Jug, G Walker, RL Davis, S Zhu, YLJ Pineda, M Meltzer, PS Kovar, H AF Bilke, Sven Schwentner, Raphaela Yang, Fan Kauer, Maximilian Jug, Gunhild Walker, Robert L. Davis, Sean Zhu, Yuelin J. Pineda, Marbin Meltzer, Paul S. Kovar, Heinrich TI Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer SO GENOME RESEARCH LA English DT Article ID TRANSCRIPTION FACTORS; RESPONSE ELEMENTS; CELLS; EWS-FLI1; TUMORS; ACTIVATION; EXPRESSION; EWS/FLI-1; TRANSLOCATION; SPECIFICITY AB Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation, and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function, but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome-wide DNA-binding and transcription data in EWSR1/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically coregulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F-ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWSR1/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target genes has a generally activating effect, EWSR1/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWSR1/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation. C1 [Bilke, Sven; Yang, Fan; Walker, Robert L.; Davis, Sean; Zhu, Yuelin J.; Pineda, Marbin; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Schwentner, Raphaela; Kauer, Maximilian; Jug, Gunhild; Kovar, Heinrich] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Kovar, Heinrich] Med Univ, Dept Pediat, A-1090 Vienna, Austria. RP Meltzer, PS (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov OI Kovar, Heinrich/0000-0001-6873-9109; Davis, Sean/0000-0002-8991-6458 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Austrian Science Fund (FWF) [22328-B09]; 7th Framework Program of the European Commission [259348]; Austrian Academy of Sciences FX This study was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and the Austrian Science Fund (FWF), grant 22328-B09; and by the 7th Framework Program of the European Commission, grant 259348 ("ASSET"). R.S. is a recipient of a DOC-fFORTE scholarship of the Austrian Academy of Sciences. We thank J. Waterfall for valuable discussions. NR 42 TC 29 Z9 30 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2013 VL 23 IS 11 BP 1797 EP 1809 DI 10.1101/gr.151340.112 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 247TA UT WOS:000326642500004 PM 23940108 ER PT J AU Donato, M Xu, ZH Tomoiaga, A Granneman, JG MacKenzie, RG Bao, RY Than, NG Westfall, PH Romero, R Draghici, S AF Donato, Michele Xu, Zhonghui Tomoiaga, Alin Granneman, James G. MacKenzie, Robert G. Bao, Riyue Than, Nandor Gabor Westfall, Peter H. Romero, Roberto Draghici, Sorin TI Analysis and correction of crosstalk effects in pathway analysis SO GENOME RESEARCH LA English DT Article ID WHITE ADIPOSE-TISSUE; GENE-EXPRESSION; CELLULAR PLASTICITY; UTERINE CERVIX; PARTURITION; PREGNANCY; IDENTIFICATION; TRANSCRIPTOME; ACTIVATION; INDUCTION AB Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a "crosstalk" phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes. C1 [Donato, Michele; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48084 USA. [Xu, Zhonghui; Romero, Roberto] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,Sch Med, Detroit, MI 48201 USA. [Tomoiaga, Alin; Westfall, Peter H.] Texas Tech Univ, Ctr Adv Analyt & Business Intelligence, Lubbock, TX 79409 USA. [Granneman, James G.; MacKenzie, Robert G.] Wayne State Univ, Ctr Integrat Metab & Endocrine Res, Detroit, MI 48084 USA. [Bao, Riyue] Wayne State Univ, Dept Biol Sci, Detroit, MI 48084 USA. [Than, Nandor Gabor] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Draghici, Sorin] Wayne State Univ, Dept Clin & Translat Sci, Detroit, MI 48084 USA. RP Draghici, S (reprint author), Wayne State Univ, Dept Comp Sci, Detroit, MI 48084 USA. EM sorin@wayne.edu RI Bao, Riyue/G-8765-2014; OI Bao, Riyue/0000-0002-6105-1704; Draghici, Sorin/0000-0002-0786-8377 FU NIH [RO1 RDK089167, R42 GM087013]; NSF [DBI-0965741]; Robert J. Sokol Endowment in Systems Biology; Perinatology Research Branch; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHH FX This work has been partially supported by the following grants: NIH RO1 RDK089167, R42 GM087013, and NSF DBI-0965741 (to S. D.), by the Robert J. Sokol Endowment in Systems Biology, and by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the NSF, NIH, or any other of the funding agencies. NR 29 TC 26 Z9 26 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2013 VL 23 IS 11 BP 1885 EP 1893 DI 10.1101/gr.153551.112 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 247TA UT WOS:000326642500012 PM 23934932 ER PT J AU Love, D Keembiyehetty, C Gavrilova, O Comly, M Harwood, K Hanover, J AF Love, Dona Keembiyehetty, Chithra Gavrilova, Oksana Comly, Marcy Harwood, Katryn Hanover, John TI A murine knockout of the human diabetes susceptibility locus Oga contributes to acute and chronic nutrient sensing defects SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Love, Dona; Keembiyehetty, Chithra; Gavrilova, Oksana; Comly, Marcy; Harwood, Katryn; Hanover, John] NIDDK, NIH, Bethesda, MD USA. NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 9 BP 1332 EP 1332 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400019 ER PT J AU Zhang, LP Ten Hagen, K AF Zhang, Liping Ten Hagen, Kelly TI Mucin-type O-glycosylation is required for polarized secretion in the Drosophila digestive system SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Zhang, Liping; Ten Hagen, Kelly] Natl Inst Dent & Craniofacial Res, Dev Glycobiol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 15 BP 1334 EP 1334 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400025 ER PT J AU Akan, I Love, D Hanover, J AF Akan, Ilhan Love, Dona Hanover, John TI Deletion of Drosophila O-GlcNAcase (Oga) causes defects in oogenesis SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Akan, Ilhan; Love, Dona; Hanover, John] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 101 BP 1365 EP 1365 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400111 ER PT J AU Ichikawa, M Scott, DA Milner, JD Su, H Freeze, HH AF Ichikawa, Mie Scott, David A. Milner, Joshua D. Su, Helen Freeze, Hudson H. TI Hexosamine Metabolism in PGM3-Deficient Patient Fibroblasts SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Ichikawa, Mie; Scott, David A.; Freeze, Hudson H.] Sanford Burnham Med Res Inst, La Jolla, CA USA. [Milner, Joshua D.; Su, Helen] NIAID, NIH, Bethesda, MD 20892 USA. RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 NR 0 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 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 140 BP 1378 EP 1378 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400150 ER PT J AU Bond, M Ghosh, S Hanover, J AF Bond, Michelle Ghosh, Salil Hanover, John TI The nutrient sensor O-GlcNAc transferase is a critical component of the C. elegans innate immune system SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Bond, Michelle; Hanover, John] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 164 BP 1387 EP 1387 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400174 ER PT J AU Harwood, K Hanover, J AF Harwood, Katryn Hanover, John TI The Enzymes of the O-GlcNAc Cycling: Writers AND Readers of the Histone Code? SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Harwood, Katryn; Hanover, John] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 165 BP 1387 EP 1387 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400175 ER PT J AU Hanover, J Bondy, C Cheng, C Bakalov, V Zirzow, A Olivier-Van Stichelen, S Love, D AF Hanover, John Bondy, Carolyn Cheng, Clara Bakalov, Vladimir Zirzow, Amanda Olivier-Van Stichelen, Stephanie Love, Dona TI OGT is an X-linked imprinted gene linked to Cardiovascular Disease Susceptibility SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [Hanover, John; Olivier-Van Stichelen, Stephanie; Love, Dona] NIDDK, NIH, Bethesda, MD 20892 USA. [Bondy, Carolyn; Cheng, Clara; Bakalov, Vladimir] NICHD, Bethesda, MD USA. [Zirzow, Amanda] Georgetown Univ, Washington, DC 20057 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 169 BP 1388 EP 1389 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400179 ER PT J AU dos Santos, M Duggal, R Sacks, D Beverley, S AF dos Santos, Marcos Duggal, Ryan Sacks, David Beverley, Stephen TI Leishmania proteophosphoglycans (PPGs): genetic analysis of a parasite mucin-like glycoprotein implicated in several key steps in the infectious cycle SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Annual Conference of the Society-for-Glycobiology CY NOV 17-20, 2013 CL St Petersburg, FL SP Soc Glycobiol C1 [dos Santos, Marcos; Duggal, Ryan; Beverley, Stephen] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Sacks, David] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2013 VL 23 IS 11 MA 186 BP 1395 EP 1395 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 251YY UT WOS:000326972400196 ER PT J AU Saranummi, N Spruijt-Metz, D Intille, SS Korhonen, I Nilsen, WJ Pavel, M AF Saranummi, Niilo Spruijt-Metz, Donna Intille, Stephen S. Korhonen, Ilkka Nilsen, Wendy J. Pavel, Misha TI Moving the Science of Behavioral Change into the 21st Century: Part 2 SO IEEE PULSE LA English DT Article C1 [Saranummi, Niilo] VTT Tech Res Ctr Finland, Tampere, Finland. [Spruijt-Metz, Donna] Univ So Calif, Los Angeles, CA 90089 USA. [Intille, Stephen S.; Pavel, Misha] Northeastern Univ, Boston, MA USA. [Korhonen, Ilkka] Tampere Univ Technol, FIN-33101 Tampere, Finland. [Nilsen, Wendy J.] US NIH, Off Behav & Social Sci Res, Bethesda, MD USA. [Pavel, Misha] Natl Sci Fdn, Comp Informat Syst & Engn Dept, Arlington, VA USA. RP Saranummi, N (reprint author), VTT Tech Res Ctr Finland, Tampere, Finland. EM niilo.saranummi@vtt.fi; dmetz@usc.edu; S.Intille@neu.edu; ilkka.korhonen@tut.fi; nilsenwj@od.nih.gov; mpavel@nsf.gov RI Korhonen, Ilkka/G-4301-2014 OI Korhonen, Ilkka/0000-0002-5322-8469 NR 3 TC 0 Z9 0 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD NOV-DEC PY 2013 VL 4 IS 6 BP 32 EP 33 DI 10.1109/MPUL.2013.2279619 PG 2 WC Engineering, Biomedical SC Engineering GA 252DL UT WOS:000326984900015 PM 24233189 ER PT J AU Berera, D Zambon, M AF Berera, Deeva Zambon, Maria TI Antivirals in the 2009 pandemic - lessons and implications for future strategies SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Article; Proceedings Paper CT 2nd isirv Antiviral Group Conference on Severe Influenza-Burden, Pathogenesis and Management CY OCT 29-31, 2012 CL Hanoi, VIETNAM DE 2009 Pandemic; antivirals; influenza ID INFLUENZA-A H1N1; NEURAMINIDASE INHIBITOR TREATMENT; UNITED-KINGDOM; OSELTAMIVIR; IMMUNIZATION; PROPHYLAXIS; CONTAINMENT; RESISTANCE; MORTALITY; CHILDREN AB The World Health Organization's declaration of an imminent swine-origin influenza A pandemic in April 2009 triggered the global launch of national pandemic preparedness plans. An integral component of pandemic preparedness in many countries was the targeted use of antiviral therapy for containment, disease mitigation, and treatment. The 2009 pandemic marked the first pandemic during which influenza antivirals were available for global use. Although most national pandemic plans included provisions for antiviral treatment, these pre-determined protocols required frequent updating as more information became available about the virus, and its susceptibility to antiviral agents, the epidemiology of infection, and the population groups that were most susceptible to severe disease. National public health agencies in countries with both plans for use of antivirals and pre-existing stockpiles, including those in Japan, the United Kingdom, and the United States, operated distinctly different antiviral distribution and treatment programs from one another. In the 3years following the pandemic, there is still little comparison of the diversity of national antiviral treatment policies and drug distribution mechanisms that were implemented, whether they had any mitigating effects and which might be most efficient. The purpose of this study is to outline roles of antiviral medicines in a pandemic period, provide insights into the diversity of antiviral treatment and distribution policies applied by selected countries between April 2009-July 2010, and to stimulate discussion on whether these policies remain appropriate for implementation in future pandemics. C1 [Berera, Deeva] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Zambon, Maria] Publ Hlth England, Reference Microbiol Serv, Colindale, England. RP Zambon, M (reprint author), Publ Hlth England, Reference Microbiol Serv, 61 Colindale Ave, London NW9 5EQ, England. EM maria.zambon@phe.gov.uk FU Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; International Influenza Unit, Office of Global Affairs, Department of Health and Human Services, USA FX DB received financial support from the Influenza Research Program of the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, which is funded by the International Influenza Unit, Office of Global Affairs, Department of Health and Human Services, USA. NR 36 TC 3 Z9 3 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1750-2640 EI 1750-2659 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD NOV PY 2013 VL 7 SU 3 SI SI BP 72 EP 79 DI 10.1111/irv.12172 PG 8 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 251VK UT WOS:000326959200010 PM 24215385 ER PT J AU Ruffin, J AF Ruffin, John TI Translating Science into Better Health: The Power of Diversity and Multicultural Engagement Preface SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Editorial Material C1 NIMHD, Natl Inst Minor Hlth & Hlth Dispar, Res Ctr Minor Inst, RCMI Program, Bethesda, MD USA. RP Ruffin, J (reprint author), NIMHD, Natl Inst Minor Hlth & Hlth Dispar, Res Ctr Minor Inst, RCMI Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD NOV PY 2013 VL 24 IS 4 SU S BP VIII EP IX PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 251CK UT WOS:000326905200001 PM 24241270 ER PT J AU Fujioka, H Phelix, CF Friedland, RP Zhu, XW Perry, EA Castellani, RJ Perry, G AF Fujioka, Hisashi Phelix, Clyde F. Friedland, Robert P. Zhu, Xiongwei Perry, Elizabeth A. Castellani, Rudy J. Perry, George TI Alipoprotein E4 Prevents Growth of Malaria at the Intraerythrocyte Stage: Implications For Differences in Racial Susceptibility to Alzheimer's Disease SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article; Proceedings Paper CT 13th Research-Centers-in-Minority-Institutions (RCMI) International Symposium on Health Disparities CY DEC, 2012 CL Univ Cent Caribe, Ponce Sch Med, RCMI Programs, San Juan, PR SP Res Ctr Minor Inst, Univ Cent Caribe, Ponce Sch Med & Hlth Sci, Univ Puerto Rico HO Univ Cent Caribe, Ponce Sch Med, RCMI Programs DE Aging; diet; evolution; health disparity; lipids; malaria ID APOLIPOPROTEIN-E POLYMORPHISM; PLASMODIUM-FALCIPARUM; NATURAL-SELECTION; AFRICA; POPULATIONS; CHLOROQUINE; DIAGNOSIS; PARASITES; DEMENTIA; PROTEIN AB ApolipoproteinE 4 (ApoE 4) has been linked to pathogenesis of Alzheimer's disease and has been suggested to be maintained through evolutionary pressure via a protective role in malaria infection. We evaluated Plasmodium falciparum viability at the intraerythrocyte stage by exposure to plasma from human subjects with ApoE 4/4 or ApoE 3/3. Plasma samples from ApoE 4/4 but not ApoE 3/3 donors inhibited growth and disrupted morphology of P. falciparum. Evolutionary history is characterized by war between pathogenic microorganisms and defense mechanisms countering their pathogenicities. ApoE 4 frequency is highest in sub-Saharan Africa and other isolated populations (e.g., Papua New Guinea) that exhibit endemic malaria. High ApoE frequency may offer selective advantage protecting against some infectious diseases (e.g., Plasmodium falciparum). These results implicate evolutionary pressure by malaria selecting humans with ApoE 4/4, even considering lower survival in late life. These selective advantages may be relevant in the exploration of possible disparities between Black and Whites in the incidence of Alzheimer's Disease. C1 [Fujioka, Hisashi] Case Western Reserve Univ, Elect Microscopy Core Facil, Cleveland, OH 44106 USA. [Phelix, Clyde F.] Univ Texas San Antonio, San Antonio, TX USA. [Friedland, Robert P.] Univ Louisville, Sch Med, Dept Neurol, Louisville, KY 40292 USA. [Friedland, Robert P.] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Perry, Elizabeth A.] Natl Inst Dent, NIH, Washington, DC USA. [Perry, Elizabeth A.] NIH, Craniofacial Res program, Washington, DC USA. [Castellani, Rudy J.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Perry, George] Univ Texas San Antonio, Coll Sci, San Antonio, TX 78249 USA. RP Perry, G (reprint author), Univ Texas San Antonio, Coll Sci, 1 UTSA Circle, San Antonio, TX 78249 USA. EM george.perry@utsa.edu RI Perry, Elizabeth/A-1628-2014; Perry, George/A-8611-2009; Friedland, Robert/A-2834-2010; Phelix, Clyde/L-8048-2015 OI Perry, Elizabeth/0000-0001-9506-2578; Perry, George/0000-0002-6547-0172; Friedland, Robert/0000-0001-5721-1843; Phelix, Clyde/0000-0002-6703-514X FU NIAID NIH HHS [AI-058186-01, R03 AI058186]; NIMHD NIH HHS [G12 MD007591, G12MD007591] NR 40 TC 6 Z9 6 U1 2 U2 5 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD NOV PY 2013 VL 24 IS 4 SU S BP 70 EP 78 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 251CK UT WOS:000326905200011 PM 24241262 ER PT J AU Chaemsaithong, P Madan, I Romero, R Than, NG Tarca, AL Draghici, S Bhatti, G Yeo, L Mazor, M Kim, CJ Hassan, SS Chaiworapongsa, T AF Chaemsaithong, Piya Madan, Ichchha Romero, Roberto Than, Nandor Gabor Tarca, Adi L. Draghici, Sorin Bhatti, Gaurav Yeo, Lami Mazor, Moshe Kim, Chong Jai Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor SO JOURNAL OF PERINATAL MEDICINE LA English DT Article DE Angiopoietin-like 4 (ANGPTL4); arrest disorders; chemokine (C-C motif) ligand 2 (CCL2); metallothionein (MT); myometrium; nitric oxide synthase (NOS); pregnancy; parturition; systems biology; TGF signaling pathway; transcriptomics ID NITRIC-OXIDE SYNTHASE; CORTICOTROPIN-RELEASING HORMONE; UTERINE SMOOTH-MUSCLE; PREGNANT HUMAN MYOMETRIUM; HUMAN-FETAL MEMBRANES; METALLOTHIONEIN GENE-EXPRESSION; MONOCYTE CHEMOTACTIC PROTEIN-1; ACTIVATED POTASSIUM CHANNEL; MESSENGER-RNA EXPRESSION; PROSTAGLANDIN-E SYNTHASE AB Objective: The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). Study design: Human myometrium was prospectively collected from women in the following groups: (1) spontaneous term labor (TL; n = 29) and (2) arrest of dilatation (AODIL; n = 14). Gene expression was characterized using Illumina (R) HumanHT-12 microarrays. A moderated Student's t-test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway ana-lysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The MetaCore knowledge base was also searched for pathway analysis. Results: (1) Forty-two differentially expressed genes were identified in women with an AODIL; (2) gene ontology analysis indicated enrichment of biological processes, which included regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included transcription repressor activity, heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; (3) MetaCore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of endothelial nitric oxide synthase (eNOS) activity in endothelial cells, and triiodothyronine and thyroxine signaling as significantly overrepresented (false discovery rate <0.05); (4) qRT-PCR confirmed the overexpression of Nitric oxide synthase 3 (NOS3); hypoxic ischemic factor 1A (HIF1A); Chemokine (C-C motif) ligand 2 (CCL2); angiopoietin-like 4 (ANGPTL4); ADAM metallopeptidase with thrombospondin type 1, motif 9 (ADAMTS9); G protein-coupled receptor 4 (GPR4); metallothionein 1A (MT1A); MT2A; and selectin E (SELE) in an AODIL. Conclusion: The myometrium of women with AODIL has a stereotypic transcriptome profile. This disorder has been associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL. C1 [Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD, NIH,DHHS,Perinatol Res Branch, Detroit, MI 48201 USA. [Chaemsaithong, Piya; Madan, Ichchha; Than, Nandor Gabor; Tarca, Adi L.; Bhatti, Gaurav; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. [Chaemsaithong, Piya; Madan, Ichchha; Than, Nandor Gabor; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Mazor, Moshe] Ben Gurion Univ Negev, Soroka Univ Med Ctr, Sch Med, Dept Obstet & Gynecol, Beer Sheva, Israel. [Kim, Chong Jai] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD, NIH,DHHS,Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov OI Draghici, Sorin/0000-0002-0786-8377 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); NICHD, NIH [HSN275201300006C] 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. HSN275201300006C. We wish to thank Dr. Susan Land and Dan Lott at the Applied Genomics Technology Center of Wayne State University for performing the microarrays and also acknowledge the contributions of the nursing staff of the Perinatology Research Branch and Hutzel Women's Hospital. NR 203 TC 12 Z9 12 U1 0 U2 10 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 NOV PY 2013 VL 41 IS 6 BP 665 EP 681 DI 10.1515/jpm-2013-0086 PG 17 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 252QO UT WOS:000327023800007 PM 23893668 ER PT J AU Cardone, G Heymann, JB Steven, AC AF Cardone, Giovanni Heymann, J. Bernard Steven, Alasdair C. TI One number does not fit all: Mapping local variations in resolution in cryo-EM reconstructions SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Resolution; Cryo-electron microscopy; Three-dimensional reconstruction; Image heterogeneity; Masking; Short-space Fourier transform ID TO-NOISE RATIO; PARTICLE ELECTRON CRYOMICROSCOPY; HEPATITIS-B-VIRUS; MOLECULAR ARCHITECTURE; 26S PROTEASOME; BINDING; RIBOSOME; MICROSCOPY; VISUALIZATION; MICROGRAPHS AB The resolution of density maps from single particle analysis is usually measured in terms of the highest spatial frequency to which consistent information has been obtained. This calculation represents an average over the entire reconstructed volume. In practice, however, substantial local variations in resolution may occur, either from intrinsic properties of the specimen or for technical reasons such as a non-isotropic distribution of viewing orientations. To address this issue, we propose the use of a space-frequency representation, the short-space Fourier transform, to assess the quality of a density map, voxel-by-voxel, i.e. by local resolution mapping. In this approach, the experimental volume is divided into small subvolumes and the resolution determined for each of them. It is illustrated in applications both to model data and to experimental density maps. Regions with lower-than-average resolution may be mobile components or ones with incomplete occupancy or result from multiple conformational states. To improve the interpretability of reconstructions, we propose an adaptive filtering approach that reconciles the resolution to which individual features are calculated with the results of the local resolution map. Published by Elsevier Inc. C1 [Cardone, Giovanni; Heymann, J. Bernard; Steven, Alasdair C.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIH, Bldg 50,Room 1517,50 South Dr MSC 8025, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov OI Heymann, Bernard/0000-0002-8872-5326 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). NR 50 TC 25 Z9 25 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 EI 1095-8657 J9 J STRUCT BIOL JI J. Struct. Biol. PD NOV PY 2013 VL 184 IS 2 BP 226 EP 236 DI 10.1016/j.jsb.2013.08.002 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 254MY UT WOS:000327171000014 PM 23954653 ER PT J AU Mittapalli, RK Liu, XL Adkins, CE Nounou, MI Bohn, KA Terrell, TB Qhattal, HS Geldenhuys, WJ Palmieri, D Steeg, PS Smith, QR Lockman, PR AF Mittapalli, Rajendar K. Liu, Xinli Adkins, Chris E. Nounou, Mohamed I. Bohn, Kaci A. Terrell, Tori B. Qhattal, Hussaini S. Geldenhuys, Werner J. Palmieri, Diane Steeg, Patricia S. Smith, Quentin R. Lockman, Paul R. TI Paclitaxel-Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TARGETED DRUG-DELIVERY; CENTRAL-NERVOUS-SYSTEM; P-GLYCOPROTEIN; STEM-CELLS; IN-VIVO; MULTIDRUG-RESISTANCE; ANTITUMOR-ACTIVITY; ACID-PACLITAXEL; CD44 EXPRESSION; LIPID RAFTS AB Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (similar to 5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G(2)-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. (C) 2013 AACR. C1 [Mittapalli, Rajendar K.; Liu, Xinli; Adkins, Chris E.; Nounou, Mohamed I.; Bohn, Kaci A.; Terrell, Tori B.; Qhattal, Hussaini S.; Smith, Quentin R.; Lockman, Paul R.] Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. [Geldenhuys, Werner J.] Northeast Ohio Med Univ, Coll Pharm, Dept Pharmaceut Sci, Rootstown, OH USA. [Palmieri, Diane; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Lockman, PR (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, 1406 S Coulter Dr, Amarillo, TX 79106 USA. EM paul.lockman@ttuhsc.edu RI Palmieri, Diane/B-4258-2015; OI Ismail Nounou, Mohamed/0000-0002-8589-2700 FU Department of Defense, Breast Cancer Research Program [W81 XWH-062-0033] FX Funding for this study was provided by the Department of Defense, Breast Cancer Research Program, grant W81 XWH-062-0033 (P.S. Steeg, D. Palmieri, Q.R. Smith, and P.R. Lockman). NR 57 TC 28 Z9 28 U1 1 U2 21 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 NOV PY 2013 VL 12 IS 11 BP 2389 EP 2399 DI 10.1158/1535-7163.MCT-13-0132 PG 11 WC Oncology SC Oncology GA 250WB UT WOS:000326886000010 PM 24002934 ER PT J AU Chen, JQ Lee, JH Herrmann, MA Park, KS Heldman, MR Goldsmith, PK Wang, Y Giaccone, G AF Chen, Jin-Qiu Lee, Jih-Hsiang Herrmann, Michelle A. Park, Kang-Seo Heldman, Madeleine R. Goldsmith, Paul K. Wang, Yisong Giaccone, Giuseppe TI Capillary Isoelectric-Focusing Immunoassays to Study Dynamic Oncoprotein Phosphorylation and Drug Response to Targeted Therapies in Non-Small Cell Lung Cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID TYROSINE KINASE; INHIBITOR SENSITIVITY; 1ST-LINE TREATMENT; MYELOID-LEUKEMIA; OPEN-LABEL; EGFR; CHEMOTHERAPY; TRIAL; ACTIVATION; ERLOTINIB AB Developing proteomic biomarkers is valuable for evaluating therapeutic effects of drugs and generating better treatment strategies. However, conventional protein analysis is often challenging due to inadequate sample size of clinical specimens, lack of assay reproducibility, accuracy, and sensitivity. A novel capillary isoelectricfocusing (IEF) immunoassay system (NanoPro) was used to study the dynamic phosphorylation status of signaling molecules in non-small cell lung cancer (NSCLC) cells treated with EGFR tyrosine kinase and MEK inhibitors. NanoPro showed the same dynamic ERK phosphorylation as Western blotting with good assay reproducibility using 1,000 times less protein. The IEF separation in NanoPro system enables multiple protein phosphorylation isoforms to be resolved and detected simultaneously. With NanoPro, we identified a specific on-target mitogen-activated protein/extracellular signal-regulated kinase (MEK) response pattern to MEK inhibitor PD325901, which was not detectable by Western blot analysis. We also revealed a MEK2 signal that may be associated with NSCLC cell sensitivity to the EGF receptor inhibitor erlotinib, and distinguished erlotinib-sensitive cells from intrinsic as well as acquired resistant cells to erlotinib. Moreover, NanoPro could differentiate human ERK1 isoforms from the mouse isoforms based on their isoelectric point differences and showed that erlotinib effectively inhibited ERK phosphorylation in targeted human xenograft cancer cells but not in surrounding mouse stromal cells. With 8 mu g of tumor aspirates, we precisely quantified the response of 18 signaling molecules to erlotinib and MEK1 inhibitor treatments in an NSCLC patient. NanoPro's higher sensitivity, better resolution of protein phosphorylation status, and reduced tissue requirement warrant NanoPro's investigation for future drug development and evaluation of drug effects of targeted therapies. Mol Cancer Ther; 12(11); 2601-13. (C) 2013 AACR. C1 [Chen, Jin-Qiu; Herrmann, Michelle A.; Heldman, Madeleine R.] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Jih-Hsiang; Park, Kang-Seo; Wang, Yisong; Giaccone, Giuseppe] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Goldsmith, Paul K.] NCI, Off Sci & Technol Partnership, Off Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), Georgetown Univ, 3970 Reservoir Rd NW, Washington, DC 20007 USA. EM gg496@georgetown.edu OI Giaccone, Giuseppe/0000-0002-5023-7562 FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH FX G. Giaccone was financially supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 35 TC 11 Z9 11 U1 0 U2 12 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 NOV PY 2013 VL 12 IS 11 BP 2601 EP 2613 DI 10.1158/1535-7163.MCT-13-0074 PG 13 WC Oncology SC Oncology GA 250WB UT WOS:000326886000028 PM 23979919 ER PT J AU Mittleman, B Neil, G Cutcher-Gershenfeld, J AF Mittleman, Barbara Neil, Garry Cutcher-Gershenfeld, Joel TI Precompetitive consortia in biomedicine-how are we doing? SO NATURE BIOTECHNOLOGY LA English DT Article ID DRUG DISCOVERY; INNOVATION C1 [Mittleman, Barbara] US NIH, Bethesda, MD 20892 USA. [Neil, Garry] Johnson & Johnson, New Brunswick, NJ USA. [Cutcher-Gershenfeld, Joel] Univ Illinois, Urbana, IL 61801 USA. RP Mittleman, B (reprint author), Nodality, San Francisco, CA USA. EM barbara.mittleman@nodality.com NR 17 TC 3 Z9 3 U1 0 U2 6 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 NOV PY 2013 VL 31 IS 11 BP 979 EP 985 DI 10.1038/nbt.2731 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 251IM UT WOS:000326921200015 PM 24213770 ER PT J AU Hinrichs, CS Restifo, NP AF Hinrichs, Christian S. Restifo, Nicholas P. TI Reassessing target antigens for adoptive T-cell therapy SO NATURE BIOTECHNOLOGY LA English DT Review ID TUMOR GENE WT1; PROSTATE-SPECIFIC ANTIGEN; COLONY-STIMULATING FACTOR; CARBONIC-ANHYDRASE-IX; BREAST-CANCER CELLS; CARCINOEMBRYONIC ANTIGEN; METASTATIC MELANOMA; NORMAL-TISSUES; TELOMERASE ACTIVITY; MULTIPLE-MYELOMA AB Adoptive T-cell therapy can target and kill widespread malignant cells thereby inducing durable clinical responses in melanoma and selected other malignances. However, many commonly targeted tumor antigens are also expressed by healthy tissues, and T cells do not distinguish between benign and malignant tissues if both express the target antigen. Autoimmune toxicity from T cell-mediated destruction of normal tissue has limited the development and adoption of this otherwise promising type of cancer therapy. A review of the unique biology of T-cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities. It is important that target antigens chosen for adoptive T-cell therapy are expressed by tumors and not by essential healthy tissues. The risk of adverse autoimmune events can be further mitigated by generating antigen receptors using strategies that reduce the chance of cross-reactivity against epitopes in unintended targets. In general, a circumspect approach to target selection and thoughtful preclinical and clinical studies are pivotal to the ongoing advancement of these promising treatments. C1 [Hinrichs, Christian S.; Restifo, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Restifo, NP (reprint author), NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. EM restifo@nih.gov OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [ZIA BC010763-07] NR 108 TC 47 Z9 48 U1 1 U2 25 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 NOV PY 2013 VL 31 IS 11 BP 999 EP 1008 DI 10.1038/nbt.2725 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 251IM UT WOS:000326921200021 PM 24142051 ER PT J AU Wu, YC Wawrzusin, P Senseney, J Fischer, RS Christensen, R Santella, A York, AG Winter, PW Waterman, CM Bao, ZR Colon-Ramos, DA McAuliffe, M Shroff, H AF Wu, Yicong Wawrzusin, Peter Senseney, Justin Fischer, Robert S. Christensen, Ryan Santella, Anthony York, Andrew G. Winter, Peter W. Waterman, Clare M. Bao, Zhirong Colon-Ramos, Daniel A. McAuliffe, Matthew Shroff, Hari TI Spatially isotropic four-dimensional imaging with dual-view plane illumination microscopy SO NATURE BIOTECHNOLOGY LA English DT Article ID LIGHT-SHEET MICROSCOPY; NEMATODE CAENORHABDITIS-ELEGANS; LIVING CELLS; C-ELEGANS; IMPROVES RESOLUTION; DYNAMICS; 3D; SPECIMENS; EMBRYOS; LIVE AB Optimal four-dimensional imaging requires high spatial resolution in all dimensions, high speed and minimal photobleaching and damage. We developed a dual-view, plane illumination microscope with improved spatiotemporal resolution by switching illumination and detection between two perpendicular objectives in an alternating duty cycle. Computationally fusing the resulting volumetric views provides an isotropic resolution of 330 nm. As the sample is stationary and only two views are required, we achieve an imaging speed of 200 images/s (i.e., 0.5 s for a 50-plane volume). Unlike spinning-disk confocal or Bessel beam methods, which illuminate the sample outside the focal plane, we maintain high spatiotemporal resolution over hundreds of volumes with negligible photobleaching. To illustrate the ability of our method to study biological systems that require high-speed volumetric visualization and/or low photobleaching, we describe microtubule tracking in live cells, nuclear imaging over 14 h during nematode embryogenesis and imaging of neural wiring during Caenorhabditis elegans brain development over 5 h. C1 [Wu, Yicong; Wawrzusin, Peter; York, Andrew G.; Winter, Peter W.; Shroff, Hari] NIH, Sect High Resolut Opt Imaging, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Senseney, Justin; McAuliffe, Matthew] NIH, Biomed Imaging Res Serv Sect, Ctr Informat Technol, Bethesda, MD 20892 USA. [Fischer, Robert S.; Waterman, Clare M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Christensen, Ryan; Colon-Ramos, Daniel A.] Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT USA. [Christensen, Ryan; Colon-Ramos, Daniel A.] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Santella, Anthony; Bao, Zhirong] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10021 USA. RP Wu, YC (reprint author), NIH, Sect High Resolut Opt Imaging, Natl Inst Biomed Imaging & Bioengn, Bldg 10, Bethesda, MD 20892 USA. EM yicong.wu@nih.gov RI Shroff, Hari/E-7247-2016; OI Shroff, Hari/0000-0003-3613-8215; Bao, Zhirong/0000-0002-2201-2745; Waterman, Clare/0000-0001-6142-6775 FU National Institutes of Health (NIH) [GM097576, HD075602]; US National Institutes of Health (NIH) [R01 NS076558, U01HD075602]; Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering; National Institute of Heart, Lung, and Blood; Center for Information Technology FX We thank J. McNally and C.-H. Lee for illuminating discussions, M. R. Reinhardt for helping us with the scientific cMOS, W. Mohler for helping us to share and view 4D data sets, G. Rondeau for help with mechanical design, A.Hoofring for help with illustrations and H. Eden for critical feedback on the manuscript. A.S. and Z.B. acknowledge funding from National Institutes of Health (NIH) grants GM097576 and HD075602. R.C. and D.C.-R. acknowledge funding from US National Institutes of Health (NIH) grants R01 NS076558 and U01HD075602. This work was supported by the Intramural Research Programs of the NIH National Institute of Biomedical Imaging and Bioengineering, the National Institute of Heart, Lung, and Blood, and the Center for Information Technology. NR 47 TC 67 Z9 68 U1 3 U2 25 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 NOV PY 2013 VL 31 IS 11 BP 1032 EP + DI 10.1038/nbt.2713 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 251IM UT WOS:000326921200026 PM 24108093 ER PT J AU Levy, D Jiang, M Szklo, A de Almeida, LM Autran, M Bloch, M AF Levy, David Jiang, Miao Szklo, Andre de Almeida, Liz Maria Autran, Mariana Bloch, Michele TI Smoking and Adverse Maternal and Child Health Outcomes in Brazil SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID LOW-BIRTH-WEIGHT; INFANT-DEATH-SYNDROME; RISK-FACTORS; LIVE BIRTHS; DEVELOPING-COUNTRY; CIGARETTE-SMOKING; SOUTHERN BRAZIL; PRETERM BIRTHS; PREGNANCY; PREVALENCE AB Introduction: Numerous studies from high-income countries document the causal relationship between cigarette smoking during pregnancy and adverse maternal and child health (MCH) outcomes. Less research has been conducted in low-and middle-income countries, but a burgeoning literature can be found for Brazil. Methods: We review Brazilian studies of the prevalence of maternal smoking, the relative risk of smoking-attributable adverse MCH outcomes, and present new estimates for these outcomes, using the attributable fraction method. Results: We found that Brazilian studies of the relative risks of smoking-attributable adverse MCH outcomes were broadly consistent with previous reviews. Based on a comparison of maternal smoking over time, smoking during pregnancy has declined by about 50% over the last 20 years in Brazil. For 2008, we estimate that 5,352 cases of spontaneous abortion, 10,929 cases of preterm birth, 20,717 cases of low birth weight, and 29 cases of sudden infant death syndrome are attributable to maternal smoking. Between 1989 and 2008, the percent of smoking-attributable adverse MCH outcomes in Brazil was at least halved. Conclusions: The results show that over a 20-year period, during which Brazil implemented numerous effective tobacco control measures, the country experienced a dramatic decrease in both maternal smoking prevalence and smoking-attributable adverse MCH outcomes. Countries that implement effective tobacco control measures can expect to reduce both maternal smoking and adverse MCH outcomes, thereby improving the public health. C1 [Levy, David] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Jiang, Miao] Harvey L Neiman Hlth Policy Inst, Reston, VA USA. [Szklo, Andre; de Almeida, Liz Maria; Autran, Mariana] Brazilian Natl Canc Inst, Dept Epidemiol, Rio De Janeiro, Brazil. [Bloch, Michele] NCI, Bethesda, MD 20892 USA. RP Levy, D (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM dl777@georgetown.edu FU Tobacco Control Research Branch of the National Cancer Institute [HHSN261201000043C] FX The funding was in the form of a Scientific and Technical Support Contract (#HHSN261201000043C) from the Tobacco Control Research Branch of the National Cancer Institute. NR 53 TC 9 Z9 10 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 EI 1469-994X J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD NOV PY 2013 VL 15 IS 11 BP 1797 EP 1804 DI 10.1093/ntr/ntt073 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 252AY UT WOS:000326977900001 PM 23873977 ER PT J AU Mason, H DeRubeis, MB Foster, JC Taylor, JMG Worden, FP AF Mason, Heidi DeRubeis, Mary Beth Foster, Jared C. Taylor, Jeremy M. G. Worden, Francis P. TI Outcomes Evaluation of a Weekly Nurse Practitioner-Managed Symptom Management Clinic for Patients With Head and Neck Cancer Treated With Chemoradiotherapy SO ONCOLOGY NURSING FORUM LA English DT Article ID QUALITY-OF-LIFE AB Purpose/Objectives: To determine whether improved monitoring through close follow-up with a nurse practitioner (NP) could enhance treatment compliance and decrease frequency of hospitalizations. Design: Retrospective chart review Setting: An academic National Cancer Institute designated comprehensive cancer center. Sample: 151 patients aged 45-65 years diagnosed with stage III or IV oropharyngeal cancer. Methods: Patients were nonrandomized to one of two groups: a prechemotherapy clinic group and a weekly NP-led clinic group. After examination of descriptive statistics, multiple linear and logistic regressions were used to compare groups across patient outcomes. Main Research Variables: Hospitalization, chemotherapy dose deviations, and chemotherapy treatment completion. Findings: The average number of visits during traditional treatment was three and, after initiation of the NP-led clinic, the number was six. The hospitalization rate was 28% in the traditional clinic group compared to 12% in the NP-led group. The rate of chemotherapy dose deviations was 48% in the traditional clinic group compared to 6% in the NP-led clinic group. Forty-six percent of patients in the traditional clinic group received the full seven scheduled doses of chemotherapy compared to 90% of patients seen in the NP-led clinic group. Conclusions: A weekly NP-led symptom management clinic reduces rates of hospitalization and chemotherapy dose deviations and increases chemotherapy completion in patients receiving intensive chemoradiotherapy for oropharyngeal cancer. Implications for Nursing: Patients receiving chemoradiotherapy benefit from close monitoring for toxicities by NPs to successfully complete their treatment and avoid hospitalization. Knowledge Translation: Early interventions to manage toxicities in patients with head and neck cancer can improve outcomes. NPs are in a key position to manage these toxicities and, when symptoms are controlled, costs are reduced. C1 [Mason, Heidi; DeRubeis, Mary Beth; Taylor, Jeremy M. G.] Univ Michigan, Med Ctr, Ann Arbor, MI 48109 USA. [Foster, Jared C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. [Worden, Francis P.] Univ Michigan Hlth Syst, Hematol Oncol Fellowship Program, Ann Arbor, MI USA. RP Mason, H (reprint author), Univ Michigan, Med Ctr, Ann Arbor, MI 48109 USA. EM derubeist@att.net FU NCI NIH HHS [CA83654, T32 CA083654] NR 11 TC 7 Z9 7 U1 1 U2 4 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 BP 581 EP 586 DI 10.1188/13.ONF.40-06AP PG 6 WC Oncology; Nursing SC Oncology; Nursing GA 250IT UT WOS:000326847100011 PM 24007925 ER PT J AU Biesecker, BB Erby, LH Woolford, S Adcock, JY Cohen, JS Lamb, A Lewis, KV Truitt, M Turriff, A Reeve, BB AF Biesecker, Barbara B. Erby, Lori H. Woolford, Samuel Adcock, Jessica Young Cohen, Julie S. Lamb, Amanda Lewis, Katie V. Truitt, Megan Turriff, Amy Reeve, Bryce B. TI Development and validation of the Psychological Adaptation Scale (PAS): Use in six studies of adaptation to a health condition or risk SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Adaptation; The Psychological Adaptation Scale; Health threat of chronic condition or risk; Outcomes of coping ID ADJUSTMENT; STRESS; HOPE AB Objective: We introduce The Psychological Adaptation Scale (PAS) for assessing adaptation to a chronic condition or risk and present validity data from six studies of genetic conditions. Methods: Informed by theory, we identified four domains of adaptation: effective coping, self-esteem, social integration, and spiritual/existential meaning. Items were selected from the PROMIS "positive illness impact" item bank and adapted from the Rosenberg self-esteem scale to create a 20-item scale. Each domain included five items, with four sub-scale scores. Data from studies of six populations: adults affected with or at risk for genetic conditions (N = 3) and caregivers of children with genetic conditions (N = 3) were analyzed using confirmatory factor analyses (CFA). Results: CFA suggested that all but five posited items converge on the domains as designed. Invariance of the PAS amongst the studies further suggested it is a valid and reliable tool to facilitate comparisons of adaptation across conditions. Conclusion: Use of the PAS will standardize assessments of adaptation and foster understanding of the relationships among related health outcomes, such as quality of life and psychological well-being. Practice implications: Clinical interventions can be designed based on PAS data to enhance dimensions of psychological adaptation to a chronic health condition or risk. Published by Elsevier Ireland Ltd. C1 [Biesecker, Barbara B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Biesecker, Barbara B.; Erby, Lori H.] Johns Hopkins Bloomberg, Sch Publ Hlth, Hlth Behav & Soc, Baltimore, MD USA. [Woolford, Samuel] Boston Univ, Boston, MA 02215 USA. [Adcock, Jessica Young] Greater Baltimore Med Ctr, Baltimore, MD USA. [Cohen, Julie S.; Lewis, Katie V.] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Lamb, Amanda] Maine Med Ctr Canc Inst, Portland, ME USA. [Truitt, Megan] Columbia Univ, Med Ctr, New York, NY USA. [Turriff, Amy] NEI, NIH, Bethesda, MD 20892 USA. [Reeve, Bryce B.] Univ N Carolina, Chapel Hill, NC USA. RP Biesecker, BB (reprint author), NHGRI, Social & Behav Res Branch, NIH, 31 Ctr Dr,MSC 2173, Bethesda, MD 20892 USA. EM barbarab@mail.nih.gov FU National Human Genome Research Institute Intramural Research Program, National Institutes of Health FX This research was funded by the National Human Genome Research Institute Intramural Research Program, National Institutes of Health. We would like to thank Sara Rosenbloom and Sophia Garcia from the PROMIS consortium for their help in assessing psychometric performance of the items. NR 24 TC 10 Z9 10 U1 1 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD NOV PY 2013 VL 93 IS 2 BP 248 EP 254 DI 10.1016/j.pec.2013.05.006 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 251CJ UT WOS:000326905100012 PM 23993396 ER PT J AU Schnellbacher, C Ciocca, G Menendez, R Aksentijevich, I Goldbach-Mansky, R Duarte, AM Rivas-Chacon, R AF Schnellbacher, Charlotte Ciocca, Giovanna Menendez, Roxanna Aksentijevich, Ivona Goldbach-Mansky, Raphaela Duarte, Ana M. Rivas-Chacon, Rafael TI Deficiency of Interleukin-1 Receptor Antagonist Responsive to Anakinra SO PEDIATRIC DERMATOLOGY LA English DT Article ID AUTOINFLAMMATORY DISEASE AB We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. C1 [Schnellbacher, Charlotte] Miami Childrens Hosp, Div Pediat, Miami, FL 33155 USA. [Ciocca, Giovanna; Duarte, Ana M.] Miami Childrens Hosp, Div Dermatol, Miami, FL 33155 USA. [Goldbach-Mansky, Raphaela] Miami Childrens Hosp, Div Rheumatol, Miami, FL 33155 USA. [Menendez, Roxanna; Rivas-Chacon, Rafael] Nova SE Univ, Columbia Hosp, Div Dermatol, W Palm Beach, FL USA. [Aksentijevich, Ivona] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ciocca, G (reprint author), Miami Childrens Hosp, Div Dermatol, 3100 SW 62nd Ave, Miami, FL 33155 USA. EM giovannaciocca@bellsouth.net FU Intramural NIH HHS [ZIA AR041138-08] NR 5 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD NOV PY 2013 VL 30 IS 6 BP 758 EP 760 DI 10.1111/j.1525-1470.2012.01725.x PG 3 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 251YA UT WOS:000326969100089 PM 22471702 ER PT J AU Firoz, EF Turnbull, RK Loomis, CA Brownell, I AF Firoz, Elnaz F. Turnbull, Rowena K. Loomis, Cynthia A. Brownell, Isaac TI Allergic Contact Dermatitis to Gamma-Irradiated WEBCOL Alcohol Prep Pads SO PEDIATRIC DERMATOLOGY LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; VOLATILE RADIOLYSIS PRODUCTS; ISOPROPYL-ALCOHOL; DISINFECTANT SWAB AB We report a case of allergic contact dermatitis to WEBCOL (R) alcohol prep pads in a healthy 17-year-old girl who showed no reaction to the individual components of the prep pads upon provocative use testing. Although several case reports have described allergic contact dermatitis to isopropyl alcohol, there have been no reports of allergic contact dermatitis to alcohol prep pads sterilized with gamma irradiation, a common sterilization technique capable of producing volatile products in this type of alcohol prep pad. C1 [Firoz, Elnaz F.] Brown Univ, Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. [Turnbull, Rowena K.; Loomis, Cynthia A.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Brownell, Isaac] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Brownell, I (reprint author), NCI, Bldg 10 Magnuson Clin Ctr,Room 12N246,10 Ctr Dr, Bethesda, MD 20892 USA. EM isaac.brownell@nih.gov NR 14 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-8046 EI 1525-1470 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD NOV PY 2013 VL 30 IS 6 BP E281 EP E282 DI 10.1111/j.1525-1470.2012.01727.x PG 2 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 251YA UT WOS:000326969100058 PM 22471753 ER PT J AU Bjorge, T Sorensen, HT Grotmol, T Engeland, A Stephansson, O Gissler, M Tretli, S Troisi, R AF Bjorge, Tone Sorensen, Henrik Toft Grotmol, Tom Engeland, Anders Stephansson, Olof Gissler, Mika Tretli, Steinar Troisi, Rebecca TI Fetal Growth and Childhood Cancer: A Population-Based Study SO PEDIATRICS LA English DT Article DE birth weight; childhood cancer; fetal growth; nested case-control study; Nordic countries ID BIRTH-WEIGHT; GESTATIONAL-AGE; QUALITY-CONTROL; WILMS-TUMORS; RISK-FACTORS; CNS TUMORS; CHILDREN; REGISTER; LEUKEMIA; NORWAY AB OBJECTIVE: The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth. METHODS: We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17 698 cases and 172 422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression. RESULTS: Risks of all childhood cancers increased with increasing birth weight (P-trend <=.001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2-3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1-4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1-3.1]). Children diagnosed with central nervous system tumors at,1 year of age had elevated risk with increasing head circumference (P-trend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5-8.7]). CONCLUSIONS: In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero. C1 [Bjorge, Tone; Engeland, Anders] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. [Bjorge, Tone; Engeland, Anders] Norwegian Inst Publ Hlth, Bergen, Norway. [Sorensen, Henrik Toft] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. [Grotmol, Tom; Tretli, Steinar] Canc Registry Norway, Oslo, Norway. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. [Stephansson, Olof] Karolinska Univ Hosp & Inst, Div Obstet & Gynecol, Dept Women & Childrens Hlth, Stockholm, Sweden. [Gissler, Mika] Natl Inst Hlth & Welf THL, Helsinki, Finland. [Gissler, Mika] Nord Sch Publ Hlth NHV, Gothenburg, Sweden. [Troisi, Rebecca] NCI, Div Canc Epidemiol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca] NCI, Div Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bjorge, T (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5020 Bergen, Norway. EM tone.bjorge@igs.uib.no FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services; National Institutes of Health (NIH) FX This research was funded by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. Funded by the National Institutes of Health (NIH). NR 35 TC 12 Z9 13 U1 0 U2 3 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 NOV PY 2013 VL 132 IS 5 BP E1265 EP E1275 DI 10.1542/peds.2013-1317 PG 11 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000018 PM 24167169 ER PT J AU Lionetti, G Kimura, Y Schanberg, LE Beukelman, T Wallace, CA Ilowite, NT Winsor, J Fox, K Natter, M Sundy, JS Brodsky, E Curtis, JR Del Gaizo, V Iyasu, S Jahreis, A Meeker-O'Connell, A Mittleman, BB Murphy, BM Peterson, ED Raymond, SC Setoguchi, S Siegel, JN Sobel, RE Solomon, D Southwood, TR Vesely, R White, PH Wulffraat, NM Sandborg, CI AF Lionetti, Geraldina Kimura, Yukiko Schanberg, Laura E. Beukelman, Timothy Wallace, Carol A. Ilowite, Norman T. Winsor, Jane Fox, Kathleen Natter, Marc Sundy, John S. Brodsky, Eric Curtis, Jeffrey R. Del Gaizo, Vincent Iyasu, Solomon Jahreis, Angelika Meeker-O'Connell, Ann Mittleman, Barbara B. Murphy, Bernard M. Peterson, Eric D. Raymond, Sandra C. Setoguchi, Soko Siegel, Jeffrey N. Sobel, Rachel E. Solomon, Daniel Southwood, Taunton R. Vesely, Richard White, Patience H. Wulffraat, Nico M. Sandborg, Christy I. TI Using Registries to Identify Adverse Events in Rheumatic Diseases SO PEDIATRICS LA English DT Article DE medication safety; immunomodulatory therapy; biologic products; juvenile rheumatic disease ID JUVENILE IDIOPATHIC ARTHRITIS; CROSS-SECTIONAL ANALYSIS; LONG-TERM SAFETY; CHILDHOOD ARTHRITIS; CARRA REGISTRY; CHILDREN; ETANERCEPT; METHOTREXATE; MALIGNANCY; DRUGS AB The proven effectiveness of biologics and other immunomodulatory products in inflammatory rheumatic diseases has resulted in their widespread use as well as reports of potential short-and long-term complications such as infection and malignancy. These complications are especially worrisome in children who often have serial exposures to multiple immunomodulatory products. Post-marketing surveillance of immunomodulatory products in juvenile idiopathic arthritis (JIA) and pediatric systemic lupus erythematosus is currently based on product-specific registries and passive surveillance, which may not accurately reflect the safety risks for children owing to low numbers, poor long-term retention, and inadequate comparators. In collaboration with the US Food and Drug Administration (FDA), patient and family advocacy groups, biopharmaceutical industry representatives and other stakeholders, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Duke Clinical Research Institute (DCRI) have developed a novel pharmacosurveillance model (CARRA Consolidated Safety Registry [CoRe]) based on a multi-center longitudinal pediatric rheumatic diseases registry with over 8000 participants. The existing CARRA infrastructure provides access to much larger numbers of subjects than is feasible in single-product registries. Enrollment regardless of medication exposure allows more accurate detection and evaluation of safety signals. Flexibility built into the model allows the addition of specific data elements and safety outcomes, and designation of appropriate disease comparator groups relevant to each product, fulfilling post-marketing requirements and commitments. The proposed model can be applied to other pediatric and adult diseases, potentially transforming the paradigm of pharmacosurveillance in response to the growing public mandate for rigorous post-marketing safety monitoring. C1 [Lionetti, Geraldina; Sandborg, Christy I.] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Kimura, Yukiko] Hackensack Univ Med Ctr, Joseph M Sanzari Childrens Hosp, Dept Pediat, Hackensack, NJ 07601 USA. [Schanberg, Laura E.] Duke Univ Med Ctr, Dept Pediat, Durham, NC USA. [Beukelman, Timothy; Curtis, Jeffrey R.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Wallace, Carol A.] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Ilowite, Norman T.] Childrens Hosp Montefiore, Dept Pediat, Bronx, NY USA. [Winsor, Jane; Fox, Kathleen; Sundy, John S.; Peterson, Eric D.; Setoguchi, Soko] Duke Clin Res Inst, Durham, NC USA. [Natter, Marc] Boston Childrens Hosp, Dept Pediat, Boston, MA USA. [Brodsky, Eric; Iyasu, Solomon; Meeker-O'Connell, Ann] US FDA, Silver Spring, MD USA. [Del Gaizo, Vincent] Friends Childhood Arthrit & Rheumatol Res Allianc, Whitehouse Stn, NJ USA. [Jahreis, Angelika; Siegel, Jeffrey N.] Genentech Inc, San Francisco, CA 94080 USA. [Mittleman, Barbara B.] NIH, Bethesda, MD 20892 USA. [Murphy, Bernard M.; White, Patience H.] Arthrit Fdn, Atlanta, GA USA. [Raymond, Sandra C.] Lupus Fdn Amer, Washington, DC USA. [Sobel, Rachel E.] Pfizer Inc, New York, NY USA. [Solomon, Daniel] Brigham & Womens Hosp, Dept Rheumatol, Boston, MA 02115 USA. [Southwood, Taunton R.] Univ Birmingham, Sch Immun & Infect, Birmingham, W Midlands, England. [Vesely, Richard] European Med Agcy, London, England. [Wulffraat, Nico M.] Univ Med Ctr Utrecht, Dept Pediat, Utrecht, Netherlands. RP Kimura, Y (reprint author), Hackensack Univ Med Ctr, Joseph M Sanzari Childrens Hosp, 30 Prospect Ave, Hackensack, NJ 07601 USA. EM YKimura@HackensackUMC.org OI Sobel, Rachel/0000-0002-4492-9562 FU NIH [AR063890]; NIH ARRA [AR058934]; Arthritis Foundation; Friends of CARRA; National Institutes of Health (NIH) FX Supported in part by NIH grant AR063890 and NIH ARRA grant AR058934, Arthritis Foundation, Friends of CARRA, and contributions from Abbott Laboratories, Amgen, Inc, Bristol Myers Squibb Company, Genentech, Inc, Human Genome Sciences, Inc, Novartis Pharmaceuticals, and Pfizer, Inc. Funded by the National Institutes of Health (NIH). NR 30 TC 6 Z9 6 U1 0 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 NOV PY 2013 VL 132 IS 5 BP E1384 EP E1394 DI 10.1542/peds.2013-0755 PG 11 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000030 PM 24144710 ER PT J AU Spergel, AR Walkovich, K Price, S Niemela, JE Wright, D Fleisher, TA Rao, VK AF Spergel, Amanda Rudman Walkovich, Kelly Price, Susan Niemela, Julie E. Wright, Dowain Fleisher, Thomas A. Rao, V. Koneti TI Autoimmune Lymphoproliferative Syndrome Misdiagnosed as Hemophagocytic Lymphohistiocytosis SO PEDIATRICS LA English DT Article DE cytopenias; splenomegaly; lymphadenopathy; HLH; ALPS; apoptosis ID SOMATIC FAS MUTATIONS; DIAGNOSIS; CHILDREN AB Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder of apoptosis, most commonly due to mutations in the FAS (TNFRSF6) gene. It presents with chronic lymphadenopathy, splenomegaly, and symptomatic multilineage cytopenias in an otherwise healthy child. Unfortunately, these clinical findings are also noted in other childhood lymphoproliferative conditions, such as leukemia, lymphoma, and hemophagocytic lymphohistiocytosis, which can confound the diagnosis. This report describes a 6-year-old girl with symptoms misdiagnosed as hemophagocytic lymphohistiocytosis and treated with chemotherapy before the recognition that her symptoms and laboratory values were consistent with a somatic FAS mutation leading to ALPS. This case should alert pediatricians to include ALPS in the differential diagnosis of a child with lymphadenopathy, splenomegaly, and cytopenias; obtain discriminating screening laboratory biomarkers, such as serum vitamin B-12 and ferritin levels; and, in the setting of a highly suspicious clinical scenario for ALPS, pursue testing for somatic FAS mutations when germ-line mutation testing is negative. C1 [Spergel, Amanda Rudman; Price, Susan; Rao, V. Koneti] NIAID, ALPS Unit, Immunol Lab, Bethesda, MD 20892 USA. [Niemela, Julie E.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Walkovich, Kelly] Univ Michigan, Div Pediat Hematol Oncol, Ann Arbor, MI 48109 USA. [Wright, Dowain] Childrens Hosp Cent Calif, Div Rheumatol & Immunol, Madera, CA USA. RP Rao, VK (reprint author), NIAID, ALPS Unit, LI, NIH,DHHS, Room 12C106,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM krao@niaid.nih.gov OI Niemela, Julie/0000-0003-4197-3792 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health Clinical Center; National Institutes of Health (NIH) FX The Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institutes of Health Clinical Center supported this research. Funded by the National Institutes of Health (NIH). NR 14 TC 9 Z9 9 U1 0 U2 3 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 NOV PY 2013 VL 132 IS 5 BP E1440 EP E1444 DI 10.1542/peds.2012-2748 PG 5 WC Pediatrics SC Pediatrics GA 245PE UT WOS:000326475000038 ER PT J AU Hosgood, HD Pao, W Rothman, N Hu, W Pan, YH Kuchinsky, K Jones, KD Xu, J Vermeulen, R Simko, J Lan, Q AF Hosgood, H. Dean, III Pao, William Rothman, Nathaniel Hu, Wei Pan, Yumei Helen Kuchinsky, Kyle Jones, Kirk D. Xu, Jun Vermeulen, Roel Simko, Jeff Lan, Qing TI Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning SO RESPIRATORY MEDICINE LA English DT Article DE EGFR; KRAS; Lung cancer; Never smoking; China; Driver mutations ID POLYCYCLIC AROMATIC-HYDROCARBONS; MAMMARY-CARCINOMA CELLS; FACTOR RECEPTOR GENE; XUAN-WEI; COMBUSTION EMISSIONS; SOMATIC MUTATIONS; EXPOSURE; SMOKERS; WOMEN; ADENOCARCINOMA AB Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Hosgood, H. Dean, III; Rothman, Nathaniel; Hu, Wei; Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Hosgood, H. Dean, III] Albert Einstein Coll Med, Div Epidemiol, Bronx, NY 10461 USA. [Pao, William; Pan, Yumei Helen] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA. [Kuchinsky, Kyle; Jones, Kirk D.; Simko, Jeff] Univ Calif San Francisco, Dept Anat Pathol, San Francisco, CA 94143 USA. [Xu, Jun] Univ Hong Kong, Sch Publ Hlth, Dept Community Med, Hong Kong, Hong Kong, Peoples R China. [Vermeulen, Roel] Univ Utrecht, Utrecht, Netherlands. RP Hosgood, HD (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Div Epidemiol, 1300 Morris Pk Ave,Belfer 1309, Bronx, NY 10461 USA. EM dean.hosgood@einstein.yu.edu RI Hu, Wei/M-3524-2013; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU The Intramural National Cancer Institute program [N01-CO-12400]; [R01-CA121210] FX Funding: The Intramural National Cancer Institute (N01-CO-12400) program funded the work. WP was also funded through R01-CA121210. NR 36 TC 6 Z9 7 U1 0 U2 18 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD NOV PY 2013 VL 107 IS 11 BP 1755 EP 1762 DI 10.1016/j.rmed.2013.08.018 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 255HU UT WOS:000327230800014 PM 24055406 ER PT J AU Weir, CH Yeatts, KB Sarnat, JA Vizuete, W Salo, PM Jaramillo, R Cohn, RD Chu, HT Zeldin, DC London, SJ AF Weir, Charles H. Yeatts, Karin B. Sarnat, Jeremy A. Vizuete, William Salo, Paivi M. Jaramillo, Renee Cohn, Richard D. Chu, Haitao Zeldin, Darryl C. London, Stephanie J. TI Nitrogen dioxide and allergic sensitization in the 2005-2006 National Health and Nutrition Examination Survey SO RESPIRATORY MEDICINE LA English DT Article DE Air pollution; Allergic; Sensitization; Epidemiology; NHANES; IgE ID LONG-TERM EXPOSURE; AIR-POLLUTION; RESPIRATORY SYMPTOMS; CHILDREN; ASTHMA; ATOPY; SCHOOLCHILDREN; POPULATION; POLLUTANTS; RESPONSES AB Background: Allergic sensitization is a risk factor for asthma and allergic diseases. The relationship between ambient air pollution and allergic sensitization is unclear. Objective: To investigate the relationship between ambient air pollution and allergic sensitization in a nationally representative sample of the US population. Methods: We linked annual average concentrations of nitrogen dioxide (NO2), particulate matter <= 10 mu m (PM10), particulate matter <= 2.5 mu m (PM2.5), and summer concentrations of ozone (03), to allergen-specific immunoglobulin E (IgE) data for participants in the 2005-2006 National Health and Nutrition Examination Survey (NHANES). In addition to the monitor-based air pollution estimates, we used the Community Multiscale Air Quality (CMAQ) model to increase the representation of rural participants in our sample. Logistic regression with population-based sampling weights was used to calculate adjusted prevalence odds ratios per 10 ppb increase in O-3 and NO2, per 10 mu g/m(3) increase in PM10, and per 5 mu g/m(3) increase in PM2.5 adjusting for race, gender, age, socioeconomic status, smoking, and urban/rural status. Results: Using CMAQ data, increased levels of NO2 were associated with positive IgE to any (OR 1.15, 95% CI 1.04, 1.27), inhalant (OR 1.17, 95% CI 1.02, 1.33), and indoor (OR 1.16, 95% CI 1.03, 1.31) allergens. Higher PM2.5 levels were associated with positivity to indoor allergen-specific IgE (OR 1.24, 95% CI 1.13, 1.36). Effect estimates were similar using monitored data. Conclusions: Increased ambient NO2 was consistently associated with increased prevalence of allergic sensitization. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Weir, Charles H.; Vizuete, William] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC USA. [Yeatts, Karin B.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Sarnat, Jeremy A.] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Jaramillo, Renee; Cohn, Richard D.] SRA Int Inc, Durham, NC USA. [Chu, Haitao] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Yeatts, KB (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. EM Karin_Yeatts@unc.edu RI Mashamba-Thompson, Tivani /B-6087-2014; OI Chu, Haitao/0000-0003-0932-598X; vizuete, william/0000-0002-1399-2948; London, Stephanie/0000-0003-4911-5290 FU Division of Health Studies Agency for Toxic Substances and Disease Registry; Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, DHHS FX This research was supported in part by Division of Health Studies Agency for Toxic Substances and Disease Registry, and the Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, DHHS. The findings and conclusions in this article are those of the authors and do not represent the views of the National Center for Environmental Health/Agency for Toxic Substances and Disease Registry or National Institute of Environmental Health Sciences. NR 49 TC 9 Z9 9 U1 1 U2 21 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD NOV PY 2013 VL 107 IS 11 BP 1763 EP 1772 DI 10.1016/j.rmed.2013.08.010 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 255HU UT WOS:000327230800015 PM 24045117 ER PT J AU Rosansky, SJ Cancarini, G Clark, WF Eggers, P Germaine, M Glassock, R Goldfarb, DS Harris, D Hwang, SJ Imperial, EB Johansen, KL Kalantar-Zadeh, K Moist, LM Rayner, B Steiner, R Zuo, L AF Rosansky, Steven J. Cancarini, Giovanni Clark, William F. Eggers, Paul Germaine, Michael Glassock, Richard Goldfarb, David S. Harris, David Hwang, Shang-Jyh Imperial, Edwina Brown Johansen, Kirsten L. Kalantar-Zadeh, Kamyar Moist, Louise M. Rayner, Brian Steiner, Robert Zuo, Li TI Dialysis Initiation: What's the Rush? SO SEMINARS IN DIALYSIS LA English DT Article ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; QUALITY-OF-LIFE; NATIONAL COOPERATIVE DIALYSIS; HEMODIALYSIS-PATIENTS; PERITONEAL-DIALYSIS; MAINTENANCE HEMODIALYSIS; NUTRITIONAL PARAMETERS; STARTING DIALYSIS; MEMBRANE FLUX AB The recent trend to early initiation of dialysis (at eGFR >10ml/min/1.73m(2)) appears to have been based on conventional wisdoms that are not supported by evidence. Observational studies using administrative databases report worse comorbidity-adjusted dialysis survival with early dialysis initiation. Although some have concluded that the IDEAL randomized controlled trial of dialysis start provided evidence that patients become symptomatic with late dialysis start, there is no definitive support for this view. The potential harms of early start of dialysis, including the loss of residual renal function (RRF), have been well documented. The rate of RRF loss (renal function trajectory) is an important consideration for the timing of the dialysis initiation decision. Patients with low glomerular filtration rate (GFR) may have sufficient RRF to be maintained off dialysis for years. Delay of dialysis start until a working arterio-venous access is in place seems prudent in light of the lack of harm and possible benefit of late dialysis initiation. Prescribing frequent hemodialysis is not recommended when dialysis is initiated early. The benefits of early initiation of chronic dialysis after episodes of congestive heart failure or acute kidney injury require further study. There are no data to show that early start benefits diabetics or other patient groups. Preemptive start of dialysis in noncompliant patients may be necessary to avoid complications. The decision to initiate dialysis requires informed patient consent and a joint decision by the patient and dialysis provider. Possible talking points for obtaining informed consent are provided. C1 [Rosansky, Steven J.] Univ SC, Sch Publ Hlth, WJBDVA Hosp, Dorn Res Inst, Columbia, SC USA. [Cancarini, Giovanni] AO Spedali Civili, OU Nephrol, Brescia, Italy. [Cancarini, Giovanni] Univ Brescia, Brescia, Italy. [Clark, William F.] Western Univ Canada, London Hlth Sci Ctr, London, ON, Canada. [Eggers, Paul] NIDDK, Bethesda, MD 20892 USA. [Germaine, Michael] Tufts Univ, Sch Med, Baystate Med Ctr, Springfield, MA 01199 USA. [Glassock, Richard] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Goldfarb, David S.] New York Harbor VA Healthcare Syst, Langone Med Ctr, Nephrol Sect, New York, NY USA. [Goldfarb, David S.] NYU, New York, NY USA. [Harris, David] Univ Sydney, Westmead Millennium Inst, Sydney, Australia. [Hwang, Shang-Jyh] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Div Nephrol, Kaohsiung, Taiwan. [Imperial, Edwina Brown] Hammersmith Hosp, Renal & Transplant Ctr, London, England. [Johansen, Kirsten L.] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Nephrol Sect, San Francisco, CA USA. [Kalantar-Zadeh, Kamyar] Univ Calif Irvine, Sch Med, UC Irvine Med Ctr, Div Nephrol & Hypertens, Irvine, CA USA. [Moist, Louise M.] Univ Western Ontario, Schulich Sch Med & Dent, London Hlth Sci Ctr, Kidney Clin Res Unit, London, ON, Canada. [Rayner, Brian] Groote Schuur Hosp, Div Nephrol & Hypertens, ZA-7925 Cape Town, South Africa. [Rayner, Brian] Univ Cape Town, ZA-7925 Cape Town, South Africa. [Steiner, Robert] Univ Calif San Diego, San Diego Med Ctr, San Diego, CA 92103 USA. [Zuo, Li] Peking Univ, Hosp 1, Inst Nephrol, Renal Div,Key Lab,Minist Hlth, Beijing, Peoples R China. RP Rosansky, SJ (reprint author), Dorn Res Inst, 526 N Trenholm Rd, Columbia, SC 29206 USA. EM sjrcra@yahoo.com OI Rayner, Brian/0000-0002-0167-9591; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725; Goldfarb, David/0000-0002-9215-1273 NR 73 TC 15 Z9 15 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 650 EP 657 DI 10.1111/sdi.12134 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200005 PM 24066675 ER PT J AU Cohen, SD Kimmel, PL AF Cohen, Scott D. Kimmel, Paul L. TI Quality of Life and Mental Health Related to Timing, Frequency and Dose of Hemodialysis SO SEMINARS IN DIALYSIS LA English DT Article ID STAGE RENAL-DISEASE; DIALYSIS PATIENTS; BEHAVIORAL COMPLIANCE; MAINTENANCE DIALYSIS; PSYCHOSOCIAL FACTORS; PRACTICE PATTERNS; DEPRESSION; ADJUSTMENT; DIAGNOSIS; OUTCOMES AB The perceived quality of life (QOL) and mental health of dialysis patients can have a significant impact on clinical outcomes in the end-stage renal disease (ESRD) population. There is growing interest in increasing dialysis frequency, dose and duration to achieve more adequate dialysis clearance, particularly of middle molecules. Over the past decade, there has been an interest in earlier initiation of dialysis; however, the results of the IDEAL study call this practice into question, and showed no difference in QOL scores between the early-start and later start dialysis patients. There are inconsistent results regarding the impact of increased dialysis frequency and dose on patients' perceived health-related QOL (HRQOL). Some studies of daily nocturnal dialysis patients show a positive impact on QOL, while others show no significant difference. The disparate outcomes may be partly related to differences in the demographic characteristics of the study populations and the specific questionnaires used to measure HRQOL. Additional research is necessary to determine whether changes in dialysis frequency, timing, and dose can positively or negatively impact patients' perceptions of their QOL and mental health. C1 [Cohen, Scott D.; Kimmel, Paul L.] George Washington Univ, Div Renal Dis & Hypertens, Washington, DC 20037 USA. [Kimmel, Paul L.] Natl Inst Diabet & Digest & Kidney Dis, Div Kidney Urol & Hematol Dis, Washington, DC USA. RP Cohen, SD (reprint author), George Washington Univ, Med Fac Associates, Div Renal Dis & Hypertens, 2150 Penn Ave,Suite 3-438, Washington, DC 20037 USA. EM scohen@mfa.gwu.edu NR 40 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV PY 2013 VL 26 IS 6 BP 697 EP 701 DI 10.1111/sdi.12124 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 252SK UT WOS:000327030200011 PM 24067246 ER PT J AU Beach, SR Chen, DT Huffman, JC AF Beach, Scott Richard Chen, Donna T. Huffman, Jeff C. TI Attitudes and Beliefs of Trainees and Nurses Regarding Delirium in the Intensive Care Unit SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID CONFUSION ASSESSMENT METHOD; EDUCATION; PROFESSIONALS; KNOWLEDGE; ICU C1 [Beach, Scott Richard; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Chen, Donna T.] NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Beach, SR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM sbeach1@partners.org NR 15 TC 1 Z9 1 U1 3 U2 11 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 EI 1545-7230 J9 ACAD PSYCHIATR JI Acad. Psych. PD NOV-DEC PY 2013 VL 37 IS 6 BP 436 EP 438 PG 3 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 246TH UT WOS:000326561500017 PM 24185295 ER PT J AU Simmler, C Fronczek, FR Pauli, GF Santarsiero, BD AF Simmler, Charlotte Fronczek, Frank R. Pauli, Guido F. Santarsiero, Bernard D. TI Absolute configuration of naturally occurring glabridin SO ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS LA English DT Article DE crystal structure; absolute configuration; glabridin; natural compounds ID LICORICE ROOT; GLYCYRRHIZA-GLABRA; ISOFLAVAN; (+/-)-GLABRIDIN; FLAVONOIDS; AVERAGES AB The title compound {systematic name: 4-[(3R)-8,8-dimethyl-3,4-dihydro-2H-pyrano[2,3-f]chromen-3-yl]benzene-1,3-diol, commonly named glabridin}, C20H20O4, is a species-specific biomarker from the roots Glycyrrhiza glabra L. (European licorice, Fabaceae). In the present study, this prenylated isoflavan has been purified from an enriched CHCl3 fraction of the extract of the root, using three steps of medium-pressure liquid chromatography (MPLC) by employing HW-40F, Sephadex LH-20 and LiChroCN as adsorbents. Pure glabridin was crystallized from an MeOH-H2O mixture (95:5v/v) to yield colorless crystals containing one molecule per asymmetric unit (Z = 1) in the space group P212121. Although the crystal structure has been reported before, the determination of the absolute configuration remained uncertain. Stereochemical analysis, including circular dichroism, NMR data and an X-ray diffraction data set with Bijvoet differences, confirms that glabridin, purified from its natural source, is found only in a C3 R configuration. These results can therefore be used as a reference for the assignment of the configuration and enantiopurity of any isolated or synthetic glabridin sample. C1 [Simmler, Charlotte; Pauli, Guido F.; Santarsiero, Bernard D.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Simmler, Charlotte; Pauli, Guido F.] Univ Illinois, Coll Pharm, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. [Fronczek, Frank R.] Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. [Santarsiero, Bernard D.] Univ Illinois, Coll Pharm, Ctr Pharmaceut Biotechnol, Chicago, IL 60607 USA. RP Santarsiero, BD (reprint author), Univ Illinois, Coll Pharm, Ctr Pharmaceut Biotechnol, MC-870,900 S Ashland Ave, Chicago, IL 60607 USA. EM bds@uic.edu OI Pauli, Guido/0000-0003-1022-4326; Simmler, Charlotte/0000-0002-6923-2630 FU NCCAM; ODS [P50 AT000155]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; [LEQSF(2011-12)-ENH-TR-01] FX This research was supported by NCCAM and ODS through grant No. P50 AT000155. The authors acknowledge use of the Life Sciences Collaborative Access Team (LS-CAT) beamline 21-ID-D for the initial data collection; 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. Upgrade of the diffractometer was made possible by grant No. LEQSF(2011-12)-ENH-TR-01, administered by the Louisiana Board of Regents. Finally, we thank Dr Jose Napolitano, UIC Chicago (Illinois), and Matthias Niemitz, Perch Solutions Ltd, Kuopio (Finland), for helpful NMR discussions and PERCH support. NR 30 TC 0 Z9 0 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0108-2701 EI 1600-5759 J9 ACTA CRYSTALLOGR C JI Acta Crystallogr. Sect. C-Cryst. Struct. Commun. PD NOV PY 2013 VL 69 SI SI BP 1212 EP + DI 10.1107/S0108270113018842 PN 11 PG 12 WC Chemistry, Multidisciplinary; Crystallography SC Chemistry; Crystallography GA 247VR UT WOS:000326651300003 PM 24192160 ER PT J AU Olsson, AC Xu, YW Schuz, J Vlaanderen, J Kromhout, H Vermeulen, R Peters, S Stucker, I Guida, F Bruske, I Wichmann, HE Consonni, D Landi, MT Caporaso, N Tse, LA Yu, ITS Siemiatycki, J Richardson, L Mirabelli, D Richiardi, L Simonato, L Gustavsson, P Plato, N Jockel, KH Ahrens, W Pohlabeln, H Tardon, A Zaridze, D Marcus, MW 't Mannetje, A Pearce, N McLaughlin, J Demers, P Szeszenia-Dabrowska, N Lissowska, J Rudnai, P Fabianova, E Dumitru, RS Bencko, V Foretova, L Janout, V Boffetta, P Fortes, C Bueno-de-Mesquita, B Kendzia, B Behrens, T Pesch, B Bruning, T Straif, K AF Olsson, Ann C. Xu, Yiwen Schuez, Joachim Vlaanderen, Jelle Kromhout, Hans Vermeulen, Roel Peters, Susan Stuecker, Isabelle Guida, Florence Brueske, Irene Wichmann, Heinz-Erich Consonni, Dario Landi, Maria Teresa Caporaso, Neil Tse, Lap Ah Yu, Ignatius Tak-sun Siemiatycki, Jack Richardson, Lesley Mirabelli, Dario Richiardi, Lorenzo Simonato, Lorenzo Gustavsson, Per Plato, Nils Joeckel, Karl-Heinz Ahrens, Wolfgang Pohlabeln, Hermann Tardon, Adonina Zaridze, David Marcus, Michael W. 't Mannetje, Andrea Pearce, Neil McLaughlin, John Demers, Paul Szeszenia-Dabrowska, Neonila Lissowska, Jolanta Rudnai, Peter Fabianova, Eleonora Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Boffetta, Paolo Fortes, Cristina Bueno-de-Mesquita, Bas Kendzia, Benjamin Behrens, Thomas Pesch, Beate Bruning, Thomas Straif, Kurt TI Lung Cancer Risk Among Hairdressers: A Pooled Analysis of Case-Control Studies Conducted Between 1985 and 2010 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; hair bleaching agents; hair color; lung neoplasms; occupational exposure ID DNA-REPAIR GENES; OCCUPATIONAL-EXPOSURE; CASE-REFERENT; POPULATION; GERMANY; EUROPE; MEN; POLYMORPHISMS; CONSORTIUM; DISEASES AB Increased lung cancer risks among hairdressers were observed in large registry-based cohort studies from Scandinavia, but these studies could not adjust for smoking. Our objective was to evaluate the lung cancer risk among hairdressers while adjusting for smoking and other confounders in a pooled database of 16 case-control studies conducted in Europe, Canada, China, and New Zealand between 1985 and 2010 (the Pooled Analysis of Case-Control Studies on the Joint Effects of Occupational Carcinogens in the Development of Lung Cancer). Lifetime occupational and smoking information was collected through interviews with 19,369 cases of lung cancer and 23,674 matched population or hospital controls. Overall, 170 cases and 167 controls had ever worked as hairdresser or barber. The odds ratios for lung cancer in women were 1.65 (95 confidence interval (CI): 1.16, 2.35) without adjustment for smoking and 1.12 (95 CI: 0.75, 1.68) with adjustment for smoking; however, women employed before 1954 also experienced an increased lung cancer risk after adjustment for smoking (odds ratio 2.66, 95 CI: 1.09, 6.47). The odds ratios in male hairdressers/barbers were generally not elevated, except for an increased odds ratio for adenocarcinoma in long-term barbers (odds ratio 2.20, 95 CI: 1.02, 4.77). Our results suggest that the increased lung cancer risks among hairdressers are due to their smoking behavior; single elevated risk estimates should be interpreted with caution and need replication in other studies. C1 [Olsson, Ann C.; Xu, Yiwen; Schuez, Joachim; Vlaanderen, Jelle; Straif, Kurt] Int Agcy Res Canc, F-69372 Lyon, France. [Olsson, Ann C.; Gustavsson, Per; Plato, Nils] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Kromhout, Hans; Vermeulen, Roel; Peters, Susan] Inst Risk Assessment Sci, Utrecht, Netherlands. [Peters, Susan] Western Australian Inst Med Res, Perth, WA, Australia. [Stuecker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Environm Epidemiol Canc Team, U1018, F-94807 Villejuif, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris Sud, UMRS 1018, F-94807 Villejuif, France. [Brueske, Irene; Wichmann, Heinz-Erich] Inst Epidemiol I, Deutsch Forschungszentrum Gesundheit & Umwelt, Neuherberg, Germany. [Consonni, Dario] Osped Maggiore Policlin, Fdn Ist Ricovero & Cura Carattere Sci IRCCS CaGra, Epidemiol Unit, Milan, Italy. [Landi, Maria Teresa; Caporaso, Neil] NCI, Bethesda, MD 20892 USA. [Tse, Lap Ah; Yu, Ignatius Tak-sun] Chinese Univ Hong Kong, Sch Publ Hlth & Primary Care, Div Occupat & Environm Hlth, Hong Kong, Hong Kong, Peoples R China. [Siemiatycki, Jack; Richardson, Lesley] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Consonni, Dario; Richiardi, Lorenzo] Univ Turin, Canc Epidemiol Unit, Dept Med Sci, Turin, Italy. [Simonato, Lorenzo] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Joeckel, Karl-Heinz] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Ahrens, Wolfgang; Pohlabeln, Hermann] Bremen Inst Prevent Res & Social Med, Bremen, Germany. [Tardon, Adonina] Univ Oviedo, Ctr Biomed Res, Network Epidemiol & Publ Hlth CIBERESP, Oviedo, Spain. [Zaridze, David] Russian Canc Res Ctr, Moscow, Russia. [Marcus, Michael W.] Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool L69 3BX, Merseyside, England. ['t Mannetje, Andrea; Pearce, Neil] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [McLaughlin, John; Demers, Paul] Occupat Canc Res Ctr, Toronto, ON, Canada. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Dumitru, Rodica Stanescu] Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, CR-77147 Olomouc, Czech Republic. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Fortes, Cristina] IRCCS, IDI, Clin Epidemiol Unit, Rome, Italy. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm Protect RIVM, Bilthoven, Netherlands. [Kendzia, Benjamin; Behrens, Thomas; Pesch, Beate; Bruning, Thomas] Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance Inst, Bochum, Germany. RP Olsson, AC (reprint author), Int Agcy Res Canc, Environm & Radiat Sect, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM olssona@iarc.fr RI Bruske, Irene/N-3125-2013; Yu, Ignatius Tak Sun/A-9936-2008; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bruning, Thomas/G-8120-2015; Consonni, Dario/K-7943-2016; Vermeulen, Roel/F-8037-2011; OI Ahrens, Wolfgang/0000-0003-3777-570X; Bruning, Thomas/0000-0001-9560-5464; Consonni, Dario/0000-0002-8935-3843; Vermeulen, Roel/0000-0003-4082-8163; Pearce, Neil/0000-0002-9938-7852; Peters, Susan/0000-0001-5662-1971; richiardi, lorenzo/0000-0003-0316-9402 FU German Social Accident Insurance (DGUV); Canadian Institutes for Health Research; Guzzo-SRC Chair in Environment and Cancer; National Cancer Institute of Canada; Canadian Cancer Society; Workplace Safety and Insurance Board; Cancer Care Ontario; French Agency of Health Security (ANSES); Fondation de France; French National Research Agency (ANR); National Institute of Cancer (INCA); Fondation for Medical Research (FRM); French Institute for Public Health Surveillance (InVS); Health Ministry (DGS); Organization for the Research on Cancer (ARC); French Ministry of work, solidarity, and public function (DGT); Organization for the Research on Cancer; Federal Ministry of Education, Science, Research, and Technology [01 HK 173/0]; Federal Ministry of Science [01 HK 546/8]; Ministry of Labour and Social Affairs [IIIb7-27/13]; European Commission [IC15-CT96-0313]; Polish State Committee for Scientific Research [SPUB-M-COPERNICUS/P-05/DZ-30/99/2000]; Roy Castle Foundation as part of the Liverpool Lung Project; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland; Environmental Epidemiology Program of the Lombardy Region, Italy; Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy; Italian Association for CancerResearch, Region Piedmont, Compagnia di San Paolo; European Union Nuclear Fission Safety Program [F14P-CT96-0055]; Lazio Region; Dutch Ministry of Health, Welfare and Sports, National Institute of Public Health and the Environment; Europe Against Cancer Program; Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias; Fondo de Investigacion Sanitaria (FIS); Ciber de Epidemiologia y Salud Publica (CIBER-ESP), Spain; SwedishCouncil for Work Life Research; Swedish Environmental Protection Agency; Research Grants Council of the Hong Kong Special Administrative Region, China [CUHK4460/03M]; Health Research Council of New Zealand; New Zealand Department of Labour, Lottery Health Research; Cancer Society of New Zealand FX The SYNERGY project is funded by the German Social Accident Insurance (DGUV). The Montreal case-control study of environmental causes of lung cancer was supported by the Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer. The Toronto lung cancer case-control study was funded by the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society, and the occupational analysis was conducted by the Occupational Cancer Research Centre, which was supported by the Workplace Safety and Insurance Board, the Canadian Cancer Society, and Cancer Care Ontario. The Investigations Cancers Respiratoires et Environnement (ICARE) study was supported by the French Agency of Health Security (ANSES), the Fondation de France, the French National Research Agency (ANR), the National Institute of Cancer (INCA), the Fondation for Medical Research (FRM), The French Institute for Public Health Surveillance (InVS), The Health Ministry (DGS), the Organization for the Research on Cancer (ARC), and the French Ministry of work, solidarity, and public function (DGT). The lung cancer in France study was supported by the Fondation de France. The lung cancer study in Paris was funded by Organization for the Research on Cancer. The Arbeit und Technik (AUT) study in Germany was funded by the Federal Ministry of Education, Science, Research, and Technology (grant 01 HK 173/0). The Humanisierung des Arbeitslebens (HdA) study was funded by the Federal Ministry of Science (grant 01 HK 546/8) and the Ministry of Labour and Social Affairs (grant IIIb7-27/13). The International Agency for Research on Cancer Multicenter Case-Control Study of Occupation, Environment, and Lung Cancer in Central and Eastern Europe and the United Kingdom (INCO) study was supported by a grant from the European Commission's INCO-Copernicus program (contract IC15-CT96-0313). In Warsaw, the study was supported by a grant from the Polish State Committee for Scientific Research (grant SPUB-M-COPERNICUS/P-05/DZ-30/99/2000). In Liverpool, the work was funded by the Roy Castle Foundation as part of the Liverpool Lung Project. The Environment and Genetics in Lung Cancer Etiology (EAGLE) study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland; the Environmental Epidemiology Program of the Lombardy Region, Italy; and the Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy. TheTurin/Venetostudy(apopulation-basedcase-controlstudy of lung cancer in the city of Turin and in the Eastern part of Veneto Region) was supported by the Italian Association for CancerResearch, Region Piedmont, Compagnia di San Paolo. The study in Rome was conducted with partial support from the European Union Nuclear Fission Safety Program (grant F14P-CT96-0055) and from the Lazio Region. The Monitoring van Risicofactoren en Gezondheid in Nederland (MORGEN) study was supported by the Dutch Ministry of Health, Welfare and Sports, National Institute of Public Health and the Environment, and the Europe Against Cancer Program. The Cancer de Pulmon en Asturias (CAPUA) study was supported by the Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias, the Fondo de Investigacion Sanitaria (FIS) and the Ciber de Epidemiologia y Salud Publica (CIBER-ESP), Spain. The Lungcancer i Stockholm (LUCAS) study was supported by the SwedishCouncil for Work Life Research and the Swedish Environmental Protection Agency.; The study in Hong Kong was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (project CUHK4460/03M). The Occupational Cancer in New Zealand (OCANZ) study was funded by the Health Research Council of New Zealand, the New Zealand Department of Labour, Lottery Health Research, and by the Cancer Society of New Zealand. NR 37 TC 1 Z9 1 U1 2 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 1 PY 2013 VL 178 IS 9 BP 1355 EP 1365 DI 10.1093/aje/kwt119 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 247SZ UT WOS:000326642300002 PM 24068200 ER PT J AU Weinberger, DM Bruden, DT Grant, LR Lipsitch, M O'Brien, KL Pelton, SI Sanders, EAM Feikin, DR AF Weinberger, Daniel M. Bruden, Dana T. Grant, Lindsay R. Lipsitch, Marc O'Brien, Katherine L. Pelton, Stephen I. Sanders, Elisabeth A. M. Feikin, Daniel R. TI Using Pneumococcal Carriage Data to Monitor Postvaccination Changes in Invasive Disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carriage; conjugate vaccine; pneumococcal; pneumococcus; surveillance; vaccine effectiveness; vaccines ID CONJUGATE VACCINE USE; STREPTOCOCCUS-PNEUMONIAE; SEROTYPE REPLACEMENT; ALASKAN CHILDREN; IMPACT; COLONIZATION; TRANSMISSION; DECADE AB Pneumococcal conjugate vaccines (PCVs) have been introduced worldwide. However, few developing countries have high-quality surveillance systems available for monitoring vaccine impact. We evaluated whether data from nasopharyngeal carriage studies can be used to accurately monitor post-PCV changes in the incidence of invasive pneumococcal disease (IPD) among children under 5 years of age. For various dates during 19912010, data on nasopharyngeal pneumococcal carriage and on IPD before and after administration of 7-valent PCV (PCV7) were available from England and Wales, the Netherlands, the Navajo and White Mountain Apache American Indian populations, and the US states of Massachusetts and Alaska. We estimated the change in carriage prevalence for each serotype in each study and then either calculated the average change (inverse variance-weighted) among vaccine and nonvaccine serotypes (model 1) or used mixed-effects models to estimate the change for each serotype individually, pooling serotype data within or between studies (models 2 and 3). We then multiplied these values by the proportion of IPD caused by each serotype during the pre-PCV7 period to obtain an estimate of post-PCV7 disease incidence. Model 1 accurately captured overall changes in IPD incidence following PCV7 introduction for most studies, while the more detailed models, models 2 and 3, were less accurate. Carriage data can be used in this simple model to estimate post-PCV changes in IPD incidence. C1 [Weinberger, Daniel M.] 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 06520 USA. [Bruden, Dana T.] Ctr Dis Control & Prevent, Arctic Invest Program, Div Preparedness & Emerging Infect, Natl Ctr Emerging & Zoonot Infect Dis, Anchorage, AK USA. [Grant, Lindsay R.; O'Brien, Katherine L.] Johns Hopkins Univ, Ctr Amer Indian Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [O'Brien, Katherine L.; Feikin, Daniel R.] Johns Hopkins Univ, Int Vaccine Access Ctr, Dept Int Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Pelton, Stephen I.] Boston Univ, Sch Med, Dept Pediat, Boston Med Ctr, Boston, MA 02118 USA. [Pelton, Stephen I.] Boston Univ, Sch Med, Sect Pediat Infect Dis, Boston Med Ctr, Boston, MA 02118 USA. [Pelton, Stephen I.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Sanders, Elisabeth A. M.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Pediat Immunol & Infect Dis, Utrecht, Netherlands. [Feikin, Daniel R.] Ctr Dis Control & Prevent, Div Preparedness & Emerging Infect, Natl Ctr Emerging & Zoonot Infect Dis, Atlanta, GA USA. RP Weinberger, DM (reprint author), Yale Univ, Sch Publ Hlth, Dept Epidemiol Microbial Dis, POB 208034, New Haven, CT 06520 USA. EM Daniel.weinberger@yale.edu OI Pelton, Stephen/0000-0003-4862-5344; Lipsitch, Marc/0000-0003-1504-9213 FU Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health; National Institutes of Health [2R01AI048935]; Bill and Melinda Gates Foundation [37875]; Native American Research Centers for Health [U26IHS300013/03, U269400012-01]; Centers for Disease Control and Prevention National Vaccine Program Office; Thrasher Research Fund [02820-9]; Wyeth Vaccines (Pfizer Inc.); US Agency for International Development; World Health Organization; Pfizer Inc. [WS950636]; Pfizer Inc. (New York, New York); GlaxoSmithKline (GSK; London); GlaxoSmithKline (GSK; United Kingdom); Pfizer; Wyeth (Overland Park, Kansas)/Pfizer; GSK; Novartis FX D.M.W. was supported by the Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health. M.L. was supported by National Institutes of Health grant 2R01AI048935. Support for the Navajo/WMA studies came from the Bill and Melinda Gates Foundation (grant 37875), The Native American Research Centers for Health (grants U26IHS300013/03 and U269400012-01), the Centers for Disease Control and Prevention National Vaccine Program Office, the Thrasher Research Fund (grant 02820-9), Wyeth Vaccines (Pfizer Inc.), the US Agency for International Development, and the World Health Organization. Support for the Alaskan postvaccine carriage study was provided, in part, by a grant from Pfizer Inc. (grant WS950636).; D.M.W. has received research funding from Pfizer Inc. (New York, New York). K.O.B. and L.R.G. have received research grant support related to pneumococcal vaccines from GlaxoSmithKline (GSK; London, United Kingdom) and Pfizer. K.O.B. has received honoraria for participation in external expert advisory committees on pneumococcal vaccines convened by Merck & Company (Whitehouse Station, New Jersey), Sanofi-Pasteur (Swiftwater, Pennsylvania), and GSK. E.A.M.S. has been given research grant support related to pneumococcal vaccines from Wyeth (Overland Park, Kansas)/Pfizer and GSK and has received honoraria for participation in external expert advisory committees on pneumococcal vaccines convened by Pfizer and GSK. S.I.P. has received honoraria for participation in advisory board activities related to pneumococcal vaccine or pneumococcal disease from Pfizer, Merck Vaccines, Novartis (Basel, Switzerland), and GSKbio. M.L. has accepted honoraria or consulting fees from Pfizer and Novartis. NR 29 TC 23 Z9 23 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD NOV 1 PY 2013 VL 178 IS 9 BP 1488 EP 1495 DI 10.1093/aje/kwt156 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 247SZ UT WOS:000326642300017 PM 24013204 ER PT J AU Pacchiarotti, I Bond, DJ Baldessarini, RJ Nolen, WA Grunze, H Licht, RW Post, RM Berk, M Goodwin, GM Sachs, GS Tondo, L Findling, RL Youngstrom, EA Tohen, M Undurraga, J Gonzalez-Pinto, A Goldberg, JF Yildiz, A Altshuler, LL Calabrese, JR Mitchell, PB Thase, ME Koukopoulos, A Colom, F Frye, MA Malhi, GS Fountoulakis, KN Vazquez, G Perlis, RH Ketter, TA Cassidy, F Akiskal, H Azorin, JM Valenti, M Mazzei, DH Lafer, B Kato, T Mazzarini, L Martinez-Aran, A Parker, G Souery, D Ozerdem, A McElroy, SL Girardi, P Bauer, M Yatham, LN Zarate, CA Nierenberg, AA Birmaher, B Kanba, S El-Mallakh, RS Serretti, A Rihmer, Z Young, AH Kotzalidis, GD MacQueen, GM Bowden, CL Ghaemi, SN Lopez-Jaramillo, C Rybakowski, J Ha, K Perugi, G Kasper, S Amsterdam, JD Hirschfeld, RM Kapczinski, F Vieta, E AF Pacchiarotti, Isabella Bond, David J. Baldessarini, Ross J. Nolen, Willem A. Grunze, Heinz Licht, Rasmus W. Post, Robert M. Berk, Michael Goodwin, Guy M. Sachs, Gary S. Tondo, Leonardo Findling, Robert L. Youngstrom, Eric A. Tohen, Mauricio Undurraga, Juan Gonzalez-Pinto, Ana Goldberg, Joseph F. Yildiz, Aysegul Altshuler, Lori L. Calabrese, Joseph R. Mitchell, Philip B. Thase, Michael E. Koukopoulos, Athanasios Colom, Francesc Frye, Mark A. Malhi, Gin S. Fountoulakis, Konstantinos N. Vazquez, Gustavo Perlis, Roy H. Ketter, Terence A. Cassidy, Frederick Akiskal, Hagop Azorin, Jean-Michel Valenti, Marc Mazzei, Diego Hidalgo Lafer, Beny Kato, Tadafumi Mazzarini, Lorenzo Martinez-Aran, Anabel Parker, Gordon Souery, Daniel Ozerdem, Aysegul McElroy, Susan L. Girardi, Paolo Bauer, Michael Yatham, Lakshmi N. Zarate, Carlos A. Nierenberg, Andrew A. Birmaher, Boris Kanba, Shigenobu El-Mallakh, Rif S. Serretti, Alessandro Rihmer, Zoltan Young, Allan H. Kotzalidis, Georgios D. MacQueen, Glenda M. Bowden, Charles L. Ghaemi, S. Nassir Lopez-Jaramillo, Carlos Rybakowski, Janusz Ha, Kyooseob Perugi, Giulio Kasper, Siegfried Amsterdam, Jay D. Hirschfeld, Robert M. Kapczinski, Flavio Vieta, Eduard TI The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID TREATMENT ENHANCEMENT PROGRAM; MAJOR DEPRESSIVE EPISODE; LONG-TERM FLUOXETINE; MOOD CONVERSION RATE; II DISORDER; STEP-BD; DOUBLE-BLIND; LONGITUDINAL-EVALUATION; LITHIUM MONOTHERAPY; CONTROLLED-TRIALS AB Objective: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. Method: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. Results: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to moodstabilizing medications. C1 [Vieta, Eduard] Univ Barcelona, CIBERSAM Ctr Biomed Res Network Mental Hlth, IDIBAPS Inst Biomed Res August Pi & Sunyer, Bipolar Disorders Program,Clin Inst Neurosci,Hosp, Barcelona, Spain. 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Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Lab Mol Psychiat, Porto Alegre, RS, Brazil. RP Vieta, E (reprint author), Univ Barcelona, CIBERSAM Ctr Biomed Res Network Mental Hlth, IDIBAPS Inst Biomed Res August Pi & Sunyer, Bipolar Disorders Program,Clin Inst Neurosci,Hosp, Barcelona, Spain. EM evieta@clinic.ub.es RI Nolen, Willem/E-9006-2014; Kato, Tadafumi/J-3583-2014; Kapczinski, Flavio/J-5803-2014; Lafer, Beny/F-9390-2015; Undurraga, Juan/F-3438-2012; Lafer, Beny/C-1055-2012; OI Colom, Francesc/0000-0002-9516-9030; Vieta, Eduard/0000-0002-0548-0053; Parker, Gordon/0000-0003-3424-5519; Grunze, Heinz/0000-0003-4712-8979; Kato, Tadafumi/0000-0001-7856-3952; Lafer, Beny/0000-0002-6132-9999; Undurraga, Juan/0000-0001-6958-2369; Lafer, Beny/0000-0002-6132-9999; Martinez-Aran, Anabel/0000-0002-0623-6263; VALENTI, MARC/0000-0002-9783-6220; Mitchell, Philip/0000-0002-7954-5235; Lopez, Carlos/0000-0002-1875-1369; Berk, Michael/0000-0002-5554-6946 FU Canadian Institutes of Health Research; UBC Institute of Mental Health/Coast Capital Depression Research Fund; Pfizer; Netherlands Organization for Health Research and Development; European Union; Stanley Medical Research Institute; AstraZeneca; GlaxoSmithKline; Wyeth; Lundbeck; Bristol-Myers Squibb; Desitin; Eli Lilly; Gedeon-Richter; Hoffmann-La Roche; Janssen-Cilag; Merck; Otsuka; Sanofi-Aventis; Servier; Sepracor; UBC; Medical Research Council; National Institute for Health Research (U.K.); Cambridge University Press; Igaku-Shoin; Solal Ed.; Ars Medica; Giovani Fioriti Ed.; Medipage; La Esfera de Los Libros; Morales i Torres Ed; Panamericana; Mayo Ed. Columna; Mayo Foundation; Myriad; NARSAD; National Institute of Alcohol Abuse and Alcoholism; H; Journal of Affective Disorders; University of Lisbon; Aristotle University of Thesaloniki; Sanofi, Nevada Psychiatric Association; Medical Education Speakers Network; Sanofi; CAPES (Coordination for the Improvement of Higher Education Personnel); FAPESP (Sao Paulo Research Foundation); CNPq (National Council for Scientific and Technological Development); Janssen; Schering; Springer Healthcare; Abbott Laboratories; Agency for Healthcare Research and Quality; American Drug Utilization Review Society; American Society for Clinical Psychopharmacology; Basilea; Biomedical Development, Boston Center for the Arts; BrainCells; Brandeis University; Cederroth; Cephalon; Corcept; Cyberonics; East Asian Bipolar Forum; Elan; Forest; Genaissance; Harold Grinspoon Charitable Foundation; Health New England; Innapharma; International Society for Bipolar Disorder; Jazz Pharmaceuticals; Lichtwer Pharma; MGH Psychiatry Academy; Mid-Atlantic Permanente Research Institute; Mylan; NIMH; Novartis; PamLab; PGx Health; Ridge Diagnostics; Roche; Schering-Plough; Shire, Somerset; Stanley Foundation; Sunovion, Takeda; Targacept; Teva, University of Pisa; University of Wisconsin at Madison; University of Texas Southwestern Medical Center at Dallas; Wyeth-Ayerst; Zucker Hillside Hospital; Astellas; Dainippon Sumitomo; Eisai; Eli Lilly Japan; Kyowa Hakko Kirin; Meiji Seika Pharma; MSD; Ono; Shionogi; Taisho Toyama; Yoshitomiyakuhin; Janssen Cilag; NIH; University of Antioquia FX Dr. Bond has received honoraria from the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Pfizer, Sunovion, Bristol-Myers Squibb, Otsuka, AstraZeneca, and Janssen-Ortho; and has received research grants from the Canadian Institutes of Health Research, the UBC Institute of Mental Health/Coast Capital Depression Research Fund, and Pfizer. Dr. Nolen has received grants from the Netherlands Organization for Health Research and Development, the European Union, the Stanley Medical Research Institute, AstraZeneca, GlaxoSmithKline, and Wyeth and honoraria or speaking fees from AstraZeneca and Lundbeck. Dr. Grunze has received research support, consulting fees, or honoraria from AstraZeneca, Bristol-Myers Squibb, Desitin, Eli Lilly, Gedeon-Richter, Hoffmann-La Roche, Janssen-Cilag, Lundbeck, Merck, Otsuka, Sanofi-Aventis, Servier, Sepracor, and UBC. Dr. Licht has served on advisory boards for Bristol-Myers Squibb, AstraZeneca, and MSD and has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Pfizer. Dr. Post has served as a consultant or speaker for AstraZeneca, Sunovion, Teva, and Validas. Dr. Berk has received research support from or served as a consultant or speaker for AstraZeneca, Beyond Blue, Bristol-Myers Squibb, Cancer Council of Victoria, Cooperative Research Centre, Eli Lilly, Geelong Medical Research Foundation, GlaxoSmithKline, Janssen Cilag, Lundbeck, Mayne Pharma, MBF, Meat and Livestock Board, Merck, National Health and Medical Research Council (Australia), NIH, Novartis, Organon, Pfizer, Rotary Health, Sanofi Synthelabo, Servier, Simons Autism Foundation, Stanley Medical Research Foundation, Solvay, Woolworths, and Wyeth and is a co-inventor on two provisional patents regarding the use of N-acetylcysteine and related compounds for psychiatric indications. Dr. Goodwin has received grants from Bailly Thomas, Medical Research Council, National Institute for Health Research (U.K.), and Servier, has served as consultant, adviser, or CME speaker for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Cephalon/Teva Janssen-Cilag, Eli Lilly, Lundbeck, Otsuka, P1Vital, Roche, Servier, Schering-Plough, Shire, Sunovion, and Takeda, and holds shares in P1Vital. Dr. Sachs has served on advisory boards for Elan, Janssen, Merck, Otsuka, Roche, Sunovion, and Takeda. Dr. Findling has received research support or served as a consultant or speaker for Alexza Pharmaceuticals, American Psychiatric Publishing, AstraZeneca, Bracket, Bristol-Myers Squibb, Clinsys, Cognition Group, Forest, GlaxoSmithKline, Guilford Press, Johns Hopkins University Press, Johnson & Johnson, KemPharm, Lilly, Lundbeck, Merck, NIH, Novartis, Noven, Otsuka, Oxford University Press, Pfizer, Physicians Postgraduate Press, Rhodes Pharmaceuticals, Roche, Sage, Seaside Pharmaceuticals, Shire, Stanley Medical Research Institute, Sunovion, Supernus Pharmaceuticals, Transcept Pharmaceuticals, Validus, and WebMD. Dr. Youngstrom has served as a consultant for Lundbeck. Dr. Tohen has received honoraria from or served as a consultant for AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Merck, Otsuka, PamLab, Roche, Sunovion, Teva, Wyeth, and Wiley Publishing; his spouse is an employee and stockholder at Eli Lilly. Dr.; Gonzalez-Pinto has received grants from or served as consultant, adviser, or CME speaker for Almirall, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Otsuka, Pfizer, Sanofi-Aventis, Servier, Schering-Plough, Solvay, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, Stanley Medical Research Institute, and Wyeth. Dr. Goldberg has served as consultant or speaker for AstraZeneca, Grunenthal Group, Medscape, Merck, Mylan Pharmaceuticals, Novartis, Sunovion, and WebMD and receives royalties from American Psychiatric Publishing. Dr. Yildiz has received research grants from or served as a consultant or speaker for Abdi Ibrahim, Actavis, Ali Raif, AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Pfizer, Sanofi-Aventis, and Servier. Dr. Altshuler has served on advisory boards or as a consultant for Eli Lilly, Takeda Pharmaceuticals North America, Lundbeck, Sepracor, and Sunovion. Dr. Calabrese has received funding or research support from or served as a consultant or CME speaker or on advisory boards for Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cleveland Foundation, Dainippon Sumitomo, Department of Defense, Eli Lilly, EPI-Q, Forest, France Foundation, GlaxoSmithKline, Health Resources Services Administration, Janssen, Johnson & Johnson, Lundbeck, Merck, NARSAD, Neurosearch, NIMH, Ortho-McNeil, Otsuka, Pfizer, Repligen, Sanofi-Aventis, Schering-Plough, Servier, Solvay, Stanley Medical Research Institute, Supernus, Synosia, Takeda, and Wyeth. Dr. Thase has received grant funding from or served as a consultant for Agency for Healthcare Research and Quality, Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb, Dey Pharma, Eli Lilly, Forest Laboratories, Forest Pharmaceuticals, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, Lundbeck, MedAvante, Merck, NeoSync, Neuronetics, NIMH, Novartis, Otsuka, Ortho-McNeil Pharmaceuticals, PamLab, Pfizer (formerly Wyeth-Ayerst Laboratories), PharmaNeuroboost, Roche Laboratories, Shire US, Sunovion, Takeda, Teva, and Transcept; he receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, Oxford University Press, and W. W. Norton and has equity holdings in MedAvante; his wife is employed by Peloton Advantage, which does business with Pfizer. Dr. Colom has served as adviser or speaker for Adamed, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, MSD-Merck, Otsuka, Pfizer, Sanofi-Aventis, Shire, and Tecnifar and has received copyright fees from Cambridge University Press, Igaku-Shoin, Solal Ed., Ars Medica, Giovani Fioriti Ed., Medipage, La Esfera de Los Libros, Morales i Torres Ed, Panamericana, and Mayo Ed. & Columna. Dr. Frye has received grant support from the Mayo Foundation, Myriad, NARSAD, the National Institute of Alcohol Abuse and Alcoholism, NIMH, and Pfizer and travel support from Advanced Health Media, AstraZeneca, Bristol-Myers Squibb, Chilean Society of Neurology, Psychiatry, and Neurosurgery, Colombian Society of Neuropsychopharmacology, GlaxoSmithKline, Otsuka, and Sanofi-Aventis; he has served as an unpaid consultant for Allergan, Merck, Myriad, Sanofi-Aventis, Sunovion, Takeda Global Research, Teva Pharmaceuticals, and United Biosource Corporation. Dr. Malhi has received research support from or served as a speaker or consultant for AstraZeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Organon, Pfizer, Ranbaxy, Servier, and Wyeth. Dr.; Fountoulakis has received research support or travel support from or served as a speaker or consultant for AstraZeneca, Bristol-Myers Squibb, Janssen-Cilag, Eli Lilly, Pfizer Foundation, and Wyeth. Dr. Vazquez has served as consultant or speaker for AstraZeneca, Gador, GlaxoSmithKline, Ivax, Eli Lilly, Lundbeck, Pfizer, Raffo, Servier, and Novartis. Dr. Perlis has served on advisory boards or as a consultant for Genomind, Healthrageous, PamLab, Pfizer, Proteus Biomedical, and RIDVentures. Dr. Ketter has received research support from or served as a consultant or speaker for Abbott, Allergan, AstraZeneca, Avanir, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Merck, Otsuka, Pfizer, Sunovion, and Teva; he receives royalties from American Psychiatric Publishing, and his spouse is an employee of and holds stock in Janssen Pharmaceuticals. Dr. Akiskal receives honoraria or fees from Journal of Affective Disorders, AstraZeneca, University of Lisbon, Aristotle University of Thesaloniki, Sanofi, Nevada Psychiatric Association, and Medical Education Speakers Network. Dr. Azorin has received grants from Eli Lilly and Sanofi and honoraria from AstraZeneca, Bristol-Myers Squibb, Lundbeck Servier, and Eli Lilly; he has served on advisory boards for Eli Lilly, Lundbeck, Bristol-Myers Squibb, and Roche and as an expert witness for Eli Lilly. Dr. Lafer has received grant or research support from Brazilian research agencies CAPES (Coordination for the Improvement of Higher Education Personnel), FAPESP (Sao Paulo Research Foundation), and CNPq (National Council for Scientific and Technological Development). Dr. Kato has received research support from Takeda and honoraria for lectures, manuscripts, or consultancy from Kyowa Hakko Kirin, Eli Lilly Japan, Otsuka, GlaxoSmithKline, Taisho Toyama Pharmaceutical, Dainippon Sumitomo, Meiji Seika Pharma, Pfizer Japan, Mochida Pharmaceutical, Shionogi, Janssen, and Astellas. Dr. Martinez-Aran has served as speaker or adviser for Bristol-Myers Squibb, Lundbeck, Otsuka, and Pfizer. Dr. Parker has served as a speaker or on advisory boards for or received travel or speaking fees from AstraZeneca, Eli Lilly, Lundbeck, Pfizer, and Servier. Dr. Souery has served on advisory boards for AstraZeneca and Lundbeck and has received unrestricted grants for clinical research and educational activities from AstraZeneca, GlaxoSmithKline, and Lundbeck. Dr. Ozerdem has received honoraria or travel support from Abdi Ibrahim, Adeka, AstraZeneca, Bristol-Myers Squibb, EGIS, GlaxoSmithKline, Lundbeck, Nobel, Pfizer, Schering-Plough, and Servier. Dr. McElroy has served as a consultant for or on scientific advisory boards for Alkermes, Bracket, Corcept, MedAvante, Shire, Sunovion, and Teva; she is a principal or co-investigator on studies sponsored by the Agency for Healthcare Research and Quality, Alkermes, AstraZeneca, Cephalon, Eli Lilly, Forest, Marriott Foundation, NIMH, Orexigen Therapeutics, Pfizer, Shire, Takeda, and Transcept; she is also an inventor on a patent for use of sulfamate derivatives for treating impulse control disorders. Dr. Girardi has received research support from, served on advisory boards for, and received honoraria from Eli Lilly, Janssen, Otsuka, Pfizer, Schering, and Springer Healthcare. Dr.; Bauer has received research support from or served as a consultant or speaker for Alkermes, American Foundation for Suicide Prevention, AstraZeneca, Bristol-Myers Squibb, Bundesministerium fur Bildung und Forschung, Deutsche Forschungsgemeinschaft, European Commission (FP7), Ferrer Internacional, GlaxoSmithKline, Janssen, Eli Lilly, Lundbeck, NARSAD, Otsuka, Pfizer, Servier, Stanley Medical Research Institute, and Takeda. Dr. Yatham has received research support from or served as a speaker or advisory board member for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, GlaxoSmithKline, Lundbeck, Novartis, Pfizer, Servier, and Sunovion. Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Nierenberg has received research support from, served as a consultant for, or received honoraria from Abbott Laboratories, Agency for Healthcare Research and Quality, American Drug Utilization Review Society, American Society for Clinical Psychopharmacology, AstraZeneca, Basilea, Biomedical Development, Boston Center for the Arts, BrainCells, Brandeis University, Bristol-Myers Squibb, Cederroth, Cephalon, Corcept, Cyberonics, East Asian Bipolar Forum, Elan, Eli Lilly, Forest, Genaissance, GlaxoSmithKline, Harold Grinspoon Charitable Foundation, Health New England, Innapharma, International Society for Bipolar Disorder, Janssen, Jazz Pharmaceuticals, Lichtwer Pharma, Lundbeck, Merck, MGH Psychiatry Academy, Mid-Atlantic Permanente Research Institute, Mylan (formerly Dey Pharmaceuticals), NARSAD, NIMH, Novartis, PamLab, Pfizer, PGx Health, Ridge Diagnostics, Roche, Sepracor, Schering-Plough, Shire, Somerset, Stanley Foundation, Sunovion, Takeda, Targacept, Teva, University of Pisa, University of Wisconsin at Madison, University of Texas Southwestern Medical Center at Dallas, Wyeth-Ayerst, and Zucker Hillside Hospital; he receives other income from legal case reviews for CRICO, MBL Publishing for past services as editor-in-chief of CNS Spectrums, Slack Inc. for services as associate editor of Psychiatric Annals, and from Belvoir Publications for serving on the editorial board of Mind, Mood, and Memory; he has copyright joint ownership with MGH for the Structured Clinical Interview for MADRS and Clinical Positive Affect Scale and is a stakeholder in Appliance Computing (MindSite), Brain Cells, and InfoMed. Dr. Birmaher has received research support from NIMH and royalties from Random House, Lippincott Williams & Wilkins, and UpToDate. Dr. Kanba has received research support or honoraria from Astellas, Dainippon Sumitomo, Eisai, Eli Lilly Japan, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Ono, Otsuka, Pfizer, Shionogi, Taisho Toyama, Wyeth, and Yoshitomiyakuhin. Dr. El-Mallakh has received research support from Merck and has served as a speaker for AstraZeneca and Otsuka. Dr. Serretti has served as a consultant or speaker for Abbott, Angelini, AstraZeneca, Bristol-Myers Squibb, Boehringer, Clinical Data, Eli Lilly, GlaxoSmithKline, Italfarmaco, Janssen, Lundbeck, Pfizer, Sanofi, and Servier. Dr. MacQueen has received research support from AstraZeneca and served as a consultant or speaker for Bristol-Myers Squibb, Canadian Psychiatric Association, Eli Lilly, Lundbeck, Norlien Foundation, Pfizer, Sanofi, and Servier. Dr. Bowden has received grant support from Novartis. Dr. Ghaemi has received research support from Takeda and has served as a consultant for Sunovion. Dr.; Lopez-Jaramillo has received research support from Janssen Cilag, Lundbeck, NIH, Novartis, Pfizer, and University of Antioquia and honoraria from Abbott, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Sanofi, and Servier. Dr. Ha has received research support or honoraria from AstraZeneca, Eli Lilly, Pfizer, and Otsuka. Dr. Perugi has received research support from or served as a consultant, speaker, or advisory board member for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Lundbeck, and Sanofi-Aventis. Dr. Kasper has received research support from or served as a consultant, speaker, or advisory board member for Angelini, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, MSD, Neuraxpharm, Novartis, Organon, Pfizer, Pierre Fabre, Schwabe, Sepracor, and Servier. Dr. Hirschfeld has served as a consultant for or received honoraria from American College of Psychiatrists, Biostrategies, Brown University, CME Alliance, CME Outfitters, Equinox Group, Grey Healthcare, Letters & Sciences, Merck Manual Editorial Board, Nevada Psychiatric Association, and Physicians Post Graduate Press Health and Wellness Partners and receives royalties from Jones & Bartlett and Taylor & Francis. Dr. Kapczinski has received research support from or served as a consultant or speaker for AstraZeneca, CNPq, CAPES, Eli Lilly, Janssen, Janssen-Cilag, NARSAD, Stanley Medical Research Institute, and Servier. Dr. Vieta has received research support from or served as consultant, adviser, or speaker for Alexza, Almirall, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Ferrer, Forest Research Institute, 7th Framework Program of the European Union, Geodon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Solvay, Schering-Plough, Shire, Spanish Ministry of Science and Innovation, Stanley Medical Research Institute, Takeda, Teva, United Biosource Corporation, and Wyeth. The remaining authors report no competing interests. NR 102 TC 172 Z9 174 U1 4 U2 30 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD NOV PY 2013 VL 170 IS 11 BP 1249 EP 1262 DI 10.1176/appi.ajp.2013.13020185 PG 14 WC Psychiatry SC Psychiatry GA 248SZ UT WOS:000326724300008 PM 24030475 ER PT J AU Wang, F Yeung, KL Chan, WC Kwok, CCH Leung, SL Wu, C Chan, EYY Yu, ITS Yang, XR Tse, LA AF Wang, F. Yeung, K. L. Chan, W. C. Kwok, C. C. H. Leung, S. L. Wu, C. Chan, E. Y. Y. Yu, I. T. S. Yang, X. R. Tse, L. A. TI A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer SO ANNALS OF ONCOLOGY LA English DT Review DE breast cancer; case-control studies; cohort studies; dose-response relationship; meta-analysis; shift work ID VITAMIN-D; NORWEGIAN NURSES; COHORT; WOMEN; HEALTH; LIGHT AB This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; P-heterogeneity < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; P-heterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work. C1 [Wang, F.; Yeung, K. L.; Chan, E. Y. Y.; Yu, I. T. S.; Tse, L. A.] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Sha Tin, Hong Kong, Peoples R China. [Chan, W. C.] North Dist Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Kwok, C. C. H.] Princess Margaret Hosp, Dept Oncol, Hong Kong, Hong Kong, Peoples R China. [Leung, S. L.] Yan Chai Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Wu, C.] North Dist Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Yang, X. R.] Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. RP Tse, LA (reprint author), Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Prince Wales Hosp, Sch Public Hlth & Primary Care 4 F, Sha Tin, Hong Kong, Peoples R China. EM shelly@cuhk.edu.hk RI Yu, Ignatius Tak Sun/A-9936-2008 FU Research Grants Council of Hong Kong [474811] FX This work was supported by Research Grants Council of Hong Kong [Grant number 474811]. NR 32 TC 53 Z9 54 U1 5 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2013 VL 24 IS 11 BP 2724 EP 2732 DI 10.1093/annonc/mdt283 PG 9 WC Oncology SC Oncology GA 247TF UT WOS:000326643200004 PM 23975662 ER PT J AU Ramalingam, S Crawford, J Chang, A Manegold, C Perez-Soler, R Douillard, JY Thatcher, N Barlesi, F Owonikoko, T Wang, Y Pultar, P Zhu, J Malik, R Giaccone, G AF Ramalingam, S. Crawford, J. Chang, A. Manegold, C. Perez-Soler, R. Douillard, J. -Y. Thatcher, N. Barlesi, F. Owonikoko, T. Wang, Y. Pultar, P. Zhu, J. Malik, R. Giaccone, G. CA FORTIS-M Study Investigators TI Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial) SO ANNALS OF ONCOLOGY LA English DT Article DE non-small-cell lung cancer; immunotherapy; phase III study; talactoferrin ID LACTOFERRIN INHIBITS GROWTH; ORAL TALACTOFERRIN; SUPPORTIVE CARE; DOUBLE-BLIND; CHEMOTHERAPY; GEFITINIB; TUMORS; THERAPY; IMMUNOTHERAPY; ERLOTINIB AB Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms. There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens. C1 [Ramalingam, S.; Owonikoko, T.] Emory Univ, Robert W Woodruff Hlth Sci Ctr, Dept Oncol, Atlanta, GA 30322 USA. [Crawford, J.] Duke Univ, Med Ctr, Dept Oncol, Durham, NC 27706 USA. [Chang, A.] Johns Hopkins Singapore Int Med Ctr, Singapore, Singapore. [Manegold, C.] Univ Med Ctr, Mannheim, Germany. [Perez-Soler, R.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Oncol, New York, NY USA. [Douillard, J. -Y.] Univ Nantes, Rene Gauducheau Canc Ctr, Dept Med Oncol, Nantes, France. [Thatcher, N.] Christie NHS Fdn Trust, Dept Oncol, Manchester, Lancs, England. [Barlesi, F.] Univ Aix Marseille 2, Marseille, France. [Wang, Y.; Pultar, P.; Zhu, J.; Malik, R.] Agennix Inc, Dept Oncol, Princeton, NJ USA. [Giaccone, G.] NCI, Dept Oncol, NIH, Bethesda, MD 20892 USA. RP Giaccone, G (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, 3970 Reservoir Rd, Washington, DC 20007 USA. EM gg496@geogetown.edu RI Ottensmeier, Christian/E-8131-2012; Giaccone, Giuseppe/E-8297-2017; OI Ottensmeier, Christian/0000-0003-3619-1657; Giaccone, Giuseppe/0000-0002-5023-7562; Schuette, Wolfgang/0000-0002-7516-5649; bearz, alessandra/0000-0003-1020-2338; MAZIERES, JULIEN/0000-0002-5921-7613; benekli, mustafa/0000-0003-3184-4946 FU Agennix Inc. FX This trial was funded by Agennix Inc. NR 25 TC 21 Z9 22 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2013 VL 24 IS 11 BP 2875 EP 2880 DI 10.1093/annonc/mdt371 PG 6 WC Oncology SC Oncology GA 247TF UT WOS:000326643200029 PM 24050956 ER PT J AU Italiano, A Le Cesne, A Bellera, C Piperno-Neumann, S Duffaud, F Penel, N Cassier, P Domont, J Takebe, N Kind, M Coindre, JM Blay, JY Bui, B AF Italiano, A. Le Cesne, A. Bellera, C. Piperno-Neumann, S. Duffaud, F. Penel, N. Cassier, P. Domont, J. Takebe, N. Kind, M. Coindre, J. -M. Blay, J. -Y. Bui, B. TI GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study SO ANNALS OF ONCOLOGY LA English DT Article DE chondrosarcoma; Hedgehog pathway; treatment; GDC-0449 ID ANTICANCER AGENTS; CHEMORESISTANCE; MUTATIONS; DESIGNS; TUMORS AB Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. NCT01267955. C1 [Italiano, A.; Bui, B.] Inst Bergonie, Dept Med Oncol, Bordeaux, France. [Le Cesne, A.; Domont, J.] Inst Gustave Roussy, Dept Med, Villejuif, France. [Bellera, C.] Inst Bergonie, Clin & Epidemiol Res Unit, Bordeaux, France. [Bellera, C.] CTD INCa, Data Ctr Canc Clin Trials, Bordeaux, France. [Piperno-Neumann, S.] Inst Curie, Dept Med, Paris, France. [Duffaud, F.] Hop Enfants La Timone, Dept Med Oncol, Marseille, France. [Penel, N.] Ctr Oscar Lambret, Dept Med, F-59020 Lille, France. [Cassier, P.] Ctr Leon Berard, Dept Med, F-69373 Lyon, France. [Takebe, N.] Natl Canc Inst, Rockville, MD USA. [Kind, M.] Inst Bergonie, Dept Radiol, Bordeaux, France. [Coindre, J. -M.] Inst Bergonie, Dept Pathol, Bordeaux, France. RP Italiano, A (reprint author), Inst Bergonie, Early Phase Trials Unit, 229 Cours Argonne, F-33076 Bordeaux, France. EM a.italiano@bordeaux.unicancer.fr RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU French National Cancer Institute (INCa) [2009-342, INCa-DGOS-Inserm 6046] FX French National Cancer Institute (INCa) (grant '2009-342' and grant 'INCa-DGOS-Inserm 6046'). NR 21 TC 13 Z9 13 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD NOV PY 2013 VL 24 IS 11 BP 2922 EP 2926 DI 10.1093/annonc/mdt391 PG 5 WC Oncology SC Oncology GA 247TF UT WOS:000326643200037 PM 24170610 ER PT J AU Chung, H Cho, H Perry, C Song, J Ylaya, K Lee, H Kim, JH AF Chung, Hyunsoo Cho, Hanbyoul Perry, Candice Song, Jaekyung Ylaya, Kris Lee, Heejeong Kim, Jae-Hoon TI Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer SO BIOMARKERS LA English DT Article DE Cervical cancer; ERp57; immunohistochemistry; survival; tissue microarray ID CELL CARCINOMA; IMMUNE ESCAPE; TIME; COMPLEX AB Objective: We investigated the clinical significance of ERp57 in the progression of cervical cancer. Methods: mRNA and protein expression of ERp57 in cervical neoplasias were examined. Results: ERp57 mRNA expression was significantly decreased in cervical cancers. Immunohistochemistry revealed that ERp57 expression in 123 cervical cancers was downregulated compared to cervical intraepithelial neoplasias or normal tissues (p<0.001). Low ERp57 expression was significantly associated with worse overall survival (HR = 12.19, p = 0.018). Conclusions: Low ERp57 expression independently predicts a poor outcome for patients with cervical cancer, supporting the notion that ERp57 may be a promising novel cancer target. C1 [Chung, Hyunsoo; Perry, Candice; Ylaya, Kris] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Cho, Hanbyoul; Song, Jaekyung; Kim, Jae-Hoon] Yonsei Univ, Coll Med, Inst Womens Life Med Sci, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Lee, Heejeong] Catholic Univ Korea, Bucheon St Marys Hosp, Dept Pathol, Seoul, South Korea. RP Kim, JH (reprint author), Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, 146-92 Dogok Dong, Seoul 135720, South Korea. EM heejung@catholic.ac.kr; jaehoonkim@yuhs.ac FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0005230, 2011-0010286, 2011-0007146]; Yonsei University College of Medicine [3-2010-0072, 6-2011-0073] FX This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286, and 2011-0007146), and faculty research grants from Yonsei University College of Medicine for 2010 and 2011 (3-2010-0072 and 6-2011-0073). NR 17 TC 7 Z9 9 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-750X EI 1366-5804 J9 BIOMARKERS JI Biomarkers PD NOV PY 2013 VL 18 IS 7 BP 573 EP 579 DI 10.3109/1354750X.2013.827742 PG 7 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 251EF UT WOS:000326909900004 PM 23957851 ER PT J AU Ross, A Sundaramurthi, T Bevans, M AF Ross, Alyson Sundaramurthi, Thiruppavai Bevans, Margaret TI A Labor of Love The Influence of Cancer Caregiving on Health Behaviors SO CANCER NURSING LA English DT Article DE Burden; Cancer; Caregivers; Health behaviors; Screening; Stress ID QUALITY-OF-LIFE; CAUSE-SPECIFIC MORTALITY; CORONARY-HEART-DISEASE; FAMILY CAREGIVERS; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; INFORMAL CAREGIVERS; ALCOHOL-CONSUMPTION; ALLOSTATIC LOAD; BREAST-CANCER AB Background: Evidence suggests that emotional distress and objective demands of cancer caregiving are comparable to those of dementia caregiving, yet little research has focused on the physical health of cancer caregivers. Whether the stress leads directly to changes in health or whether the stress leads to changes in health behaviors, which in turn affect health, has not been systematically examined. Objective: The objective of this study was to review the research literature regarding changes in health behaviors associated with caring for an individual with cancer. Methods: Literature was reviewed from multiple databases including CINAHL (Cumulative Index to Nursing and Allied Health Literature), CINAHL Plus, PsycNET, PubMed, SCOPUS, EMBASE, and Web of Science. Key words included health behavior, health promotion, caregivers/caregiving, cancer/oncology, diet/nutrition, exercise/physical activity, stress management, smoking and alcohol. Studies were included if they involved informal adult caregivers and at least 1 behavior associated with a healthy lifestyle. Of the 866 studies identified, 8 met the criteria. Results: Studies revealed conflicting information, with some suggesting deleterious changes in behaviors, whereas others found the changes protective. Conclusions: The lack of uniformity of terminology and conflicting findings make it difficult to conclude the impact of the caregiving experience on the health behaviors of cancer caregivers. Something is placing caregivers at risk for illness and early death, but the mechanisms behind the risk and the role of unhealthy behaviors are not clear. Implications for Practice: At a minimum, cancer caregivers should be screened for behavior changes and disease risk. Developing standardized measures for future research including controlled, longitudinal studies is needed. C1 [Ross, Alyson; Sundaramurthi, Thiruppavai; Bevans, Margaret] NIH, Nursing & Patient Care Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Bevans, M (reprint author), NIH, Ctr Clin, Bldg 10,Room 2B13, Bethesda, MD 20892 USA. EM mbevans@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 57 TC 6 Z9 6 U1 4 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X EI 1538-9804 J9 CANCER NURS JI Cancer Nurs. PD NOV-DEC PY 2013 VL 36 IS 6 BP 474 EP 483 DI 10.1097/NCC.0b013e3182747b75 PG 10 WC Oncology; Nursing SC Oncology; Nursing GA 246IR UT WOS:000326532000016 PM 23132126 ER PT J AU Maunakea, AK Chepelev, I Cui, KR Zhao, KJ AF Maunakea, Alika K. Chepelev, Iouri Cui, Kairong Zhao, Keji TI Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition SO CELL RESEARCH LA English DT Article DE MeCP2; splicing; chromatin; intragenic DNA methylation; epigenomics; histone acetylation ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RETT-SYNDROME; PROTEIN MECP2; CANCER-CELLS; HUMAN GENOME; CPG ISLANDS; SEQ; HYPERACETYLATION; DEMETHYLATION; EPIGENETICS AB Although the function of DNA methylation in gene promoter regions is well established in transcriptional repression, the function of the evolutionarily conserved widespread distribution of DNA methylation in gene body regions remains incompletely understood. Here, we show that DNA methylation is enriched in included alternatively spliced exons (ASEs), and that inhibition of DNA methylation results in aberrant splicing of ASEs. The methyl-CpG-binding protein MeCP2 is enriched in included ASEs, particularly those that are also highly methylated, and inhibition of DNA methylation disrupts specific targeting of MeCP2 to exons. Interestingly, ablation of MeCP2 results in increased histone acetylation and aberrant ASE-skipping events. We further show that inhibition of histone deacetylase (HDAC) activity leads to exon skipping that shows a highly significant degree of overlap with that caused by MeCP2 knockdown. Together, our data indicate that intragenic DNA methylation operates in exon definition to modulate alternative RNA splicing and can enhance exon recognition via recruitment of the multifunctional protein MeCP2, which thereby maintains local histone hypoacetylation through the subsequent recruitment of HDACs. C1 [Maunakea, Alika K.; Chepelev, Iouri; Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute; UGSP, National Institutes of Health FX We thank Dr B Volgelstein (Johns Hopkins University) for providing HCT116-WT and HCT116-DKO cells [17]. We also thank Dr R Nagarajan (University of California, San Francisco) for ChIP-PCR primer sequences of SNRPN and GABRB3 regions, and Qingsong Tang (NHLBI) for assistance with GAII sequencing. The sequencing of RNA-Seq samples was performed by the DNA Sequencing and Genomics Core facility of NHLBI. This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (KZ). AKM was additionally supported by a fellowship from the UGSP, National Institutes of Health. NR 46 TC 149 Z9 155 U1 8 U2 43 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD NOV PY 2013 VL 23 IS 11 BP 1256 EP 1269 DI 10.1038/cr.2013.110 PG 14 WC Cell Biology SC Cell Biology GA 248GE UT WOS:000326683600008 PM 23938295 ER PT J AU Sun, Y Li, Q Gui, H Xu, DP Yang, YL Su, DF Liu, X AF Sun, Yang Li, Qi Gui, Huan Xu, Dong-Ping Yang, Yi-Li Su, Ding-Feng Liu, Xia TI MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines SO CELL RESEARCH LA English DT Article DE microRNA-124; cholinergic anti-inflammatory action; alpha 7nAChR; macrophages; septic shock; STAT3; TACE ID KAPPA-B-ZETA; VAGUS NERVE; NICOTINIC RECEPTOR; SIGNAL TRANSDUCER; ENDOTOXIN-SHOCK; CUTTING EDGE; PATHWAY; ACETYLCHOLINE; CELLS; TNF AB The vagus nerve can control inflammatory response through a 'cholinergic anti-inflammatory pathway', which is mediated by the alpha 7-nicotinic acetylcholine receptor (alpha 7nAChR) on macrophages. However, the intracellular mechanisms that link alpha 7nAChR activation and pro-inflammatory cytokine production remain not well understood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cholinergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 (STAT3) to decrease IL-6 production and TNF-alpha converting enzyme (TACE) to reduce TNF-alpha release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases. C1 [Sun, Yang; Li, Qi; Gui, Huan; Xu, Dong-Ping; Su, Ding-Feng; Liu, Xia] Second Mil Med Univ, Sch Pharm, Dept Pharmacol, Shanghai 200433, Peoples R China. [Yang, Yi-Li] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. RP Liu, X (reprint author), Second Mil Med Univ, Sch Pharm, Dept Pharmacol, Shanghai 200433, Peoples R China. EM yiliyang@mail.nih.gov; dfsu2008@gmail.com; lxflying@aliyun.com FU National Key Basic Research Program of China (973 Program) [2009CB521901]; National Natural Science Foundation of China [30973525, 81273606] FX We thank Dr Alan O Perantoni (National Institutes of Health, USA) for critical reading of the manuscript, and Dr Luis G Rodriguez for the STAT3-/- MEFs. This work was supported by the National Key Basic Research Program of China (973 Program; 2009CB521901 to Ding-Feng Su) and the National Natural Science Foundation of China (30973525 and 81273606 to Xia Liu). NR 51 TC 39 Z9 41 U1 3 U2 23 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD NOV PY 2013 VL 23 IS 11 BP 1270 EP 1283 DI 10.1038/cr.2013.116 PG 14 WC Cell Biology SC Cell Biology GA 248GE UT WOS:000326683600009 PM 23979021 ER PT J AU Comlekoglu, DU Thompson, IA Sen, HN AF Comlekoglu, Didar U. Thompson, Ian A. Sen, H. Nida TI Autoimmune retinopathy SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Review DE anti-retinal autoantibodies; autoimmune retinopathy; cancer-associated retinopathy; immunosuppression; melanoma-associated retinopathy; recoverin; uveitis ID CANCER-ASSOCIATED RETINOPATHY; MELANOMA-ASSOCIATED RETINOPATHY; ANTI-RETINAL ANTIBODIES; PARANEOPLASTIC RETINOPATHY; BIPOLAR CELLS; PHOTORECEPTOR DEGENERATION; ANTIRETINAL ANTIBODIES; MALIGNANT-MELANOMA; ALPHA-ENOLASE; CAR SYNDROME AB Purpose of reviewAutoimmune retinopathy (AIR) is an immune-mediated disorder characterized by progressive visual loss, abnormal electroretinographic and visual field findings in the presence of circulating anti-retinal antibodies. This review highlights advances made toward understanding the pathophysiology, clinical manifestations, and trends in the management of AIR.Recent findingsThe pathophysiology of AIR is likely antibody-mediated. AIR serum autoantibodies are variable in their size and retinal tissue they target and can also be present in healthy controls and multiple autoimmune diseases. Rarely, AIR may be associated with dysregulated self-tolerance mechanisms in the thymus. Despite progress in research, our understanding of AIR remains incomplete. Lack of standardized methods for anti-retinal antibody testing continues to challenge the interpretation of seropositivity. Conventional immunosuppressives have been further studied, and promising immunomodulatory therapies, such as targeted B-cell therapy, have been introduced. Newer imaging modalities such as fundus autofluorescence and spectral domain optical coherence tomography may be helpful in diagnosis, monitoring progression of disease and response to treatment.SummaryAIR is a rare but vision-threatening disease whose pathogenesis is poorly defined. Lack of standardized clinical or laboratory criteria further complicates the diagnosis and management. Despite recent progress, further basic science research into the autoimmune process is needed. Prospective controlled clinical trials with immunomodulatory therapy can help define future treatment paradigms C1 [Comlekoglu, Didar U.; Thompson, Ian A.; Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. RP Comlekoglu, DU (reprint author), NEI, NIH, 10 Ctr Dr,10-10N109, Bethesda, MD 20892 USA. EM senh@nei.nih.gov OI Comlekoglu, Erhan/0000-0002-0915-5821 FU National Eye Institute's Intramural Research Program FX None of the authors have any conflicts of interest. This research is supported by the National Eye Institute's Intramural Research Program. NR 74 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 EI 1531-7021 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD NOV PY 2013 VL 24 IS 6 BP 598 EP 605 DI 10.1097/ICU.0b013e3283654e1e PG 8 WC Ophthalmology SC Ophthalmology GA 247BL UT WOS:000326588500011 PM 24100366 ER PT J AU Samsel, L Dagur, PK Raghavachari, N Seamon, C Kato, GJ McCoy, JP AF Samsel, Leigh Dagur, Pradeep K. Raghavachari, Nalini Seamon, Catherine Kato, Gregory J. McCoy, J. Philip, Jr. TI Imaging Flow Cytometry for Morphologic and Phenotypic Characterization of Rare Circulating Endothelial Cells SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE circulating endothelial cells; imaging cytometry; rare event cytometry ID METASTATIC CARCINOMAS; PERIPHERAL-BLOOD AB Endothelial cells in the peripheral circulation are rare events that require technically rigorous approaches for detection by flow cytometry. Visualization of these cells has been even more demanding, as this has historically required extensive enrichment and processing prior to attempting imaging. As a result, few, if any, examples exist on images of peripheral blood circulating endothelial cells (CECs) that include verification of the cell lineage both phenotypically and genomically. In this study, we have devised a method whereby CECs can be directly visualized after lysis of red blood cells and staining, without pre-enrichment or additional processing. Peripheral blood is stained with CD45, CD146, CD3, Hoechst, and DAPI to permit identification of CD146 positive, nonleukocyte, nucleated, and live cells that fit the description of CECs. These cells are imaged using the Amnis ImageStream(X), an imaging flow cytometer. Genomic verification of the endothelial nature of these cells is accomplished by using an aliquot of the same stained samples for sorting CECs using similar gating strategies. This proof of principle of direct imaging of CECs by imaging flow cytometry will permit studies to be conducted heretofore not possible, as the ImageStream(X) has the capability of detecting additional fluorochromes other than those used to identify the CECs. Such potential investigations include antigen colocalization or capping, autophagy and apoptosis, morphologic changes in response to therapy, and others. Thus, this method will enable a broad range of novel studies to be conducted using CECs as surrogates of the endothelium. Published 2013 Wiley-Periodicals, Inc.-/- mice. We also thank J. Wood for Nav1.8-cre mice, C. Pritchard and R. Marais for Brafv650E mice, and Q. Liu, M. Jacquin, G. Giesler, and lab members for comments. J. Jeffry has been supported by a NIDA training grant. The research was supported by RO1 grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to Z.-F. Chen (RO1 AR056318-01A1) and the National Eye Institute (1R01EY022409 and administrative supplement 3R01EY022409-01S1), the Whitehall Foundation (2010-08-61) to J. Zhong, and a NIH RO1 grant to R. Kopan (R01DK066408). NR 60 TC 26 Z9 26 U1 2 U2 21 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 NOV PY 2013 VL 123 IS 11 BP 4769 EP 4780 DI 10.1172/JCI70528 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900024 PM 24216512 ER PT J AU Stewart, CA Metheny, H Iida, N Smith, L Hanson, M Steinhagen, F Leighty, RM Roers, A Karp, CL Muller, W Trinchieri, G AF Stewart, C. Andrew Metheny, Hannah Iida, Noriho Smith, Loretta Hanson, Miranda Steinhagen, Folkert Leighty, Robert M. Roers, Axel Karp, Christopher L. Mueller, Werner Trinchieri, Giorgio TI Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID REGULATORY T-CELLS; PERSISTENT LCMV INFECTION; I INTERFERON; DENDRITIC CELLS; C-MAF; INTERLEUKIN-10-DEFICIENT MICE; ESTABLISHED MELANOMA; IMMUNE SURVEILLANCE; CYTOKINE PRODUCTION; VIRAL-INFECTION AB The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10-producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth. C1 [Stewart, C. Andrew; Metheny, Hannah; Iida, Noriho; Smith, Loretta; Hanson, Miranda; Steinhagen, Folkert; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Steinhagen, Folkert] Univ Hosp Bonn, Dept Anesthesiol & Intens Care Med, Bonn, Germany. [Leighty, Robert M.] Data Management Serv Inc, Frederick Natl Lab Canc Res, Frederick, MD USA. [Roers, Axel] Tech Univ Dresden, Med Fac Carl Gustav Carus, Dresden, Germany. [Karp, Christopher L.] Cincinnati Childrens Hosp Res Fdn, Div Mol Immunol, Cincinnati, OH USA. [Mueller, Werner] Univ Manchester, Fac Life Sci, Bill Ford Chair Cellular Immunol, Manchester, Lancs, England. RP Trinchieri, G (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Bldg 560 Room 31-93, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov RI Stewart, Charles/G-2470-2012; Muller, Werner/B-9044-2008 OI Muller, Werner/0000-0002-1297-9725 FU National Cancer Institute, NIH (NCI/NIH) [HHSN261200800001E] FX We wish to thank Dragana Jankovic, Yasmine Belkaid, Amiran Dzutsev, Romina Goldszmid, Marco Cardone, Elena Riboldi, Rosalba Salcedo, Xin Chen, Cristina Bergamaschi, Howard Young, and Andy Hurwitz for their insight and discussion. We thank Robin Winkler-Pickett and Tim Back for expert technical assistance. We are very grateful to Kathleen Noer and Roberta Matthai of the Cancer and Inflammation Program Flow Cytometry Core for assistance with flow sorting. We also thank Bob Jack, Brian Kelsall, Christian Schindler, Vijay Kuchroo, David Levy, Michel Aguet, Sergei Nedospasov, Shizuo Akira, Christian Saris, and Amgen Inc. for their kind provision of mice. This work was supported by the Intramural Research Program of the National Cancer Institute, NIH (NCI/NIH) under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 100 TC 42 Z9 46 U1 1 U2 21 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 NOV PY 2013 VL 123 IS 11 BP 4859 EP 4874 DI 10.1172/BCI65180 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900032 PM 24216477 ER PT J AU Roy, S Ryals, MM Van den Bruele, AB Fitzgerald, TS Cunningham, LL AF Roy, Soumen Ryals, Matthew M. Van den Bruele, Astrid Botty Fitzgerald, Tracy S. Cunningham, Lisa L. TI Sound preconditioning therapy inhibits ototoxic hearing loss in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HAIR CELL-DEATH; CISPLATIN-INDUCED OTOTOXICITY; HEAT-SHOCK; THRESHOLD SHIFT; HSP70; RATS; CHEMOTHERAPY; PROTECTION; STRESS; INJURY AB Therapeutic drugs with ototoxic side effects cause significant hearing loss for thousands of patients annually. Two major classes of ototoxic drugs are cisplatin and the aminoglycoside antibiotics, both of which are toxic to mechanosensory hair cells, the receptor cells of the inner ear. A critical need exists for therapies that protect the inner ear without inhibiting the therapeutic efficacy of these drugs. The induction of heat shock proteins (HSPs) inhibits both aminoglycoside- and cisplatin-induced hair cell death and hearing loss. We hypothesized that exposure to sound that is titrated to stress the inner ear without causing permanent damage would induce HSPs in the cochlea and inhibit ototoxic drug-induced hearing loss. We developed a sound exposure protocol that induces HSPs without causing permanent hearing loss. We used this protocol in conjunction with a newly developed mouse model of cisplatin ototoxicity and found that preconditioning mouse inner ears with sound has a robust protective effect against cisplatin-induced hearing loss and hair cell death. Sound therapy also provided protection against aminoglycoside-induced hearing loss. These data indicate that sound preconditioning protects against both classes of ototoxic drugs, and they suggest that sound therapy holds promise for preventing hearing loss in patients receiving these drugs. C1 [Roy, Soumen; Ryals, Matthew M.; Van den Bruele, Astrid Botty; Fitzgerald, Tracy S.; Cunningham, Lisa L.] Natl Inst Deafness & Other Commun Disorders NIDCD, NIH, Rockville, MD USA. RP Cunningham, LL (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Ct, Rockville, MD 20850 USA. EM Lisa.cunningham@nih.gov FU NIH/NIDCD [ZIA DC 000079] FX This work was supported by the NIH/NIDCD Division of Intramural Research (ZIA DC 000079). The authors thank Su-Hua Sha, Mark Warchol, Nicole Schmitt, and Tiffany Baker for their insightful discussions about mouse models of cisplatin ototoxicity. We are indebted to Donnie Catts and the NIDCD veterinary staff for their excellent animal care. Our thanks to Dennis Drayna, Thomas Friedman, Andrew Griffith, and Carter VanWaes for their helpful comments on the manuscript. NR 29 TC 17 Z9 17 U1 1 U2 10 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 NOV PY 2013 VL 123 IS 11 BP 4945 EP 4949 DI 10.1172/JCI71353 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900040 PM 24216513 ER PT J AU Goyama, S Schibler, J Cunningham, L Zhang, Y Rao, Y Nishimoto, N Nakagawa, M Olsson, A Wunderlich, M Link, KA Mizukawa, B Grimes, HL Kurokawa, M Liu, PP Huang, G Mulloy, JC AF Goyama, Susumu Schibler, Janet Cunningham, Lea Zhang, Yue Rao, Yalan Nishimoto, Nahoko Nakagawa, Masahiro Olsson, Andre Wunderlich, Mark Link, Kevin A. Mizukawa, Benjamin Grimes, H. Leighton Kurokawa, Mineo Liu, P. Paul Huang, Gang Mulloy, James C. TI Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells (vol 123, pg 3876, 2013) SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Correction C1 [Goyama, Susumu; Schibler, Janet; Zhang, Yue; Rao, Yalan; Wunderlich, Mark; Link, Kevin A.; Mizukawa, Benjamin; Grimes, H. Leighton; Huang, Gang; Mulloy, James C.] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45221 USA. [Cunningham, Lea; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Nishimoto, Nahoko; Nakagawa, Masahiro; Kurokawa, Mineo] Univ Tokyo, Grad Sch Med, Dept Hematol & Oncol, Tokyo, Japan. [Olsson, Andre; Grimes, H. Leighton] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH 45229 USA. RP Goyama, S (reprint author), Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45221 USA. RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 1 TC 2 Z9 2 U1 0 U2 4 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2013 VL 123 IS 11 BP 4979 EP 4979 DI 10.1172/JCI73313 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 247IU UT WOS:000326611900048 ER PT J AU Killian, MS Teque, F Walker, RL Meltzer, PS Killian, JK AF Killian, M. Scott Teque, Fernando Walker, Robert L. Meltzer, Paul S. Killian, J. Keith TI CD8(+) Lymphocytes Suppress Human Immunodeficiency Virus 1 Replication by Secreting Type I Interferons SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID ANTI-HIV RESPONSE; LONG TERMINAL REPEAT; CD8+ T-CELLS; ANTIVIRAL FACTOR; BETA-CHEMOKINES; GENE-EXPRESSION; ANTIRETROVIRAL THERAPY; INFECTED INDIVIDUALS; ANTI-HIV-1 ACTIVITY; ALPHA PRODUCTION AB CD8(+) cells can suppress human immunodeficiency virus 1 (HIV-1) replication by releasing soluble factors. In 26 years of intensive research efforts, the identity of the major CD8(+) cell antiviral factor has remained elusive. To investigate the mechanism for this antiviral immune response, we performed gene expression analyses on primary CD4(+) cells that were exposed to HIV-suppressing CD8(+) cells or CD8(+) cell-conditioned medium having HIV-suppressing activity. These experiments revealed increased levels of multiple genes stimulated by type I interferons (IFN; eg, IFN- and IFN-). Further evaluation revealed that primary CD8(+) cells, particularly those from elite controllers and other asymptomatic HIV-1-infected individuals, secrete IFN, and this response directly contributes to the in vitro suppression of HIV replication in CD4(+) cells. This novel immune response, likely mediated by memory CD8(+) T cells, may play an important role in a wide variety of viral infections, cancers, and autoimmune diseases. C1 [Killian, M. Scott; Teque, Fernando] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Walker, Robert L.; Meltzer, Paul S.; Killian, J. Keith] NCI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Killian, MS (reprint author), Univ Calif San Francisco, Dept Med, 513 Parnassus Ave, San Francisco, CA 94143 USA. EM m.scott.killian@gmail.com FU National Institutes of Health [3P30AI027763-19S2]; California HIV/AIDS Research Program [ID09-SF-058]; NIH National Cancer Institute FX This research was funded by grants from the National Institutes of Health (3P30AI027763-19S2) and the California HIV/AIDS Research Program (ID09-SF-058) and was supported in part by the Intramural Research Program of the NIH National Cancer Institute. NR 65 TC 3 Z9 3 U1 0 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 EI 1557-7465 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD NOV 1 PY 2013 VL 33 IS 11 BP 632 EP 645 DI 10.1089/jir.2012.0067 PG 14 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 242KA UT WOS:000326238100002 PM 23402527 ER PT J AU Doyle, TA de Groot, M Harris, T Schwartz, F Strotmeyer, ES Johnson, KC Kanaya, A AF Doyle, Todd A. de Groot, Mary Harris, Tamara Schwartz, Frank Strotmeyer, Elsa S. Johnson, Karen C. Kanaya, Alka TI Diabetes, depressive symptoms, and inflammation in older adults: Results from the Health, Aging, and Body Composition Study SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Diabetes; Depressive symptoms; Inflammation; Interleukin-6; Tumor necrosis factor-alpha; C-reactive protein ID C-REACTIVE PROTEIN; TUMOR-NECROSIS-FACTOR; LOW-GRADE INFLAMMATION; CELL-ADHESION MOLECULES; CORONARY-HEART-DISEASE; ACUTE-PHASE REACTANTS; FACTOR-ALPHA LEVELS; SCALE CES-D; INSULIN-RESISTANCE; ENDOTHELIAL DYSFUNCTION AB Objective: Up-regulated levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) are common to both type 2 diabetes mellitus (T2DM) and elevated depressive symptoms, yet little attention has been given to the biological mechanisms associated with these co-morbidities. This study examined the association between inflammation and both T2DM and elevated depressive symptoms. Methods: Baseline data were analyzed from 3009 adults, aged 70-79, participating in the Health, Aging, and Body Composition Study. Diabetes was assessed per self-report, medication use, fasting glucose and/or glucose tolerance tests. Elevated depressive symptoms were categorized using the Center for Epidemiologic Studies Depression scale (cut-score >= 20). Log-transformed IL-6, TNF-alpha, and CRP were analyzed using ANCOVA. Results: Participants with T2DM and elevated depressive symptoms (T2DM + DEP n = 14) demonstrated significantly (p < .05) higher IL-6 compared to (T2DM Only n = 628), (DEP Only n = 49), and (No T2DM or DEP n = 2067) groups following covariate adjustment. Similarly, participants with T2DM + DEP (n = 14) had significantly (p < .05) higher CRP, after covariate adjustment, compared to DEP Only (n = 50) and No T2DM or DEP groups (n = 2153). No association was observed for TNF-alpha. Conclusions: These findings provide evidence that inflammation is associated with T2DM and elevated depressive symptoms. Participants with T2DM + DEP demonstrated the highest IL-6 levels compared to all other groups. Greater CRP levels were also observed in T2DM, but not elevated depressive symptoms, which may suggest that differential associations between T2DM and depressive symptoms exist for various inflammatory markers. Further investigation into these associations could aid in understanding the biological pathways underlying both T2DM and depressive symptoms. (C) 2013 Elsevier Inc. All rights reserved. C1 [Doyle, Todd A.] Ohio Univ, Dept Psychol, Athens, OH 45701 USA. [de Groot, Mary] Indiana Univ, Sch Med, Indianapolis, IN USA. [Harris, Tamara] NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. [Schwartz, Frank] Ohio Univ, Inst Diabet, Heritage Coll Osteopath Med, Athens, OH 45701 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Johnson, Karen C.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kanaya, Alka] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. RP Doyle, TA (reprint author), Loyola Univ, Med Ctr, Dept Psychiat & Behav Neurosci, 2160 S 1st Ave, Maywood, IL 60153 USA. EM todddoyle1@lumc.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036 FU Intramural Research Program of the NIH; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; NIDDK [R34DK071545, R18DK092765]; Ohio University Diabetes Research Initiative FX This research was supported by the Intramural Research Program of the NIH, the National Institute on Aging (NIA), and the NIA Contracts N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, NIA grant R01-AG028050, NINR grant R01-NR012459, NIDDK R34DK071545 and NIDDK R18DK092765. The authors would also like to thank the Ohio University Diabetes Research Initiative for their support of this project. NR 62 TC 21 Z9 22 U1 4 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 EI 1879-1360 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD NOV PY 2013 VL 75 IS 5 BP 419 EP 424 DI 10.1016/j.jpsychores.2013.08.006 PG 6 WC Psychiatry SC Psychiatry GA 248NZ UT WOS:000326709500004 PM 24182629 ER PT J AU Weyant, RJ Tracy, SL Anselmo, T Beltran-Aguilar, ED Donly, KJ Frese, WA Hujoel, PP Iafolla, T Kohn, W Kumar, J Levy, SM Tinanoff, N Wright, JT Zero, D Aravamudhan, K Frantsve-Hawley, J Meyer, DM AF Weyant, Robert J. Tracy, Sharon L. Anselmo, Theresa (Tracy) Beltran-Aguilar, Eugenio D. Donly, Kevin J. Frese, William A. Hujoel, Philippe P. Iafolla, Timothy Kohn, William Kumar, Jayanth Levy, Steven M. Tinanoff, Norman Wright, J. Timothy Zero, Domenick Aravamudhan, Krishna Frantsve-Hawley, Julie Meyer, Daniel M. CA Amer Dent Assoc Council Sci TI Topical fluoride for caries prevention Executive summary of the updated clinical recommendations and supporting systematic review SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Caries prevention; caries; evidence-based dentistry; fluoride; practice guidelines; preventive dentistry ID ACIDULATED PHOSPHATE-FLUORIDE; RANDOMIZED CONTROLLED-TRIAL; DENTAL-CARIES; VARNISH DURAPHAT; PRESCHOOL-CHILDREN; APPROXIMAL CARIES; PRIMARY TEETH; ROOT CARIES; PROFESSIONAL APPLICATION; PROPHYLACTIC PASTE AB Background. A panel of experts convened by the American Dental Association (ADA) Council on Scientific Affairs presents evidence-based clinical recommendations regarding professionally applied and prescription-strength, home-use topical fluoride agents for caries prevention. These recommendations are an update of the 2006 ADA recommendations regarding professionally applied topical fluoride and were developed by using a new process that includes conducting a systematic review of primary studies. Types of Studies Reviewed. The authors conducted a search of MEDLINE and the Cochrane Library for clinical trials of professionally applied and prescription-strength topical fluoride agents-including mouthrinses, varnishes, gels, foams and pastes-with caries increment outcomes published in English through October 2012. Results. The panel included 71 trials from 82 articles in its review and assessed the efficacy of various topical fluoride caries-preventive agents. The panel makes recommendations for further research. Practical Implications. The panel recommends the following for people at risk of developing dental caries: 2.26 percent fluoride varnish or 1.23 percent fluoride (acidulated phosphate fluoride) gel, or a prescription-strength, home-use 0.05 percent fluoride gel or paste or 0.09 percent fluoride mouthrinse for patients 6 years or older. Only 2.26 percent fluoride varnish is recommended for children younger than 6 years. The strengths of the recommendations for the recommended products varied from "in favor" to "expert opinion for." As part of the evidence-based approach to care, these clinical recommendations should be integrated with the practitioner's professional judgment and the patient's needs and preferences. C1 [Weyant, Robert J.] Univ Pittsburgh, Dept Dent Publ Hlth, Sch Dent Med, Pittsburgh, PA 15260 USA. [Tracy, Sharon L.] Amer Dent Assoc, Div Sci, Ctr Evidence Based Dent, Chicago, IL 60611 USA. [Anselmo, Theresa (Tracy)] San Luis Obispo Hlth Agcy, Oral Hlth Program, San Luis Obispo, CA USA. [Beltran-Aguilar, Eugenio D.] Ctr Dis Control & Prevent, Div Oral Hlth, Atlanta, GA USA. [Donly, Kevin J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Frese, William A.] Univ Illinois, Dept Pediat, Chicago, IL USA. [Hujoel, Philippe P.] Univ Washington, Sch Dent, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. [Iafolla, Timothy] Natl Inst Dent & Craniofacial Res, Off Sci Policy & Anal, NIH, Bethesda, MD USA. [Kohn, William] Delta Dent Plans Assoc, Oak Brook, IL USA. [Kumar, Jayanth] New York State Dept Hlth, Bur Dent Hlth, Albany, NY 12237 USA. [Kumar, Jayanth] SUNY Albany, Sch Publ Hlth, Albany, NY 12222 USA. [Levy, Steven M.] Univ Iowa, Coll Dent, Dept Prevent & Community Dent, Iowa City, IA 52242 USA. [Levy, Steven M.] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA. [Tinanoff, Norman] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. [Wright, J. Timothy] Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC USA. [Zero, Domenick] Indiana Univ Sch Dent, Dept Prevent & Community Dent, Indianapolis, IN USA. [Zero, Domenick] Indiana Univ Sch Dent, Oral Hlth Res Inst, Indianapolis, IN USA. [Zero, Domenick] Indiana Univ Sch Dent, Indianapolis, IN USA. [Aravamudhan, Krishna] Amer Dent Assoc, Div Dent Practice, Off Qual Assessment & Improvement, Chicago, IL USA. [Frantsve-Hawley, Julie] Amer Dent Assoc, Div Sci, Ctr Evidence Based Dent, Chicago, IL USA. [Meyer, Daniel M.] Amer Dent Assoc, Chicago, IL USA. RP Tracy, SL (reprint author), Amer Dent Assoc, Div Sci, Ctr Evidence Based Dent, 211 E Chicago Ave, Chicago, IL 60611 USA. EM tracys@ada.org FU Centers for Disease Control and Prevention, Atlanta FX The American Dental Association Council on Scientific Affairs Expert Panel on Topical Fluoride Agents commissioned this study, which was supported in part by the Centers for Disease Control and Prevention, Atlanta. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 96 TC 55 Z9 58 U1 3 U2 16 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD NOV PY 2013 VL 144 IS 11 BP 1279 EP 1291 PG 13 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 246DF UT WOS:000326516600012 PM 24177407 ER PT J AU Povsic, TJ Najjar, SS Prather, K Zhou, JY Adams, SD Zavodni, KL Kelly, F Melton, LG Hasselblad, V Heitner, JF Raman, SV Barsness, GW Patel, MR Kim, RJ Lakatta, EG Harrington, RA Rao, SV AF Povsic, Thomas J. Najjar, Samer S. Prather, Kristi Zhou, Jiying Adams, Stacie D. Zavodni, Katherine L. Kelly, Francine Melton, Laura G. Hasselblad, Vic Heitner, John F. Raman, Subha V. Barsness, Gregory W. Patel, Manesh R. Kim, Raymond J. Lakatta, Edward G. Harrington, Robert A. Rao, Sunil V. TI EPC mobilization after erythropoietin treatment in acute ST-elevation myocardial infarction: the REVEAL EPC substudy SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Erythropoietin; Endothelial progenitor cells; Myocardial infarction; Cryopreservation ID ENDOTHELIAL PROGENITOR CELLS; ALDEHYDE DEHYDROGENASE-ACTIVITY; RECOMBINANT-HUMAN-ERYTHROPOIETIN; PERIPHERAL-BLOOD; THERAPY; TRIAL AB Erythropoietin (EPO) was hypothesized to mitigate reperfusion injury, in part via mobilization of endothelial progenitor cells (EPCs). The REVEAL trial found no reduction in infarct size with a single dose of EPO (60,000 U) in patients with ST-segment elevation myocardial infarction. In a substudy, we aimed to determine the feasibility of cryopreserving and centrally analyzing EPC levels to assess the relationship between EPC numbers, EPO administration, and infarct size. As a prespecified substudy, mononuclear cells were locally cryopreserved before as well as 24 and 48-72 h after primary percutaneous coronary intervention. EPC samples were collected in 163 of 222 enrolled patients. At least one sample was obtained from 125 patients, and all three time points were available in 83 patients. There were no significant differences in the absolute EPC numbers over time or between EPO- and placebo-treated patients; however, there was a trend toward a greater increase in EPC levels from 24 to 48-72 h postintervention in patients receiving a parts per thousand yen30,000 U of EPO (P = 0.099 for CD133(+) cells, 0.049 for CD34(+) cells, 0.099 for ALDH(br) cells). EPC numbers at baseline were inversely related to infarct size (P = 0.03 for CD133(+) cells, 0.006 for CD34(+) cells). Local whole cell cryopreservation and central EPC analysis in the context of a multicenter randomized trial is feasible but challenging. High-dose (a parts per thousand yen30,000 U) EPO may mobilize EPCs at 48-72 h, and baseline EPC levels may be inversely associated with infarct size. C1 [Povsic, Thomas J.; Prather, Kristi; Melton, Laura G.; Hasselblad, Vic; Patel, Manesh R.; Harrington, Robert A.; Rao, Sunil V.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Povsic, Thomas J.; Zhou, Jiying; Adams, Stacie D.; Zavodni, Katherine L.; Kelly, Francine; Patel, Manesh R.; Kim, Raymond J.; Harrington, Robert A.; Rao, Sunil V.] Duke Univ, Sch Med, Div Cardiol, Dept Med, Durham, NC 27710 USA. [Povsic, Thomas J.; Rao, Sunil V.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Najjar, Samer S.] MedStar Hlth Res Inst, Washington, DC USA. [Najjar, Samer S.; Lakatta, Edward G.] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Heitner, John F.] New York Methodist Hosp, Brooklyn, NY USA. [Raman, Subha V.] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. [Barsness, Gregory W.] Mayo Clin, Rochester, MN USA. RP Povsic, TJ (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Box 103208, Durham, NC 27710 USA. EM thomas.povsic@duke.edu FU National Institute on Aging, Bethesda, MD, USA [HHS-N-260-2005-00010-C]; Duke Pepper Older Americans Independence Center Research Career Development Program in Aging Research Award, Durham, NC, USA [5P30AG028716] FX The authors would like to thank Peter Hoffmann for thoughtful editorial and logistical support. The REVEAL study was supported by Intramural Research Program contract HHS-N-260-2005-00010-C from the National Institute on Aging, Bethesda, MD, USA. The first author was the recipient of a Duke Pepper Older Americans Independence Center Research Career Development Program in Aging Research Award (5P30AG028716), Durham, NC, USA. NR 21 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2013 VL 36 IS 4 BP 375 EP 383 DI 10.1007/s11239-013-0944-6 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 249UH UT WOS:000326802500003 PM 23700090 ER PT J AU Koutakis, P Weiss, DJ Nella, AA Swanson, SA Zhu, Z Miserlis, D Papoutsi, E Johanning, JM Pipinos, II Casale, GP AF Koutakis, Panagiotis Weiss, Dustin J. Nella, Aikaterini A. Swanson, Stanley A. Zhu, Zhen Miserlis, Dimitrios Papoutsi, Evlampia Johanning, Jason M. Pipinos, Iraklis I. Casale, George P. TI Myofiber Type Sensitivity of Gastrocnemius Muscle to Oxidative Stress in Peripheral Arterial Disease Patients SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT Annual Meeting of the Midwestern-Vascular-Surgical-Society CY SEP 06-08, 2013 CL Chicago, IL SP Midwestern Vasc Surg Soc C1 Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA. Yale Univ Med, New Haven, CT USA. NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD NOV PY 2013 VL 58 IS 5 BP 1436 EP 1436 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 247DE UT WOS:000326593900066 ER PT J AU Law, SHW Sargent, TD AF Law, Sheran H. W. Sargent, Thomas D. TI Maternal pak4 expression is required for primitive myelopoiesis in zebrafish (vol 130, pg 181, 2013) SO MECHANISMS OF DEVELOPMENT LA English DT Correction C1 [Law, Sheran H. W.; Sargent, Thomas D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Sect Vertebrate Dev, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Sargent, TD (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Sect Vertebrate Dev, Program Genom Differentiat, NIH, Bethesda, MD USA. EM sargentt@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 EI 1872-6356 J9 MECH DEVELOP JI Mech. Dev. PD NOV-DEC PY 2013 VL 130 IS 11-12 BP 640 EP 640 DI 10.1016/j.mod.2013.07.003 PG 1 WC Developmental Biology SC Developmental Biology GA 252CV UT WOS:000326983200009 ER PT J AU Lee, HJ Wu, KN Cox, DG Hunter, D Hankinson, SE Willett, WC Sinha, R Cho, EY AF Lee, Hae-Jeung Wu, Kana Cox, David G. Hunter, David Hankinson, Susan E. Willett, Walter C. Sinha, Rashmi Cho, Eunyoung TI Polymorphisms in Xenobiotic Metabolizing Genes, Intakes of Heterocyclic Amines and Red Meat, and Postmenopausal Breast Cancer SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID N-ACETYLTRANSFERASE 2; AROMATIC-AMINES; COLORECTAL-CANCER; MAMMARY-GLAND; O-ACETYLATION; RISK; EXPOSURE; NAT2; HUMANS; WOMEN AB Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly because of genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2-164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses' Health Study. HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk. C1 [Lee, Hae-Jeung; Hunter, David; Hankinson, Susan E.; Willett, Walter C.; Cho, Eunyoung] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Lee, Hae-Jeung; Hankinson, Susan E.; Willett, Walter C.; Cho, Eunyoung] Harvard Univ, Sch Med, Boston, MA USA. [Lee, Hae-Jeung; Wu, Kana; Hunter, David; Willett, Walter C.; Cho, Eunyoung] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Lee, Hae-Jeung] Korea Hlth Ind Dev Inst, Ctr Nutr Policy & Promot, Seoul, South Korea. [Cox, David G.] INSERM, Canc Res Ctr Lyon, UMR1052, F-69008 Lyon, France. [Hunter, David; Hankinson, Susan E.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. [Sinha, Rashmi] Natl Canc Inst, NIH, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Cho, EY (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. EM eunyoung.cho@channing.harvard.edu RI Sinha, Rashmi/G-7446-2015; Cox, David/A-2023-2009 OI Sinha, Rashmi/0000-0002-2466-7462; Cox, David/0000-0002-2152-9259 FU American Institute for Cancer Research; National Cancer Institute, National Institutes of Health [CA 87969] FX This work was supported by a grant from the American Institute for Cancer Research as well as grant CA 87969 from the National Cancer Institute, National Institutes of Health. We are indebted to Rong Tilney for computer support. In addition, we thank the participants and staff of the Nurses' Health Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. NR 56 TC 6 Z9 6 U1 0 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 EI 1532-7914 J9 NUTR CANCER JI Nutr. Cancer PD NOV 1 PY 2013 VL 65 IS 8 BP 1122 EP 1131 DI 10.1080/01635581.2013.824991 PG 10 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 251HL UT WOS:000326918300003 PM 24099317 ER PT J AU Galgani, JE Kelley, DE Albu, JB Krakoff, J Smith, SR Bray, GA Ravussin, E AF Galgani, Jose E. Kelley, David E. Albu, Jeanine B. Krakoff, Jonathan Smith, Steven R. Bray, George A. Ravussin, Eric CA Look AHEAD Adipose Res Grp TI Adipose Tissue Expression of Adipose (WDTC1) Gene Is Associated with Lower Fat Mass and Enhanced Insulin Sensitivity in Humans SO OBESITY LA English DT Article ID OBESITY AB Objective: The overexpression of the adipose gene (adp/WDTC1) in mice inhibits lipid accumulation and improves the metabolic profile. Subcutaneous fat adp expression in humans and its relation to metabolic parameters was evaluated. Design and Methods: Abdominal subcutaneous fat adp expression, insulin sensitivity (clamp), and respiratory quotient (RQ; indirect calorimetry) were assessed in: 36 obese and 56 BMI-, race-, and sex-matched type 2 diabetic volunteers (Look AHEAD Adipose Ancillary Study); 37 nondiabetic Pima Indians including obese (n=18) and nonobese (n=19) subjects and; 62 nonobese nondiabetic subjects at the Pennington Center in the ADAPT study. Results: In the Look AHEAD Study, adp expression normalized for cyclophilin B was higher in males versus females (1.27 +/- 0.06 vs. 1.11 +/- 0.04; P < 0.01) but not after controlling for body fat. Adp expression was not influenced by the presence of diabetes but was related to body fat (r = -0.23; P = 0.03), insulin sensitivity (r = 0.23; P = 0.03) and fasting/insulin-stimulated RQ (r = 0.31 and 0.33; P < 0.01). In Pima Indians, adp expression was also higher in males versus females (1.00 +/- 0.05 vs. 0.77 +/- 0.05; P = 0.02) and higher in nonobese versus obese (1.02 +/- 0.05 vs. 0.80 +/- 0.06; P = 0.03). In the ADAPT study, there was no difference in adp expression between males and females. Conclusion: Consistent with animal studies, our results suggest that high adp expression in human adipose tissue is associated with lower adiposity and enhanced glucose utilization. C1 [Galgani, Jose E.; Bray, George A.; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Galgani, Jose E.] Pontificia Univ Catolica Chile, Dept Nutr Diabet & Metab, Sch Med, Santiago, Chile. [Kelley, David E.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Albu, Jeanine B.] St Lukes Roosevelt Hosp, New York Obes Nutr Res Ctr, New York, NY 10025 USA. [Krakoff, Jonathan] NIDDK, Obes & Diabet Clin Res Section, NIH, Phoenix, AZ USA. [Smith, Steven R.] Sanford Burnham Med Res Inst, Diabet Obes Res Ctr, Sanford, FL USA. RP Ravussin, E (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM eric.ravussin@pbrc.edu FU USDA [2010-34323-21052]; University of Pittsburgh Obesity & Nutrition Research Center [P30-DK46204]; University of Pittsburgh General Clinical Research Center [MO1-RR000056]; Pennington Biomedical Research Center Nutrition Obesity Research Center [P30-DK072476]; Columbia University Diabetes and Endocrinology Research Center [P30-DK63608]; New York Obesity Research Center [P30-DK26687]; Columbia University Clinical Translational Service Award (CTSA) [UL1 RR024156]; International Nutrition Foundation/Ellison Medical Foundation; [DK60412]; [U01 DK056990] FX This study was funded by DK60412 (ER), U01 DK056990 (DEK), USDA 2010-34323-21052 (GAB), University of Pittsburgh Obesity & Nutrition Research Center (P30-DK46204), the University of Pittsburgh General Clinical Research Center (MO1-RR000056), Pennington Biomedical Research Center Nutrition Obesity Research Center (P30-DK072476), the Columbia University Diabetes and Endocrinology Research Center (P30-DK63608), the New York Obesity Research Center (P30-DK26687) and the Columbia University Clinical Translational Service Award (CTSA, UL1 RR024156). JEG was supported by a fellowship from The International Nutrition Foundation/Ellison Medical Foundation. NR 12 TC 2 Z9 3 U1 0 U2 4 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 NOV PY 2013 VL 21 IS 11 BP 2244 EP 2248 DI 10.1002/oby.20371 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 247RO UT WOS:000326637400013 PM 23512946 ER PT J AU Mitchell, S Castro, K St Germain, D Denicoff, A Watkins-Bruner, D O'Mara, A AF Mitchell, Sandra Castro, Kathleen St Germain, Diane Denicoff, Andrea Watkins-Bruner, Deborah O'Mara, Ann TI CAPTURING SYMPTOM BURDEN AND TREATMENT TOLERABILITY IN CANCER CLINICAL TRIALS: NCI'S PATIENT-REPORTED OUTCOMES VERSION OF THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (PRO-CTCAE) SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Mitchell, Sandra; Castro, Kathleen; St Germain, Diane; Denicoff, Andrea; O'Mara, Ann] NCI, Rockville, MD USA. [Watkins-Bruner, Deborah] Emory Univ, Nell Hodgson Woodruff Sch Nursing, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD NOV PY 2013 VL 40 IS 6 SU S BP E454 EP E454 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 250IV UT WOS:000326847400106 ER PT J AU Elder, AM Henderson, DM Nalls, AV Wilham, JM Caughey, BW Hoover, EA Kincaid, AE Bartz, JC Mathiason, CK AF Elder, Alan M. Henderson, Davin M. Nalls, Amy V. Wilham, Jason M. Caughey, Byron W. Hoover, Edward A. Kincaid, Anthony E. Bartz, Jason C. Mathiason, Candace K. TI In Vitro Detection of prionemia in TSE-Infected Cervids and Hamsters SO PLOS ONE LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; CHRONIC WASTING DISEASE; SCRAPIE VIRUS-INFECTION; BLOOD-TRANSFUSION; CYCLIC AMPLIFICATION; SEEDED CONVERSION; PROTEIN; TRANSMISSION; SHEEP; DEER AB Blood-borne transmission of infectious prions during the symptomatic and asymptomatic stages of disease occurs for both human and animal transmissible spongiform encephalopathies (TSEs). The geographical distribution of the cervid TSE, chronic wasting disease (CWD), continues to spread across North America and the prospective number of individuals harboring an asymptomatic infection of human variant Creutzfeldt-Jakob Disease (vCJD) in the United Kingdom has been projected to be similar to 1 in 3000 residents. Thus, it is important to monitor cervid and human blood products to ensure herd health and human safety. Current methods for detecting blood-associated prions rely primarily upon bioassay in laboratory animals. While bioassay provides high sensitivity and specificity, it requires many months, animals, and it is costly. Here we report modification of the real time quaking-induced conversion (RT-QuIC) assay to detect blood-borne prions in whole blood from prion-infected preclinical white-tailed deer, muntjac deer, and Syrian hamsters, attaining sensitivity of > 90% while maintaining 100% specificity. Our results indicate that RT-QuIC methodology as modified can provide consistent and reliable detection of blood-borne prions in preclinical and symptomatic stages of two animal TSEs, offering promise for prionemia detection in other species, including humans. C1 [Elder, Alan M.; Henderson, Davin M.; Nalls, Amy V.; Hoover, Edward A.; Mathiason, Candace K.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Wilham, Jason M.; Caughey, Byron W.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Kincaid, Anthony E.; Bartz, Jason C.] Creighton Univ, Omaha, NE 68178 USA. RP Mathiason, CK (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. EM candace.mathiason@colostate.edu RI Mathiason, Candace/E-7843-2017; OI Mathiason, Candace/0000-0002-5920-4556; Bartz, Jason/0000-0003-4081-7886 FU Morris Animal Foundation [D12ZO-045]; [NIH-RO1 093634-01]; [NIH-R01 N5061902]; [NIAID-NO1-AI-25491]; [RO1 NS061994]; [RO1 NS061994-03S1] FX The work at Colorado State University was supported by NIH-RO1 093634-01, NIH-R01 N5061902, NIAID-NO1-AI-25491 and Morris Animal Foundation D12ZO-045. Work done at Creighton University was supported by RO1 NS061994 and RO1 NS061994-03S1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 28 Z9 28 U1 0 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 NOV 1 PY 2013 VL 8 IS 11 AR e80203 DI 10.1371/journal.pone.0080203 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245XZ UT WOS:000326499300097 PM 24224043 ER PT J AU Weng, MT Luo, J AF Weng, Meng-Tzu Luo, Ji TI The enigmatic ERH protein: its role in cell cycle, RNA splicing and cancer SO PROTEIN & CELL LA English DT Review DE enhancer of rudimentary homolog; mRNA splicing; mitosis; CENP-E; KRAS; colorectal cancer ID RUDIMENTARY HOMOLOG ERH; ZINC-FINGER PROTEIN; TRANSCRIPTIONAL REPRESSOR; DROSOPHILA-MELANOGASTER; MOLECULAR PARTNER; CRYSTAL-STRUCTURE; HUMAN ENHANCER; RAS ONCOGENE; GENE; CHROMOSOME AB Enhancer of rudimentary homolog (ERH) is a small, highly conserved protein among eukaryotes. Since its discovery nearly 20 years ago, its molecular function has remained enigmatic. It has been implicated to play a role in transcriptional regulation and in cell cycle. We recently showed that ERH binds to the Sm complex and is required for the mRNA splicing of the mitotic motor protein CENP-E. Furthermore, cancer cells driven by mutations in the KRAS oncogene are particularly sensitive to RNAi-mediated suppression of ERH function, and ERH expression is inversely correlated with survival in colorectal cancer patients whose tumors harbor KRAS mutation. These recent findings indicate that ERH plays an important role in cell cycle through its mRNA splicing activity and is critically required for genomic stability and cancer cell survival. C1 [Weng, Meng-Tzu; Luo, Ji] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Luo, J (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM ji.luo@nih.gov FU Liver Disease Prevention and Treatment Research Foundation of Taiwan; U.S. National Cancer Institute FX This work is supported by the Liver Disease Prevention and Treatment Research Foundation of Taiwan to M.Z.W. and by the Intramural Program of the U.S. National Cancer Institute to J.L. NR 35 TC 6 Z9 6 U1 0 U2 5 PU HIGHER EDUCATION PRESS PI BEIJING PA SHATANHOU ST 55, BEIJING 100009, PEOPLES R CHINA SN 1674-800X EI 1674-8018 J9 PROTEIN CELL JI Protein Cell PD NOV PY 2013 VL 4 IS 11 BP 807 EP 812 DI 10.1007/s13238-013-3056-3 PG 6 WC Cell Biology SC Cell Biology GA 251OQ UT WOS:000326939900002 PM 24078386 ER PT J AU Geras-Raaka, E Neumann, S Gershengorn, MC AF Geras-Raaka, Elizabeth Neumann, Susanne Gershengorn, Marvin C. TI Persistent cAMP Signaling by TSH Receptors Revealed by Phosphodiesterase Inhibition SO THYROID LA English DT Article ID THYROTROPIN RECEPTOR; HORMONE-RECEPTOR; AGONIST AB Background: It is controversial whether persistent signaling by the thyrotropin (TSH) receptor (TSHR) is cell-type specific. We reported persistent TSHR signaling in human embryonic kidney 293 (HEK293) cells expressing human TSHRs (HEK-TSHRs), whereas another group reported persistent signaling in mouse thyroid follicles but not in HEK293 cells. Herein, we test this hypothesis directly. Methods: We used two methods to measure persistent signaling in HEK-TSHRs and confirm our previous observations. In Method 1, we used a chemiluminescent immunoassay to measure intracellular cAMP accumulation over 30-60min by adding a phosphodiesterase inhibitor to the incubation medium. In Method 2, we used an intracellular biosensor to record cAMP levels continuously. Results: Using Method 1, we show that TSHR signals persistently in human thyrocytes and human osteosarcoma U2OS-TSHR cells. Using Method 1 in HEK-TSHRs, we show that after 5min, the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) increases cAMP to 2.5 pmol/well, TSH increases cAMP to 1.6 pmol/well, but IBMX added 30min after TSH withdrawal increases cAMP to 105 pmol/well. Using Method 2 in HEK-TSHRs, we confirm that without IBMX, TSH causes a transient increase in cAMP and 30min after TSH withdrawal, IBMX increases cAMP in cells pretreated with TSH more rapidly and to a higher level than IBMX added to cells not pre-exposed to TSH. Lastly, using Method 2, we show that in HEK-TSHRs phosphodiesterases types 3 and 4 are involved in degrading cAMP as the specific inhibitors Rolipram and Milrinone expose persistent TSHR signaling. Conclusions: We conclude that persistent TSHR activation occurs in human thyrocytes, U2OS-TSHR cells and HEK-TSHRs; it is not cell-type specific but is revealed by inhibiting phosphodiesterases. C1 [Geras-Raaka, Elizabeth; Neumann, Susanne; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, LERB, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU Intramural Research Program of the NIH [1 Z01 DK011006] FX This research was supported by the Intramural Research Program of the NIH (1 Z01 DK011006). We thank Bernice Samuels for her excellent technical assistance and Alisa Boutin for generating U2OS-TSHR cells. NR 13 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD NOV 1 PY 2013 VL 23 IS 11 BP 1484 EP 1489 DI 10.1089/thy.2013.0089 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 246YV UT WOS:000326578800019 PM 23713896 ER PT J AU Flegel, WA Chiosea, I Sachs, UJ Bein, G AF Flegel, Willy A. Chiosea, Ion Sachs, Ulrich J. Bein, Gregor TI External quality assessment in molecular immunohematology: the INSTAND proficiency test program SO TRANSFUSION LA English DT Editorial Material ID INTERNATIONAL WORKSHOP; ALLOIMMUNE THROMBOCYTOPENIA; NEUTROPHIL ALLOANTIGENS; SEROLOGY WORKSHOP; HUMAN PLATELET; BLOOD; TRANSFUSION; DNA; ANTIGENS; SOCIETY AB BackgroundGenotyping for red blood cell (RBC), platelet (PLT), and granulocyte antigens is a new tool for clinical pathology, transfusion medicine services, and blood banks. Proficiency in laboratory tests can be established by external quality assessments (EQAs), which are required for clinical application in many health care systems. There are few EQAs for molecular immunohematology. Study Design and MethodsWe analyzed the participation and pass rates in an EQA for RBC, PLT, and granulocyte antigens. This EQA was distributed by INSTAND, a large nonprofit provider of proficiency tests, twice per year since Fall 2006 as EQA Number 235 Immunohematology A (molecular diagnostic). The coordinators defined at the outset which alleles are mandatory for detection. ResultsThe number of participants steadily increased from 51 to 73 per proficiency by Fall 2012. More than 60 institutions utilized this EQA at least once a year. Approximately 80% of them participated in RBC, 68% in PLT, and 22% in granulocyte systems. With the exceptions of RHD (82%) and granulocytes (85%), pass rates exceeded 93%. While the pass rate increased for granulocyte and decreased for the ABO system, the pass rates for the other systems changed little over 61/2 years. ConclusionsThe INSTAND proficiency test program was regularly used for EQA by many institutions, particularly in Central Europe. While the technical standards and pass rates in the participating laboratories were high, there has been little improvement in pass rates since 2006. C1 [Flegel, Willy A.; Chiosea, Ion] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Sachs, Ulrich J.; Bein, Gregor] Univ Giessen, Inst Clin Immunol & Transfus Med, Giessen, Germany. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 55 TC 3 Z9 3 U1 0 U2 4 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 NOV PY 2013 VL 53 IS 11 SI SI BP 2850 EP 2858 DI 10.1111/trf.12414 PN PT2 PG 9 WC Hematology SC Hematology GA 249HP UT WOS:000326768600007 PM 24111785 ER PT J AU Velliquette, RW Hue-Roye, K Lomas-Francis, C Gillen, B Schierts, J Gentzkow, K Peyrard, T von Zabern, I Flegel, WA Rodberg, K Debnath, AK Lee, S Reid, ME AF Velliquette, Randall W. Hue-Roye, Kim Lomas-Francis, Christine Gillen, Barbara Schierts, Jennifer Gentzkow, Kristie Peyrard, Thierry von Zabern, Inge Flegel, Willy A. Rodberg, Karen Debnath, Asim K. Lee, Soohee Reid, Marion E. TI Molecular basis of two novel and related high-prevalence antigens in the Kell blood group system, KUCI and KANT, and their serologic and spatial association with K11 and KETI SO TRANSFUSION LA English DT Article ID INTERNATIONAL SOCIETY; POINT MUTATIONS; GROUP PROTEIN; PHENOTYPE; EXPRESSION; GLYCOPROTEIN; TERMINOLOGY; VARIANT; SERINE; ALLELE AB BackgroundThe numerous antigens in the Kell blood group system result from missense nucleotide changes in KEL. Antibodies to antigens in this system can be clinically important. We describe six probands whose plasma contained antibodies to high-prevalence Kell antigens and discuss their relationship. Study Design and MethodsPolymerase chain reaction amplification, direct sequencing, restriction fragment length polymorphism assays, hemagglutination, flow cytometry, and protein modeling were performed by standard methods. ResultsProband 1 (KUCI) and her serologically compatible sister were heterozygous for a nucleotide change in Exon 11 (KEL*1271C/T; Ala424Val). Proband 2 (KANT) was heterozygous for KEL*1283G/T (Arg428Leu) and KEL*1216C/T (Arg406Stop) in Exon 11. Red blood cells (RBCs) from Proband 1 and her sister were not agglutinated by plasma from Proband 2; however, RBCs from Proband 2 were agglutinated by plasma from Proband 1. Probands 3, 4, 5, and 6 had the KEL*1391C>T change associated with the previously reported KETI- phenotype. Proband 5 was also homozygous for KEL*905T>C encoding the K11-K17+ phenotype. Hemagglutination studies revealed an association between KUCI, KANT, KETI, and K11. Protein modeling indicated that whereas Ala424 and Arg428 are clustered, Val302 and Thr464 are not. ConclusionAla424 in the Kell glycoprotein is associated with the high-prevalence Kell antigen, KUCI (ISBT 006032), which is detected by the antibody of Proband 1. Arg428 is associated with the high-prevalence Kell antigen, KANT (ISBT 006033). The association between KUCI, KANT, KETI, and K11 and the results of protein modeling are discussed. C1 New York Blood Ctr, Lab Immunohematol & Genom, Long Isl City, NY USA. New York Blood Ctr, Lab Immunochem, Lab Mol Modeling & Drug Design, New York, NY 10065 USA. New York Blood Ctr, Lab Membrane Biochem, New York, NY 10065 USA. Mem Blood Ctr, St Paul, MN USA. Medctr One, Bismarck, ND USA. Natl Inst Blood Transfus, Natl Reference Ctr Blood Grp, Paris, France. Univ Hosp Ulm, Dept Transfus Med, Inst Clin Transfus Med & Immunogenet, Ulm, Germany. Baden Wurttemberg Hessen, Inst Ulm, German Red Cross Blood Donor Serv, Ulm, Germany. NIH, Lab Serv Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Amer Red Cross, Pomona, CA USA. RP Reid, ME (reprint author), New York Blood Ctr, Lab Immunochem, 310 East 67 St, New York, NY 10065 USA. EM mreid@nybloodcenter.org FU NIH [R01 HL075716] FX This study was funded in part by NIH grant R01 HL075716 (SL). NR 43 TC 5 Z9 5 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 NOV PY 2013 VL 53 IS 11 SI SI BP 2872 EP 2881 DI 10.1111/trf.12200 PN PT2 PG 10 WC Hematology SC Hematology GA 249HP UT WOS:000326768600010 PM 23560718 ER PT J AU Orzinska, A Guz, K Polin, H Pelc-Klopotowska, M Bednarz, J Gielezynska, A Sliwa, B Kowalewska, M Pawlowska, E Wlodarczyk, B Malaga, M Zmudzin, A Krzemienowska, M Srivastava, K Michalewska, B Gabriel, C Flegel, WA Brojer, E AF Orzinska, Agnieszka Guz, Katarzyna Polin, Helene Pelc-Klopotowska, Monika Bednarz, Justyna Gielezynska, Agata Sliwa, Beata Kowalewska, Malgorzata Pawlowska, Elzbieta Wlodarczyk, Boguslawa Malaga, Malgorzata Zmudzin, Alicja Krzemienowska, Magdalena Srivastava, Kshitij Michalewska, Bogumila Gabriel, Christian Flegel, Willy A. Brojer, Ewa TI RHD variants in Polish blood donors routinely typed as D- SO TRANSFUSION LA English DT Article ID ANTI-D IMMUNIZATION; WEAK-D PHENOTYPES; MOLECULAR-BASIS; D ALLOIMMUNIZATION; CELL UNITS; D-EL; ALLELES; GENE; IDENTIFICATION; GERMANY AB BackgroundBlood donors exhibiting a weak D or DEL phenotypical expression may be mistyped D- by standard serology hence permitting incompatible transfusion to D- recipients. Molecular methods may overcome these technical limits. Our aim was to estimate the frequency of RHD alleles among the apparently D- Polish donor population and to characterize its molecular background. Study Design and MethodsPlasma pools collected from 31,200 consecutive Polish donors typed as D- were tested by real-time polymerase chain reaction (PCR) for the presence of RHD-specific markers located in Intron 4 and Exons 7 and 10. RHD+ individuals were characterized by PCR or cDNA sequencing and serology. ResultsPlasma cross-pool strategy revealed 63 RHD+ donors harboring RHD*01N.03 (n=17), RHD*15 (n=12), RHD*11 (n=7), RHD*DEL8 (n=3), RHD*01W.2 (n=3), RHD-CE(10) (n=3), RHD*01W.3, RHD*01W.9, RHD*01N.05, RHD*01N.07, RHD*01N.23, and RHD(IVS1-29G>C) and two novel alleles, RHD*(767C>G) (n=3) and RHD*(1029C>A). Among 47 cases available for serology, 27 were shown to express the D antigen Conclusion1) Plasma cross-pool strategy is a reliable and cost-effective tool for RHD screening. 2) Only 0.2% of D- Polish donors carry some fragments of the RHD gene; all of them were C or E+. 3) Almost 60% of the detected RHD alleles may be potentially immunogenic when transfused to a D- recipient. C1 Inst Hematol & Blood Transfus, Dept Immunohematol & Immunol Transfus Med, PL-00957 Warsaw, Poland. Reg Blood Transfus Ctr, Warsaw, Poland. Reg Blood Transfus Ctr, Krakow, Poland. Reg Blood Transfus Ctr, Gdansk, Poland. Reg Blood Transfus Ctr, Raciborz, Poland. Reg Blood Transfus Ctr, Kalisz, Poland. Reg Blood Transfus Ctr, Kielce, Poland. Reg Blood Transfus Ctr, Radom, Poland. Red Cross Transfus Ctr Upper Austria, Linz, Austria. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Orzinska, A (reprint author), Inst Hematol & Blood Transfus, 5th Chocimska St, PL-00957 Warsaw, Poland. EM aorzinska@ihit.waw.pl; kguz@ihit.waw.pl RI Gabriel, Christian/A-1689-2014 OI Gabriel, Christian/0000-0003-2043-9320 FU Polish Committee for Scientific Research [N N404 188036] FX This study was supported by Grant N N404 188036 from the Polish Committee for Scientific Research. NR 39 TC 6 Z9 6 U1 0 U2 7 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 NOV PY 2013 VL 53 IS 11 SI SI BP 2945 EP 2953 DI 10.1111/trf.12230 PN PT2 PG 9 WC Hematology SC Hematology GA 249HP UT WOS:000326768600019 PM 23634715 ER PT J AU von Zabern, I Wagner, FF Moulds, JM Moulds, JJ Flegel, WA AF von Zabern, Inge Wagner, Franz F. Moulds, Joann M. Moulds, John J. Flegel, Willy A. TI D category IV: a group of clinically relevant and phylogenetically diverse partial D SO TRANSFUSION LA English DT Article ID BLOOD-GROUP SYSTEM; RH ANTIGEN-D; WEAK-D-TYPES; MOLECULAR-BASIS; D-EPITOPES; COORDINATORS REPORT; D PHENOTYPES; AMINO-ACIDS; ALLELES; EXPRESSION AB BackgroundThe D typing strategies in several European countries protect carriers of D category VI (DVI) from anti-D immunization but not carriers of other partial D. Besides DVI, one of the clinically most important partial D is D category IV (DIV). A detailed description and direct comparison of the different DIV types was missing. Study Design and MethodsRHD nucleotide sequences were determined from genomic DNA. D epitope patterns were established with commercial monoclonal anti-D panels. ResultsDIV comprises several variants of the D antigen with distinct serology, molecular structures, evolutionary origins, and ethnic prevalences. The DIV phenotype is determined by 350H shared by all, but not limited to, DIV variants which are further divided into DIVa and DIVb. The DIVa phenotype is expressed by DIV Type 1.0 harboring 350H and the dispersed amino acids 62F, 137V, and 152T. The DIVb phenotype is expressed by DIV Type 3 to Type 5 representing RHD-CE-D hybrids. Four of the six postulated DIV variants were encountered among 23 DIV samples analyzed. Of 12 DIV carriers with anti-D, 10 were female and seven likely immunized by pregnancy. Two DIV-related alleles are newly described: DWN, which differs from DIV Type 4 by 350D and epitope pattern. DNT carries 152T, known to cause a large D antigen density. ConclusionDIV alleles arose from at least two independent evolutionary events. DIV Type 1.0 with DIVa phenotype belongs to the oldest extant human RHD alleles. DIV Type 2 to Type 5 with DIVb phenotype arose from more recent gene conversions. Anti-D immunization, especially dreaded in pregnancies, will be avoided not only in carriers of DVI but also in carriers of other D variants like DIV, if our proposed D typing strategy is adopted. C1 Univ Hosp, Dept Transfus Med, Ulm, Germany. Inst Clin Transfus Med & Immunogenet, Ulm, Germany. Inst Ulm, DRK German Red Cross Blood Donor Serv Baden Wurtt, Ulm, Germany. Inst Springe, DRK Blood Donor Serv NSTOB, Springe, Germany. LifeShare Blood Ctrs, Sci Support Serv, Shreveport, LA USA. [Flegel, Willy A.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Flegel, WA (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10,Room 1C733C,10 Ctr Dr, Bethesda, MD 20892 USA. EM bill.flegel@nih.gov FU Intramural Research Programs of the DRK-Blutspendedienst Baden-Wurttemberg-Hessen, Mannheim; NIH Clinical Center FX This work was supported by the Intramural Research Programs of the DRK-Blutspendedienst Baden-Wurttemberg-Hessen, Mannheim, and the NIH Clinical Center. NR 74 TC 5 Z9 5 U1 0 U2 3 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 NOV PY 2013 VL 53 IS 11 SI SI BP 2960 EP 2973 DI 10.1111/trf.12145 PN PT2 PG 14 WC Hematology SC Hematology GA 249HP UT WOS:000326768600021 PM 23461862 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, DR Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean R. Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a new national approach to surveillance for ventilator-associated events: Executive summary SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Ventilator-associated pneumonia; Intensive care unit; Epidemiology; Public health; Critical care; Mechanical ventilation AB In September 2011, the Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group to organize a formal process for leaders and experts of key stakeholder organizations to discuss the challenges of VAP surveillance definitions and to propose new approaches to VAP surveillance in adult patients (Table 1). The charges to the Working Group were to (1) critically review a draft, streamlined VAP surveillance definition developed for use in adult patients; (2) suggest modifications to enhance the reliability and credibility of the surveillance definition within the critical care and infection prevention communities; and (3) propose a final adult surveillance definition algorithm to be implemented in the CDC's National Healthcare Safety Network (NHSN), taking into consideration the potential future use of the definition algorithm in public reporting, interfacility comparisons, and pay-for-reporting and pay-for-performance programs. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30329 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Div Infect Dis, Carver Coll Med, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Surveillance Working Grp, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Zablocki VA Med Ctr, Dept Cardiol, Milwaukee, WI USA. [Henderson, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean R.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Hess, Dean R.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Hess, Dean R.] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Hlth Sci Ctr, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Territorial Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-24, Atlanta, GA 30329 USA. EM smagill@cdc.gov OI Diekema, Daniel/0000-0003-1273-0724 FU Centers for Disease Control and Prevention (CDC) FX Supported by the Centers for Disease Control and Prevention (CDC). NR 2 TC 3 Z9 4 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD NOV PY 2013 VL 41 IS 11 BP 1096 EP 1099 DI 10.1016/j.ajic.2013.07.001 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 242KY UT WOS:000326241700031 PM 24176770 ER PT J AU Bailit, JL Grobman, WA Rice, MM Spong, CY Wapner, RJ Varner, MW Thorp, JM Leveno, KJ Caritis, SN Shubert, PJ Tita, AT Saade, G Sorokin, Y Rouse, DJ Blackwell, SC Tolosa, JE Van Dorsten, JP AF Bailit, Jennifer L. Grobman, William A. Rice, Madeline Murguia Spong, Catherine Y. Wapner, Ronald J. Varner, Michael W. Thorp, John M. Leveno, Kenneth J. Caritis, Steve N. Shubert, Phillip J. Tita, Alan T. Saade, George Sorokin, Yoram Rouse, Dwight J. Blackwell, Sean C. Tolosa, Jorge E. Van Dorsten, J. Peter CA Eunice Kennedy Shriver Natl Inst C TI Risk-adjusted models for adverse obstetric outcomes and variation in risk-adjusted outcomes across hospitals SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE obstetrics; performance improvement; quality; risk adjustment ID QUALITY IMPROVEMENT; CARE; HEMORRHAGE; INDICATORS; DELIVERY; DATABASE; SOCIETY; SURGERY AB OBJECTIVE: Regulatory bodies and insurers evaluate hospital quality using obstetrical outcomes, however meaningful comparisons should take preexisting patient characteristics into account. Furthermore, if risk-adjusted outcomes are consistent within a hospital, fewer measures and resources would be needed to assess obstetrical quality. Our objective was to establish risk-adjusted models for 5 obstetric outcomes and assess hospital performance across these outcomes. STUDY DESIGN: We studied a cohort of 115,502 women and their neonates born in 25 hospitals in the United States from March 2008 through February 2011. Hospitals were ranked according to their unadjusted and risk-adjusted frequency of venous thromboembolism, postpartum hemorrhage, peripartum infection, severe perineal laceration, and a composite neonatal adverse outcome. Correlations between hospital risk-adjusted outcome frequencies were assessed. RESULTS: Venous thromboembolism occurred too infrequently (0.03%; 95% confidence interval [CI], 0.02-0.04%) for meaningful assessment. Other outcomes occurred frequently enough for assessment (postpartum hemorrhage, 2.29%; 95% CI, 2.20-2.38, peripartum infection, 5.06%; 95% CI, 4.93e5.19, severe perineal laceration at spontaneous vaginal delivery, 2.16%; 95% CI, 2.06-2.27, neonatal composite, 2.73%; 95% CI, 2.63-2.84). Although there was high concordance between unadjusted and adjusted hospital rankings, several individual hospitals had an adjusted rank that was substantially different (as much as 12 rank tiers) than their unadjusted rank. None of the correlations between hospital-adjusted outcome frequencies was significant. For example, the hospital with the lowest adjusted frequency of peripartum infection had the highest adjusted frequency of severe perineal laceration. CONCLUSION: Evaluations based on a single risk-adjusted outcome cannot be generalized to overall hospital obstetric performance. C1 [Bailit, Jennifer L.] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet, Cleveland, OH 44106 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, MetroHlth Med Ctr, Dept Gynecol, Cleveland, OH 44106 USA. [Grobman, William A.] Northwestern Univ, Chicago, IL 60611 USA. [Wapner, Ronald J.] Columbia Univ, New York, NY USA. [Varner, Michael W.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Shubert, Phillip J.] Ohio State Univ, St Anns Hosp, Columbus, OH 43210 USA. [Tita, Alan T.] Univ Alabama Birmingham, Birmingham, AL USA. [Saade, George] Univ Texas Med Branch, Galveston, TX 77555 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Rouse, Dwight J.] Brown Univ, Providence, RI 02912 USA. [Blackwell, Sean C.] Univ Texas Hlth Sci Ctr Houston, Childrens Mem Hermann Hosp, Houston, TX 77030 USA. [Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Van Dorsten, J. Peter] Med Univ S Carolina, Charleston, SC 29425 USA. [Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, MetroHlth Med Ctr, Dept Obstet, Cleveland, OH 44106 USA. RI Romano, Patrick/N-4225-2014; Varner, Michael/K-9890-2013 OI Romano, Patrick/0000-0001-6749-3979; caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118]; National Center for Research Resources (NCRR) [UL1 RR024989, 5UL1 RR025764] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD21410, HD27869, HD27915, HD27917, HD34116, HD34208, HD36801, HD40500, HD40512, HD40544, HD40545, HD40560, HD40485, HD53097, HD53118) and the National Center for Research Resources (NCRR) (UL1 RR024989; 5UL1 RR025764) and its contents do not necessarily represent the official views of the NICHD, NCRR, or National Institutes of Health. NR 23 TC 5 Z9 5 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD NOV PY 2013 VL 209 IS 5 AR 446.e1 DI 10.1016/j.ajog.2013.07.019 PG 30 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 242LP UT WOS:000326243700017 PM 23891630 ER PT J AU Rom, S Zuluaga-Ramirez, V Dykstra, H Reichenbach, NL Pacher, P Persidsky, Y AF Rom, Slava Zuluaga-Ramirez, Viviana Dykstra, Holly Reichenbach, Nancy L. Pacher, Pal Persidsky, Yuri TI Selective Activation of Cannabinoid Receptor 2 in Leukocytes Suppresses Their Engagement of the Brain Endothelium and Protects the Blood-Brain Barrier SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TRANSENDOTHELIAL MIGRATION; INTEGRIN CONFORMATION; MONOCYTE MIGRATION; HUMAN NEUTROPHILS; CELL-ACTIVATION; POTENTIAL ROLE; IMMUNE CELLS; INFLAMMATION; ADHESION AB Cannabinoid receptor 2 (CB2) is highly expressed in immune cells and stimulation decreases inflammatory responses. We tested the idea that selective CB2 activation in human monocytes suppresses their ability to engage the brain endothelium and migrate across the blood-brain barrier (BBB), preventing consequent injury. Intravital videomicroscopy was used to quantify adhesion of leukocytes to cortical vessels in lipopolysaccharide-induced neuroinflammation, after injection of ex vivo CB2-activated leukocytes into mice; CB2 agonists markedly decreased adhesion of ex vivo Labeled cells in vivo. In an in vitro BBB model, CB2 activation in monocytes Largely attenuated adhesion to and migration across monotayers of primary human brain microvascular endothelial cells and diminished BBB damage. CB2 stimulation in monocytes down-regulated active forms of integrins, lymphocyte function-associated antigen 1 (LFA-1), and very late antigen 4 (VLA-4). Cells treated with CB2 agonists exhibited increased phosphorylation levels of inhibitory sites of the actin-binding proteins cofilin and VASP, which are upstream regulators of conformational integrin changes. Up-regulated by relevant stimuli, Rac1 and RhoA were suppressed by CB2 agonists in monocytes. CB2 stimulation decreased formation of lamellipodia, which play a key role in monocyte migration. These results indicate that selective CB2 activation in Leukocytes decreases key steps in monocyte-BBB engagement, thus suppressing inflammatory leukocyte responses and preventing neuroinflammation. C1 [Rom, Slava; Zuluaga-Ramirez, Viviana; Dykstra, Holly; Reichenbach, Nancy L.; Persidsky, Yuri] Temple Univ, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19140 USA. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Persidsky, Y (reprint author), Temple Univ, Sch Med, Dept Pathol & Lab Med, 3401 N Broad St, Philadelphia, PA 19140 USA. EM srom@temple.edu; persidsky@tuhs.temple.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU NIH [R01 AA015913, R01 MH65151]; Intramural Research Program of the NIH-NIAAA FX Supported in part by NIH grants R01 AA015913 and R01 MH65151 (Y.P.) and by the Intramural Research Program of the NIH-NIAAA (P.P.). NR 55 TC 18 Z9 19 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2013 VL 183 IS 5 BP 1548 EP 1558 DI 10.1016/j.ajpath.2013.07.033 PG 11 WC Pathology SC Pathology GA 246QE UT WOS:000326553400021 PM 24055259 ER PT J AU Gallos, G Remy, KE Danielsson, J Funayama, H Fu, XW Chang, HYS Yim, P Xu, DB Emala, CW AF Gallos, George Remy, Kenneth E. Danielsson, Jennifer Funayama, Hiromi Fu, Xiao Wen Chang, Herng-Yu Sucie Yim, Peter Xu, Dingbang Emala, Charles W., Sr. TI Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE RT-PCR; MQAE; immunohistochemistry; electrophysiology; airway smooth muscle ID CA2+-ACTIVATED CL-CHANNELS; MUSCARINIC SIGNALING PATHWAY; PIG TRACHEAL MYOCYTES; RABBIT COLONOCYTES; PRIMARY CULTURES; CA2+ SPARKS; CELLS; CONTRACTION; CURRENTS; CANINE AB Airway smooth muscle hyperresponsiveness is a key component in the pathophysiology of asthma. Although calcium-activated chloride channel (CaCC) flux has been described in many cell types, including human airway smooth muscle (HASM), the true molecular identity of the channels responsible for this chloride conductance remains controversial. Recently, a new family of proteins thought to represent the true CaCCs was identified as the TMEM16 family. This led us to question whether members of this family are functionally expressed in native and cultured HASM. We further questioned whether expression of these channels contributes to the contractile function of HASM. We identified the mRNA expression of eight members of the TMEM16 family in HASM cells and show immunohistochemical evidence of TMEM16A in both cultured and native HASM. Functionally, we demonstrate that the classic chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), inhibited halide flux in cultured HASM cells. Moreover, HASM cells displayed classical electrophysiological properties of CaCCs during whole cell electrophysiological recordings, which were blocked by using an antibody selective for TMEM16A. Furthermore, two distinct TMEM16A antagonists (tannic acid and benzbromarone) impaired a substance P-induced contraction in isolated guinea pig tracheal rings. These findings demonstrate that multiple members of this recently described family of CaCCs are expressed in HASM cells, they display classic electrophysiological properties of CaCCs, and they modulate contractile tone in airway smooth muscle. The TMEM16 family may provide a novel therapeutic target for limiting airway constriction in asthma. C1 [Gallos, George; Danielsson, Jennifer; Fu, Xiao Wen; Chang, Herng-Yu Sucie; Yim, Peter; Xu, Dingbang; Emala, Charles W., Sr.] Columbia Univ Coll Phys & Surg, Dept Anesthesiol, New York, NY 10032 USA. [Remy, Kenneth E.] NIH, Ctr Clin, Dept Crit Care, Bethesda, MD 20892 USA. [Funayama, Hiromi] Tsurumi Univ, Sch Dent Med, Dept Pediat Dent, Tsurumi Ku, Yokohama, Kanagawa, Japan. RP Gallos, G (reprint author), Columbia Univ Coll Phys & Surg, Dept Anesthesiol, 622 W 168th St P&S Box 46, New York, NY 10032 USA. EM gg2125@columbia.edu OI Remy, Kenneth/0000-0001-5222-9884 FU National Institutes of Health [GM093137, GM065281, GM008464]; Foundation for Anesthesia Education and Research; National Center for Research Resources [ULI RR 024156] FX This work was supported by National Institutes of Health grants [G. Gallos (GM093137); C. W. Emala (GM065281); and P. D. Yim (GM008464)]; The Foundation for Anesthesia Education and Research (H. S. Chang); and the National Center for Research Resources ULI RR 024156. NR 32 TC 14 Z9 15 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 EI 1522-1504 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD NOV PY 2013 VL 305 IS 9 BP L625 EP L634 DI 10.1152/ajplung.00068.2013 PG 10 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 246WK UT WOS:000326571100005 PM 23997176 ER PT J AU Schnermann, J Huang, YN Mizel, D AF Schnermann, Jurgen Huang, Yuning Mizel, Diane TI Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE micropuncture; iothalamate; tubular fluid osmolarity; paracellular; transcellular ID GLOMERULAR-FILTRATION-RATE; TIGHT JUNCTION; LUMINAL HYPOTONICITY; WATER PERMEABILITY; MEDIATED REDUCTION; MEMBRANE-PROTEINS; EPITHELIAL-CELLS; NEPHRON FUNCTION; DEFICIENT MICE; DRIVING-FORCE AB Deletions of claudin-2 (Cldn2) and aquaporin1 (AQP1) reduce proximal fluid reabsorption (PFR) by about 30% and 50%, respectively. Experiments were done to replicate these observations and to determine in AQP1/claudin-2 double knockout mice (DKO) if the effects of deletions of these established water pores are additive. PFR was determined in inactin/ketamine-anesthetized mice by free-flow micropuncture using single-nephron I-125-iothalamate (io) clearance. Animal means of PFR [% of glomerular filtration rate (GFR)] derived from TF/Piothalamate ratios in 12 mice in each of four groups [wild type (WT), Cldn2(-/-), AQP1(-/-), and DKO) were 45.8 +/- 0.85 (51 tubules), 35.4 +/- 1 (54 tubules; P < 0.01 vs. WT), 36.8 +/- 1 (63 tubules; P < 0.05 vs. WT), and 33.9 +/- 1.4 (69 tubules; P < 0.01 vs. WT). Kidney and single-nephron GFRs (SNGFR) were significantly reduced in all mutant strains. The direct relationship between PFR and SNGFR was maintained in mutant mice, but the slope of this relationship was reduced in the absence of Cldn2 and/or AQP1. Transtubular osmotic pressure differences were not different between WT and Cldn2(-/-) mice, but markedly increased in DKO. In conclusion, the deletion of Cldn2, AQP1, or of both Cldn2 and AQP1 reduces PFR by 22.7%, 19.6%, and 26%, respectively. Our data are consistent with an up to 25% paracellular contribution to PFR. The reduced osmotic water permeability caused by absence of AQP1 augments luminal hypotonicity. Aided by a fall in filtered load, the capacity of non-AQP1-dependent transcellular reabsorption is sufficient to maintain PFR without AQP1 and claudin-2 at 75% of control. C1 [Schnermann, Jurgen; Huang, Yuning; Mizel, Diane] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Rm 4D51,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK-043408-12] FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK-043408-12 to the Kidney Disease Branch). The authors acknowledge valuable discussions with Drs. Mark Knepper and Josephine Briggs. NR 46 TC 20 Z9 20 U1 0 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD NOV PY 2013 VL 305 IS 9 BP F1352 EP F1364 DI 10.1152/ajprenal.00342.2013 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 247BI UT WOS:000326588100012 PM 24049145 ER PT J AU Roth, MY Ilani, N Wang, C Page, ST Bremner, WJ Swerdloff, RS Dart, C Sitruk-Ware, R Kumar, N Blithe, D Amory, JK AF Roth, M. Y. Ilani, N. Wang, C. Page, S. T. Bremner, W. J. Swerdloff, R. S. Dart, C. Sitruk-Ware, R. Kumar, N. Blithe, D. Amory, J. K. TI Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone (R) gels SO ANDROLOGY LA English DT Article DE contraception; gonadotropins; nestorone; spermatogenesis; testosterone ID NORMAL MEN; INDUCED AZOOSPERMIA; CHINESE MEN; UNDECANOATE; EFFICACY; DISCONTINUATION; LEVONORGESTREL; GONADOTROPINS; COMBINATION; SECRETION AB Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5-10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to <1million/mL after 24weeks. Indeed, luteinizing hormone or follicle-stimulating hormone concentrations greater than 1IU/L after 4weeks of transdermal testosterone/nestorone treatment were 97% sensitive for predicting failure to suppress spermatogenesis after 24weeks of treatment. Serum nestorone concentrations were significantly associated with suppression, but serum testosterone concentrations were not. Early suppression of gonadotropins is associated with, but does not ensure, adequate suppression of spermatogenesis. This information may allow for rapid identification of non-responders in male hormonal contraceptive trials. C1 [Roth, M. Y.; Page, S. T.; Bremner, W. J.; Amory, J. K.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Ilani, N.; Wang, C.; Swerdloff, R. S.] Harbor UCLA Med Ctr, Dept Med, Div Endocrinol, Torrance, CA 90509 USA. [Ilani, N.; Wang, C.; Swerdloff, R. S.] Los Angeles Biomed Res Inst, Torrance, CA USA. [Dart, C.] Hlth Decis, Durham, NC USA. [Sitruk-Ware, R.; Kumar, N.] Populat Council, Ctr Biomed Res, New York, NY 10021 USA. [Blithe, D.] NICHHD, Contracept & Reprod Hlth Branch, NIH, Bethesda, MD 20892 USA. RP Roth, MY (reprint author), Univ Washington, 1959 NE Pacific St,Box 357138, Seattle, WA 98195 USA. EM mylang@u.washington.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN 2752004033691, HHSN 2751008060044U, U54 HD-42454, K12 HD053984]; Population Council; Endocrinology, Metabolism and Nutrition Training Grant [T32 DK007571]; UCLA Clinical and Translational Science Institute at Harbor-UCLA Medical Center [UL1TR000124]; Los Angeles Biomedical Research Institute FX The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development contracts HHSN 2752004033691 and HHSN 2751008060044U, and the Population Council. The University of Washington site was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development through cooperative agreement U54 HD-42454 as part of the Cooperative Contraceptive Research Centers Program and through K12 HD053984. The Los Angeles Center was supported by the Endocrinology, Metabolism and Nutrition Training Grant (T32 DK007571), and the UCLA Clinical and Translational Science Institute (UL1TR000124) at Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute. The authors acknowledge the gift of testosterone gel through Paul Piette, MD, Besins Health Care International; the help and assistance provided by Sharon Midler and her team for monitoring the study at Health Decisions; Elizabeth Ruiz, Xiao-Dan Han, Kathy Winter, Robert Bale Jr., Iris Nielsen, Connie Pete and Dorothy McGuinness for their help in coordinating the study; Christin Snyder, MD, for helping recruit and evaluate patients at the UW site; Andrew Leung, HTC, Sima Baravarian, PhD and technologists of the Hormone and Metabolic Research Laboratory at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center for all the hormone analyses. NR 27 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD NOV PY 2013 VL 1 IS 6 BP 899 EP 905 DI 10.1111/j.2047-2927.2013.00135.x PG 7 WC Andrology SC Endocrinology & Metabolism GA 239MT UT WOS:000326030400016 PM 24123845 ER PT J AU Tsilidis, KK Rohrmann, S McGlynn, KA Nyante, SJ Lopez, DS Bradwin, G Feinleib, M Joshu, CE Kanarek, N Nelson, WG Selvin, E Platz, EA AF Tsilidis, K. K. Rohrmann, S. McGlynn, K. A. Nyante, S. J. Lopez, D. S. Bradwin, G. Feinleib, M. Joshu, C. E. Kanarek, N. Nelson, W. G. Selvin, E. Platz, E. A. TI Association between endogenous sex steroid hormones and inflammatory biomarkers in US men SO ANDROLOGY LA English DT Article DE C-reactive protein; cross-sectional study; estradiol; testosterone; white blood cell ID C-REACTIVE PROTEIN; MIDDLE-AGED MEN; HYPOGONADAL MEN; PROSTATE-CANCER; OLDER MEN; TESTOSTERONE REPLACEMENT; SERUM TESTOSTERONE; METABOLIC SYNDROME; ANDROGEN RECEPTOR; ELDERLY-MEN AB Sex steroid hormones and inflammatory biomarkers are both associated with the development and progression of chronic diseases, but their interrelationship is relatively uncharacterized. We examined the association of sex hormones and sex hormone-binding globulin (SHBG) with biomarkers of inflammation, C-reactive protein (CRP) and white blood cell (WBC) count. The study included data from 809 adult men in the National Health and Nutrition Examination Survey 1999-2004. Geometric means and 95% confidence intervals were estimated separately for CRP and WBC concentrations by sex steroid hormones and SHBG using weighted linear regression models. Higher concentrations of total (slope per one quintile in concentration, -0.18; p-trend, 0.001) and calculated free (slope, -0.13; p-trend, 0.03) testosterone were statistically significantly associated with lower concentrations of CRP, but not with WBC count. Men in the bottom quintile of total testosterone (3.3ng/mL), who might be considered to have clinically low testosterone, were more likely to have elevated CRP (3mg/L) compared with men in the top four quintiles (OR, 1.61; 95% CI, 1.00-2.61). Total and calculated free estradiol (E2) were positively associated with both CRP (Total E2: slope, 0.14; p-trend, <0.001; Free E2: slope, 0.15; p-trend, <0.001) and WBC (Total E2: slope, 0.02; p-trend, 0.08; Free E2: slope, 0.02; p-trend, 0.02) concentrations. SHBG concentrations were inversely associated with WBC count (slope, -0.03; p-trend, 0.04), but not with CRP. These cross-sectional findings are consistent with the hypothesis that higher androgen and lower oestrogen concentrations may have an anti-inflammatory effect in men. C1 [Tsilidis, K. K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Rohrmann, S.] Univ Zurich, Inst Social & Prevent Med, CH-8006 Zurich, Switzerland. [McGlynn, K. A.; Nyante, S. J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lopez, D. S.] Univ Texas Sch Publ Hlth, Div Epidemiol, Houston, TX USA. [Bradwin, G.] Harvard Univ, Sch Med, Dept Lab Med, Boston, MA USA. [Bradwin, G.] Childrens Hosp, Boston, MA 02115 USA. [Feinleib, M.; Joshu, C. E.; Selvin, E.; Platz, E. A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Kanarek, N.; Nelson, W. G.; Platz, E. A.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Kanarek, N.; Nelson, W. G.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Nelson, W. G.; Platz, E. A.] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Nelson, W. G.] Johns Hopkins Med Inst, Dept Oncol, Baltimore, MD 21205 USA. [Nelson, W. G.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Nelson, W. G.] Johns Hopkins Med Inst, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Nelson, W. G.] Johns Hopkins Med Inst, Dept Radiat Oncol, Baltimore, MD 21205 USA. [Nelson, W. G.] Johns Hopkins Med Inst, Dept Mol Radiat Sci, Baltimore, MD 21205 USA. [Selvin, E.; Platz, E. A.] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. RP Tsilidis, KK (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Stavros Niarchos Av, GR-45110 Ioannina, Greece. EM ktsilidi@cc.uoi.gr FU Maryland Cigarette Restitution Fund at Johns Hopkins University FX This is the 11th paper from the Hormone Demonstration Program, which was funded by the Maryland Cigarette Restitution Fund at Johns Hopkins University. The measurement of sex steroid hormone concentrations was supported by the Intramural Research Program of the National Cancer Institute, USA. NR 46 TC 5 Z9 6 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD NOV PY 2013 VL 1 IS 6 BP 919 EP 928 DI 10.1111/j.2047-2927.2013.00129.x PG 10 WC Andrology SC Endocrinology & Metabolism GA 239MT UT WOS:000326030400019 PM 24124163 ER PT J AU McManus, DD Beaulieu, LM Mick, E Tanriverdi, K Larson, MG Keaney, JF Benjamin, EJ Freedman, JE AF McManus, David D. Beaulieu, Lea M. Mick, Eric Tanriverdi, Kahraman Larson, Martin G. Keaney, John F. Benjamin, Emelia J. Freedman, Jane E. TI Relationship Among Circulating Inflammatory Proteins, Platelet Gene Expression, and Cardiovascular Risk SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE cardiovascular disease; inflammation; mRNA platelets ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; INTERCELLULAR-ADHESION MOLECULE-1; GENOME-WIDE ASSOCIATION; BLOOD MONONUCLEAR-CELLS; TOLL-LIKE RECEPTOR-4; INTERLEUKIN-6 RECEPTOR; METABOLIC SYNDROME; PLASMA; MEN AB Objective Cardiovascular disease is a complex disorder influenced by interactions of genetic variants with environmental factors. However, there is no information from large community-based studies examining the relationship of circulating cell-specific RNA to inflammatory proteins. In light of the associations among inflammatory biomarkers, obesity, platelet function, and cardiovascular disease, we sought to examine the relationships of C-reactive protein (CRP) and interleukin-6 (IL-6) to the expression of key inflammatory transcripts in platelets. Approach and Results We quantified circulating levels of CRP and IL-6 in 1625 participants of the Framingham Heart Study (FHS) Offspring cohort examination 8 (mean age, 66.66.6 years; 46% men). We measured the expression of 15 relevant genes by high-throughput quantitative reverse transcriptase polymerase chain reaction from platelet-derived RNA and used multivariable regression to relate serum concentrations of CRP and IL-6 with gene expression. Levels of CRP and IL-6 were associated with 10 of the 15 platelet-derived inflammatory transcripts, ALOX5, CRP, IFIT1, IL6, PTGER2, S100A9, SELENBP1, TLR2, TLR4, and TNFRSF1B (P<0.001). Associations between platelet mRNA expression with CRP and IL-6 persisted after multivariable adjustment for potentially confounding factors. Six genes positively associated with CRP or IL-6 in the FHS sample were also upregulated in megakaryocytes in response to CRP or IL-6 exposure. Conclusions Our data highlight the strong connection between the circulating inflammatory biomarkers CRP and IL-6 and platelet gene expression, adjusting for cardiovascular disease risk factors. Our results also suggest that body weight may directly influence these associations. C1 [McManus, David D.; Tanriverdi, Kahraman; Larson, Martin G.; Freedman, Jane E.] NHLBI, Framingham, MA USA. [McManus, David D.; Tanriverdi, Kahraman; Larson, Martin G.; Freedman, Jane E.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [McManus, David D.; Beaulieu, Lea M.; Tanriverdi, Kahraman; Keaney, John F.; Freedman, Jane E.] Univ Massachusetts, Sch Med, Dept Med, Div Cardiol, Worcester, MA USA. [McManus, David D.; Mick, Eric] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Worcester, MA USA. [Benjamin, Emelia J.] Boston Univ, Dept Med, Sect Cardiovasc Med, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Dept Med, Prevent Med Sect, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP McManus, DD (reprint author), Univ Massachusetts, Sch Med, Div Cardiol, Worcester, MA 01655 USA. EM mcmanusd@ummhc.org OI Benjamin, Emelia/0000-0003-4076-2336; Mick, Eric/0000-0001-8505-8145 FU National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) [N01-HC 25195, RFA-HL-12-008, RO1 HL087201A, 1RO1 HL64753, R01 HL076784, 1 R01 AG028321]; NIH [1U01HL105268-01, KL2RR031981]; National Institute of Allergy and Infectious Disease [P01 AI078894] FX This work was supported by N01-HC 25195, RFA-HL-12-008 (to J.E. Freedman, E. Mick), RO1 HL087201A (to J.E. Freedman, K. Tanriverdi), RFA-HL-12-008 (to J.E. Freedman), and 1RO1 HL64753, R01 HL076784, and 1 R01 AG028321 (to E.J. Benjamin) from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH). Partial salary support is additionally provided by NIH grants 1U01HL105268-01 (to D. D. McManus) and KL2RR031981 (to D. D. McManus). L. M. Beaulieu is supported by P01 AI078894 from the National Institute of Allergy and Infectious Disease. NR 62 TC 15 Z9 15 U1 7 U2 16 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 NOV PY 2013 VL 33 IS 11 BP 2666 EP 2673 DI 10.1161/ATVBAHA.112.301112 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 244VQ UT WOS:000326418700030 PM 23968978 ER PT J AU Aibara, D Matsusue, K Matsuo, K Takiguchi, S Gonzalez, FJ Yamano, S AF Aibara, Daisuke Matsusue, Kimihiko Matsuo, Kohei Takiguchi, Soichi Gonzalez, Frank J. Yamano, Shigeru TI Expression of Hepatic Fat-Specific Protein 27 Depends on the Specific Etiology of Fatty Liver SO BIOLOGICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE fat-specific protein 27; peroxisome proliferator-activated receptor; fatty liver ID ACTIVATED RECEPTOR-GAMMA; DIET-INDUCED STEATOHEPATITIS; DNA-FRAGMENTATION-FACTOR; LEPTIN-DEFICIENT MICE; PPAR-GAMMA; CELL-DEATH; ADIPOCYTE DIFFERENTIATION; EFFECTOR C; FSP27; STEATOSIS AB Fat-specific protein 27 gene (FSP27), isolated by screening for genes specifically expressed in fully differentiated mouse adipocytes, belongs to the cell death-inducing DNA fragmentation factor, alpha subunit-like effector family. FSP27 is induced in not only adipose tissue but also the liver of ob/ob mice, and it promotes the development of fatty liver. The FSP27 gene is expressed in a fatty liver-specific manner and is not detected in the normal mouse liver. FSP27 expression is directly regulated by the induction of the hepatic peroxisome proliferator-activated receptor gamma (PPAR gamma) in ob/ob fatty liver. In the present study, expression of hepatic FSP27 mRNA was determined in non-genetic fatty liver models. The FSP27 gene was markedly induced in the high-fat- or methionine- and choline-deficient (MCD) diet-induced fatty liver, but it was not elevated in alcohol-induced fatty liver. Interestingly, the induction of FSP27 mRNA due to the MCD diet was independent of PPAR gamma levels and completely absent in the liver from PPAR gamma-null mice. These results suggest that FSP27 mRNA expression in the liver depends on the etiology of fatty liver. C1 [Aibara, Daisuke; Matsusue, Kimihiko; Matsuo, Kohei; Yamano, Shigeru] Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, Fukuoka 8140180, Japan. [Takiguchi, Soichi] Natl Kyushu Canc Ctr, Inst Clin Res, Minami Ku, Fukuoka 8111395, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Matsusue, K (reprint author), Fukuoka Univ, Fac Pharmaceut Sci, Jonan Ku, 8-19-1 Nanakuma, Fukuoka 8140180, Japan. EM matsusuk@fukuoka-u.ac.jp FU Mochida Memorial Foundation for Medical; KAKENHI [22590253] FX This work was supported by a Grant from the Mochida Memorial Foundation for Medical and from KAKENHI (22590253). NR 31 TC 6 Z9 6 U1 0 U2 0 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0918-6158 J9 BIOL PHARM BULL JI Biol. Pharm. Bull. PD NOV PY 2013 VL 36 IS 11 BP 1766 EP 1772 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 244AQ UT WOS:000326359900019 PM 24189421 ER PT J AU Chang, CM Chia, VM Gunter, MJ Zanetti, KA Ryan, BM Goodman, JE Harris, CC Weissfeld, J Huang, WY Chanock, S Yeager, M Hayes, RB Berndt, SI AF Chang, Cindy M. Chia, Victoria M. Gunter, Marc J. Zanetti, Krista A. Ryan, Brid M. Goodman, Julie E. Harris, Curtis C. Weissfeld, Joel Huang, Wen-Yi Chanock, Stephen Yeager, Meredith Hayes, Richard B. Berndt, Sonja I. CA Genetics Epidemiology Colorectal C TI Innate immunity gene polymorphisms and the risk of colorectal neoplasia SO CARCINOGENESIS LA English DT Article ID FACTOR-KAPPA-B; COLON-CANCER; INTESTINAL TUMORIGENESIS; BACTERIAL-INFECTIONS; RANDOMIZED-TRIALS; RECTAL-CANCER; METAANALYSIS; ASSOCIATION; ASPIRIN; INFLAMMATION AB Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested casecontrol study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (ORper T allele 0.68, 95% CI: 0.570.83, P 7.7 10(5), adjusted P 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (ORper T allele 0.41, 95% CI: 0.300.55, P 2.4 10(9)) than for adenoma (ORper T allele 0.84, 95%CI: 0.691.03, P 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (ORper T allele 0.5, 95% CI: 0.370.69 and ORper T allele 0.72, 95% CI: 0.540.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia. C1 [Chang, Cindy M.; Chia, Victoria M.; Huang, Wen-Yi; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Gunter, Marc J.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Zanetti, Krista A.] Div Canc Control & Populat Sci, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Rockville, MD 20892 USA. [Zanetti, Krista A.; Ryan, Brid M.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Goodman, Julie E.] Gradient Corp, Cambridge, MA 02138 USA. [Weissfeld, Joel] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA. [Chanock, Stephen] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Gaithersburg, MD 20892 USA. [Chanock, Stephen; Yeager, Meredith] NCI, Canc Genom Res Lab, SAIC Frederick, Frederick, MD 20892 USA. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. RP Berndt, SI (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS, 9609 Med Ctr Dr,Room 6E610,MSC 9771, Bethesda, MD 20892 USA. EM berndts@mail.nih.gov RI KURY, Sebastien/G-5971-2015; Brenner, Hermann/B-4627-2017; OI KURY, Sebastien/0000-0001-5497-0465; Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Center for Cancer Research at the National Cancer Institute, National Institutes of Health; National Institutes of Health [U01 CA137088, R01 CA059045, U01 CA074783, R01 CA60987, K05 CA154337]; Canadian Institutes of Health Research; Canadian Cancer Society Research Institute; Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NHLBI; HHS [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics and the Center for Cancer Research at the National Cancer Institute, National Institutes of Health; National Institutes of Health (U01 CA137088, R01 CA059045) to The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Funding for participating studies from GECCO follows: ARCTIC: National Institutes of Health (U01 CA074783); a GL2 grant from the Canadian Institutes of Health Research; and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1) and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). VITAL: National Institutes of Health (K05 CA154337). WHI: National Institutes of Health, NHLBI and HHS (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C). NR 52 TC 0 Z9 0 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD NOV PY 2013 VL 34 IS 11 BP 2512 EP 2520 DI 10.1093/carcin/bgt228 PG 9 WC Oncology SC Oncology GA 247WV UT WOS:000326655200009 PM 23803696 ER PT J AU Nagababu, E Rifkind, JM AF Nagababu, Enika Rifkind, Joseph M. TI Routes for Formation of S-Nitrosothiols in Blood SO CELL BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE S-nitrosothiols; Nitric oxide; Blood; Hemoglobin; S-nitrosation; Metalloproteins ID NITRIC-OXIDE SYNTHASE; DINITROSYL-IRON COMPLEXES; VASCULAR SMOOTH-MUSCLE; FREE-RADICAL MECHANISM; SERUM-ALBUMIN; BIOLOGICAL-SYSTEMS; NITROGEN MONOXIDE; HUMAN PLASMA; RED-CELL; IN-VIVO AB S-nitrosothiols (RSNO) are involved in post-translational modifications of many proteins analogous to protein phosphorylation. In addition, RSNO have many physiological roles similar to nitric oxide ((NO)-N-aEuro cent), which are presumably involving the release of (NO)-N-aEuro cent from the RSNO. However, the much longer life span in biological systems for RSNO than (NO)-N-aEuro cent suggests a dominant role for RSNO in mediating (NO)-N-aEuro cent bioactivity. RSNO are detected in plasma in low nanomolar levels in healthy human subjects. These RSNO are believed to be redirecting the (NO)-N-aEuro cent to the vasculature. However, the mechanism for the formation of RSNO in vivo has not been established. We have reviewed the reactions of (NO)-N-aEuro cent with oxygen, metalloproteins, and free radicals that can lead to the formation of RSNO and have evaluated the potential for each mechanism to provide a source for RSNO in vivo. C1 [Nagababu, Enika; Rifkind, Joseph M.] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Nagababu, E (reprint author), NIA, Mol Dynam Sect, NIH, 251 Bayview Blvd,Rm 5B131, Baltimore, MD 21224 USA. EM enikan@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health, and USA FX This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, and USA. NR 163 TC 8 Z9 8 U1 0 U2 20 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1085-9195 EI 1559-0283 J9 CELL BIOCHEM BIOPHYS JI Cell Biochem. Biophys. PD NOV PY 2013 VL 67 IS 2 SI SI BP 385 EP 398 DI 10.1007/s12013-011-9321-2 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 242YP UT WOS:000326282900018 PM 22161622 ER PT J AU Yang, CZ Rahimpour, S Yu, ACH Lonser, RR Zhuang, ZP AF Yang, Chunzhang Rahimpour, Shervin Yu, Albert C. H. Lonser, Russell R. Zhuang, Zhengping TI Regulation and dysregulation of astrocyte activation and implications in tumor formation SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Glia; Astrocytoma; Gliosis; Brain tumor; Tumorigenesis; Central nervous system ID FIBRILLARY ACIDIC PROTEIN; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ENDOTHELIAL GROWTH-FACTOR; GLIOBLASTOMA STEM-CELLS; P2 PURINERGIC RECEPTORS; CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD-INJURY; NF-KAPPA-B; REACTIVE ASTROCYTES; BETA-CATENIN AB Astrocytic activation is a cellular response to disturbances of the central nervous system (CNS). Recent advances in cellular and molecular biology have demonstrated the remarkable changes in molecular signaling, morphology, and metabolism that occur during astrocyte activation. Based on these studies, it has become clear that the astrocyte activation process is regulated by a variety of signaling pathways, which result in metabolic support, wound healing and scar formation. While normal astrocyte activation pathways drive homeostasis and/or repair in the CNS, dysregulation of these pathways can lead to astrocyte abnormalities, including glioma formation with similar phenotypes as reactive astrocytes. We review the principle pathways responsible for astrocytic activation, as well as their potential contribution to tumor formation in the CNS. C1 [Yang, Chunzhang; Rahimpour, Shervin; Lonser, Russell R.; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Yu, Albert C. H.] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci,Minist Educ,Neurosci Res Inst, Dept Neurobiol,Minist Publ Hlth,Key Lab Neurosci, Beijing 100871, Peoples R China. RP Yang, CZ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 3D20, Bethesda, MD 20892 USA. EM yangc2@ninds.nih.gov; zhuangp@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX This research was supported by the intramural research program in the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 116 TC 5 Z9 6 U1 1 U2 20 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD NOV PY 2013 VL 70 IS 22 BP 4201 EP 4211 DI 10.1007/s00018-013-1274-8 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 239VD UT WOS:000326052900001 PM 23420481 ER PT J AU Magill, SS Klompas, M Balk, R Burns, SM Deutschman, CS Diekema, D Fridkin, S Greene, L Guh, A Gutterman, D Hammer, B Henderson, D Hess, D Hill, NS Horan, T Kollef, M Levy, M Septimus, E VanAntwerpen, C Wright, D Lipsett, P AF Magill, Shelley S. Klompas, Michael Balk, Robert Burns, Suzanne M. Deutschman, Clifford S. Diekema, Daniel Fridkin, Scott Greene, Linda Guh, Alice Gutterman, David Hammer, Beth Henderson, David Hess, Dean Hill, Nicholas S. Horan, Teresa Kollef, Marin Levy, Mitchell Septimus, Edward VanAntwerpen, Carole Wright, Don Lipsett, Pamela TI Developing a New, National Approach to Surveillance for Ventilator-Associated Events SO CRITICAL CARE MEDICINE LA English DT Article DE ventilator-associated pneumonia; intensive care unit; epidemiology; public health; critical care; mechanical ventilation ID DIAGNOSTIC-TECHNIQUES; RANDOMIZED-TRIAL; PNEUMONIA RATES; INFECTIONS; VALIDATION; CRITERIA; DEFINITIONS AB Objective: To develop and implement an objective, reliable approach to surveillance for ventilator-associated events in adult patients. Design: The Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group in September 2011. Working Group members included representatives of stakeholder societies and organizations and federal partners. Main results: The Working Group finalized a three-tier, adult surveillance definition algorithm for ventilator-associated events. The algorithm uses objective, readily available data elements and can identify a broad range of conditions and complications occurring in mechanically ventilated adult patients, including but not limited to VAP. The first tier definition, ventilator-associated condition (VAC), identifies patients with a period of sustained respiratory deterioration following a sustained period of stability or improvement on the ventilator, defined by changes in the daily minimum fraction of inspired oxygen or positive end-expiratory pressure. The second tier definition, infection-related ventilator-associated complication (IVAC), requires that patients with VAC also have an abnormal temperature or white blood cell count, and be started on a new antimicrobial agent. The third tier definitions, possible and probable VAP, require that patients with IVAC also have laboratory and/or microbiological evidence of respiratory infection. Conclusions: Ventilator-associated events surveillance was implemented in January 2013 in the CDC's National Healthcare Safety Network. Modifications to improve surveillance may be made as additional data become available and users gain experience with the new definitions. C1 [Magill, Shelley S.; Fridkin, Scott; Guh, Alice; Horan, Teresa] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Klompas, Michael] Brigham & Womens Hosp, Infect Control Dept, Boston, MA 02115 USA. [Klompas, Michael] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Balk, Robert] Rush Univ, Sch Med, Div Pulm & Crit Care Med, Chicago, IL 60612 USA. [Balk, Robert; Burns, Suzanne M.; Deutschman, Clifford S.; Gutterman, David; Hammer, Beth; Hill, Nicholas S.; Kollef, Marin; Levy, Mitchell; Lipsett, Pamela] Amer Thorac Soc, Amer Coll Chest Phys, Soc Crit Care Med, Crit Care Soc Collaborat Amer Assoc Crit Care Nur, New York, NY USA. [Burns, Suzanne M.] Univ Virginia, Sch Nursing Crit & Acute Care, Charlottesville, VA USA. [Deutschman, Clifford S.] Univ Penn, Perelman Sch Med, Dept Anesthesiol & Crit Care, Philadelphia, PA 19104 USA. [Diekema, Daniel] Univ Iowa, Carver Coll Med, Div Infect Dis, Iowa City, IA USA. [Diekema, Daniel] Healthcare Infect Control Practices Advisory Comm, Atlanta, GA USA. [Greene, Linda] Rochester Gen Hlth Syst, Infect Prevent & Control Dept, Rochester, NY USA. [Greene, Linda] Assoc Profess Infect Control & Epidemi, Washington, DC USA. [Gutterman, David] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Hammer, Beth] Med Coll Wisconsin, Zablocki Vet Adm Med Ctr, Dept Cardiol, Milwaukee, WI 53226 USA. [Henderson, David] NIH, Hosp Epidemiol & Qual Improvement, Ctr Clin, Bethesda, MD 20892 USA. [Hess, Dean] Massachusetts Gen Hosp, Dept Res Care, Boston, MA 02114 USA. [Hess, Dean] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hess, Dean] Amer Assoc Resp Care, Irving, TX USA. [Hill, Nicholas S.] Tufts Med Ctr, Div Pulm & Crit Care Med, Boston, MA USA. [Kollef, Marin] Washington Univ, Div Pulm & Crit Care Med, St Louis, MO USA. [Levy, Mitchell] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Divis Pulm Crit Care & Sleep, Providence, RI 02903 USA. [Septimus, Edward] Texas A&M Univ, Ctr Sci, Dept Internal Med, College Stn, TX USA. [Septimus, Edward] Infect Dis Soc Amer, Arlington, VA USA. [VanAntwerpen, Carole] New York State Dept Hlth, Bur Healthcare Associated Infect, Albany, NY USA. [VanAntwerpen, Carole] Council State & Terr Epidemiologists, Atlanta, GA USA. [Wright, Don] US Dept HHS, Off Dis Prevent & Hlth Promot, Washington, DC 20201 USA. [Lipsett, Pamela] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. RP Magill, SS (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. EM smagill@cdc.gov OI Diekema, Daniel/0000-0003-1273-0724 FU Centers for Disease Control and Prevention (CDC); Centers for Disease Control (CDC); U.S. Food and Drug Administration; Office of the National Co-ordinator for Health IT; CDC; bioMerieux; National Institute of General Medical Sciences; Merck; Cerexa; bioMeriuex; PurThread Technologies; Pfizer; Society of Critical Care Medicine FX The work described herein was supported by the Centers for Disease Control and Prevention (CDC).; Dr. Klompas received grant support from the Centers for Disease Control (CDC), U.S. Food and Drug Administration, and the Office of the National Co-ordinator for Health IT. Dr. Balk received grant support from the CDC and bioMerieux for participation in the EPIC CAP study (CDC) and the Procalcitonin in ICU antibiotic stewardship study (CDC and bioMerieux). Dr. Deutschman received grant support from the National Institute of General Medical Sciences. Dr. Diekema received grant support from Merck, Cerexa, bioMeriuex, PurThread Technologies, and Pfizer.; Ms. Greene is employed by the Rochester General Hospital. Dr. Lipsett has board membership with the Society of Critical Care Medicine. Dr. Deutschman received a stipend for his Presidency with the Society of Critical Care Medicine. NR 37 TC 71 Z9 71 U1 1 U2 6 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 NOV PY 2013 VL 41 IS 11 BP 2467 EP 2475 DI 10.1097/CCM.0b013e3182a262db PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 243BO UT WOS:000326291600032 PM 24162674 ER PT J AU Ito, T Igarashi, H Jensen, RT AF Ito, Tetsuhide Igarashi, Hisato Jensen, Robert T. TI Zollinger-Ellison syndrome: recent advances and controversies SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE gastrin; gastrinoma; neuroendocrine tumor; pancreatic endocrine tumor syndrome; Zollinger-Ellison syndrome ID PANCREATIC NEUROENDOCRINE TUMORS; ENDOCRINE NEOPLASIA TYPE-1; LYMPH-NODE GASTRINOMA; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; PROTON PUMP INHIBITORS; ISLET CELL TUMORS; ENETS CONSENSUS GUIDELINES; INSTITUTES-OF-HEALTH; LONG-TERM; GEP-NETS AB Purpose of reviewTo review the recent advances and current controversies in patients with Zollinger-Ellison syndrome (ZES).Recent findingsRecent advances in the management of ZES include: improved understanding of the pathogenesis of gastrinoma and pancreatic neuroendocrine tumors, new prognostic classification systems, new diagnostic algorithms, more sensitive localization studies, new treatment strategies including improved control of gastric acid secretion and role for surgery, and new approaches to patients with advanced disease. Controversies include: the best approach to a patient with hypergastrinemia suspected of possibly having ZES, the appropriate gastrin assay to use, the role of surgery in patients with ZES, especially those with multiple endocrine neoplasia type 1, and the precise order of therapeutic modalities in the treatment of patients with advanced disease.SummaryThis review updates clinicians regarding important advances and controversies required to optimally diagnose and manage patients with ZES. C1 [Ito, Tetsuhide; Igarashi, Hisato] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan. [Jensen, Robert T.] NIDDK, NIH, DDB, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU NIDDK, NIH FX This research was supported in part by funding from the intramural research program of the NIDDK, NIH. NR 153 TC 13 Z9 13 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2013 VL 29 IS 6 BP 650 EP 661 DI 10.1097/MOG.0b013e328365efb1 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 247AH UT WOS:000326583900012 PM 24100728 ER PT J AU Leung, JM Olivier, KN AF Leung, Janice M. Olivier, Kenneth N. TI Nontuberculous mycobacteria: the changing epidemiology and treatment challenges in cystic fibrosis SO CURRENT OPINION IN PULMONARY MEDICINE LA English DT Review DE cystic fibrosis; Mycobacterium abscessus; Mycobacterium avium complex; nontuberculous mycobacteria ID FATAL PULMONARY INFECTION; LUNG-TRANSPLANT; PSEUDOMONAS-AERUGINOSA; MULTICENTER PREVALENCE; CLINICAL-SIGNIFICANCE; ADULT PATIENTS; AVIUM COMPLEX; SP-NOV; ABSCESSUS; DISEASE AB Purpose of reviewAlthough patients with cystic fibrosis (CF) face numerous infectious pathogens over the course of their lifespan, increasing attention has recently been paid to nontuberculous mycobacteria (NTM). As reported prevalence rates rise across many countries such as the United States, the ability to recognize disease caused by NTM and subsequently treat such disease has become increasingly important. This review summarizes new observations on the epidemiology of NTM in CF as well as key elements to consider during the treatment phase.Recent findingsAlthough overall rates of NTM isolation appear to be increasing, particular concern has focused on the emerging predominance of Mycobacterium abscessus. New data suggest that chronic macrolide therapy now part of routine CF care has contributed to this rise; however, these have yet to be confirmed prospectively. Transmission of M. abscessus between CF patients has also now been described through the use of genome sequencing. Although the greater virulence of M. abscessus makes it a challenging species to treat, identification of the subspecies type can now determine the presence of inducible macrolide resistance, thereby helping to guide treatment.SummaryGiven increasing prevalence rates, clinicians should maintain a high level of suspicion for NTM as disease-causing organisms in CF, particularly for M. abscessus. New knowledge regarding this species, however, can help to tailor appropriate therapy. C1 [Leung, Janice M.] NIAID, Ctr Clin, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NIH, Bldg 10,Room 12C103, Bethesda, MD 20892 USA. EM olivierk@niaid.nih.gov FU Division of Intramural Research, the National Institute of Allergy and Infectious Diseases; National Institutes of Health Clinical Center FX This work was supported in part by the Division of Intramural Research, the National Institute of Allergy and Infectious Diseases, and the National Institutes of Health Clinical Center. NR 92 TC 33 Z9 33 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-5287 EI 1531-6971 J9 CURR OPIN PULM MED JI Curr. Opin. Pulm. Med. PD NOV PY 2013 VL 19 IS 6 BP 662 EP 669 DI 10.1097/MCP.0b013e328365ab33 PG 8 WC Respiratory System SC Respiratory System GA 247FW UT WOS:000326602900011 PM 24048085 ER PT J AU Spruijt-Metz, D Belcher, BR Hsu, YW McClain, AD Chou, CP Nguyen-Rodriguez, S Weigensberg, MJ Goran, MI AF Spruijt-Metz, Donna Belcher, Britni R. Hsu, Ya-Wen McClain, Arianna D. Chou, Chih-Ping Nguyen-Rodriguez, Selena Weigensberg, Marc J. Goran, Michael I. TI Temporal Relationship Between Insulin Sensitivity and the Pubertal Decline in Physical Activity in Peripubertal Hispanic and African American Females SO DIABETES CARE LA English DT Article ID AGE-RELATED DECLINE; METABOLIC SYNDROME; UNITED-STATES; ENERGY HOMEOSTASIS; YOUTH; RESISTANCE; CHILDREN; GLUCOSE; ACCELEROMETER; RESPONSIVITY AB OBJECTIVELittle attention has been paid to possible intrinsic biological mechanisms for the decline in physical activity that occurs during puberty. This longitudinal observational study examined the association between baseline insulin sensitivity (SI) and declines in physical activity and increases in sedentary behavior in peripubertal minority females over a year.RESEARCH DESIGN AND METHODSParticipants were Hispanic and African American girls (n = 55; 76% Hispanic; mean age 9.4 years; 36% obese). SI and other insulin indices were measured at baseline using the frequently sampled intravenous glucose tolerance test. Physical activity was measured on a quarterly basis by accelerometry and self-report.RESULTSPhysical activity declined by 25% and time spent in sedentary behaviors increased by approximate to 13% over 1 year. Lower baseline SI predicted the decline in physical activity measured by accelerometry, whereas higher baseline acute insulin response to glucose predicted the decline in physical activity measured by self-report. Time spent in sedentary behavior increased by similar to 13% over 1 year, and this was predicted by lower baseline SI. All models controlled for adiposity, age, pubertal stage, and ethnicity.CONCLUSIONSWhen evaluated using a longitudinal design with strong outcome measures, this study suggests that lower baseline SI predicts a greater decline in physical activity in peripubertal minority females. C1 [Spruijt-Metz, Donna; Chou, Chih-Ping; Weigensberg, Marc J.; Goran, Michael I.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Belcher, Britni R.] NCI, Appl Res Program, Risk Factor Monitoring & Methods Branch, Canc Prevent Div, Bethesda, MD 20892 USA. [Hsu, Ya-Wen] Chia Nan Univ Pharm & Sci, Dept Hosp & Hlth Care Adm, Coll Hlth & Informat, Tainan, Taiwan. [McClain, Arianna D.] Stanford Univ, Stanford Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA. [Nguyen-Rodriguez, Selena] Calif State Univ Long Beach, Dept Hlth Sci, Coll Hlth & Human Serv, Long Beach, CA 90840 USA. [Weigensberg, Marc J.] Univ So Calif, Dept Pediat, Los Angeles, CA 90089 USA. RP Spruijt-Metz, D (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM dmetz@usc.edu FU University of Southern California Center for Transdisciplinary Research on Energetics and Cancer [U54 CA 116848] FX This work was supported by the University of Southern California Center for Transdisciplinary Research on Energetics and Cancer (grant U54 CA 116848). NR 39 TC 2 Z9 2 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 NOV PY 2013 VL 36 IS 11 BP 3739 EP 3745 DI 10.2337/dc13-0083 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 242VZ UT WOS:000326274100061 PM 23846812 ER PT J AU Maldonado-Baez, L Williamson, C Donaldson, JG AF Maldonado-Baez, Lymarie Williamson, Chad Donaldson, Julie G. TI Clathrin-independent endocytosis: A cargo-centric view SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Endocytosis; Clathrin-independent endocytosis; Plasma membrane protein; Protein sorting; Nutrient transporters; Ion channels; Cell adhesion molecules ID INTERCELLULAR-ADHESION MOLECULE-1; DENSITY-LIPOPROTEIN RECEPTOR; FIBROBLAST-GROWTH-FACTOR; AMINO-ACID-TRANSPORT; MHC CLASS-II; CYTOPLASMIC DOMAINS; ENDOSOMAL TRANSPORT; MEMBRANE-TRANSPORT; RECYCLING PATHWAY; SURFACE-RECEPTOR AB Clathrin-independent endocytosis occurs in all cells and interest in this mode of cellular entry has grown. Although this form of endocytosis was first described for entry of bacterial toxins, here we focus our attention on the endogenous cell surface "cargo" proteins that enter cells by this mechanism. The cargo proteins entering by this mechanism are varied and include nutrient transporters, ion channels, cell adhesion molecules and proteins associated with the immune system. Despite the apparent lack of selection at the cell surface, we provide some examples of specific sorting of these cargo proteins after entry, leading to distinct itineraries and cellular fates. Published by Elsevier Inc. C1 [Maldonado-Baez, Lymarie; Williamson, Chad; Donaldson, Julie G.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, NIH, Bld 50,Rm 2503, Bethesda, MD 20892 USA. EM donaldsonj@helix.nih.gov FU Intramural NIH HHS [ZIA HL006130-03, ZIA HL006060-04] NR 115 TC 30 Z9 30 U1 1 U2 23 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 NOV 1 PY 2013 VL 319 IS 18 BP 2759 EP 2769 DI 10.1016/j.yexcr.2013.08.008 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 245BA UT WOS:000326432700001 PM 23954817 ER PT J AU Kilari, RS Weaver, JD Shears, SB Safrany, ST AF Kilari, Rajagopal S. Weaver, Jeremy D. Shears, Stephen B. Safrany, Stephen T. TI Understanding inositol pyrophosphate metabolism and function: Kinetic characterization of the DIPPs SO FEBS LETTERS LA English DT Article DE Nudix; Diphosphoinositol; Phosphohydrolase; CDK5RAP1 ID DIPHOSPHOINOSITOL POLYPHOSPHATE PHOSPHOHYDROLASE; SCHIZOSACCHAROMYCES-POMBE; BINDING; PROTEIN; INHIBITOR; CDK5; IDENTIFICATION; HYDROLASES; FAMILY; GROWTH AB We illuminate the metabolism and the cell-signaling activities of inositol pyrophosphates, by showing that regulation of yeast cyclin-kinase by 1-InsP(7) is not conserved for mammalian CDK5, and by kinetically characterizing Ddp1p/DIPP-mediated dephosphorylation of 1-InsP(7), 5-InsP(7) and InsP(8). Each phosphatase exhibited similar Km values for every substrate (range: 35-148 nM). The rank order of k(cat) values (1-InsP(7) > 5-InsP(7) = InsP(8)) was identical for each enzyme, although DIPP1 was 10- to 60-fold more active than DIPP2 alpha/beta and DIPP3 alpha/beta. We demonstrate InsP(8) dephosphorylation preferentially progresses through 1-InsP(7). Conversely, we conclude that the more metabolically and functionally significant steady-state route of InsP(8) synthesis proceeds via 5-InsP(7). Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Kilari, Rajagopal S.; Safrany, Stephen T.] Wolverhampton Univ, Fac Sci & Engn, Dept Pharm, Wolverhampton WV1 1LY, England. [Weaver, Jeremy D.; Shears, Stephen B.] NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov; S.Safrany@wlv.ac.uk FU University of Wolverhampton's Research Institute of Healthcare Science; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX RS Kilari was supported by a PhD studentship from the University of Wolverhampton's Research Institute of Healthcare Science. This research was also supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 30 TC 18 Z9 18 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD NOV 1 PY 2013 VL 587 IS 21 BP 3464 EP 3470 DI 10.1016/j.febslet.2013.08.035 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 238VE UT WOS:000325978700016 PM 24021644 ER PT J AU Hill, MJ Whitcomb, BW Lewis, TD Wu, M Terry, N DeCherney, AH Levens, ED Propst, AM AF Hill, Micah J. Whitcomb, Brian W. Lewis, Terrence D. Wu, Mae Terry, Nancy DeCherney, Alan H. Levens, Eric D. Propst, Anthony M. TI Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis SO FERTILITY AND STERILITY LA English DT Review DE Progesterone; luteal support; ovulation induction; intrauterine insemination ID CLOMIPHENE CITRATE; MIDLUTEAL PHASE; LUTEINIZING-HORMONE; OVARIAN STIMULATION; PREGNANCY RATES; CORPUS-LUTEUM; GNRH AGONIST; CYCLES; IMPLANTATION; ESTRADIOL AB Objective: To evaluate the effect of luteal phase P support after ovulation induction IUI. Design: A systematic review and meta-analysis. Setting: Not applicable. Patient(s): Undergoing ovulation induction IUI. Intervention(s): Any form of exogenous P in ovulation induction IUI cycles. Main Outcome Measure(s): Clinical pregnancy and live birth. Result(s): Five trials were identified that met inclusion criteria and comprised 1,298 patients undergoing 1,938 cycles. Clinical pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.15-1.98) and live birth (OR 2.11, 95% CI 1.21-3.67) were more likely in P-supplemented patients. These findings persisted in analyses evaluating per IUI cycle, per patient, and first cycle only data. In subgroup analysis, patients receiving gonadotropins for ovulation induction had the most increase in clinical pregnancy with P support (OR 1.77, 95% CI 1.20-2.6). Conversely, patients receiving clomiphene citrate (CC) for ovulation induction showed no difference in clinical pregnancy with P support (OR 0.89, 95% CI 0.47-1.67). Conclusion(s): Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUI cycles. Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction. (C) 2013 by American Society for Reproductive Medicine. C1 [Hill, Micah J.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Whitcomb, Brian W.] Univ Massachusetts, Dept Biostat & Epidemiol, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Lewis, Terrence D.; Wu, Mae; Propst, Anthony M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Terry, Nancy] Natl Inst Hlth Lib, Bethesda, MD USA. [Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Hill, MJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov FU Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland FX Supported, in part, by the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 30 TC 16 Z9 18 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD NOV PY 2013 VL 100 IS 5 BP 1373 EP + DI 10.1016/j.fertnstert.2013.06.034 PG 14 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 242IU UT WOS:000326233700039 PM 23876537 ER PT J AU Bukh, J Lanford, RE Purcell, RH AF Bukh, Jens Lanford, Robert E. Purcell, Robert H. TI Persistent Human Hepatitis B Virus Infection in Cynomolgus Monkeys: A Novel Animal Model in the Search for a Cure? SO HEPATOLOGY LA English DT Editorial Material ID WOOLLY MONKEY; LIVER; HEPADNAVIRUS C1 [Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis C Program CO HEP, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Copenhagen Univ Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Bukh, Jens] Univ Copenhagen, Fac Hlth & Med Sci, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Lanford, Robert E.] Southwest Natl Primate Res Ctr, Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Purcell, Robert H.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis C Program CO HEP, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. EM jbukh@sund.ku.dk FU Intramural NIH HHS [Z01 AI000311-27]; NIH HHS [P51 OD011133] NR 20 TC 3 Z9 4 U1 1 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 NOV PY 2013 VL 58 IS 5 BP 1533 EP 1536 DI 10.1002/hep.26560 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600004 PM 23775673 ER PT J AU Noureddin, M Wright, EC Alter, HJ Clark, S Thomas, E Chen, R Zhao, XC Conry-Cantilena, C Kleiner, DE Liang, TJ Ghany, MG AF Noureddin, Mazen Wright, Elizabeth C. Alter, Harvey J. Clark, Shauna Thomas, Emmanuel Chen, Richard Zhao, Xiongce Conry-Cantilena, Cathy Kleiner, David E. Liang, T. Jake Ghany, Marc G. TI Association of IL28B Genotype With Fibrosis Progression and Clinical Outcomes in Patients With Chronic Hepatitis C: A Longitudinal Analysis SO HEPATOLOGY LA English DT Article ID GENOME-WIDE-ASSOCIATION; INDUCED VIRAL CLEARANCE; VIRUS-RELATED CIRRHOSIS; GENETIC-VARIATION; INTERFERON; INFECTION; PEGINTERFERON; EPIDEMIOLOGY; INFLAMMATION; FREQUENCY AB Interleukin (IL)28B polymorphisms are associated with spontaneous clearance of hepatitis C virus (HCV) infection and response to therapy. Whether IL28B genotype affects fibrosis progression or clinical outcome is unclear. Our aim was to study the relationship between IL28B genotype and both histological and clinical outcomes in patients with chronic hepatitis C (CHC). Hepatic fibrosis was scored using the Ishak (0-6) scale; progression was defined as a 2-point increase in Ishak score between biopsies. Multiple logistic and Cox regressions were used to identify variables associated with fibrosis progression. In all, 1,483 patients were included in a baseline cross-sectional analysis, from which 276 were eligible for a paired biopsy analysis (median time between biopsies 4 years), and 400 for a clinical outcome analysis. At baseline biopsy, patients with IL28B CC genotype had significantly higher portal inflammation (2.4 versus 2.2) and alanine aminotransferase (ALT) levels (133 versus 105 U/L; P < 0.05 for all). In the paired biopsy analysis, there was no difference in the frequency of fibrosis progression between patients with IL28B CC and non-CC genotypes (17% versus 23%). In logistic regression, only higher baseline alkaline phosphatase, lower platelets, and greater hepatic steatosis were associated with fibrosis progression. Patients with IL28B CC were twice as likely to develop adverse clinical outcomes compared to non-CC (32% versus 16%; P = 0.007). Conclusion: IL28B CC genotype was associated with greater hepatic necroinflammation, higher ALT, and worse clinical outcomes in CHC patients. This suggests that IL28B CC is associated with a state of enhanced immunity that, on the one hand, can promote viral clearance, but alternately can increase necroinflammation and hepatic decompensation without enhancing fibrosis progression. (Hepatology 2013;58:1548-1557) C1 [Noureddin, Mazen; Clark, Shauna; Thomas, Emmanuel; Liang, T. Jake; Ghany, Marc G.] Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Wright, Elizabeth C.; Chen, Richard; Zhao, Xiongce] Natl Inst Diabet & Digest & Kidney Dis, Off Director, NIH, Bethesda, MD 20892 USA. [Alter, Harvey J.; Conry-Cantilena, Cathy] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Ghany, MG (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Liver Dis Branch, NIH, Bldg 10,Rm 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM marcg@intra.niddk.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS [ZIA DK075009-07] NR 31 TC 49 Z9 50 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 NOV PY 2013 VL 58 IS 5 BP 1548 EP 1557 DI 10.1002/hep.26506 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600006 PM 23703931 ER PT J AU Pedersen, J Carlsen, THR Prentoe, J Ramirez, S Jensen, TB Forns, X Alter, H Foung, SKH Law, M Gottwein, J Weis, N Bukh, J AF Pedersen, Jannie Carlsen, Thomas H. R. Prentoe, Jannick Ramirez, Santseharay Jensen, Tanja B. Forns, Xavier Alter, Harvey Foung, Steven K. H. Law, Mansun Gottwein, Judith Weis, Nina Bukh, Jens TI Neutralization Resistance of Hepatitis C Virus Can Be Overcome by Recombinant Human Monoclonal Antibodies SO HEPATOLOGY LA English DT Article ID CELL-CULTURE SYSTEMS; GENOTYPE 2A; INFECTION; SEQUENCE; MUTATIONS; SUBTYPE; FAILURE; GENOME; REPLICATION; CHIMPANZEES AB Immunotherapy and vaccine development for hepatitis C virus (HCV) will depend on broadly reactive neutralizing antibodies (NAbs). However, studies in infectious strain JFH1-based culture systems expressing patient-derived Core-NS2 proteins have suggested neutralization resistance for specific HCV strains, in particular, of genotype 2. To further examine this phenomenon, we developed a panel of HCV genotype 2 recombinants for testing of sensitivity to neutralization by chronic-phase patient sera and lead human monoclonal antibodies (HMAbs). The novel Core-NS2 recombinants, with patient-derived genotype 2a (strain T9), 2b (strains DH8 and DH10), and 2c (strain S83) consensus sequences, were viable in Huh7.5 hepatoma cells without requirement for adaptive mutations, reaching HCV infectivity titers of 3.9-4.5 log(10) focus-forming units per milliliter. In in vitro neutralization assays, we demonstrated that the novel genotype 2 viruses as well as prototype strains J6/JFH1(2a) and J8/JFH1(2b), all with authentic envelope proteins, were resistant to neutralization by genotype 2a, 2b, 2c, 2j, 2i, and 2q patient sera. However, these patient sera had high titers of HCV-specific NAbs, because they efficiently reduced the infectivity of J6(2a) and J8(2b) with deleted hypervariable region 1. The genotype 2a, 2b, and 2c viruses, found resistant to polyclonal patient sera neutralization, were efficiently neutralized by two lead HMAbs (AR4A and HC84.26). Conclusion: Using novel 2a, 2b, and 2c cell-culture systems, expressing authentic envelope proteins, we demonstrated resistance of HCV to patient-derived polyclonal high-titer NAbs. However, the same genotype 2 culture viruses were all sensitive to HMAbs recognizing conformational epitopes, indicating that neutralization resistance of HCV can be overcome by applying recombinant antibodies. These findings have important implications for HCV immunotherapy and vaccine development. (Hepatology 2013;58:1587-1597) C1 [Pedersen, Jannie; Carlsen, Thomas H. R.; Prentoe, Jannick; Ramirez, Santseharay; Jensen, Tanja B.; Gottwein, Judith; Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis Program CO HEP C, DK-2650 Hvidovre, Denmark. [Pedersen, Jannie; Carlsen, Thomas H. R.; Prentoe, Jannick; Ramirez, Santseharay; Jensen, Tanja B.; Gottwein, Judith; Bukh, Jens] Copenhagen Univ Hosp, Clin Res Ctr, DK-2650 Hvidovre, Denmark. [Pedersen, Jannie; Carlsen, Thomas H. R.; Prentoe, Jannick; Ramirez, Santseharay; Jensen, Tanja B.; Gottwein, Judith; Bukh, Jens] Univ Copenhagen, Fac Hlth & Med Sci, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Forns, Xavier] CIBERehd, IDIBAPS, Hosp Clin Barcelona, Liver Unit, Barcelona, Spain. [Forns, Xavier] Univ Barcelona, Barcelona, Spain. [Alter, Harvey] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Foung, Steven K. H.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Law, Mansun] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Weis, Nina; Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, DK-2650 Hvidovre, Denmark. [Weis, Nina] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark. RP Bukh, J (reprint author), Copenhagen Univ Hosp, Dept Infect Dis, Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. EM jbukh@sund.ku.dk RI Ramirez, Santseharay/R-9257-2016; OI Ramirez, Santseharay/0000-0003-3699-1814; Pedersen, Jannie/0000-0003-2822-3014; Prentoe, Jannick/0000-0003-2203-9478 FU Lundbeck Foundation; Danish Cancer Society; Novo Nordisk Foundation; RegionH Research Fund; The Danish Agency for Science Technology and Innovation; Faculty of Health and Medical Sciences, University of Copenhagen; Danish Council for Independent Research (FSS); U.S. National Institutes of Health [AI79031] FX This work was supported by the Lundbeck Foundation (to J.G. and J.B.), the Danish Cancer Society (to J.G. and J.B.), the Novo Nordisk Foundation (to J.G. and J.B.), the RegionH Research Fund (to J.B.), The Danish Agency for Science Technology and Innovation (to J.P. and N.W.), and Ph.D. stipends from the Faculty of Health and Medical Sciences, University of Copenhagen (to T. H. R. C., J.P. R., and T.B.J.). J.P. R. and S. R. are the recipients of Individual Postdoctoral Stipends from the Danish Council for Independent Research (FSS). M. L. is supported by the U.S. National Institutes of Health (grant no.: AI79031). NR 37 TC 18 Z9 18 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 NOV PY 2013 VL 58 IS 5 BP 1587 EP 1597 DI 10.1002/hep.26524 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600010 PM 23729237 ER PT J AU Werner, JM Heller, T Gordon, AM Sheets, A Sherker, AH Kessler, E Bean, KS Stevens, M Schmitt, J Rehermann, B AF Werner, Jens Martin Heller, Theo Gordon, Ann Marie Sheets, Arlene Sherker, Averell H. Kessler, Ellen Bean, Kathleen S. Stevens, M'Lou Schmitt, James Rehermann, Barbara TI Innate Immune Responses in Hepatitis C Virus-Exposed Healthcare Workers Who Do Not Develop Acute Infection SO HEPATOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; HUMAN DENDRITIC CELLS; NK CELLS; T-CELLS; B-VIRUS; ACTIVATION; EXPRESSION; RECEPTORS; THERAPY; MANNER AB Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN- production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia. Conclusion: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity. (Hepatology 2013;58:1621-1631) C1 [Werner, Jens Martin; Heller, Theo; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Gordon, Ann Marie; Sheets, Arlene] Medstar Washington Hosp Ctr, Washington, DC USA. [Sherker, Averell H.] Washington Hosp Ctr, Ctr Liver Dis, Washington, DC 20010 USA. [Kessler, Ellen; Bean, Kathleen S.] Inova Fairfax Hosp, Falls Church, VA USA. [Stevens, M'Lou; Schmitt, James] NIH, Occupat Med Serv, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr,Bldg 10,Rm 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov OI Werner, Jens/0000-0001-7156-4370 FU Deutsche Forschungsgemeinschaft, Bonn, Germany [We- 4675/1-1]; NIDDK NIH intramural research program FX Supported by grant We- 4675/1-1 from the Deutsche Forschungsgemeinschaft, Bonn, Germany (to J.M.W.) and by the NIDDK NIH intramural research program. NR 33 TC 26 Z9 27 U1 0 U2 3 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 NOV PY 2013 VL 58 IS 5 BP 1621 EP 1631 DI 10.1002/hep.26353 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600013 PM 23463364 ER PT J AU Noureddin, M Yates, KP Vaughn, IA Neuschwander-Tetri, BA Sanyal, AJ McCullough, A Merriman, R Hameed, B Doo, E Kleiner, DE Behling, C Loomba, R AF Noureddin, Mazen Yates, Katherine P. Vaughn, Ivana A. Neuschwander-Tetri, Brent A. Sanyal, Arun J. McCullough, Arthur Merriman, Raphael Hameed, Bilal Doo, Edward Kleiner, David E. Behling, Cynthia Loomba, Rohit CA NASH CRN TI Clinical and Histological Determinants of Nonalcoholic Steatohepatitis and Advanced Fibrosis in Elderly Patients SO HEPATOLOGY LA English DT Article ID FATTY LIVER-DISEASE; NATURAL-HISTORY; UNITED-STATES; HEPATIC STEATOSIS; CONTROLLED-TRIAL; SCORING SYSTEM; VITAMIN-E; POPULATION; PREVALENCE; NAFLD AB The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age 65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P=0.02), and advanced fibrosis (25% versus 44%, P=0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P=0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR]=1.12, P=0.007) and lower platelets (OR=0.98, P=0.02); and independent determinants of advanced fibrosis included higher AST (OR=1.08, P=0.007), lower alanine aminotransferase value (OR=0.91, P=0.002), and an increased odds of having low high-density lipoprotein (OR=8.35, P=0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. (HEPATOLOGY 2013;58:1644-1654) C1 [Noureddin, Mazen; Loomba, Rohit] Univ Calif San Diego, Sch Med, Div Gastroenterol & Epidemiol, La Jolla, CA 92093 USA. [Yates, Katherine P.; Vaughn, Ivana A.] Johns Hopkins Univ, Data Coordinating Ctr, Baltimore, MD USA. [Neuschwander-Tetri, Brent A.] St Louis Univ, Div Gastroenterol, 6, St Louis, MO 63103 USA. [Sanyal, Arun J.] Virginia Commonwealth Univ, Dept Internal Med, Div Internal Med, Div Gastroenterol, Richmond, VA USA. [McCullough, Arthur] Cleveland Clin Fdn, Metro Hlth Clin Ctr, Case Western Reserve Sch Med, Dept Gastroenterol Hepatol, Cleveland, OH 44195 USA. [Merriman, Raphael; Hameed, Bilal] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Doo, Edward] NIDDK, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Behling, Cynthia] Univ Calif San Diego, Dept Pathol, Sharp Mem Hosp, San Diego, CA 92103 USA. RP Loomba, R (reprint author), Univ Calif San Diego, Sch Med, Div Gastroenterol & Epidemiol, UC 303,MC 0063,9500 Gilman Dr, La Jolla, CA 92093 USA. EM roloomba@ucsd.edu RI Vaughn, Ivana/B-6138-2016; OI Vaughn, Ivana/0000-0002-7201-0289; Kleiner, David/0000-0003-3442-4453 FU NIDDK, NIH FX The study was sponsored by the NIDDK, NIH. As per the policy of the network, the article was reviewed by the NIDDK prior to publication. The authors take full responsibility for the data analyses and credibility of findings. NR 51 TC 35 Z9 36 U1 0 U2 7 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 NOV PY 2013 VL 58 IS 5 BP 1644 EP 1654 DI 10.1002/hep.26465 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600015 PM 23686698 ER PT J AU Morales-Ibanez, O Dominguez, M Ki, SH Marcos, M Chaves, JF Nguyen-Khac, E Houchi, H Affo, S Sancho-Bru, P Altamirano, J Michelena, J Garcia-Pagan, JC Abraldes, JG Arroyo, V Caballeria, J Laso, FJ Gao, B Bataller, R AF Morales-Ibanez, Oriol Dominguez, Marlene Ki, Sung H. Marcos, Miguel Chaves, Javier F. Nguyen-Khac, Eric Houchi, Hakim Affo, Silvia Sancho-Bru, Pau Altamirano, Jose Michelena, Javier Garcia-Pagan, Juan Carlos Abraldes, Juan G. Arroyo, Vicente Caballeria, Juan Laso, Francisco-Javier Gao, Bin Bataller, Ramon TI Human and Experimental Evidence Supporting a Role for Osteopontin in Alcoholic Hepatitis SO HEPATOLOGY LA English DT Article ID LIVER-DISEASE PATHOGENESIS; INDUCED INFLAMMATION; GENE-EXPRESSION; SCORING SYSTEM; MURINE MODEL; FIBROSIS; STRESS; POLYMORPHISMS; HEDGEHOG; TARGETS AB We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme-linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN-/- mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single-nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN-/- mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. Conclusion: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. (Hepatology 2013;58:1742-1756) C1 [Morales-Ibanez, Oriol; Dominguez, Marlene; Affo, Silvia; Sancho-Bru, Pau; Altamirano, Jose; Michelena, Javier; Garcia-Pagan, Juan Carlos; Abraldes, Juan G.; Arroyo, Vicente; Caballeria, Juan; Bataller, Ramon] Hosp Clin Barcelona, CIBER Enfermedades Hepaticas Digest CIBERehd, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Liver Unit, Barcelona, Spain. [Ki, Sung H.; Gao, Bin] Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Lab Liver Dis, Bethesda, MD USA. [Marcos, Miguel; Laso, Francisco-Javier] IBSAL Univ, Hosp Salamanca, Dept Internal Med, Alcoholism Unit, Salamanca, Spain. [Chaves, Javier F.] Res Fdn Hosp Clin, Genotyping & Genet Diag Unit, Valencia, Spain. [Nguyen-Khac, Eric; Houchi, Hakim] Univ Picardie, Amiens Univ Hosp, INSERM, Serv Hepatogastroenterol,GRAP,ERI 24, Amiens, France. [Bataller, Ramon] Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Bataller, Ramon] Univ N Carolina, Dept Nutr, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. RP Bataller, R (reprint author), Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, 2209 McGavran Greensberg, Chapel Hill, NC 27599 USA. EM ramon_bataller@med.unc.edu RI Sancho-Bru, Pau/D-4900-2014; Arroyo, Vicente/F-9189-2015; Marcos, Miguel/B-3550-2008; Garcia-Pagan, Juan Carlos/P-6291-2015; OI Sancho-Bru, Pau/0000-0001-5569-9259; Arroyo, Vicente/0000-0002-2728-1848; Marcos, Miguel/0000-0003-1269-4487; Garcia-Pagan, Juan Carlos/0000-0001-9032-4954; CHAVES, FELIPE J/0000-0001-8009-3689; Affo, Silvia/0000-0002-9731-3913 FU Instituto de Salud Carlos III [FIS PI080237, FIS PS09/01164]; IDI-BAPS; Instituto Carlos III, Miguel Servet [CP11/00071]; European Commission; European Cosmetics Association (COLIPA) [HeMiBio-HEALTH-F5-2010-266777]; Fundacion Banco Bilbao Vizcaya Argentaria FX This work was supported by grants from the Instituto de Salud Carlos III (FIS PI080237 and FIS PS09/01164; to R. B. and J.C., respectively). S. A. received a grant from IDI-BAPS. P.S.-B. received grants from Instituto Carlos III, Miguel Servet (CP11/00071), and from the European Commission (within its FP7 Cooperation Program) and the European Cosmetics Association (COLIPA; o HeMiBio-HEALTH-F5-2010-266777). J.A. received a grant from Fundacion Banco Bilbao Vizcaya Argentaria. NR 29 TC 39 Z9 39 U1 3 U2 14 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 NOV PY 2013 VL 58 IS 5 BP 1742 EP 1756 DI 10.1002/hep.26521 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600024 PM 23729174 ER PT J AU Bertola, A Park, O Gao, B AF Bertola, Adeline Park, Ogyi Gao, Bin TI Chronic Plus Binge Ethanol Feeding Synergistically Induces Neutrophil Infiltration and Liver Injury in Mice: A Critical Role for E-selectin SO HEPATOLOGY LA English DT Article ID SEVERE ALCOHOLIC HEPATITIS; A-INDUCED HEPATITIS; LEUKOCYTE RECRUITMENT; ADHESION MOLECULES; ENDOTHELIAL-CELLS; GROWTH-FACTOR; DISEASE; EXPRESSION; PATHOGENESIS; INFLAMMATION AB Chronic plus binge ethanol feeding acts synergistically to induce liver injury in mice, but the mechanisms underlying this phenomenon remain unclear. Here, we show that chronic plus binge ethanol feeding synergistically up-regulated the hepatic expression of interleukin-1 and tumor necrosis factor alpha and induced neutrophil accumulation in the liver, compared with chronic or binge feeding alone. In vivo depletion of neutrophils through administration of an anti-Ly6G antibody markedly reduced chronic-binge ethanol feeding-induced liver injury. Real-time polymerase chain reaction analyses revealed that hepatic E-selectin expression was up-regulated 10-fold, whereas expression of other neutrophil infiltration-related adhesion molecules (e.g., P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1) was slightly up- or down-regulated in this chronic-binge model. The genetic deletion of E-selectin prevented chronic-binge ethanol-induced hepatic neutrophil infiltration as well as elevation of serum transaminases without affecting ethanol-induced steatosis. In addition, E-selectin-deficient mice showed reduced hepatic expression of several proinflammatory cytokines, chemokines, and adhesion molecules, compared to wild-type mice, after chronic-binge ethanol feeding. Finally, the expression of E-selectin was highly up-regulated in human alcoholic fatty livers, but not in alcoholic cirrhosis. Conclusions: Chronic-binge ethanol feeding up-regulates expression of proinflammatory cytokines, followed by the induction of E-selectin. Elevated E-selectin plays an important role in hepatic neutrophil infiltration and injury induced by chronic-binge feeding in mice and may also contribute to the pathogenesis of early stages of human alcoholic liver disease. C1 [Bertola, Adeline; Park, Ogyi; Gao, Bin] NIAAA, Natl Inst Hlth, Lab Liver Dis, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Natl Inst Hlth, Lab Liver Dis, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov OI Bertola, Adeline/0000-0002-4885-8423 FU National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health FX This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health. NR 39 TC 16 Z9 17 U1 1 U2 6 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 NOV PY 2013 VL 58 IS 5 BP 1814 EP 1823 DI 10.1002/hep.26419 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 243OZ UT WOS:000326327600030 ER PT J AU Mukherjee, G Geliebter, A Babad, J Santamaria, P Serreze, DV Freeman, GJ Tarbell, KV Sharpe, A DiLorenzo, TP AF Mukherjee, Gayatri Geliebter, Ari Babad, Jeffrey Santamaria, Pere Serreze, David V. Freeman, Gordon J. Tarbell, Kristin V. Sharpe, Arlene DiLorenzo, Teresa P. TI DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8 T cells independently of PD-1 and PD-L1 SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE Autoimmunity; diabetes; NOD mice ID NONOBESE DIABETIC MICE; IN-VIVO; NOD MICE; MONOCLONAL-ANTIBODY; RECEPTOR DEC-205; ISLET ANTIGENS; EXPRESSION; TOLERANCE; RESPONSES; SUBSETS AB Targeting antigen to steady state DCs causes deletion of endogenous islet-specific T cells.CD8 T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) have been implicated in type 1 diabetes in both humans and non-obese diabetic (NOD) mice, in which T cells specific for IGRP(206214) are highly prevalent. We sought to manipulate these pathogenic T cells by exploiting the ability of steady-state dendritic cells (DCs) to present antigens in a tolerogenic manner. The endocytic receptor DEC-205 was utilized to deliver an IGRP(206214) mimotope to DCs in NOD mice, and the impact of this delivery on a polyclonal population of endogenous islet-reactive cognate T cells was determined. Assessment of islet-infiltrating CD8 T cells showed a decrease in the percentage, and the absolute number, of endogenous IGRP(206214)-specific T cells when the mimotope was delivered to DCs, compared with delivery of a specificity control. Employing an adoptive transfer system, deletion of CD8 T cells as a result of DEC-205-mediated antigen targeting was found to occur independently of programmed death-1 (PD-1) and its ligand (PD-L1), both often implicated in the regulation of peripheral T-cell tolerance. Given its promise for the manipulation of self-reactive polyclonal T cells demonstrated here, the distinctive characteristics of this antigen delivery system will be important to appreciate as its potential as an intervention for autoimmune diseases continues to be investigated. C1 [Mukherjee, Gayatri; Geliebter, Ari; Babad, Jeffrey; DiLorenzo, Teresa P.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Santamaria, Pere] Univ Calgary, Julia McFarlane Diabet Res Ctr, Calgary, AB T2N 4N1, Canada. [Santamaria, Pere] Univ Calgary, Fac Med, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Santamaria, Pere] Inst Invest Biomed August Pi & Sunyer, Barcelona 08036, Spain. [Serreze, David V.] Jackson Lab, Bar Harbor, ME 04609 USA. [Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Tarbell, Kristin V.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Diabet Endocrinol & Obes Branch, Immune Tolerance Sect, Bethesda, MD 20892 USA. [Sharpe, Arlene] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02215 USA. [Sharpe, Arlene] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [DiLorenzo, Teresa P.] Albert Einstein Coll Med, Dept Med, Div Endocrinol, Bronx, NY 10461 USA. RP DiLorenzo, TP (reprint author), Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. EM teresa.dilorenzo@einstein.yu.edu OI Tarbell, Kristin/0000-0003-3738-379X FU National Institutes of Health [R01 DK094327, R01 DK064315, R01 DK046266, U01 DK072473, P01 AI056299, P60 DK020541]; Juvenile Diabetes Research Foundation; American Diabetes Association; Irma T. Hirschl/Monique Weill-Caulier Trust; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institutes of Health Research; Canadian Diabetes Association; National Institutes of Health Cancer Center [P30 CA013330] FX National Institutes of Health [R01 DK094327 and R01 DK064315 to T.P.D., R01 DK046266 and U01 DK072473 (Beta Cell Biology Consortium) to D.V.S., P01 AI056299 to A.S., P60 DK020541 (Albert Einstein College of Medicine's Diabetes Research Center)]; the Juvenile Diabetes Research Foundation to D. V. S. and T. P. D.; the American Diabetes Association to D. V. S. and T. P. D.; the Irma T. Hirschl/Monique Weill-Caulier Trust to T. P. D.; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases to K. V. T.; Canadian Institutes of Health Research to P. S.; Canadian Diabetes Association to Julia McFarlane Diabetes Research Centre; National Institutes of Health Cancer Center (P30 CA013330 for flow cytometry facility at Albert Einstein College of Medicine). P.S. is scientific founder of Parvus Therapeutics, Inc. and a scientist of Alberta Innovates-Health Solutions. T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research. NR 49 TC 7 Z9 7 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 EI 1460-2377 J9 INT IMMUNOL JI Int. Immunol. PD NOV PY 2013 VL 25 IS 11 BP 651 EP 660 DI 10.1093/intimm/dxt031 PG 10 WC Immunology SC Immunology GA 244GR UT WOS:000326375900005 PM 24021877 ER PT J AU Xu, H Lasso, A Guion, P Krieger, A Kaushal, A Singh, AK Pinto, PA Coleman, J Grubb, RL Lattouf, JB Menard, C Whitcomb, LL Fichtinger, G AF Xu, Helen Lasso, Andras Guion, Peter Krieger, Axel Kaushal, Aradhana Singh, Anurag K. Pinto, Peter A. Coleman, Jonathan Grubb, Robert L., III Lattouf, Jean-Baptiste Menard, Cynthia Whitcomb, Louis L. Fichtinger, Gabor TI Accuracy analysis in MRI-guided robotic prostate biopsy SO INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY LA English DT Article DE Prostate biopsy; Accuracy validation; MRI-guidance; Image registration ID CANCER; REGISTRATION; BRACHYTHERAPY; INTERVENTIONS; DESIGN AB To assess retrospectively the clinical accuracy of an magnetic resonance imaging-guided robotic prostate biopsy system that has been used in the US National Cancer Institute for over 6 years. Series of 2D transverse volumetric MR image slices of the prostate both pre (high-resolution T2-weighted)- and post (low-resolution)- needle insertions were used to evaluate biopsy accuracy. A three-stage registration algorithm consisting of an initial two-step rigid registration followed by a B-spline deformable alignment was developed to capture prostate motion during biopsy. The target displacement (distance between planned and actual biopsy target), needle placement error (distance from planned biopsy target to needle trajectory), and biopsy error (distance from actual biopsy target to needle trajectory) were calculated as accuracy assessment. A total of 90 biopsies from 24 patients were studied. The registrations were validated by checking prostate contour alignment using image overlay, and the results were accurate to within 2 mm. The mean target displacement, needle placement error, and clinical biopsy error were 5.2, 2.5, and 4.3 mm, respectively. The biopsy error reported suggests that quantitative imaging techniques for prostate registration and motion compensation may improve prostate biopsy targeting accuracy. C1 [Xu, Helen; Lasso, Andras; Fichtinger, Gabor] Queens Univ, Kingston, ON, Canada. [Guion, Peter; Kaushal, Aradhana; Pinto, Peter A.] NIH, Bethesda, MD 20892 USA. [Krieger, Axel] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Singh, Anurag K.] Rosewell Pk Canc Inst, Buffalo, NY USA. [Coleman, Jonathan] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Grubb, Robert L., III] Washington Univ, St Louis, MO USA. [Lattouf, Jean-Baptiste] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Menard, Cynthia] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Whitcomb, Louis L.; Fichtinger, Gabor] Johns Hopkins Univ, Baltimore, MD USA. RP Xu, H (reprint author), Queens Univ, Kingston, ON, Canada. EM helen@cs.queensu.ca OI Coleman, Jonathan/0000-0002-6428-7835 FU US National Institutes of Health (NIH) [5R01CA111288-04, 5R01EB002963-05]; Canadian Ontario Graduate Scholarship (OGS); Applied Cancer Research Unit program of Cancer Care Ontario; Ontario Ministry of Health and Long-Term Care; Cancer Ontario Research Chair FX This work is supported by: US National Institutes of Health (NIH) 5R01CA111288-04 and 5R01EB002963-05, Canadian Ontario Graduate Scholarship (OGS), and Applied Cancer Research Unit program of Cancer Care Ontario with funds provided by the Ontario Ministry of Health and Long-Term Care. Gabor Fichtinger was funded as a Cancer Ontario Research Chair. NR 26 TC 6 Z9 6 U1 2 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1861-6410 EI 1861-6429 J9 INT J COMPUT ASS RAD JI Int. J. Comput. Assist. Radiol. Surg. PD NOV PY 2013 VL 8 IS 6 BP 937 EP 944 DI 10.1007/s11548-013-0831-9 PG 8 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging; Surgery SC Engineering; Radiology, Nuclear Medicine & Medical Imaging; Surgery GA 245HZ UT WOS:000326455900007 PM 23532560 ER PT J AU Glasofer, DR Haaga, DAF Hannallah, L Field, SE Kozlosky, M Reynolds, J Yanovski, JA Tanofsky-Kraff, M AF Glasofer, Deborah R. Haaga, David A. F. Hannallah, Louise Field, Sara E. Kozlosky, Merel Reynolds, James Yanovski, Jack A. Tanofsky-Kraff, Marian TI Self-Efficacy Beliefs and Eating Behavior in Adolescent Girls At-Risk for Excess Weight Gain and Binge Eating Disorder SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE self-efficacy; loss of control; adolescents; toxic food environment; binge eating disorder; obesity ID OVERWEIGHT CHILDREN; ADVERSE OUTCOMES; ADULT OBESITY; ENERGY-INTAKE; BODY-FAT; YOUTH; PSYCHOPATHOLOGY; AVAILABILITY; ASSOCIATIONS; PREVALENCE AB ObjectiveTo examine the relationship between self-related agency beliefs and observed eating behavior in adolescent girls with loss of control (LOC) eating. MethodOne-hundred eleven adolescent girls (14.51.7 years; BMI: 27.12.6 kg/m(2)) were administered the General Self-Efficacy Scale and the Weight Efficacy Lifestyle Questionnaire (WEL). Adolescents then participated in a laboratory test meal. ResultsGreater general and eating self-efficacy were associated with fewer episodes of LOC eating. General self-efficacy was inversely related to total intake at the meal (p<.01). Only the WEL availability subscale score, but not the other WEL subscales, was inversely related to total energy, snack, and dessert intake (ps<0.05). DiscussionGeneral self-related agency beliefs may be important in relation to energy consumption. Among girls susceptible to disordered eating and obesity, the domain-specific belief in one's ability to refrain from eating when food is widely available may be especially salient in determining overeating in the current food environment. Further research is therefore needed to assess the predictive validity of these beliefs on eating and weight outcomes. (c) 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013; 46:663-668) C1 [Glasofer, Deborah R.] New York State Psychiat Inst & Hosp, Div Clin Therapeut, New York, NY 10032 USA. [Glasofer, Deborah R.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [Haaga, David A. F.] Amer Univ, Dept Psychol, Washington, DC 20016 USA. [Hannallah, Louise; Field, Sara E.; Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Hannallah, Louise; Field, Sara E.; Yanovski, Jack A.; Tanofsky-Kraff, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Kozlosky, Merel] NIH, Dept Nutr, Ctr Clin, DHHS, Bethesda, MD 20892 USA. [Reynolds, James] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, DHHS, Bethesda, MD USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marian.tanofsky-kraff@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z99 HD999999, ZIA HD000641-18]; NIDDK NIH HHS [R01 DK080906] NR 48 TC 9 Z9 9 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2013 VL 46 IS 7 BP 663 EP 668 DI 10.1002/eat.22160 PG 6 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 241OG UT WOS:000326175900003 PM 23881587 ER PT J AU Oakley, RH Cidlowski, JA AF Oakley, Robert H. Cidlowski, John A. TI The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Glucocorticoid receptor; glucocorticoid; isoforms; glucocorticoid signaling ID TRABECULAR MESHWORK CELLS; NF-KAPPA-B; GENE-EXPRESSION PROFILES; ACTIVATED PROTEIN-KINASE; PRE-MESSENGER-RNA; BETA-ISOFORM; TRANSCRIPTIONAL ACTIVITY; TRANSLATIONAL ISOFORMS; DNA-BINDING; ANTIINFLAMMATORY ACTIONS AB Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiologic processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematologic cancers. The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by means of alternative splicing and alternative translation initiation mechanisms. Posttranslational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues. C1 [Oakley, Robert H.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, POB 12233,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU National Institutes of Health/National Institute of Environmental Health Sciences FX Supported by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences. NR 128 TC 101 Z9 106 U1 3 U2 46 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 NOV PY 2013 VL 132 IS 5 BP 1033 EP 1044 DI 10.1016/j.jaci.2013.09.007 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA 242JH UT WOS:000326235600002 PM 24084075 ER PT J AU Zhang, YE Newfeld, SJ AF Zhang, Ying E. Newfeld, Stuart J. TI Meeting report - TGF-beta superfamily: signaling in development and disease SO JOURNAL OF CELL SCIENCE LA English DT Article ID GROWTH-FACTOR-BETA; RECEPTOR; METASTASIS C1 [Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Newfeld, Stuart J.] Arizona State Univ, Sch Life Sci, Tempe, AZ 85287 USA. RP Zhang, YE (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zhangyin@mail.nih.gov; newfeld@asu.edu RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU National Institutes of Health (National Cancer Institute Center for Cancer Research); National Human Genome Research Institute, National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke FX Y.E.Z. is supported by the intramural research program of National Institutes of Health (National Cancer Institute Center for Cancer Research); S.J.N. is supported by the National Human Genome Research Institute, National Institute of General Medical Sciences and the National Institute of Neurological Disorders and Stroke. NR 17 TC 0 Z9 0 U1 2 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD NOV 1 PY 2013 VL 126 IS 21 BP 4809 EP 4813 DI 10.1242/jcs.142398 PG 5 WC Cell Biology SC Cell Biology GA 244MH UT WOS:000326392500001 PM 24172535 ER PT J AU Webster, BR Scott, I Han, K Li, JH Lu, ZP Stevens, MV Malide, D Chen, Y Samsel, L Connelly, PS Daniels, MP Mccoy, JP Combs, CA Gucek, M Sack, MN AF Webster, Bradley R. Scott, Iain Han, Kim Li, Jian H. Lu, Zhongping Stevens, Mark V. Malide, Daniela Chen, Yong Samsel, Leigh Connelly, Patricia S. Daniels, Mathew P. Mccoy, J. Philip, Jr. Combs, Christian A. Gucek, Marjan Sack, Michael N. TI Restricted mitochondrial protein acetylation initiates mitochondrial autophagy SO JOURNAL OF CELL SCIENCE LA English DT Article DE GCN5L1; SIRT3; Mitochondrial autophagy; Acetylation; Parkin ID OXIDATIVE DAMAGE; CELL-DEATH; SIRT3; DEACETYLASE; IDENTIFICATION; SPERMIDINE; MECHANISM; MITOPHAGY; PROMOTES; MUTATION AB Because nutrient-sensing nuclear and cytosolic acetylation mediates cellular autophagy, we investigated whether mitochondrial acetylation modulates mitochondrial autophagy (mitophagy). Knockdown of GCN5L1, a component of the mitochondrial acetyltransferase machinery, diminished mitochondrial protein acetylation and augmented mitochondrial enrichment of autophagy mediators. This program was disrupted by SIRT3 knockdown. Chronic GCN5L1 depletion increased mitochondrial turnover and reduced mitochondrial protein content and/or mass. In parallel, mitochondria showed blunted respiration and enhanced 'stress-resilience'. Genetic disruption of autophagy mediators Atg5 and p62 (also known as SQSTM1), as well as GCN5L1 reconstitution, abolished deacetylation-induced mitochondrial autophagy. Interestingly, this program is independent of the mitophagy E3-ligase Parkin (also known as PARK2). Taken together, these data suggest that deacetylation of mitochondrial proteins initiates mitochondrial autophagy in a canonical autophagy-mediator-dependent program and shows that modulation of this regulatory program has ameliorative mitochondrial homeostatic effects. C1 [Webster, Bradley R.; Scott, Iain; Han, Kim; Li, Jian H.; Lu, Zhongping; Stevens, Mark V.; Sack, Michael N.] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Malide, Daniela; Combs, Christian A.] NHLBI, Light Microscopy Core, NIH, Bethesda, MD 20892 USA. [Chen, Yong; Gucek, Marjan] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. [Samsel, Leigh; Mccoy, J. Philip, Jr.] NHLBI, Flow Cytometry Core, NIH, Bethesda, MD 20892 USA. [Connelly, Patricia S.; Daniels, Mathew P.] NHLBI, Electron Microscopy Core, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov RI chen, yong/E-2432-2011 FU National Institute of Heart, Lung, and Blood Institute Division of Intramural Research [HL006047-01] FX This work was supported by the National Institute of Heart, Lung, and Blood Institute Division of Intramural Research [grant number HL006047-01 to M.N.S.]. Deposited in PMC for release after 12 months. NR 24 TC 29 Z9 29 U1 0 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD NOV 1 PY 2013 VL 126 IS 21 BP 4843 EP 4849 DI 10.1242/jcs.131300 PG 7 WC Cell Biology SC Cell Biology GA 244MH UT WOS:000326392500005 PM 24006259 ER PT J AU Richards, VP Greig, TW Fair, PA McCulloch, SD Politz, C Natoli, A Driscoll, CA Hoelzel, AR David, V Bossart, GD Lopez, JV AF Richards, Vincent P. Greig, Thomas W. Fair, Patricia A. McCulloch, Stephen D. Politz, Christine Natoli, Ada Driscoll, Carlos A. Hoelzel, A. Rus David, Victor Bossart, Gregory D. Lopez, Jose V. TI Patterns of Population Structure for Inshore Bottlenose Dolphins along the Eastern United States SO JOURNAL OF HEREDITY LA English DT Article DE Indian River Lagoon; microsatellite; mtDNA; Tursiops truncatus ID INDIAN-RIVER LAGOON; SEX-BIASED DISPERSAL; GULF-OF-MEXICO; TURSIOPS-TRUNCATUS; GENETIC-STRUCTURE; MICROSATELLITE MARKERS; CETACEAN POPULATIONS; WESTERN-AUSTRALIA; SOUTH-CAROLINA; SPECIES TREES AB Globally distributed, the bottlenose dolphin (Tursiops truncatus) is found in a range of offshore and coastal habitats. Using 15 microsatellite loci and mtDNA control region sequences, we investigated patterns of genetic differentiation among putative populations along the eastern US shoreline (the Indian River Lagoon, Florida, and Charleston Harbor, South Carolina) (microsatellite analyses: n = 125, mtDNA analyses: n = 132). We further utilized the mtDNA to compare these populations with those from the Northwest Atlantic, Gulf of Mexico, and Caribbean. Results showed strong differentiation among inshore, alongshore, and offshore habitats (Phi(ST) = 0.744). In addition, Bayesian clustering analyses revealed the presence of 2 genetic clusters (populations) within the 250 km Indian River Lagoon. Habitat heterogeneity is likely an important force diversifying bottlenose dolphin populations through its influence on social behavior and foraging strategy. We propose that the spatial pattern of genetic variation within the lagoon reflects both its steep longitudinal transition of climate and also its historical discontinuity and recent connection as part of Intracoastal Waterway development. These findings have important management implications as they emphasize the role of habitat and the consequence of its modification in shaping bottlenose dolphin population structure and highlight the possibility of multiple management units existing in discrete inshore habitats along the entire eastern US shoreline. C1 [Richards, Vincent P.] Cornell Univ, Dept Populat Med & Diagnost Sci, Coll Vet Med, Ithaca, NY 14853 USA. [Greig, Thomas W.; Fair, Patricia A.] Florida Atlantic Univ, Marine Mammal Res & Conservat Program, Harbor Branch Oceanog Inst, Pierce, FL USA. [McCulloch, Stephen D.; Politz, Christine; Driscoll, Carlos A.; Bossart, Gregory D.; Lopez, Jose V.] NOAA, Ctr Coastal Environm Hlth & Biomol Res, Charleston, SC USA. [Natoli, Ada; Hoelzel, A. Rus] Univ Durham, Sch Biol & Biomed Sci, Durham, England. [David, Victor] Natl Canc Inst, Basic Res Lab Genom Div, Frederick, MD USA. [Bossart, Gregory D.] Georgia Aquarium, Nw Atlanta, GA USA. [Lopez, Jose V.] Nova SE Univ, Oceanog Ctr, Dania, FL USA. RP Richards, VP (reprint author), Cornell Univ, Dept Populat Med & Diagnost Sci, Coll Vet Med, Ithaca, NY 14853 USA. EM vpr3@cornell.edu OI Driscoll, Carlos/0000-0003-2392-505X FU State of Florida's Protect Wild Dolphins Specialty License Plate Fund; NOAA/Center for Coastal Environmental Health and Biomolecular Research (CCEHBR); NOAA/NMFS Marine Mammal Health and Stranding Response Program; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX State of Florida's Protect Wild Dolphins Specialty License Plate Fund; NOAA/Center for Coastal Environmental Health and Biomolecular Research (CCEHBR); NOAA/NMFS Marine Mammal Health and Stranding Response Program; Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 95 TC 6 Z9 6 U1 8 U2 45 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 EI 1465-7333 J9 J HERED JI J. Hered. PD NOV-DEC PY 2013 VL 104 IS 6 BP 765 EP 778 DI 10.1093/jhered/est070 PG 14 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 239RL UT WOS:000326043000003 PM 24129993 ER PT J AU Chun, TW Fauci, AS AF Chun, Tae-Wook Fauci, Anthony S. TI Viral Persistence in HIV Infection: Much Known, Much to Learn SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE HIV; antiretroviral therapy; viral reservoirs; 2-LTR HIV DNA; intensification; eradication; plasma viremia ID ACTIVE ANTIRETROVIRAL THERAPY; RALTEGRAVIR INTENSIFICATION; REPLICATION; RESERVOIR; CURE; GUT; ERADICATION; SUPPRESSION; ACTIVATION; DYNAMICS C1 [Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike,Bldg 10,Rm 6A32, Bethesda, MD 20892 USA. EM twchun@nih.gov NR 26 TC 3 Z9 3 U1 0 U2 10 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 NOV 1 PY 2013 VL 208 IS 9 BP 1356 EP 1358 DI 10.1093/infdis/jit455 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 244HD UT WOS:000326377500002 PM 23975884 ER PT J AU Chun, TW Justement, JS Murray, D Kim, CJ Blazkova, J Hallahan, CW Benko, E Costiniuk, CT Kandel, G Ostrowski, M Kaul, R Moir, S Casazza, JP Koup, RA Kovacs, C Fauci, AS AF Chun, Tae-Wook Justement, J. Shawn Murray, Danielle Kim, Connie J. Blazkova, Jana Hallahan, Claire W. Benko, Erika Costiniuk, Cecilia T. Kandel, Gabor Ostrowski, Mario Kaul, Rupert Moir, Susan Casazza, Joseph P. Koup, Richard A. Kovacs, Colin Fauci, Anthony S. TI Effect of Antiretroviral Therapy on HIV Reservoirs in Elite Controllers SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE human immunodeficiency virus; viral reservoirs; antiretroviral therapy; elite controllers ID LOW-LEVEL VIREMIA; VIRUS; INTENSIFICATION; INDIVIDUALS; REPLICATION; SUPPRESSORS; INFECTION AB Elite controllers suppress human immunodeficiency virus (HIV) viremia to below the limit of detection in the absence of antiretroviral therapy (ART). However, precise frequencies of CD4(+) T cells carrying replication-competent HIV and/or the dynamics of the infectious viral reservoirs in response to initiation and discontinuation of ART in elite controllers are unknown. We show that the size of the pool of CD4(+) T cells harboring infectious HIV diminished significantly after initiation of ART and rebounded to baseline upon cessation of therapy. Our data provide compelling evidence that persistent viral replication occurs in untreated elite controllers even in the absence of detectable plasma viremia. C1 [Chun, Tae-Wook; Justement, J. Shawn; Murray, Danielle; Blazkova, Jana; Hallahan, Claire W.; Moir, Susan; Casazza, Joseph P.; Koup, Richard A.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. [Kim, Connie J.; Ostrowski, Mario; Kaul, Rupert; Kovacs, Colin] Univ Toronto, Dept Med, Toronto, ON, Canada. [Benko, Erika; Kovacs, Colin] Maple Leaf Med Clin, Toronto, ON, Canada. [Costiniuk, Cecilia T.] Ottawa Hosp, Dept Med, Toronto, ON, Canada. [Kandel, Gabor; Ostrowski, Mario] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Kandel, Gabor; Ostrowski, Mario] Li Ka Shing Knowledge Inst, Toronto, ON, Canada. RP Chun, TW (reprint author), NIH, Bldg 10,Rm 6A32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 25 Z9 25 U1 0 U2 9 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 NOV 1 PY 2013 VL 208 IS 9 BP 1443 EP 1447 DI 10.1093/infdis/jit306 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 244HD UT WOS:000326377500014 PM 23847057 ER PT J AU Shobab, L Pleyer, U Johnsen, J Metzner, S James, ER Torun, N Fay, MP Liesenfeld, O Grigg, ME AF Shobab, Leila Pleyer, Uwe Johnsen, Joerdis Metzner, Sylvia James, Erick R. Torun, N. Fay, Michael P. Liesenfeld, Oliver Grigg, Michael E. TI Toxoplasma Serotype Is Associated With Development of Ocular Toxoplasmosis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Diagnosis; ocular inflammatory disease; serotype; toxoplasmosis; uveitis ID CONGENITAL TOXOPLASMOSIS; HIGH PREVALENCE; GONDII STRAINS; POPULATION-STRUCTURE; GLOBAL REASSESSMENT; MEMORIAL-LECTURE; AQUEOUS-HUMOR; I STRAINS; PCR; VIRULENCE AB Background. Worldwide, ocular toxoplasmosis (OT) is the principal cause of posterior uveitis, a severe, life-altering disease. A Toxoplasma gondii enzyme-linked immunoassay that detects strain-specific antibodies present in serum was used to correlate serotype with disease. Methods. Toxoplasma serotypes in consecutive serum samples from German uveitis patients with OT were compared with non-OT seropositive patients with noninfectious autoimmune posterior uveitis. OT patients were tested for association of parasite serotype with age, gender, location, clinical onset, size, visual acuity, or number of lesions (mean follow-up, 3.8 years) to determine association with recurrences. Results. A novel, nonreactive (NR) serotype was detected more frequently in serum samples of OT patients (50/114, 44%) than in non-OT patients (4/56, 7%) (odds ratio, 10.0; 95% confidence interval 3.4-40.8; P < .0001). Non-OT patients were predominantly infected with Type II strains (39/56; 70%), consistent with expected frequencies in Central Europe. Among OT patients, those with NR serotypes experienced more frequent recurrences (P = .037). Polymerase chain reaction detected parasite DNA in 8/60 OT aqueous humor specimens but failed to identify Type II strain alleles. Conclusions. Toxoplasma NR and Type II serotypes predominate in German OT patients. The NR serotype is associated with OT recurrences, underscoring the value of screening for management of disease. C1 [Shobab, Leila; Grigg, Michael E.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Pleyer, Uwe; Johnsen, Joerdis; Metzner, Sylvia; Torun, N.] Charite Univ Med Berlin, Dept Ophthalmol, Berlin, Germany. [Liesenfeld, Oliver] Charite Univ Med Berlin, Inst Microbiol & Hyg, Berlin, Germany. [James, Erick R.; Grigg, Michael E.] Univ British Columbia, Dept Med, Vancouver, BC, Canada. RP Grigg, ME (reprint author), 4 Ctr Dr, Bethesda, MD 20892 USA. EM griggm@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); ToxoNet, a program of the German Bundesministerium fur Bildung und Forschung (BMBF) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID; M. E. G.). M. E. G. is a scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity. U. P., N. T., and O. L. were supported by ToxoNet, a program of the German Bundesministerium fur Bildung und Forschung (BMBF). NR 43 TC 17 Z9 17 U1 0 U2 5 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 NOV 1 PY 2013 VL 208 IS 9 BP 1520 EP 1528 DI 10.1093/infdis/jit313 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 244HD UT WOS:000326377500024 PM 23878321 ER PT J AU Tanpaiboon, P Venditti, CP AF Tanpaiboon, Pranoot Venditti, Charles P. TI Noncompaction of the ventricular myocardium and hydrops fetalis in cobalamin C disease SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Letter C1 [Tanpaiboon, Pranoot] Childrens Natl Med Ctr, Div Genet & Metab, Washington, DC 20010 USA. [Venditti, Charles P.] NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Organ Acid Res Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov FU Intramural NIH HHS [ZIA HG200318-09] NR 2 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2013 VL 36 IS 6 BP 1085 EP 1085 DI 10.1007/s10545-013-9644-9 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 244GQ UT WOS:000326375800023 PM 23974651 ER PT J AU Stefl, S Nishi, H Petukh, M Panchenko, AR Alexov, E AF Stefl, Shannon Nishi, Hafumi Petukh, Marharyta Panchenko, Anna R. Alexov, Emil TI Molecular Mechanisms of Disease-Causing Missense Mutations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Review ID SINGLE-NUCLEOTIDE POLYMORPHISMS; PROTEIN INTRINSIC DISORDER; AMINO-ACID SUBSTITUTIONS; SUPPORT VECTOR MACHINES; HYDROGEN-BOND NETWORK; FREE-ENERGY CHANGES; STABILITY CHANGES; SUBCELLULAR-LOCALIZATION; FUNCTIONAL SITES; RARE VARIANTS AB Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions and may influence susceptibility to disease and drug treatment. The plausible effects of nnissense mutations range from affecting the macromolecular stability to perturbing macronnolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies that illustrate the association between missense mutations and diseases. In addition, we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally, we report the current state-of-the-art methodologies that predict the effects of mutations on protein stability, the hydrogen bond network, pH dependence, conformational dynamics and protein function. Published by Elsevier Ltd. C1 [Stefl, Shannon; Petukh, Marharyta; Alexov, Emil] Clemson Univ, Dept Phys, Clemson, SC 29634 USA. [Nishi, Hafumi; Panchenko, Anna R.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov; ealexov@clemson.edu OI Nishi, Hafumi/0000-0002-0846-0330 FU National Institutes of Health [R01GM093937]; Intramural Research Program of the National Library of Medicine at the US National Institutes of Health FX S.S., M.P, and E.A. acknowledge the support from the National Institutes of Health grant number R01GM093937. H.N. and A.R.P. were supported by the Intramural Research Program of the National Library of Medicine at the US National Institutes of Health. NR 192 TC 46 Z9 47 U1 5 U2 28 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 NOV 1 PY 2013 VL 425 IS 21 BP 3919 EP 3936 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 242QM UT WOS:000326257100003 PM 23871686 ER PT J AU Hamasaki-Katagiri, N Salari, R Wu, A Ql, Y Schiller, T Filiberto, AC Schisterman, EF Komar, AA Przytycka, TM Kimchi-Sarfaty, C AF Hamasaki-Katagiri, Nobuko Salari, Raheleh Wu, Andrew Ql, Yini Schiller, Tal Filiberto, Amanda C. Schisterman, Enrique F. Komar, Anton A. Przytycka, Teresa M. Kimchi-Sarfaty, Chava TI A Gene-Specific Method for Predicting Hemophilia-Causing Point Mutations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; COAGULATION-FACTOR-VIII; MISSENSE MUTATIONS; PROTEIN; DISEASE; RNA; PHOSPHORYLATION; IDENTIFICATION; VARIANTS; RESOURCE AB A fundamental goal of medical genetics is the accurate prediction of genotype phenotype correlations. As an approach to develop more accurate in silico tools for prediction of disease-causing mutations of structural proteins, we present a gene- and disease-specific prediction tool based on a large systematic analysis of missense mutations from hemophilia A (HA) patients. Our HA-specific prediction tool, HApredictor, showed disease prediction accuracy comparable to other publicly available prediction software. In contrast to those methods, its performance is not limited to non-synonymous mutations. Given the role of synonymous mutations in disease and drug codon optimization, we propose that utilizing a gene- and disease-specific method can be highly useful to make functional predictions possible even for synonymous mutations. Incorporating computational metrics at both nucleotide and amino acid levels along with multiple protein sequence/structure alignment significantly improved the predictive performance of our tool. HApredictor is freely available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/HA_Predict/index.htm. Published by Elsevier Ltd. C1 [Hamasaki-Katagiri, Nobuko; Wu, Andrew; Ql, Yini; Kimchi-Sarfaty, Chava] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Salari, Raheleh] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Filiberto, Amanda C.; Schisterman, Enrique F.] NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Komar, Anton A.] Cleveland State Univ, Dept Biol, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. [Przytycka, Teresa M.] NCI, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Kimchi-Sarfaty, C (reprint author), 29 Lincoln Dr, Bethesda, MD 20892 USA. EM Chava.kimchi-sarfaty@fda.hhs.gov FU National Institutes of Health Intramural Research Funding (National Library of Medicine); Natural Sciences and Engineering Research Council Postdoctoral Fellowships FX We would like to thank Ms. Erin Needlman, Ms. Natasha Nelson, Mr. Max Katz, Mr. Jeong Lee, Mr. Stephen Gross, and Mr. Matt landoli for helping with construction of datasets. We are grateful to Ms. Sandra C. Tseng, Dr. Ryan Hunt, Dr. Zuben Sauna (Center for Biologics Evaluation and Research, Food and Drug Administration), Dr. Deanna Church, and Mr. John Garner (NCBI, National Institutes of Health) for insightful commentary. We thank Dr. Geoffrey Kemball-Cook (University College London) for maintaining HADB, data from which is now included in CHAMP. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency determination or policy. T.M.P. is supported by National Institutes of Health Intramural Research Funding (National Library of Medicine). R.S. was funded partially by Natural Sciences and Engineering Research Council Postdoctoral Fellowships. NR 33 TC 9 Z9 9 U1 2 U2 14 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 NOV 1 PY 2013 VL 425 IS 21 BP 4023 EP 4033 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 242QM UT WOS:000326257100011 PM 23920358 ER PT J AU Xu, Z Chen, WY Merke, DP McDonnell, NB AF Xu, Zhi Chen, Wuyan Merke, Deborah P. McDonnell, Nazli B. TI Comprehensive Mutation Analysis of the CYP21A2 Gene An Efficient Multistep Approach to the Molecular Diagnosis of Congenital Adrenal Hyperplasia SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID STEROID 21-HYDROXYLASE DEFICIENCY; DEPENDENT PROBE AMPLIFICATION; CHIMERIC CYP21P/CYP21 GENE; POLYMERASE-CHAIN-REACTION; EHLERS-DANLOS-SYNDROME; QUANTITATIVE PCR; LARGE COHORT; RCCX MODULE; HYPERPLASIA; DELETION AB Congenital adrenal hyperplasia, due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of adrenal steroidogenesis caused by mutations in the CYP21A2 gene. Direct comparison of established and novel methodologies of CYP21A2 genetic analysis in a large cohort representing a wide range of genotypes has not been previously reported. We genotyped a cohort of 129 unrelated patients with 21-OHD, along with 145 available parents, using Southern blot (SB) analysis, multiplex ligation-dependent probe amplification (MLPA), PCR-based restriction fragment length polymorphism (RFLP) analysis, multiplex minisequencing and conversion-specific PCR, duplication-specific amplification, and DNA sequencing. CYP21A2 genotyping identified four duplicated CYP21A2 genes (1.53%) and 79 chimeric CYP21A1P/CYP21A2 genes (30.15%). Parental SB data were essential for determining the CYP21 haplotype in three cases, whereas PCR-based RFLP analysis was necessary for MLPA results to be accurately interpreted in the majority of cases. The comparison of different methods in detecting deletion and duplication showed that MLPA with PCR-based RFLP was comparable with SB analysis, with parental data of 100% sensitivity and specificity. DNA sequencing was required for the identification of 16 (6.1%) rare point mutations and determination of clinically significant chimera junction sites. MLPA with PCR-based RFLP analysis is an excellent substitute for SB analysis in detecting CYP21A2 deletion and duplication and a combination of MLPA, PCR-based RFLP, duplication-specific amplification, and DNA sequencing is a convenient and comprehensive strategy for mutation analysis of the CYP21A2 gene in patients with 21-OHD. C1 [Xu, Zhi; Chen, Wuyan; McDonnell, Nazli B.] NIA, Lab Clin Invest, Bethesda, MD 20892 USA. [Merke, Deborah P.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Program Dev Endocrinol & Genet, Bethesda, MD USA. RP McDonnell, NB (reprint author), NIA, Lab Clin Invest, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mcdonnellna@grc.nia.nih.gov RI Xu, Zhi/I-2546-2012 FU NTH; National Institute on Aging; Clinical Center; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the Intramural Research Programs of the NTH, National Institute on Aging, the Clinical Center, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 40 TC 5 Z9 6 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 745 EP 753 DI 10.1016/j.jmoldx.2013.06.001 PG 9 WC Pathology SC Pathology GA 248BF UT WOS:000326668000003 PM 24071710 ER PT J AU Church, D Funke, B Hegde, M Chao, C Trow, J Slotta, D Halavi, M Meric, PA Ananiev, V Frishberg, D Rubinstein, W da Silva, C Gowrisankar, S Ajay, S Chapman, B Compton, J Dames, S Das, S Feng, Y Hambuch, T Kulkarni, S Mao, R O'Fallon, BD Shrivastava, S Toji, L Zhang, V Zook, J Kalman, L AF Church, D. Funke, B. Hegde, M. Chao, C. Trow, J. Slotta, D. Halavi, M. Meric, P. A. Ananiev, V. Frishberg, D. Rubinstein, W. da Silva, C. Gowrisankar, S. Ajay, S. Chapman, B. Compton, J. Dames, S. Das, S. Feng, Y. Hambuch, T. Kulkarni, S. Mao, R. O'Fallon, B. D. Shrivastava, S. Toji, L. Zhang, V. Zook, J. Kalman, L. TI Development of Consensus Reference Material Tools for Clinical Next-Generation Sequencing Tests SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Church, D.] NIH, Bethesda, MD 20892 USA. [Funke, B.] Massachusetts Gen Hosp, Cambridge, MA USA. [Funke, B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hegde, M.; da Silva, C.] Emory Univ, Sch Med, Atlanta, GA USA. [Chao, C.; Trow, J.; Slotta, D.; Halavi, M.; Meric, P. A.; Ananiev, V.; Frishberg, D.; Rubinstein, W.] NIH, Bethesda, MD 20892 USA. [Gowrisankar, S.] Partners Healthcare Ctr Personalized Genet Med, Cambridge, MA USA. [Ajay, S.; Hambuch, T.] Illumina, San Diego, CA USA. [Chapman, B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Compton, J.] GeneDx Inc, Gaithersburg, MD USA. [Dames, S.; Mao, R.; O'Fallon, B. D.] ARUP Labs, Salt Lake City, UT USA. [Das, S.] Univ Chicago, Chicago, IL 60637 USA. [Feng, Y.; Zhang, V.] Baylor Coll Med, Houston, TX 77030 USA. [Kulkarni, S.; Shrivastava, S.] Washington Univ, Sch Med, St Louis, MO USA. [Toji, L.] Coriell Inst Med Res, Camden, NJ USA. [Zook, J.] NIST, Gaithersburg, MD 20899 USA. [Kalman, L.] Ctr Dis Control & Prevent, Atlanta, GA USA. 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 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 847 EP 847 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000032 ER PT J AU Rubinstein, WS Kattman, BL Malheiro, AJ Lee, J Hem, V Ovetsky, M Song, G Maglott, D AF Rubinstein, W. S. Kattman, B. L. Malheiro, A. J. Lee, J. Hem, V. Ovetsky, M. Song, G. Maglott, D. TI The NIH Genetic Testing Registry: A Survey of the Genetic Testing Landscape SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Rubinstein, W. S.; Kattman, B. L.; Malheiro, A. J.; Lee, J.; Hem, V.; Ovetsky, M.; Song, G.; Maglott, D.] NIH, Bethesda, MD 20892 USA. 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 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 853 EP 853 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000054 ER PT J AU Castellar, ERP Jaffe, ES Said, J Swerdlow, SH Ketterling, RP Knudson, RA Sidhu, JS Hsi, ED Karikehalli, S Jiang, L Vasmatzis, G Gibson, SE Ondrejka, S Nicolae, A Grogg, KL Allmer, C Ristow, KM Macon, WR Law, ME Cerhan, JR Habermann, TM Ansell, SM Dogan, A Maurer, MJ Feldman, AL AF Castellar, E. R. Parrilla Jaffe, E. S. Said, J. Swerdlow, S. H. Ketterling, R. P. Knudson, R. A. Sidhu, J. S. Hsi, E. D. Karikehalli, S. Jiang, L. Vasmatzis, G. Gibson, S. E. Ondrejka, S. Nicolae, A. Grogg, K. L. Allmer, C. Ristow, K. M. Macon, W. R. Law, M. E. Cerhan, J. R. Habermann, T. M. Ansell, S. M. Dogan, A. Maurer, M. J. Feldman, A. L. TI Genetic Risk Stratification of CD30-Positive Peripheral T-Cell Lymphomas: Results of a Multi-Institutional Study SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 14-16, 2013 CL Phoenix, AZ SP Assoc Mol Pathol C1 [Castellar, E. R. Parrilla; Ketterling, R. P.; Knudson, R. A.; Jiang, L.; Vasmatzis, G.; Grogg, K. L.; Allmer, C.; Ristow, K. M.; Macon, W. R.; Law, M. E.; Cerhan, J. R.; Habermann, T. M.; Ansell, S. M.; Dogan, A.; Maurer, M. J.; Feldman, A. L.] Mayo Clin, Rochester, MN USA. [Jaffe, E. S.; Nicolae, A.] NCI, Bethesda, MD 20892 USA. [Said, J.] Univ Calif Los Angeles, Los Angeles, CA USA. [Swerdlow, S. H.; Gibson, S. E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Sidhu, J. S.] United Hlth Serv Hosp, Johnson City, NY USA. [Hsi, E. D.; Ondrejka, S.] Cleveland Clin, Cleveland, OH 44106 USA. [Karikehalli, S.] Centrex Clin Labs, Utica, NY USA. RI Jaffe, Elaine/G-8984-2014 OI Jaffe, Elaine/0000-0003-4632-0301 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 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2013 VL 15 IS 6 BP 860 EP 860 PG 1 WC Pathology SC Pathology GA 248BF UT WOS:000326668000080 ER PT J AU Lenoir, M Kiyatkin, EA AF Lenoir, Magalie Kiyatkin, Eugene A. TI Intravenous nictotine injection induces rapid, experience-dependent sensitization of glutamate release in the ventral tegmental area and nucleus accumbens SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE electrochemistry; enzyme-based glutamate biosensors; experience-dependent neuroplasticity of glutamate neurotransmission; glutamate release ID STRIATAL NEURONAL-ACTIVITY; EXCITATORY AMINO-ACIDS; SENSORY NERVE-ENDINGS; EXTRACELLULAR GLUTAMATE; LOCOMOTOR SENSITIZATION; DOPAMINERGIC-NEURONS; UNRESTRAINED RATS; SUBSTANTIA-NIGRA; NICOTINE; BRAIN AB Although numerous data suggest that glutamate (GLU) is involved in mediating the neural effects of nicotine, direct data on nicotine-induced changes in GLU release are still lacking. Here, we used high-speed amperometry with enzyme-based GLU and enzyme-free GLU-null biosensors to examine changes in extracellular GLU levels in the ventral tegmental area (VTA) and nucleus accumbens shell (NAcc) induced by intravenous nicotine in a low, behaviorally active dose (30g/kg) in freely moving rats. Using this approach, we found that the initial nicotine injection in drug-naive conditions induces rapid, transient, and relatively small GLU release (similar to 90nM; latency similar to 15s, duration similar to 60s) that is correlative in the VTA and NAcc. Following subsequent nicotine injections within the same session, this phasic GLU release was supplemented by stronger tonic increases in GLU levels (100-300nM) that paralleled increases in drug-induced locomotor activation. GLU responses induced by repeated nicotine injections were more phasic and stronger in the NAcc than in VTA. Therefore, GLU is phasically released within the brain's reinforcement circuit following intravenous nicotine administration. Robust enhancement of nicotine-induced GLU responses following repeated injections suggests this change as an important mediator of sensitized behavioral and neural effects of nicotine. C1 [Lenoir, Magalie; 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 This study was supported by the Intramural Research Program of NIDA-IRP. We thank Dr Ken T. Wakabayashi and Stephanie Myal for valuable comments on the content and language of this manuscript as well as assistance in data analysis. NR 50 TC 6 Z9 7 U1 2 U2 5 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 NOV PY 2013 VL 127 IS 4 BP 541 EP 551 DI 10.1111/jnc.12450 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 245ME UT WOS:000326467000014 PM 24032718 ER PT J AU Kweon, SS Shu, XO Xiang, YB Cai, H Yang, G Ji, BT Li, HL Gao, YT Zheng, W Epplein, M AF Kweon, Sun-Seog Shu, Xiao-Ou Xiang, Yongbing Cai, Hui Yang, Gong Ji, Bu-Tian Li, Honglan Gao, Yu-Tang Zheng, Wei Epplein, Meira TI Intake of Specific Nonfermented Soy Foods May Be Inversely Associated with Risk of Distal Gastric Cancer in a Chinese Population SO JOURNAL OF NUTRITION LA English DT Article ID HELICOBACTER-PYLORI INFECTION; SHANGHAI WOMENS HEALTH; STOMACH-CANCER; PHASEOLUS-VULGARIS; COLORECTAL-CANCER; DIETARY FACTORS; GLYCEMIC LOAD; MENS HEALTH; IN-VITRO; ESTROGEN AB Because the association between soy consumption and gastric cancer is inconsistent, we evaluated the putative preventive effect of soy food on gastric cancer risk in the Shanghai Women's and Men's Health Studies, comprising a total of 128,687 participants. Intake of nonfermented soy foods was estimated using 2 validated food-frequency questionnaires. HRs were calculated with 95% CIs for intake amounts of total nonfermented soy food intake, soy protein, and isoflavones as well as individual soy food groups using Cox proportional hazards regression. A total of 493 distal gastric cancer cases were identified by 2010. Although all risk estimates for summary measures of soy food intake above the lowest quartile (quartile 1) were suggestive of a protective effect, no statistically significant associations with risk of distal gastric cancer were found. Among the separate soy food groups, significant reductions in risk of distal gastric cancer by increasing intake of tofu were found in men in quartile 2 (HR: 0.59; 95% Cl: 0.40, 0.86), quartile 3 (HR: 0.62; 95% Cl: 0.44, 0.88), and quartile 4 (HR: 0.64; 95% CI: 0.42, 0.99), resulting in a significant trend (P-trend = 0.02). Dry bean intake was also inversely associated with decreased risk of gastric cancer, but in postmenopausal women only [quartile 2 (HR: 0.54; 95% CI: 0.30, 0.96); quartile 3 (HR: 0.90; 95% CI: 0.64, 1.27); and quartile 4 (HR: 0.63; 95% CI: 0.43, 0.91)1, resulting in a significant trend (P-trend = 0.03). Overall, our study found no statistically significant association between nonfermented soy food intake and distal gastric cancer risk, though the data supported the hypothesis that tofu may protect against distal gastric cancer in men and dry bean consumption may decrease the risk of gastric cancer in postmenopausal women. C1 [Kweon, Sun-Seog; Shu, Xiao-Ou; Cai, Hui; Yang, Gong; Zheng, Wei; Epplein, Meira] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Kweon, Sun-Seog] Chonnam Natl Univ, Sch Med, Dept Prevent Med, Kwangju, South Korea. [Xiang, Yongbing; Li, Honglan; Gao, Yu-Tang] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Renji Hosp, Dept Epidemiol,Sch Med, Shanghai 200030, Peoples R China. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Epplein, M (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA. EM meira.epplein@vanderbilt.edu OI Epplein, Meira/0000-0001-5646-6430; KWEON, SUNSEOG/0000-0003-2378-8550 FU National Cancer Institute [R37 CA70867, R01 CA82729] FX Supported by National Cancer Institute grants R37 CA70867 and R01 CA82729. NR 56 TC 7 Z9 7 U1 2 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD NOV PY 2013 VL 143 IS 11 BP 1736 EP 1742 DI 10.3945/jn.113.177675 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 240VQ UT WOS:000326126200006 PM 23986366 ER PT J AU Beydoun, MA Kuczmarski, MTF Beydoun, HA Hibbeln, JR Evans, MK Zonderman, AB AF Beydoun, May A. Kuczmarski, Marie T. Fanelli Beydoun, Hind A. Hibbeln, Joseph R. Evans, Michele K. Zonderman, Alan B. TI omega-3 Fatty Acid Intakes Are Inversely Related to Elevated Depressive Symptoms among United States Women SO JOURNAL OF NUTRITION LA English DT Article ID MULTIPLE-PASS METHOD; POLYUNSATURATED FATTY-ACIDS; VITAMIN-E LEVELS; MAJOR DEPRESSION; FISH CONSUMPTION; DIETARY-INTAKE; FOLLOW-UP; ATHEROSCLEROSIS RISK; SOCIOECONOMIC-STATUS; UNIPOLAR DEPRESSION AB Evidence that depressive symptoms are inversely related to n-3 (w-3) fatty acids is growing among United States adults. We assessed whether self-reported depressive symptoms were inversely associated with n-3 fatty acid intakes by using a cross-sectional study in 1746 adults (aged 30-65 y) in Baltimore City, MD (2004-2009). The 20-item Center for Epidemiologic Studies-Depression Scale (CES-D) was used, with a CES-D score >= 16 suggestive of elevated depressive symptoms (EDS). By using the mean of two 24-h dietary recalls, n-3 highly unsaturated fatty acids (HUFAs; carbons), n-3 polyunsaturated fatty acids (PUFAs; >= 18 carbons), and plausible ratios with n-6 (omega 6) fatty acids were estimated. EDS prevalence was 18.1% among men and 25.6% among women. In women, the uppermost tertile (tertile 3) of n-3 PUFAs (compared with tertile 1) was associated with reduced odds of EDS by 49%, with a substantial sex differential. The n-3 PUFA:n-6:PUFA ratio was inversely related to EDS among women (tertile 2 vs. tertile 1, OR: 0.74; 95% CI: 0.41, 1.32; tertile 3 vs. tertile 1, OR: 0.47; 95% Cl: 0.27, 0.83). A similar pattern was noted for n-3 HUFA:n-6 HUFA among women. For CES-D subscales, n-3 PUFA 1% of energy) was inversely related to somatic complaints, whereas positive affect was directly related to n-3 HUFA (% of energy; total population and among women), n-3 HUFA:n-6 HUFA (women), and n-3 HUFA:n-6 PUFA (total population and among women). In sum, among United States women, higher intakes of n-3 fatty acids [absolute (n-3) and relative to n-6 fatty acids (n-3:n-6)) were associated with lower risk of elevated depressive symptoms, specifically in domains of somatic complaints (mainly n-3 PUFAs) and positive affect (mainly n-3 HUFAs). C1 [Beydoun, May A.; Evans, Michele K.; Zonderman, Alan B.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Kuczmarski, Marie T. Fanelli] Univ Delaware, Dept Behav Hlth & Nutr, Newark, DE USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Hibbeln, Joseph R.] NIAAA, Nutr Neurosci Sect, Intramural Res Program, NIH, Bethesda, MD USA. RP Beydoun, MA (reprint author), NIA, Intramural Res Program, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov FU National Institute on Aging, Intramural Research Program NIA/NIH/IRP FX Supported by the National Institute on Aging, Intramural Research Program NIA/NIH/IRP). NR 80 TC 17 Z9 18 U1 1 U2 22 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD NOV PY 2013 VL 143 IS 11 BP 1743 EP 1752 DI 10.3945/jn.113.179119 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 240VQ UT WOS:000326126200007 PM 24005610 ER PT J AU Nelson, WL Suls, J AF Nelson, Wendy L. Suls, Jerry TI New Approaches to Understand Cognitive Changes Associated With Chemotherapy for Non-Central Nervous System Tumors SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Cancer; chemotherapy; cognitive impairment; neuropsychological testing; computational modeling ID BREAST-CANCER SURVIVORS; HIGH-DOSE CHEMOTHERAPY; CEREBRAL WHITE-MATTER; OF-THE-LITERATURE; ADJUVANT CHEMOTHERAPY; ECOLOGICAL VALIDITY; SPATIAL NAVIGATION; VIRTUAL-REALITY; POOLED ANALYSIS; BONE-MARROW AB Context. Researchers have described a constellation of cognitive deficits (e. g., impairments in executive functions, working memory, attention, and information-processing speed) associated with cancer treatment, and specifically chemotherapy, for non-central nervous system tumors. However, findings have been inconsistent, largely because of measurement and study design issues. Objectives. To propose ways for researchers to more clearly delineate and characterize the mild cognitive deficits and related outcomes that appear to affect a subset of cancer patients and suggest methods to make more effective use of the existing data to understand risk factors for impaired neuropsychological functioning. Methods. We examined the literature on the relationship between chemotherapy and cognitive impairment, as well as related literature on neuropsychological measurement, structural and functional neuroimaging, alternative measures of health outcomes, and integrative data analysis. Results. A more comprehensive picture of cognitive functioning might be obtained by incorporating nontraditional ecological measures, self-reports, computational modeling, new neuroimaging methods, and markers of occupational functioning. Case-control and integrative data analytic techniques potentially could leverage existing data to identify risk factors for cognitive dysfunction and test hypotheses about the etiology of these effects. Conclusion. There is a need to apply new research approaches to understand the real-world functional implications of the cognitive side effects of chemotherapy to develop and implement strategies to minimize and remediate these effects before, during, and after cancer treatment. (C) 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Nelson, Wendy L.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Basic Biobehav & Psychol Sci Branch, Bethesda, MD 20892 USA. [Suls, Jerry] Univ Iowa, Dept Psychol, Iowa City, IA USA. RP Nelson, WL (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Basic Biobehav & Psychol Sci Branch, 6130 Executive Blvd,EPN 4064, Bethesda, MD 20892 USA. EM nelsonw@mail.nih.gov NR 120 TC 12 Z9 12 U1 3 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 EI 1873-6513 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD NOV PY 2013 VL 46 IS 5 BP 707 EP 721 DI 10.1016/j.jpainsymman.2012.11.005 PG 15 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 242JQ UT WOS:000326236900014 PM 23522517 ER PT J AU Nomani, F Kamal, AK AF Nomani, Fauzia Kamal, Ayeesha Kamran TI Citicoline in the treatment of acute ischaemic stroke: an international, randomized, multicentre, placebo-controlled study (ICTUS trial)Is the use of Citicoline is beneficial for acute ischaemic stroke? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. Aga Khan Univ Hosp, Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv, Karachi, Pakistan. EM ayeesha.kamal@aku.edu NR 1 TC 0 Z9 1 U1 0 U2 3 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD NOV PY 2013 VL 63 IS 11 BP 1445 EP 1445 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 244XD UT WOS:000326422600031 PM 24392540 ER PT J AU Tonelli, MA Wanner, C Cass, A Garg, AX Holdaas, H Jardine, AG Jiang, LX Kronenberg, F Parekh, RS Shoji, T Walker, RJ Kasiske, BL Wheeler, DC Upadhyay, A Balk, EM Earley, A Haynes, S Lamont, J AF Tonelli, Marcello A. Wanner, Christoph Cass, Alan Garg, Amit X. Holdaas, Hallvard Jardine, Alan G. Jiang, Lixin Kronenberg, Florian Parekh, Rulan S. Shoji, Tetsuo Walker, Robert J. Kasiske, Bertram L. Wheeler, David C. Upadhyay, Ashish Balk, Ethan M. Earley, Amy Haynes, Shana Lamont, Jenny TI Introduction: The case for updating and context SO KIDNEY INTERNATIONAL SUPPLEMENTS LA English DT Article DE cholesterol; chronic kidney disease; clinical practice guideline; dyslipidemia; evidence-based recommendation; KDIGO; systematic review; triglycerides ID DENSITY-LIPOPROTEIN CHOLESTEROL; CHRONIC KIDNEY-DISEASE; HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA; RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; PLACEBO-CONTROLLED TRIAL; EDUCATION-PROGRAM RECOMMENDATIONS; CLINICAL-PRACTICE GUIDELINES; CORONARY-HEART-DISEASE; RENAL-TRANSPLANT RECIPIENTS AB The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) provides guidance on lipid management and treatment for all patients with CKD (non-dialysis-dependent, dialysis-dependent, kidney transplant recipients and children). This guideline contains chapters on the assessment of lipid status and treatment for dyslipidemia in adults and children. Development of the guideline followed an explicit process of evidence review and appraisal. Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Ongoing areas of controversies and limitations of the evidence are discussed and additional suggestions are also provided for future research. C1 [Tonelli, Marcello A.] Univ Alberta, Edmonton, AB T6G 2M7, Canada. [Tonelli, Marcello A.] Univ Alberta & Hosp Civil Guadalajara, Guadalajara, Spain. [Wanner, Christoph] Univ Wurzburg, Dept Med, Wurzburg, Germany. [Cass, Alan] Menzies Sch Hlth Res, Darwin, NT, Australia. [Cass, Alan] George Inst Global Hlth, Renal & Metab Div, Sydney, NSW, Australia. [Garg, Amit X.] Univ Western Ontario, London, ON N6A 3K7, Canada. [Garg, Amit X.] London Kidney Clin Res Unit, London, England. [Holdaas, Hallvard] Natl Hosp Norway, Oslo Univ Hosp, Dept Transplant Med, Oslo, Norway. [Jardine, Alan G.] Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland. [Jardine, Alan G.] BHF Glasgow Cardiovasc Res Ctr, Renal Res Grp, Glasgow, Lanark, Scotland. [Jardine, Alan G.] Undergrad Med Sch, Glasgow, Lanark, Scotland. [Jiang, Lixin] Chinese Acad Med Sci, Beijing, Peoples R China. [Jiang, Lixin] Peking Union Med Coll, Beijing, Peoples R China. [Jiang, Lixin] Univ Oxford, Oxford OX1 2JD, England. [Kronenberg, Florian] Univ Utah, Salt Lake City, UT USA. [Kronenberg, Florian] Helmholtz Ctr, Inst Epidemiol, Munich, Germany. [Kronenberg, Florian] Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, A-6020 Innsbruck, Austria. [Parekh, Rulan S.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Parekh, Rulan S.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Shoji, Tetsuo] Osaka City Univ, Grad Sch Med, Dept Geriatr & Vasc Med, Osaka 558, Japan. [Shoji, Tetsuo] Osaka City Univ Hospital, Dept Internal Med 2, Osaka, Japan. [Walker, Robert J.] Univ Otago, Christchurch, New Zealand. [Walker, Robert J.] Univ Otago, Dunedin Sch Med, Christchurch, New Zealand. [Walker, Robert J.] Healthcare Otago, Christchurch, New Zealand. [Walker, Robert J.] Healthcare Otago, Nephrol, Christchurch, New Zealand. [Kasiske, Bertram L.] Univ Minnesota, Minneapolis, MN 55455 USA. [Kasiske, Bertram L.] NIH, Bethesda, MD USA. [Wheeler, David C.] UCL, London WC1E 6BT, England. [Upadhyay, Ashish] Boston Univ, Sch Med, Renal Sect, Boston, MA 02118 USA. [Upadhyay, Ashish] Boston Univ, Sch Med, Internal Med Residency Program, Boston, MA 02118 USA. [Upadhyay, Ashish; Balk, Ethan M.] Tufts Univ, Sch Med, Medford, MA USA. [Upadhyay, Ashish] Tufts Med Ctr, William B Schwartz MD Div Nephrol, Medford, MA USA. [Balk, Ethan M.; Earley, Amy; Haynes, Shana; Lamont, Jenny] Tufts Ctr Kidney Dis Guideline Dev & Implementat, Boston, MA USA. [Balk, Ethan M.] Tufts Evidence Based Practice Ctr, Medford, MA USA. RP Tonelli, MA (reprint author), Univ Alberta, Edmonton, AB T6G 2M7, Canada. RI Kronenberg, Florian/B-1736-2008 OI Kronenberg, Florian/0000-0003-2229-1120 NR 114 TC 1 Z9 1 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2157-1724 EI 2157-1716 J9 KIDNEY INT SUPPL JI Kidney Int. Suppl. PD NOV PY 2013 VL 3 IS 3 BP 266 EP + DI 10.1038/kisup.2013.32 PG 41 WC Urology & Nephrology SC Urology & Nephrology GA 245YT UT WOS:000326502000002 ER PT J AU Silk, SB Brown, P AF Silk, Susan Brust Brown, Patricia TI Clarification of OLAW's position on rodent cage changes SO LAB ANIMAL LA English DT Letter C1 [Silk, Susan Brust; Brown, Patricia] NIH, Off Lab Anim Welf, Off Extramural Res, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Silk, SB (reprint author), NIH, Off Lab Anim Welf, Off Extramural Res, US Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. EM olaw@od.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD NOV PY 2013 VL 42 IS 11 BP 409 EP 409 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 245UB UT WOS:000326488200012 PM 24150161 ER PT J AU Hu, XB Wei, H Xiang, LM Chertov, O Wayne, AS Bera, TK Pastan, I AF Hu, Xiaobo Wei, Hui Xiang, Laiman Chertov, Oleg Wayne, Alan S. Bera, Tapan K. Pastan, Ira TI Methylation of the DPH1 promoter causes immunotoxin resistance in acute lymphoblastic leukemia cell line KOPN-8 SO LEUKEMIA RESEARCH LA English DT Article DE DNA methylation; Drug resistance; ADP-ribosylation; Diphthamide synthesis; Epigenetic regulation ID PSEUDOMONAS-EXOTOXIN; SACCHAROMYCES-CEREVISIAE; DIPHTHERIA-TOXIN; DIPHTHAMIDE BIOSYNTHESIS; MYELOID-LEUKEMIA; IN-VITRO; GENE; CANCER; 5-AZA-2'-DEOXYCYTIDINE; EXPRESSION AB Moxetumomab pasudotox (HA22) is an immunotoxin with an anti-CD22 Fv fused to a portion of Pseudomonas exotoxin A that kills CD22 expressing ALL cells. HA22 produced significant responses in some cases of ALL. To understand how to increase response rate, we isolated HA22-resistant KOPN-8 cells and found that HA22 cannot inactivate elongation factor-2 (EF2) due to low levels of DPH1 RNA and protein. Resistance was associated with methylation of the CpG island in the DPH1 promoter. 5-Azacytidine prevented resistance and methylation of the CpG residues and merits evaluation to determine if it can increase the efficacy of HA22 in ALL. Published by Elsevier Ltd. C1 [Hu, Xiaobo; Wei, Hui; Xiang, Laiman; Wayne, Alan S.; Bera, Tapan K.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Chertov, Oleg] NCI, Prot Chem Lab, Adv Technol Program, SAIC Frederick,Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU NIH, NCI, Center for Cancer Research; NCI, NIH [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research, in part with federal funds from the NCI, NIH, under contract No. HHSN261200800001E, and in part with a Cooperative Research and Development Agreement with MedImmune, LLC. NR 39 TC 7 Z9 7 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD NOV PY 2013 VL 37 IS 11 BP 1551 EP 1556 DI 10.1016/j.leukres.2013.08.005 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 242UV UT WOS:000326269500029 PM 24070652 ER PT J AU Lasota, J Xi, LQ Coates, T Dennis, R Evbuomwan, MO Wang, ZF Raffeld, M Miettinen, M AF Lasota, Jerzy Xi, Liqiang Coates, Tiffany Dennis, RaShonda Evbuomwan, Moses O. Wang, Zeng-Feng Raffeld, Mark Miettinen, Markku TI No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases SO MODERN PATHOLOGY LA English DT Article DE GIST; KIT mutations; KRAS mutations; PDGFRA mutations; pyrosequencing; Sanger sequencing ID TYROSINE KINASE INHIBITORS; RAS GENE; BRAF MUTATIONS; CARCINOMA; SARCOMA; RESISTANCE; BLADDER; EVENTS; HARVEY AB Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. A great majority of GISTs is driven by pathological activation of KIT or platelet-derived growth factor receptor-alpha (PDGFRA), two closely related receptor tyrosine kinases. However, other genetic changes including gain-of-function BRAF mutations and loss of succinate dehydrogenase (SDH) complex activity have been identified in the subsets of KIT-, PDGFRA-wild type tumors. Genetic mutations affecting KIT, PDGFRA, BRAF and SDH complex functions are believed to be mutually exclusive events. Recently, KRAS codon 12 and 13 mutations were reported in a small subset of KIT or PDGFRA mutant GISTs. Moreover, in in vitro experiments, KIT mutants with concurrent KRAS mutation showed resistance to imatinib, a receptor tyrosine kinase inhibitor used in GIST treatment. The aim of this study was to evaluate a large cohort of GISTs to define frequency and clinical significance of KRAS mutations in this type of cancer. A well-characterized cohort of 514 GISTs was screened for KRAS mutations using Sanger sequencing (n = 450) and pyrosequencing (n = 64). In all, 350 gastric, 100 intestinal and 64 primary disseminated GISTs were analyzed. No KRAS mutations were found. In GIST, KRAS mutations are extremely rare if they exist (<0.2%). Thus, mutational activation of KRAS does not seem to play any significant role in the development and progression of this type of cancer. C1 [Lasota, Jerzy; Xi, Liqiang; Coates, Tiffany; Dennis, RaShonda; Evbuomwan, Moses O.; Wang, Zeng-Feng; Raffeld, Mark; Miettinen, Markku] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Lasota, J (reprint author), NCI, Pathol Lab, 9000 Rockville Pike,Bldg 10,Room B1B47, Bethesda, MD 20892 USA. EM jerzy.lasota@nih.gov FU NCI's Intramural Research Program FX This work was supported in part by NCI's Intramural Research Program. NR 22 TC 10 Z9 11 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2013 VL 26 IS 11 BP 1488 EP 1491 DI 10.1038/modpathol.2013.89 PG 4 WC Pathology SC Pathology GA 248GV UT WOS:000326686700009 PM 23702733 ER PT J AU Barbash, ZS Weissman, JD Campbell, JA Mu, J Singer, DS AF Barbash, Zohar S. Weissman, Jocelyn D. Campbell, John A., Jr. Mu, Jie Singer, Dinah S. TI Major Histocompatibility Complex Class I Core Promoter Elements Are Not Essential for Transcription In Vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; TRANSGENE COPY NUMBER; FUNCTIONAL-CHARACTERIZATION; HUMAN GENOME; DNA-BINDING; GENE; EXPRESSION; INITIATOR; SEQUENCE; PROTEIN AB The role of core promoter elements in regulating transcription initiation is largely unknown for genes subject to complex regulation. Major histocompatibility complex class I genes are ubiquitously expressed and governed by tissue-specific and hormonal signals. Transcription initiates at multiple sites within the core promoter, which contains elements homologous to the canonical elements CCAAT, TATAA, Sp1 binding site (Sp1BS), and Initiator (Inr). To determine their functions, expression of class I transgenes with individually mutated elements was assessed. Surprisingly, all mutant promoters supported transcription. However, each mutated core promoter element had a distinct effect on expression: CAAT box mutations modulated constitutive expression in nonlymphoid tissues, whereas TATAA-like element mutations dysregulated transcription in lymphoid tissues. Inr mutations aberrantly elevated expression. Sp1BS element mutations resulted in variegated transgene expression. RNA polymerase II binding and histone H3K4me3 patterns correlated with transgene expression; H3K9me3 marks partially correlated. Whereas the wild-type, TATAA-like, and CAAT mutant promoters were activated by gamma interferon, the Sp1 and Inr mutants were repressed, implicating these elements in regulation of hormonal responses. These results lead to the surprising conclusion that no single element is required for promoter activity. Rather, each plays a distinct role in promoter activity, chromatin structure, tissue-specific expression, and extracellular signaling. C1 [Barbash, Zohar S.; Weissman, Jocelyn D.; Campbell, John A., Jr.; Mu, Jie; Singer, Dinah S.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 49 TC 4 Z9 4 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 22 BP 4395 EP 4407 DI 10.1128/MCB.00553-13 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 240LX UT WOS:000326099000004 PM 24019072 ER PT J AU Laurent, G de Boer, VCJ Finley, LWS Sweeney, M Lu, H Schug, TT Cen, YN Jeong, SM Li, XL Sauve, AA Haigis, MC AF Laurent, Gaelle de Boer, Vincent C. J. Finley, Lydia W. S. Sweeney, Meredith Lu, Hong Schug, Thaddeus T. Cen, Yana Jeong, Seung Min Li, Xiaoling Sauve, Anthony A. Haigis, Marcia C. TI SIRT4 Represses Peroxisome Proliferator-Activated Receptor alpha Activity To Suppress Hepatic Fat Oxidation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SILENCING PROTEIN SIR2; GENE-EXPRESSION; ACID OXIDATION; ENERGY-METABOLISM; PPAR-ALPHA; DEACETYLASE; STRESS; FAMILY; LIVER; MICE AB Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor alpha (PPAR alpha) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism. C1 [Laurent, Gaelle; de Boer, Vincent C. J.; Finley, Lydia W. S.; Sweeney, Meredith; Lu, Hong; Jeong, Seung Min; Haigis, Marcia C.] Harvard Univ, Sch Med, Dept Cell Biol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02114 USA. [Schug, Thaddeus T.; Li, Xiaoling] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Cen, Yana; Sauve, Anthony A.] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA. RP Haigis, MC (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02114 USA. EM marcia_haigis@hms.harvard.edu RI de Boer, Vincent/F-4879-2010; Cen, Yana/F-4731-2014; de Boer, Vincent/L-2196-2016 OI de Boer, Vincent/0000-0001-9928-1698; Cen, Yana/0000-0001-6436-5744; FU Human Frontier Science Program; Netherlands Organization for Scientific Research; Brookdale Leadership in Aging Fellowship; Ellison Medical Foundation; NIA [R01/AG032375]; Glenn Foundation for Medical Research FX G.L. was supported by a fellowship from the Human Frontier Science Program. V.C.J.D.B. was supported by a Rubicon fellowship from the Netherlands Organization for Scientific Research. M. C. H. was supported by a Brookdale Leadership in Aging Fellowship, Ellison Medical Foundation New Scholar Award, funding from NIA R01/AG032375, and the Glenn Foundation for Medical Research. NR 43 TC 24 Z9 30 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 22 BP 4552 EP 4561 DI 10.1128/MCB.00087-13 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 240LX UT WOS:000326099000016 PM 24043310 ER PT J AU Baltanas, FC Perez-Andres, M Ginel-Picardo, A Diaz, D Jimeno, D Liceras-Boillos, P Kortum, RL Samelson, LE Orfao, A Santos, E AF Baltanas, Fernando C. Perez-Andres, Martin Ginel-Picardo, Alicia Diaz, David Jimeno, David Liceras-Boillos, Pilar Kortum, Robert L. Samelson, Lawrence E. Orfao, Alberto Santos, Eugenio TI Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID B-CELL DEVELOPMENT; RAS ACTIVATION; T-CELLS; PATHWAY; DIFFERENTIATION; EXPRESSION; LEUKEMIA AB Sos1 and Sos2 are ubiquitously expressed, universal Ras guanine nucleotide exchange factors (Ras-GEFs) acting in multiple signal transduction pathways activated by upstream cellular kinases. The embryonic lethality of Sos1 null mutants has hampered ascertaining the specific in vivo contributions of Sos1 and Sos2 to processes controlling adult organism survival or development of hematopoietic and nonhematopoietic organs, tissues, and cell lineages. Here, we generated a tamoxifen-inducible Sos1-null mouse strain allowing analysis of the combined disruption of Sos1 and Sos2 (Sos1/2) during adulthood. Sos1/2 double-knockout (DKO) animals died precipitously, whereas individual Sos1 and Sos2 knockout (KO) mice were perfectly viable. A reduced percentage of total bone marrow precursors occurred in single-KO animals, but a dramatic depletion of B-cell progenitors was specifically detected in Sos1/2 DKO mice. We also confirmed a dominant role of Sos1 over Sos2 in early thymocyte maturation, with almost complete thymus disappearance and dramatically higher reduction of absolute thymocyte counts in Sos1/2 DKO animals. Absolute counts of mature B and T cells in spleen and peripheral blood were unchanged in single-KO mutants, while significantly reduced in Sos1/2 DKO mice. Our data demonstrate functional redundancy between Sos1 and Sos2 for homeostasis and survival of the full organism and for development and maturation of T and B lymphocytes. C1 [Baltanas, Fernando C.; Ginel-Picardo, Alicia; Jimeno, David; Liceras-Boillos, Pilar; Santos, Eugenio] Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Ctr Invest Canc,Lab 1, E-37008 Salamanca, Spain. [Perez-Andres, Martin; Orfao, Alberto] Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Ctr Invest Canc,Lab 11, E-37008 Salamanca, Spain. [Diaz, David] Univ Salamanca, INCYL, E-37008 Salamanca, Spain. [Kortum, Robert L.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Santos, E (reprint author), Univ Salamanca, CSIC, Inst Biol Mol & Celular Canc, Ctr Invest Canc,Lab 1, E-37008 Salamanca, Spain. EM esantos@usal.es OI Diaz, David/0000-0003-3705-817X; Jimeno, David/0000-0001-7876-0083 FU Instituto de Salud Carlos III (Madrid, Spain) [FIS-PS09/01979, RTICC-RD12/0036/0001, RD12/0036/0048]; Fundacion Samuel Solorzano (Salamanca, Spain); CCR, NCI, NIH FX Work was supported by grants FIS-PS09/01979, RTICC-RD12/0036/0001, and RD12/0036/0048 from Instituto de Salud Carlos III (Madrid, Spain) and Fundacion Samuel Solorzano (Salamanca, Spain). This research was also supported by the Intramural Research Program of the CCR, NCI, NIH. NR 35 TC 5 Z9 5 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 22 BP 4562 EP 4578 DI 10.1128/MCB.01026-13 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 240LX UT WOS:000326099000017 PM 24043312 ER PT J AU Evans, AN Liu, Y MacGregor, R Huang, V Aguilera, G AF Evans, Andrew N. Liu, Ying MacGregor, Robert Huang, Victoria Aguilera, Greti TI Regulation of Hypothalamic Corticotropin-Releasing Hormone Transcription by Elevated Glucocorticoids SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BINDING PROTEIN-ACTIVITY; SALT-INDUCIBLE KINASE; PARAVENTRICULAR NUCLEUS; GENE-EXPRESSION; CELL-LINE; MESSENGER-RNA; RECEPTOR; STRESS; CRH; ACTIVATION AB Negative glucocorticoid feedback is essential for preventing the deleterious effects of excessive hypothalamic pituitary adrenal axis axis activation, with an important target being CRH transcription in the hypothalamic paraventricular nucleus. The aim of these studies was to determine whether glucocorticoids repress CRH transcription directly in CRH neurons, by examining glucocorticoid effects on glucocorticoid receptor (GR)-CRH promoter interaction and the activation of proteins required for CRH transcription. Immunoprecipitation of hypothalamic chromatin from intact or adrenalectomized rats subjected to either stress or corticosterone injections showed minor association of the proximal CRH promoter with the GR compared with that with phospho-CREB (pCREB). In contrast, the Period-1 (Per1, a glucocorticoid-responsive gene) promoter markedly recruited GR. Stress increased pCREB recruitment by the CRH but not the Per1 promoter, irrespective of circulating glucocorticoids. In vitro, corticosterone pretreatment (30 minutes or 18 hours) only slightly inhibited basal and forskolin-stimulated CRH heteronuclear RNA in primary hypothalamic neuronal cultures and CRH promoter activity in hypothalamic 4B cells. In 4B cells, 30 minutes or 18 hours of corticosterone exposure had no effect on forskolin-induced nuclear accumulation of the recognized CRH transcriptional regulators, pCREB and transducer of regulated CREB activity 2. The data show that inhibition of CRH transcription by physiological glucocorticoids in vitro is minor and that direct interaction of GR with DNA in the proximal CRH promoter may not be a major mechanism of CRH gene repression. Although GR interaction with distal promoter elements may have a role, the data suggest that transcriptional repression of CRH by glucocorticoids involves protein-protein interactions and/or modulation of afferent inputs to the hypothalamic paraventricular nucleus. C1 [Evans, Andrew N.; Liu, Ying; MacGregor, Robert; Huang, Victoria; Aguilera, Greti] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Aguilera, G (reprint author), NIH, Sect Endocrine Physiol, Eunice Kennedy Shriver Inst Child Hlth & Human De, Bldg 10-CRC,Room 1E-3330, Bethesda, MD 20892 USA. EM greti_aguilera@nih.gov OI Evans, Andrew/0000-0002-5366-9942 FU Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 42 TC 15 Z9 16 U1 1 U2 7 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD NOV PY 2013 VL 27 IS 11 BP 1796 EP 1807 DI 10.1210/me.2013-1095 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 241LL UT WOS:000326168300003 PM 24065704 ER PT J AU Kucka, M Bjelobaba, I Clokie, SJH Klein, DC Stojilkovic, SS AF Kucka, Marek Bjelobaba, Ivana Clokie, Samuel J. H. Klein, David C. Stojilkovic, Stanko S. TI Female-Specific Induction of Rat Pituitary Dentin Matrix Protein-1 by GnRH SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; SUBUNIT GENE-TRANSCRIPTION; LUTEINIZING-HORMONE; ANTERIOR-PITUITARY; BETA GENE; L-BETA-T2 CELLS; IN-VIVO; RNA-SEQ; C-FOS; EXPRESSION AB Hypothalamic GnRH is the primary regulator of reproduction in vertebrates, acting via the G protein-coupled GnRH receptor (GnRHR) in pituitary gonadotrophs to control synthesis and release of gonadotropins. To identify elements of the GnRHR-coupled gene network, GnRH was applied in a pulsatile manner for 6 hours to a mixed population of perifused pituitary cells from cycling females, mRNA was extracted, and RNA sequencing analysis was performed. This revealed 83 candidate-regulated genes, including a large number coding for secreted proteins. Most notably, GnRH induces a greater than 600-fold increase in expression of dentin matrix protein-1 (Dmp1), one of five members of the small integrin-binding ligand N-linked glycoprotein gene family. The Dmp1 response is mediated by the GnRHR, not elicited by other hypothalamic releasing factors, and is approximately 20-fold smaller in adult male pituitary cells. The sex-dependent Dmp1 response is established during the peripubertal period and independent of the developmental pattern of Gnrhr expression. In vitro, GnRH-induced expression of this gene is coupled with release of DMP1 in extracellular medium through the regulated secretory pathway. In vivo, pituitary Dmp1 expression in identified gonadotrophs is elevated after ovulation. Cell signaling studies revealed that the GnRH induction of Dmp1 is mediated by the protein kinase C signaling pathway and reflects opposing roles of ERK1/2 and p38 MAPK; in addition, the response is facilitated by progesterone. These results establish that DMP1 is a novel secretory protein of female rat gonadotrophs, the synthesis and release of which are controlled by the hypothalamus through the GnRHR signaling pathway. This advance raises intriguing questions about the intrapituitary and downstream effects of this new player in GnRH signaling. C1 [Kucka, Marek; Bjelobaba, Ivana; Stojilkovic, Stanko S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Cellular Signaling, Bethesda, MD 20892 USA. [Clokie, Samuel J. H.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Neuroendocrinol, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stojilks@mail.nih.gov OI Clokie, Samuel/0000-0002-0025-3652 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 76 TC 6 Z9 6 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD NOV PY 2013 VL 27 IS 11 BP 1840 EP 1855 DI 10.1210/me.2013-1068 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 241LL UT WOS:000326168300006 PM 24085820 ER PT J AU Willer, CJ Schmidt, EM Sengupta, S Peloso, GM Gustafsson, S Kanoni, S Ganna, A Chen, J Buchkovich, ML Mora, S Beckmann, JS Bragg-Gresham, JL Chang, HY Demirkan, A Den Hertog, HM Do, R Donnelly, LA Ehret, GB Esko, T Feitosa, MF Ferreira, T Fischer, K Fontanillas, P Fraser, RM Freitag, DF Gurdasani, D Heikkila, K Hypponen, E Isaacs, A Jackson, AU Johansson, A Johnson, T Kaakinen, M Kettunen, J Kleber, ME Li, XH Luan, JA Lyytikainen, LP Magnusson, PKE Mangino, M Mihailov, E Montasser, ME Muller-Nurasyid, M Nolte, IM O'Connell, JR Palmer, CD Perola, M Petersen, AK Sanna, S Saxena, R Service, SK Shah, S Shungin, D Sidore, C Song, C Strawbridge, RJ Surakka, I Tanaka, T Teslovich, TM Thorleifsson, G Van den Herik, EG Voight, BF Volcik, KA Waite, LL Wong, A Wu, Y Zhang, WH Absher, D Asiki, G Barroso, I Been, LF Bolton, JL Bonnycastle, LL Brambilla, P Burnett, MS Cesana, G Dimitriou, M Doney, ASF Doring, A Elliott, P Epstein, SE Eyjolfsson, GI Gigante, B Goodarzi, MO Grallert, H Gravito, ML Groves, CJ Hallmans, G Hartikainen, AL Hayward, C Hernandez, D Hicks, AA Holm, H Hung, YJ Illig, T Jones, MR Kaleebu, P Kastelein, JJP Khaw, KT Kim, E Klopp, N Komulainen, P Kumari, M Langenberg, C Lehtimaki, T Lin, SY Lindstrom, J Loos, RJF Mach, F McArdle, WL Meisinger, C Mitchell, BD Muller, G Nagaraja, R Narisu, N Nieminen, TVM Nsubuga, RN Olafsson, I Ong, KK Palotie, A Papamarkou, T Pomilla, C Pouta, A Rader, DJ Reilly, MP Ridker, PM Rivadeneira, F Rudan, I Ruokonen, A Samani, N Scharnagl, H Seeley, J Silander, K Stancakova, A Stirrups, K Swift, AJ Tiret, L Uitterlinden, AG van Pelt, LJ Vedantam, S Wainwright, N Wijmenga, C Wild, SH Willemsen, G Wilsgaard, T Wilson, JF Young, EH Zhao, JH Adair, LS Arveiler, D Assimes, TL Bandinelli, S Bennett, F Bochud, M Boehm, BO Boomsma, DI Borecki, IB Bornstein, SR Bovet, P Burnier, M Campbell, H Chakravarti, A Chambers, JC Chen, YDI Collins, FS Cooper, RS Danesh, J Dedoussis, G de Faire, U Feranil, AB Ferrieres, J Ferrucci, L Freimer, NB Gieger, C Groop, LC Gudnason, V Gyllensten, U Hamsten, A Harris, TB Hingorani, A Hirschhorn, JN Hofman, A Hovingh, GK Hsiung, CA Humphries, SE Hunt, SC Hveem, K Iribarren, C Jarvelin, MR Jula, A Kahonen, M Kaprio, J Kesaniemi, A Kivimaki, M Kooner, JS Koudstaal, PJ Krauss, RM Kuh, D Kuusisto, J Kyvik, KO Laakso, M Lakka, TA Lind, L Lindgren, CM Martin, NG Marz, W McCarthy, MI McKenzie, CA Meneton, P Metspalu, A Moilanen, L Morris, AD Munroe, PB Njolstad, I Pedersen, NL Power, C Pramstaller, PP Price, JF Psaty, BM Quertermous, T Rauramaa, R Saleheen, D Salomaa, V Sanghera, DK Saramies, J Schwarz, PEH Sheu, WHH Shuldiner, AR Siegbahn, A Spector, TD Stefansson, K Strachan, DP Tayo, BO Tremoli, E Tuomilehto, J Uusitupa, M van Duijn, CM Vollenweider, P Wallentin, L Wareham, NJ Whitfield, JB Wolffenbuttel, BHR Ordovas, JM Boerwinkle, E Palmer, CNA Thorsteinsdottir, U Chasman, DI Rotter, JI Franks, PW Ripatti, S Cupples, LA Sandhu, MS Rich, SS Boehnke, M Deloukas, P Kathiresan, S Mohlke, KL Ingelsson, E Abecasis, GR AF Willer, Cristen J. Schmidt, Ellen M. Sengupta, Sebanti Peloso, Gina M. Gustafsson, Stefan Kanoni, Stavroula Ganna, Andrea Chen, Jin Buchkovich, Martin L. Mora, Samia Beckmann, Jacques S. Bragg-Gresham, Jennifer L. Chang, Hsing-Yi Demirkan, Ayse Den Hertog, Heleen M. Do, Ron Donnelly, Louise A. Ehret, Georg B. Esko, Tonu Feitosa, Mary F. Ferreira, Teresa Fischer, Krista Fontanillas, Pierre Fraser, Ross M. Freitag, Daniel F. Gurdasani, Deepti Heikkila, Kauko Hyppoenen, Elina Isaacs, Aaron Jackson, Anne U. Johansson, Asa Johnson, Toby Kaakinen, Marika Kettunen, Johannes Kleber, Marcus E. Li, Xiaohui Luan, Jian'an Lyytikainen, Leo-Pekka Magnusson, Patrik K. E. Mangino, Massimo Mihailov, Evelin Montasser, May E. Mueller-Nurasyid, Martina Nolte, Ilja M. O'Connell, Jeffrey R. Palmer, Cameron D. Perola, Markus Petersen, Ann-Kristin Sanna, Serena Saxena, Richa Service, Susan K. Shah, Sonia Shungin, Dmitry Sidore, Carlo Song, Ci Strawbridge, Rona J. Surakka, Ida Tanaka, Toshiko Teslovich, Tanya M. Thorleifsson, Gudmar Van den Herik, Evita G. Voight, Benjamin F. Volcik, Kelly A. Waite, Lindsay L. Wong, Andrew Wu, Ying Zhang, Weihua Absher, Devin Asiki, Gershim Barroso, Ines Been, Latonya F. Bolton, Jennifer L. Bonnycastle, Lori L. Brambilla, Paolo Burnett, Mary S. Cesana, Giancarlo Dimitriou, Maria Doney, Alex S. F. Doering, Angela Elliott, Paul Epstein, Stephen E. Eyjolfsson, Gudmundur Ingi Gigante, Bruna Goodarzi, Mark O. Grallert, Harald Gravito, Martha L. Groves, Christopher J. Hallmans, Goran Hartikainen, Anna-Liisa Hayward, Caroline Hernandez, Dena Hicks, Andrew A. Holm, Hilma Hung, Yi-Jen Illig, Thomas Jones, Michelle R. Kaleebu, Pontiano Kastelein, John J. P. Khaw, Kay-Tee Kim, Eric Klopp, Norman Komulainen, Pirjo Kumari, Meena Langenberg, Claudia Lehtimaki, Terho Lin, Shih-Yi Lindstrom, Jaana Loos, Ruth J. F. Mach, Francois McArdle, Wendy L. Meisinger, Christa Mitchell, Braxton D. Mueller, Gabrielle Nagaraja, Ramaiah Narisu, Narisu Nieminen, Tuomo V. M. Nsubuga, Rebecca N. Olafsson, Isleifur Ong, Ken K. Palotie, Aarno Papamarkou, Theodore Pomilla, Cristina Pouta, Anneli Rader, Daniel J. Reilly, Muredach P. Ridker, Paul M. Rivadeneira, Fernando Rudan, Igor Ruokonen, Aimo Samani, Nilesh Scharnagl, Hubert Seeley, Janet Silander, Kaisa Stancakova, Alena Stirrups, Kathleen Swift, Amy J. Tiret, Laurence Uitterlinden, Andre G. van Pelt, L. Joost Vedantam, Sailaja Wainwright, Nicholas Wijmenga, Cisca Wild, Sarah H. Willemsen, Gonneke Wilsgaard, Tom Wilson, James F. Young, Elizabeth H. Zhao, Jing Hua Adair, Linda S. Arveiler, Dominique Assimes, Themistocles L. Bandinelli, Stefania Bennett, Franklyn Bochud, Murielle Boehm, Bernhard O. Boomsma, Dorret I. Borecki, Ingrid B. Bornstein, Stefan R. Bovet, Pascal Burnier, Michel Campbell, Harry Chakravarti, Aravinda Chambers, John C. Chen, Yii-Der Ida Collins, Francis S. Cooper, Richard S. Danesh, John Dedoussis, George de Faire, Ulf Feranil, Alan B. Ferrieres, Jean Ferrucci, Luigi Freimer, Nelson B. Gieger, Christian Groop, Leif C. Gudnason, Vilmundur Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Hingorani, Aroon Hirschhorn, Joel N. Hofman, Albert Hovingh, G. Kees Hsiung, Chao Agnes Humphries, Steve E. Hunt, Steven C. Hveem, Kristian Iribarren, Carlos Jarvelin, Marjo-Riitta Jula, Antti Kahonen, Mika Kaprio, Jaakko Kesaniemi, Antero Kivimaki, Mika Kooner, Jaspal S. Koudstaal, Peter J. Krauss, Ronald M. Kuh, Diana Kuusisto, Johanna Kyvik, Kirsten O. Laakso, Markku Lakka, Timo A. Lind, Lars Lindgren, Cecilia M. Martin, Nicholas G. Maerz, Winfried McCarthy, Mark I. McKenzie, Colin A. Meneton, Pierre Metspalu, Andres Moilanen, Leena Morris, Andrew D. Munroe, Patricia B. Njolstad, Inger Pedersen, Nancy L. Power, Chris Pramstaller, Peter P. Price, Jackie F. Psaty, Bruce M. Quertermous, Thomas Rauramaa, Rainer Saleheen, Danish Salomaa, Veikko Sanghera, Dharambir K. Saramies, Jouko Schwarz, Peter E. H. Sheu, Wayne H-H Shuldiner, Alan R. Siegbahn, Agneta Spector, Tim D. Stefansson, Kari Strachan, David P. Tayo, Bamidele O. Tremoli, Elena Tuomilehto, Jaakko Uusitupa, Matti van Duijn, Cornelia M. Vollenweider, Peter Wallentin, Lars Wareham, Nicholas J. Whitfield, John B. Wolffenbuttel, Bruce H. R. Ordovas, Jose M. Boerwinkle, Eric Palmer, Colin N. A. Thorsteinsdottir, Unnur Chasman, Daniel I. Rotter, Jerome I. Franks, Paul W. Ripatti, Samuli Cupples, L. Adrienne Sandhu, Manjinder S. Rich, Stephen S. Boehnke, Michael Deloukas, Panos Kathiresan, Sekar Mohlke, Karen L. Ingelsson, Erik Abecasis, Goncalo R. CA Global Lipids Genetics Consortium TI Discovery and refinement of loci associated with lipid levels SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; GENOME-WIDE ASSOCIATION; HEART-DISEASE; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCI; IDENTIFIES 13; RISK; GENE; METAANALYSIS AB Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. C1 [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen J.; Schmidt, Ellen M.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen J.; Sengupta, Sebanti; Chen, Jin; Bragg-Gresham, Jennifer L.; Jackson, Anne U.; Sidore, Carlo; Teslovich, Tanya M.; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Peloso, Gina M.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Peloso, Gina M.; Do, Ron; Saxena, Richa; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Peloso, Gina M.; Esko, Tonu; Fontanillas, Pierre; Palmer, Cameron D.; Vedantam, Sailaja; Hirschhorn, Joel N.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Gustafsson, Stefan; Ganna, Andrea; Song, Ci; Siegbahn, Agneta; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Gustafsson, Stefan; Ganna, Andrea; Song, Ci; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, Uppsala, Sweden. [Kanoni, Stavroula; Gurdasani, Deepti; Barroso, Ines; Papamarkou, Theodore; Pomilla, Cristina; Stirrups, Kathleen; Wainwright, Nicholas; Young, Elizabeth H.; Ripatti, Samuli; Sandhu, Manjinder S.; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Ganna, Andrea; Magnusson, Patrik K. E.; Song, Ci; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Buchkovich, Martin L.; Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Mora, Samia; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Mora, Samia; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA USA. [Beckmann, Jacques S.] Univ Lausanne Hosp, Serv Med Genet, Lausanne, Switzerland. [Beckmann, Jacques S.] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Chang, Hsing-Yi] Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Prevent Med & Hlth Serv Res, Zhunan, Taiwan. [Demirkan, Ayse; Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Den Hertog, Heleen M.; Van den Herik, Evita G.; Koudstaal, Peter J.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Donnelly, Louise A.; Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland. [Ehret, Georg B.; Mach, Francois] Univ Hosp Geneva, Dept Special Med, Geneva, Switzerland. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Esko, Tonu; Fischer, Krista; Mihailov, Evelin; Perola, Markus; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Ferreira, Teresa; Lindgren, Cecilia M.; McCarthy, Mark I.; Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Fraser, Ross M.; Bolton, Jennifer L.; Rudan, Igor; Wild, Sarah H.; Wilson, James F.; Campbell, Harry; Price, Jackie F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Freitag, Daniel F.; Gurdasani, Deepti; Papamarkou, Theodore; Pomilla, Cristina; Wainwright, Nicholas; Young, Elizabeth H.; Danesh, John; Saleheen, Danish; Sandhu, Manjinder S.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Heikkila, Kauko; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Hyppoenen, Elina; Power, Chris] UCL, Inst Child Hlth, MRC, Ctr Paediat Epidemiol & Biostat,Ctr Epidemiol Chi, London, England. [Isaacs, Aaron; van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Johansson, Asa; Siegbahn, Agneta; Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Johnson, Toby; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, Genome Ctr, London, England. [Johnson, Toby; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Natl Inst Hlth Res,Cardiovasc Biomed Res Unit, London, England. [Kaakinen, Marika; Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Kaakinen, Marika; Elliott, Paul; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kettunen, Johannes; Perola, Markus; Surakka, Ida; Palotie, Aarno; Silander, Kaisa; Kaprio, Jaakko; Ripatti, Samuli] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Kettunen, Johannes; Perola, Markus; Surakka, Ida; Silander, Kaisa; Ripatti, Samuli] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Kleber, Marcus E.] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Li, Xiaohui; Kim, Eric; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Luan, Jian'an; Langenberg, Claudia; Loos, Ruth J. F.; Ong, Ken K.; Zhao, Jing Hua; Wareham, Nicholas J.] Addenbrookes Hosp, MRC, Inst Metab Sci, Epidemiol Unit, Cambridge, England. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Tampere Univ Hosp, Dept Clin Chem, Fimlab Labs, FIN-33521 Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland. [Mangino, Massimo; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Montasser, May E.; O'Connell, Jeffrey R.; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Mueller-Nurasyid, Martina; Petersen, Ann-Kristin; Gieger, Christian] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Nolte, Ilja M.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Palmer, Cameron D.; Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Program Genom, Boston, MA 02115 USA. [Sanna, Serena; Sidore, Carlo] CNR, Ist Ric Genet & Biomed, Monserrato, Italy. [Service, Susan K.; Freimer, Nelson B.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. [Shah, Sonia; Kumari, Meena; Hingorani, Aroon; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England. [Shungin, Dmitry; Franks, Paul W.] Lund Univ, Scania Univ Hosp, Ctr Diabet, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, Umea, Sweden. [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Med Unit, Dept Publ Hlth & Primary Care, Umea, Sweden. [Sidore, Carlo] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Strawbridge, Rona J.; Hamsten, Anders] Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden. [Strawbridge, Rona J.; Hamsten, Anders] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden. [Tanaka, Toshiko; Ferrucci, Luigi] US Natl Inst Hlth, Clin Res Branch, Baltimore, MD USA. [Thorleifsson, Gudmar; Holm, Hilma; Stefansson, Kari; Thorsteinsdottir, Unnur] deCODE Genet Amgen, Reykjavik, Iceland. 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[Barroso, Ines] Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge, England. [Been, Latonya F.; Gravito, Martha L.; Sanghera, Dharambir K.] Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Oklahoma City, OK 73190 USA. [Bonnycastle, Lori L.; Narisu, Narisu; Swift, Amy J.; Collins, Francis S.] NHGRI, Genome Technol Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Brambilla, Paolo] Univ Milano Bicocca, Dept Expt Med, Milan, Italy. [Burnett, Mary S.; Epstein, Stephen E.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Cesana, Giancarlo] Univ Milano Bicocca, Res Ctr Publ Hlth, Milan, Italy. [Dimitriou, Maria; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Doering, Angela; Meisinger, Christa] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Doering, Angela] Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ctr Environm & Hlth, Dept Epidemiol & Biostat,MRC,Hlth Protect Agcy, London, England. [Eyjolfsson, Gudmundur Ingi] Lab Mjodd, Reykjavik, Iceland. [Gigante, Bruna; de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [Goodarzi, Mark O.; Jones, Michelle R.] Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Grallert, Harald; Illig, Thomas; Klopp, Norman] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Hartikainen, Anna-Liisa; Pouta, Anneli] Oulu Univ Hosp, Dept Clin Sci Obstet & Gynecol, Oulu, Finland. 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[Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Tremoli, Elena] Univ Milan, Monzino Cardiol Ctr, IRCCS, Dept Pharmacol Sci, Milan, Italy. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Tuomilehto, Jaakko] King Abdulaziz Univ, Fac Med, Jeddah 21413, Saudi Arabia. [Tuomilehto, Jaakko] Hosp Univ La Paz, La Red Temat Invest Cooperat Enfermedades Cardiov, Madrid, Spain. [Uusitupa, Matti] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [Vollenweider, Peter] Univ Lausanne Hosp, Dept Med, Lausanne, Switzerland. [Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Ordovas, Jose M.] Natl Ctr Cardiovasc Investigat, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] Inst Madrileno Estudios Avanzados Alimentac, Madrid Inst Adv Studies, Madrid, Spain. [Ordovas, Jose M.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Nutr & Genom Lab, Boston, MA 02111 USA. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Willer, CJ (reprint author), Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. EM cristen@umich.edu; mohlke@med.unc.edu; erik.ingelsson@medsci.uu.se; goncalo@umich.edu RI Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Magnusson, Patrik/C-4458-2017; Beckmann, Jacques S /A-9772-2008; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Lyytikainen, Leo-Pekka/C-8544-2016; Bovet, Pascal/F-4477-2011; Rudan, Igor/I-1467-2012; Papamarkou, Theodore/A-2958-2012; Kyvik, Kirsten /K-5680-2016; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Shah, Sonia/N-7547-2013; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Grallert, Harald/B-3424-2013; Colaus, PsyColaus/K-6607-2013; Hypponen, Elina/B-2596-2014; Meisinger, Christine/B-5358-2014; Hsiung, Chao Agnes/E-3994-2010; Wijmenga, Cisca/D-2173-2009; Chang, Hsing-Yi /E-3973-2010; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008; Deloukas, Panos/B-2922-2013 OI Johansson, Asa/0000-0002-2915-4498; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Nieminen, Tuomo/0000-0003-1755-1688; Meisinger, Christa/0000-0002-9026-6544; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Esko, Tonu/0000-0003-1982-6569; Lakka, Timo/0000-0002-9199-2871; Gigante, Bruna/0000-0003-4508-7990; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Franks, Paul/0000-0002-0520-7604; Kumari, Meena/0000-0001-9716-1035; Kaakinen, Marika/0000-0002-9228-0462; Sidore, Carlo/0000-0001-7504-7477; Shungin, Dmitry/0000-0001-7900-5856; Seeley, Janet/0000-0002-0583-5272; Song, Ci/0000-0002-0947-9068; TREMOLI, ELENA/0000-0002-0929-6106; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Beckmann, Jacques S /0000-0002-9741-1900; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Fraser, Ross/0000-0003-0488-2592; Willer, Cristen/0000-0001-5645-4966; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Papamarkou, Theodore/0000-0002-9689-543X; Kyvik, Kirsten /0000-0003-2981-0245; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Shah, Sonia/0000-0001-5860-4526; Strawbridge, Rona/0000-0001-8506-3585; Hypponen, Elina/0000-0003-3670-9399; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X NR 48 TC 304 Z9 309 U1 9 U2 84 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1274 EP + DI 10.1038/ng.2797 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100007 ER PT J AU Lessard, CJ Li, H Adrianto, I Ice, JA Rasmussen, A Grundahl, KM Kelly, JA Dozmorov, MG Miceli-Richard, C Bowman, S Lester, S Eriksson, P Eloranta, ML Brun, JG Goransson, LG Harboe, E Guthridge, JM Kaufman, KM Kvarnstrom, M Jazebi, H Graham, DSC Grandits, ME Nazmul-Hossain, ANM Patel, K Adler, AJ Maier-Moore, JS Farris, AD Brennan, MT Lessard, JA Chodosh, J Gopalakrishnan, R Hefner, KS Houston, GD Huang, AJW Hughes, PJ Lewis, DM Radfar, L Rohrer, MD Stone, DU Wren, JD Vyse, TJ Gaffney, PM James, JA Omdal, R Wahren-Herlenius, M Illei, GG Witte, T Jonsson, R Rischmueller, M Ronnblom, L Nordmark, G Ng, WF Mariette, X Anaya, JM Rhodus, NL Segal, BM Scofield, RH Montgomery, CG Harley, JB Sivils, KL AF Lessard, Christopher J. Li, He Adrianto, Indra Ice, John A. Rasmussen, Astrid Grundahl, Kiely M. Kelly, Jennifer A. Dozmorov, Mikhail G. Miceli-Richard, Corinne Bowman, Simon Lester, Sue Eriksson, Per Eloranta, Maija-Leena Brun, Johan G. Goransson, Lasse G. Harboe, Erna Guthridge, Joel M. Kaufman, Kenneth M. Kvarnstrom, Marika Jazebi, Helmi Graham, Deborah S. Cunninghame Grandits, Martha E. Nazmul-Hossain, Abu N. M. Patel, Ketan Adler, Adam J. Maier-Moore, Jacen S. Farris, A. Darise Brennan, Michael T. Lessard, James A. Chodosh, James Gopalakrishnan, Rajaram Hefner, Kimberly S. Houston, Glen D. Huang, Andrew J. W. Hughes, Pamela J. Lewis, David M. Radfar, Lida Rohrer, Michael D. Stone, Donald U. Wren, Jonathan D. Vyse, Timothy J. Gaffney, Patrick M. James, Judith A. Omdal, Roald Wahren-Herlenius, Marie Illei, Gabor G. Witte, Torsten Jonsson, Roland Rischmueller, Maureen Ronnblom, Lars Nordmark, Gunnel Wan-Fai Ng Mariette, Xavier Anaya, Juan-Manuel Rhodus, Nelson L. Segal, Barbara M. Scofield, R. Hal Montgomery, Courtney G. Harley, John B. Sivils, Kathy L. CA UK Primary Sjogren's Syndrome Regi TI Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome SO NATURE GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENOME-WIDE ASSOCIATION; PRIMARY BILIARY-CIRRHOSIS; STRONG RISK-FACTOR; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; FUNCTIONAL POLYMORPHISM; SUSCEPTIBILITY LOCI; CLASS-II; B-CELLS AB Sjogren's syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta < 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogren's syndrome. C1 [Lessard, Christopher J.; Li, He; Adrianto, Indra; Ice, John A.; Rasmussen, Astrid; Grundahl, Kiely M.; Kelly, Jennifer A.; Dozmorov, Mikhail G.; Guthridge, Joel M.; Adler, Adam J.; Maier-Moore, Jacen S.; Farris, A. Darise; Wren, Jonathan D.; Gaffney, Patrick M.; James, Judith A.; Scofield, R. Hal; Montgomery, Courtney G.; Sivils, Kathy L.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Lessard, Christopher J.; Li, He; James, Judith A.; Sivils, Kathy L.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Miceli-Richard, Corinne; Mariette, Xavier] Univ Paris 11, AP HP, Hop Univ Paris Sud, INSERM,U1012, Paris, France. [Bowman, Simon] Univ Hosp Birmingham, Dept Rheumatol, Birmingham, W Midlands, England. [Lester, Sue; Rischmueller, Maureen] Queen Elizabeth Hosp, Dept Rheumatol, Woodville South, SA, Australia. [Eriksson, Per] Linkoping Univ, Fac Hlth Sci, Dept Rheumatol Clin & Expt Med, Linkoping, Sweden. [Eloranta, Maija-Leena; Ronnblom, Lars; Nordmark, Gunnel] Uppsala Univ, Dept Med Sci, Rheumatol & Sci Life Lab, Uppsala, Sweden. [Brun, Johan G.] Univ Bergen, Dept Clin Sci, Rheumatol Sect, Bergen, Norway. [Brun, Johan G.; Jonsson, Roland] Haukeland Hosp, Dept Rheumatol, N-5021 Bergen, Norway. [Goransson, Lasse G.; Harboe, Erna; Omdal, Roald] Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway. [Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] Dept Vet Affairs Med Ctr, Cincinnati, OH USA. [Kvarnstrom, Marika; Jazebi, Helmi; Wahren-Herlenius, Marie] Karolinska Inst, Dept Med, Stockholm, Sweden. [Jazebi, Helmi] Orebro Univ Hosp, Dept Rheumatol, Orebro, Sweden. [Graham, Deborah S. Cunninghame; Vyse, Timothy J.] Kings Coll London, Dept Med & Mol Genet, London, England. [Grandits, Martha E.] United Med Specialties, St Paul, MN USA. [Nazmul-Hossain, Abu N. M.] Univ Colorado, Sch Dent Med, Denver, CO 80202 USA. [Patel, Ketan] Univ Minnesota, Sch Dent, Dept Dev & Surg Sci, Div Oral & Maxillofacial Surg, Minneapolis, MN 55455 USA. [Maier-Moore, Jacen S.; James, Judith A.; Scofield, R. Hal] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Brennan, Michael T.] Carolinas Med Ctr, Dept Oral Med, Charlotte, NC 28203 USA. [Lessard, James A.] Valley Bone & Joint Clin, Grand Forks, ND USA. [Chodosh, James] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Gopalakrishnan, Rajaram] Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Div Oral & Maxillofacial Pathol, Minneapolis, MN 55455 USA. [Hefner, Kimberly S.] Hefner Eye Care & Opt Ctr, Oklahoma City, OK USA. [Houston, Glen D.; Lewis, David M.] Univ Oklahoma, Coll Dent, Dept Oral & Maxillofacial Pathol, Oklahoma City, OK USA. [Huang, Andrew J. W.] Washington Univ, Dept Ophthalmol & Visual Sci, St Louis, MO 63130 USA. [Radfar, Lida] Univ Oklahoma, Coll Dent, Oral Diag & Radiol Dept, Oklahoma City, OK USA. [Rohrer, Michael D.] Univ Minnesota, Sch Dent, Hard Tissue Res Lab, Minneapolis, MN 55455 USA. [Stone, Donald U.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK USA. [Wren, Jonathan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73190 USA. [Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Witte, Torsten] Hannover Med Sch, Dept Clin Immunol & Rheumatol, Hannover, Germany. [Jonsson, Roland] Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway. [Rischmueller, Maureen] Univ Adelaide, Queen Elizabeth Hosp, Dept Rheumatol, Adelaide, SA 5005, Australia. [Rischmueller, Maureen] Univ Adelaide, Discipline Med, Adelaide, SA 5005, Australia. [Wan-Fai Ng] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Anaya, Juan-Manuel] Univ Rosario, Ctr Autoimmune Dis Res CREA, Bogota, Colombia. [Rhodus, Nelson L.] Univ Minnesota, Sch Dent, Dept Oral Surg, Minneapolis, MN 55455 USA. [Segal, Barbara M.] Univ Minnesota, Sch Med, Div Rheumatol, Minneapolis, MN 55455 USA. [Scofield, R. Hal] Dept Vet Affairs Med Ctr, Oklahoma City, OK USA. RP Sivils, KL (reprint author), Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM sivilsk@omrf.org RI Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016; OI Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Dozmorov, Mikhail/0000-0002-0086-8358; Houston, Graeme/0000-0002-9786-7975; Adrianto, Indra/0000-0002-9973-3057; Wahren-Herlenius, Marie/0000-0002-0915-7245; Huang, Andrew JW/0000-0003-1939-9149 FU NIH [P50 AR0608040, 5P01 AR049084-10, 5P30 AR053483, 1U01 AI101934, 5P30 GM103510]; Intramural Research Program of the National Institute of Dental and Craniofacial Research; American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award FX We thank the following funding agencies for their support: this publication was made possible by grants P50 AR0608040 (K. L. S., C. J. L., R. H. S. and A. D. F.), 5R01 DE015223 (K. L. S. and J. B. H.), 5RC2 AR058959 (P. M. G.), 5P01 AR049084-10 (J. B. H.), 5P30 AR053483 (J. A. J. and J. M. G.), 5U19 AI082714 (K. L. S., J. A. J. and C. J. L.), 1R01 DE018209-02 (K. L. S. and J. B. H.), 5R01 DE018209 (K. L. S.), 8P20 GM103456 (P. M. G., C. J. L., J. D. W. and I. A.), P20 GM103636 (M. G. D. and J. D. W.), 5R37 AI024717-25 (J. B. H.), 5P01 AI083194-03 (K. L. S. and J. B. H.), 7S10 RR027190-02 (J. B. H.), 1U01 AI101934 (J. A. J. and J. M. G.), 1RC1 AR058554 (J. A. J. and J. M. G.) and 5P30 GM103510 (J. A. J. and J. M. G.) from the NIH. The contents are the sole responsibility of the authors and do not necessarily represent the official views of the NIH. Additional funding was obtained from Intramural Research Program of the National Institute of Dental and Craniofacial Research (G. G. I.), US Department of Veterans Affairs IMMA 9 (J. B. H.), US Department of Defense PR094002 (J. B. H.), American College of Rheumatology Research and Education Foundation/Abbott Health Professional Graduate Student Preceptorship Award 2009 (C. J. L. and K. L. S.), Oklahoma Medical Research Foundation (C. J. L. and K. L. S.), Sjogren's Syndrome Foundation (K. L. S.), Phileona Foundation (K. L. S.), the French ministry of health (PHRC 2006-AOM06133) and the French ministry of research (ANR-2010-BLAN-1133) (X. M. and C. M.-R.), The Strategic Research Program at Helse Bergen, Western Norway Regional Health Authority (L. G. G., J. G. B. and R. J.), The Broegelmann Foundation (J. G. B. and R. J.), Norwegian Foundation for Health and Rehabilitation (E. H.), KFO 250 TP03, WI 1031/6-1 (T. W.), KFO 250, Z1 (T. W.), Medical Research Council, UK G0800629 (W.-F. N. and S. B.), Northumberland, Tyne and Wear Comprehensive Local Research Network (CLRN) (W.-F. N.), The Swedish Research Council (M. W.-H. and L. R~nnblom), The King Gustaf the V-th 80-year Foundation (M. W.-H.), Knut and Alice Wallenberg Foundation (L. Ronnblom) and The Swedish Rheumatism Association (M. W.-H., G. N., L. Ronnblom and P. E.). This study made use of genotypes available through dbGAP, with acknowledgments provided in the Supplementary Note. NR 84 TC 97 Z9 99 U1 3 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1284 EP + DI 10.1038/ng.2792 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100008 PM 24097067 ER PT J AU Do, R Willer, CJ Schmidt, EM Sengupta, S Gao, C Peloso, GM Gustafsson, S Kanoni, S Ganna, A Chen, J Buchkovich, ML Mora, S Beckmann, JS Bragg-Gresham, JL Chang, HY Demirkan, A Den Hertog, HM Donnelly, LA Ehret, GB Esko, T Feitosa, MF Ferreira, T Fischer, K Fontanillas, P Fraser, RM Freitag, DF Gurdasani, D Heikkila, K Hypponen, E Isaacs, A Jackson, AU Johansson, A Johnson, T Kaakinen, M Kettunen, J Kleber, ME Li, XH Luan, JA Lyytikainen, LP Magnusson, PKE Mangino, M Mihailov, E Montasser, ME Muller-Nurasyid, M Nolte, IM O'Connell, JR Palmer, CD Perola, M Petersen, AK Sanna, S Saxena, R Service, SK Shah, S Shungin, D Sidore, C Song, C Strawbridge, RJ Surakka, I Tanaka, T Teslovich, TM Thorleifsson, G Van den Herik, EG Voight, BF Volcik, KA Waite, LL Wong, A Wu, Y Zhang, WH Absher, D Asiki, G Barroso, I Been, LF Bolton, JL Bonnycastle, LL Brambilla, P Burnett, MS Cesana, G Dimitriou, M Doney, ASF Doring, A Elliott, P Epstein, SE Eyjolfsson, GI Gigante, B Goodarzi, MO Grallert, H Gravito, ML Groves, CJ Hallmans, G Hartikainen, AL Hayward, C Hernandez, D Hicks, AA Holm, H Hung, YJ Illig, T Jones, MR Kaleebu, P Kastelein, JJP Khaw, KT Kim, E Klopp, N Komulainen, P Kumari, M Langenberg, C Lehtimaki, T Lin, SY Lindstrom, J Loos, RJF Mach, F McArdle, WL Meisinger, C Mitchell, BD Muller, G Nagaraja, R Narisu, N Nieminen, TVM Nsubuga, RN Olafsson, I Ong, KK Palotie, A Papamarkou, T Pomilla, C Pouta, A Rader, DJ Reilly, MP Ridker, PM Rivadeneira, F Rudan, I Ruokonen, A Samani, N Scharnagl, H Seeley, J Silander, K Stancakova, A Stirrups, K Swift, AJ Tiret, L Uitterlinden, AG van Pelt, LJ Vedantam, S Wainwright, N Wijmenga, C Wild, SH Willemsen, G Wilsgaard, T Wilson, JF Young, EH Zhao, JH Adair, LS Arveiler, D Assimes, TL Bandinelli, S Bennett, F Bochud, M Boehm, BO Boomsma, DI Borecki, IB Bornstein, SR Bovet, P Burnier, M Campbell, H Chakravarti, A Chambers, JC Chen, YDI Collins, FS Cooper, RS Danesh, J Dedoussis, G de Faire, U Feranil, AB Ferrieres, J Ferrucci, L Freimer, NB Gieger, C Groop, LC Gudnason, V Gyllensten, U Hamsten, A Harris, TB Hingorani, A Hirschhorn, JN Hofman, A Hovingh, GK Hsiung, CA Humphries, SE Hunt, SC Hveem, K Iribarren, C Jarvelin, MR Jula, A Kahonen, M Kaprio, J Kesaniemi, A Kivimaki, M Kooner, JS Koudstaal, PJ Krauss, RM Kuh, D Kuusisto, J Kyvik, KO Laakso, M Lakka, TA Lind, L Lindgren, CM Martin, NG Marz, W McCarthy, MI McKenzie, CA Meneton, P Metspalu, A Moilanen, L Morris, AD Munroe, PB Njolstad, I Pedersen, NL Power, C Pramstaller, PP Price, JF Psaty, BM Quertermous, T Rauramaa, R Saleheen, D Salomaa, V Sanghera, DK Saramies, J Schwarz, PEH Sheu, WHH Shuldiner, AR Siegbahn, A Spector, TD Stefansson, K Strachan, DP Tayo, BO Tremoli, E Tuomilehto, J Uusitupa, M van Duijn, CM Vollenweider, P Wallentin, L Wareham, NJ Whitfield, JB Wolffenbuttel, BHR Altshuler, D Ordovas, JM Boerwinkle, E Palmer, CNA Thorsteinsdottir, U Chasman, DI Rotter, JI Franks, PW Ripatti, S Cupples, LA Sandhu, MS Rich, SS Boehnke, M Deloukas, P Mohlke, KL Ingelsson, E Abecasis, GR Daly, MJ Neale, BM Kathiresan, S AF Do, Ron Willer, Cristen J. Schmidt, Ellen M. Sengupta, Sebanti Gao, Chi Peloso, Gina M. Gustafsson, Stefan Kanoni, Stavroula Ganna, Andrea Chen, Jin Buchkovich, Martin L. Mora, Samia Beckmann, Jacques S. Bragg-Gresham, Jennifer L. Chang, Hsing-Yi Demirkan, Ayse Den Hertog, Heleen M. Donnelly, Louise A. Ehret, Georg B. Esko, Tonu Feitosa, Mary F. Ferreira, Teresa Fischer, Krista Fontanillas, Pierre Fraser, Ross M. Freitag, Daniel F. Gurdasani, Deepti Heikkila, Kauko Hyppoenen, Elina Isaacs, Aaron Jackson, Anne U. Johansson, Asa Johnson, Toby Kaakinen, Marika Kettunen, Johannes Kleber, Marcus E. Li, Xiaohui Luan, Jian'an Lyytikainen, Leo-Pekka Magnusson, Patrik K. E. Mangino, Massimo Mihailov, Evelin Montasser, May E. Mueller-Nurasyid, Martina Nolte, Ilja M. O'Connell, Jeffrey R. Palmer, Cameron D. Perola, Markus Petersen, Ann-Kristin Sanna, Serena Saxena, Richa Service, Susan K. Shah, Sonia Shungin, Dmitry Sidore, Carlo Song, Ci Strawbridge, Rona J. Surakka, Ida Tanaka, Toshiko Teslovich, Tanya M. Thorleifsson, Gudmar Van den Herik, Evita G. Voight, Benjamin F. Volcik, Kelly A. Waite, Lindsay L. Wong, Andrew Wu, Ying Zhang, Weihua Absher, Devin Asiki, Gershim Barroso, Ines Been, Latonya F. Bolton, Jennifer L. Bonnycastle, Lori L. Brambilla, Paolo Burnett, Mary S. Cesana, Giancarlo Dimitriou, Maria Doney, Alex S. F. Doering, Angela Elliott, Paul Epstein, Stephen E. Eyjolfsson, Gudmundur Ingi Gigante, Bruna Goodarzi, Mark O. Grallert, Harald Gravito, Martha L. Groves, Christopher J. Hallmans, Goran Hartikainen, Anna-Liisa Hayward, Caroline Hernandez, Dena Hicks, Andrew A. Holm, Hilma Hung, Yi-Jen Illig, Thomas Jones, Michelle R. Kaleebu, Pontiano Kastelein, John J. P. Khaw, Kay-Tee Kim, Eric Klopp, Norman Komulainen, Pirjo Kumari, Meena Langenberg, Claudia Lehtimaki, Terho Lin, Shih-Yi Lindstrom, Jaana Loos, Ruth J. F. Mach, Francois McArdle, Wendy L. Meisinger, Christa Mitchell, Braxton D. Mueller, Gabrielle Nagaraja, Ramaiah Narisu, Narisu Nieminen, Tuomo V. M. Nsubuga, Rebecca N. Olafsson, Isleifur Ong, Ken K. Palotie, Aarno Papamarkou, Theodore Pomilla, Cristina Pouta, Anneli Rader, Daniel J. Reilly, Muredach P. Ridker, Paul M. Rivadeneira, Fernando Rudan, Igor Ruokonen, Aimo Samani, Nilesh Scharnagl, Hubert Seeley, Janet Silander, Kaisa Stancakova, Alena Stirrups, Kathleen Swift, Amy J. Tiret, Laurence Uitterlinden, Andre G. van Pelt, L. Joost Vedantam, Sailaja Wainwright, Nicholas Wijmenga, Cisca Wild, Sarah H. Willemsen, Gonneke Wilsgaard, Tom Wilson, James F. Young, Elizabeth H. Zhao, Jing Hua Adair, Linda S. Arveiler, Dominique Assimes, Themistocles L. Bandinelli, Stefania Bennett, Franklyn Bochud, Murielle Boehm, Bernhard O. Boomsma, Dorret I. Borecki, Ingrid B. Bornstein, Stefan R. Bovet, Pascal Burnier, Michel Campbell, Harry Chakravarti, Aravinda Chambers, John C. Chen, Yii-Der Ida Collins, Francis S. Cooper, Richard S. Danesh, John Dedoussis, George de Faire, Ulf Feranil, Alan B. Ferrieres, Jean Ferrucci, Luigi Freimer, Nelson B. Gieger, Christian Groop, Leif C. Gudnason, Vilmundur Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Hingorani, Aroon Hirschhorn, Joel N. Hofman, Albert Hovingh, G. Kees Hsiung, Chao Agnes Humphries, Steve E. Hunt, Steven C. Hveem, Kristian Iribarren, Carlos Jarvelin, Marjo-Riitta Jula, Antti Kahonen, Mika Kaprio, Jaakko Kesaniemi, Antero Kivimaki, Mika Kooner, Jaspal S. Koudstaal, Peter J. Krauss, Ronald M. Kuh, Diana Kuusisto, Johanna Kyvik, Kirsten O. Laakso, Markku Lakka, Timo A. Lind, Lars Lindgren, Cecilia M. Martin, Nicholas G. Maerz, Winfried McCarthy, Mark I. McKenzie, Colin A. Meneton, Pierre Metspalu, Andres Moilanen, Leena Morris, Andrew D. Munroe, Patricia B. Njolstad, Inger Pedersen, Nancy L. Power, Chris Pramstaller, Peter P. Price, Jackie F. Psaty, Bruce M. Quertermous, Thomas Rauramaa, Rainer Saleheen, Danish Salomaa, Veikko Sanghera, Dharambir K. Saramies, Jouko Schwarz, Peter E. H. Sheu, Wayne H-H Shuldiner, Alan R. Siegbahn, Agneta Spector, Tim D. Stefansson, Kari Strachan, David P. Tayo, Bamidele O. Tremoli, Elena Tuomilehto, Jaakko Uusitupa, Matti van Duijn, Cornelia M. Vollenweider, Peter Wallentin, Lars Wareham, Nicholas J. Whitfield, John B. Wolffenbuttel, Bruce H. R. Altshuler, David Ordovas, Jose M. Boerwinkle, Eric Palmer, Colin N. A. Thorsteinsdottir, Unnur Chasman, Daniel I. Rotter, Jerome I. Franks, Paul W. Ripatti, Samuli Cupples, L. Adrienne Sandhu, Manjinder S. Rich, Stephen S. Boehnke, Michael Deloukas, Panos Mohlke, Karen L. Ingelsson, Erik Abecasis, Goncalo R. Daly, Mark J. Neale, Benjamin M. Kathiresan, Sekar TI Common variants associated with plasma triglycerides and risk for coronary artery disease SO NATURE GENETICS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; ISCHEMIC-HEART-DISEASE; TYPE-2 DIABETES-MELLITUS; MENDELIAN RANDOMIZATION; CARDIOVASCULAR-DISEASE; GENETIC EPIDEMIOLOGY; CHOLESTEROL LEVELS; LOCI; CONTRIBUTE; THERAPY AB Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Uppsala Univ, Dept Med Sci, Uppsala, Sweden. Uppsala Univ, Sci Life Lab, Uppsala, Sweden. Wellcome Trust Sanger Inst, Cambridge, England. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Lausanne Hosp, Serv Med Genet, Lausanne, Switzerland. Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Prevent Med & Hlth Serv Res, Zhunan, Taiwan. Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Den Hertog, Heleen M.; Van den Herik, Evita G.; Koudstaal, Peter J.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Donnelly, Louise A.; Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Med Res Inst, Dundee, Scotland. [Donnelly, Louise A.; Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Sch Med, Dundee, Scotland. [Ehret, Georg B.; Mach, Francois] Univ Hosp Geneva, Dept Special Med, Geneva, Switzerland. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA. [Esko, Tonu; Fischer, Krista; Mihailov, Evelin; Perola, Markus; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. 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[Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Rich, Stephen S.; Neale, Benjamin M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM mjdaly@atgu.mgh.harvard.edu; bneale@broadinstitute.org; skathiresan@partners.org RI Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Wong, Andrew/M-8899-2016; Magnusson, Patrik/C-4458-2017; Beckmann, Jacques S /A-9772-2008; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Grallert, Harald/B-3424-2013; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Rivadeneira, Fernando/O-5385-2015; Lyytikainen, Leo-Pekka/C-8544-2016; Bovet, Pascal/F-4477-2011; Rudan, Igor/I-1467-2012; Papamarkou, Theodore/A-2958-2012; Kyvik, Kirsten /K-5680-2016; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Altshuler, David/A-4476-2009; Shah, Sonia/N-7547-2013; Boehm, Bernhard/F-8750-2015; Colaus, PsyColaus/K-6607-2013; Hypponen, Elina/B-2596-2014; Meisinger, Christine/B-5358-2014; Hsiung, Chao Agnes/E-3994-2010; Wijmenga, Cisca/D-2173-2009; Chang, Hsing-Yi /E-3973-2010; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008; Deloukas, Panos/B-2922-2013; Strawbridge, Rona/H-5422-2012 OI Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Mitchell, Braxton/0000-0003-4920-4744; Kaprio, Jaakko/0000-0002-3716-2455; Johansson, Asa/0000-0002-2915-4498; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Lakka, Timo/0000-0002-9199-2871; Franks, Paul/0000-0002-0520-7604; Meisinger, Christa/0000-0002-9026-6544; Gigante, Bruna/0000-0003-4508-7990; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Kumari, Meena/0000-0001-9716-1035; Nieminen, Tuomo/0000-0003-1755-1688; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Shungin, Dmitry/0000-0001-7900-5856; Seeley, Janet/0000-0002-0583-5272; Song, Ci/0000-0002-0947-9068; TREMOLI, ELENA/0000-0002-0929-6106; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; Fraser, Ross/0000-0003-0488-2592; Esko, Tonu/0000-0003-1982-6569; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Wong, Andrew/0000-0003-2079-4779; Beckmann, Jacques S /0000-0002-9741-1900; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Willer, Cristen/0000-0001-5645-4966; Kaakinen, Marika/0000-0002-9228-0462; Sidore, Carlo/0000-0001-7504-7477; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Rivadeneira, Fernando/0000-0001-9435-9441; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Papamarkou, Theodore/0000-0002-9689-543X; Kyvik, Kirsten /0000-0003-2981-0245; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Altshuler, David/0000-0002-7250-4107; Shah, Sonia/0000-0001-5860-4526; Hypponen, Elina/0000-0003-3670-9399; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Strawbridge, Rona/0000-0001-8506-3585 FU Massachusetts General Hospital; Donovan Family Foundation; US National Institutes of Health [R01HL107816]; Fondation Leducq; Canadian Institutes of Health Research; National Heart, Lung, and Blood Institute [T32HL007208] FX We thank the Global Lipids Genetics Consortium for early access to the association results of the Metabochip study. S. Kathiresan is supported by a Research Scholar award from the Massachusetts General Hospital, the Howard Goodman Fellowship from Massachusetts General Hospital, the Donovan Family Foundation, R01HL107816 from the US National Institutes of Health and a grant from Fondation Leducq. R.D. is supported by a Banting Fellowship from the Canadian Institutes of Health Research. G. P. is supported by award T32HL007208 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the US National Institutes of Health. NR 34 TC 205 Z9 211 U1 2 U2 49 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1345 EP + DI 10.1038/ng.2795 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100015 PM 24097064 ER PT J AU Zhan, XW Larson, DE Wang, CL Koboldt, DC Sergeev, YV Fulton, RS Fulton, LL Fronick, CC Branham, KE Bragg-Gresham, J Jun, G Hu, YN Kang, HM Liu, DJ Othman, M Brooks, M Ratnapriya, R Boleda, A Grassmann, F von Strachwitz, C Olson, LM Buitendijk, GHS Hofman, A van Duijn, CM Cipriani, V Moore, AT Shahid, H Jiang, YD Conley, YP Morgan, DJ Kim, IK Johnson, MP Cantsilieris, S Richardson, AJ Guymer, RH Luo, HR Ouyang, H Licht, C Pluthero, FG Zhang, MM Zhang, K Baird, PN Blangero, J Klein, ML Farrer, LA DeAngelis, MM Weeks, DE Gorin, MB Yates, JRW Klaver, CCW Pericak-Vance, MA Haines, JL Weber, BHF Wilson, RK Heckenlively, JR Chew, EY Stambolian, D Mardis, ER Swaroop, A Abecasis, GR AF Zhan, Xiaowei Larson, David E. Wang, Chaolong Koboldt, Daniel C. Sergeev, Yuri V. Fulton, Robert S. Fulton, Lucinda L. Fronick, Catrina C. Branham, Kari E. Bragg-Gresham, Jennifer Jun, Goo Hu, Youna Kang, Hyun Min Liu, Dajiang Othman, Mohammad Brooks, Matthew Ratnapriya, Rinki Boleda, Alexis Grassmann, Felix von Strachwitz, Claudia Olson, Lana M. Buitendijk, Gabrielle H. S. Hofman, Albert van Duijn, Cornelia M. Cipriani, Valentina Moore, Anthony T. Shahid, Humma Jiang, Yingda Conley, Yvette P. Morgan, Denise J. Kim, Ivana K. Johnson, Matthew P. Cantsilieris, Stuart Richardson, Andrea J. Guymer, Robyn H. Luo, Hongrong Ouyang, Hong Licht, Christoph Pluthero, Fred G. Zhang, Mindy M. Zhang, Kang Baird, Paul N. Blangero, John Klein, Michael L. Farrer, Lindsay A. DeAngelis, Margaret M. Weeks, Daniel E. Gorin, Michael B. Yates, John R. W. Klaver, Caroline C. W. Pericak-Vance, Margaret A. Haines, Jonathan L. Weber, Bernhard H. F. Wilson, Richard K. Heckenlively, John R. Chew, Emily Y. Stambolian, Dwight Mardis, Elaine R. Swaroop, Anand Abecasis, Goncalo R. TI Identification of a rare coding variant in complement 3 associated with age-related macular degeneration SO NATURE GENETICS LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; GENOME-WIDE ASSOCIATION; FACTOR-H POLYMORPHISM; COMMON DISEASES; SEQUENCING DATA; EYE DISEASE; FACTOR-B; RISK; SUSCEPTIBILITY; MUTATIONS AB Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p. Arg1210Cys encoded in the CFH gene (case frequency (f(case)) = 0.51%; control frequency (f(control)) = 0.02%; odds ratio (OR) = 23.11) and newly identified p. Lys155Gln encoded in the C3 gene (f(case) = 1.06%; f(control) = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology. C1 [Zhan, Xiaowei; Wang, Chaolong; Bragg-Gresham, Jennifer; Jun, Goo; Hu, Youna; Kang, Hyun Min; Liu, Dajiang; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Larson, David E.; Koboldt, Daniel C.; Fulton, Robert S.; Fulton, Lucinda L.; Fronick, Catrina C.; Wilson, Richard K.; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. [Wang, Chaolong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Branham, Kari E.; Othman, Mohammad; Heckenlively, John R.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brooks, Matthew; Ratnapriya, Rinki; Boleda, Alexis; Swaroop, Anand] NEI, US Natl Inst Hlth, Neurobiol Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. [Grassmann, Felix; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [von Strachwitz, Claudia] Southwest Eye Ctr, Stuttgart, Germany. [Olson, Lana M.; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. [Olson, Lana M.; Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Buitendijk, Gabrielle H. S.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; Hofman, Albert; van Duijn, Cornelia M.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hofman, Albert] Netherlands Genom Initiat, Netherlands Consortium Hlth Aging, The Hague, Netherlands. [Cipriani, Valentina; Moore, Anthony T.; Yates, John R. W.] UCL, UCL Inst Ophthalmol, London, England. [Cipriani, Valentina; Moore, Anthony T.; Yates, John R. W.] Moorfields Eye Hosp, London, England. [Shahid, Humma; Yates, John R. W.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Shahid, Humma] Cambridge Univ Hosp Natl Hlth Serv NHS Fdn Trust, Cambridge, England. [Jiang, Yingda; Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Conley, Yvette P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Promot & Dev, Pittsburgh, PA USA. [Morgan, Denise J.; DeAngelis, Margaret M.] Univ Utah, John A Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. [Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA USA. [Kim, Ivana K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Johnson, Matthew P.; Blangero, John] Texas Biomed Res Inst, San Antonio, TX USA. [Cantsilieris, Stuart; Richardson, Andrea J.; Guymer, Robyn H.; Baird, Paul N.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Luo, Hongrong; Ouyang, Hong; Zhang, Mindy M.; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Luo, Hongrong; Ouyang, Hong; Zhang, Mindy M.; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Licht, Christoph] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Pluthero, Fred G.] Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. [Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97201 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Chew, Emily Y.] NEI, US Natl Inst Hlth, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Stambolian, Dwight] Univ Penn, Sch Med, Dept Ophthalmol & Human Genet, Philadelphia, PA 19104 USA. RP Abecasis, GR (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM goncalo@umich.edu RI Cipriani, Valentina/A-8549-2012; luo, hongrong/B-2714-2015; DeAngelis, e/J-7863-2015; Klaver, Caroline/A-2013-2016; Jun, Goo/M-5235-2016; Jun, Goo/F-1941-2017; OI Weeks, Daniel/0000-0001-9410-7228; Pluthero, Fred/0000-0002-0451-5840; Baird, Paul/0000-0002-1305-3502; Swaroop, Anand/0000-0002-1975-1141; Cipriani, Valentina/0000-0002-0839-9955; luo, hongrong/0000-0001-7994-1193; Jun, Goo/0000-0003-0891-0204; Jun, Goo/0000-0003-0891-0204; Farrer, Lindsay/0000-0001-5533-4225 FU US National Institutes of Health (National Eye Institute, National Human Genome Research Institute) [EY022005, HG007022, HG005552, EY016862, U54HG003079, EY09859]; Medical Research Council, UK [G0000067]; Deutsche Forschungsgemeinschaft [WE1259/19-2]; Thome Memorial Foundation; Harold and Pauline Price Foundation FX We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders. NR 43 TC 63 Z9 63 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1375 EP + DI 10.1038/ng.2758 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100020 PM 24036949 ER PT J AU Flannick, J Beer, NL Bick, AG Agarwala, V Molnes, J Gupta, N Burtt, NP Florez, JC Meigs, JB Taylor, H Lyssenko, V Irgens, H Fox, E Burslem, F Johansson, S Brosnan, MJ Trimmer, JK Newton-Cheh, C Tuomi, T Molven, A Wilson, JG O'Donnell, CJ Kathiresan, S Hirschhorn, JN Njolstad, PR Rolph, T Seidman, JG Gabriel, S Cox, DR Seidman, CE Groop, L Altshuler, D AF Flannick, Jason Beer, Nicola L. Bick, Alexander G. Agarwala, Vineeta Molnes, Janne Gupta, Namrata Burtt, Noel P. Florez, Jose C. Meigs, James B. Taylor, Herman Lyssenko, Valeriya Irgens, Henrik Fox, Ervin Burslem, Frank Johansson, Stefan Brosnan, M. Julia Trimmer, Jeff K. Newton-Cheh, Christopher Tuomi, Tiinamaija Molven, Anders Wilson, James G. O'Donnell, Christopher J. Kathiresan, Sekar Hirschhorn, Joel N. Njolstad, Pal R. Rolph, Tim Seidman, J. G. Gabriel, Stacey Cox, David R. Seidman, Christine E. Groop, Leif Altshuler, David TI Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes SO NATURE GENETICS LA English DT Article ID BURROWS-WHEELER TRANSFORM; NORWEGIAN MODY REGISTRY; BETA-CELL FUNCTION; FACTOR-I; NUCLEAR FACTOR-1-ALPHA; READ ALIGNMENT; ALPHA-GENE; YOUNG MODY; ONSET; MUTATIONS AB Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1-7 and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates8-12. We sequenced seven genes for maturity-onset diabetes of the young (MODY) 13 in well-phenotyped population samples14,15 (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases. C1 [Flannick, Jason; Beer, Nicola L.; Bick, Alexander G.; Agarwala, Vineeta; Gupta, Namrata; Burtt, Noel P.; Florez, Jose C.; Newton-Cheh, Christopher; Kathiresan, Sekar; Hirschhorn, Joel N.; Njolstad, Pal R.; Gabriel, Stacey; Altshuler, David] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Flannick, Jason; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Flannick, Jason] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Bick, Alexander G.; Hirschhorn, Joel N.; Seidman, J. G.; Seidman, Christine E.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Agarwala, Vineeta] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Agarwala, Vineeta] Harvard Univ, Grad Sch Arts & Sci, Program Biophys, Cambridge, MA 02138 USA. [Molnes, Janne; Irgens, Henrik; Johansson, Stefan; Molven, Anders; Njolstad, Pal R.] Univ Bergen, KG Jebsen Ctr Diabet Res, Dept Clin Sci, Bergen, Norway. [Florez, Jose C.; Newton-Cheh, Christopher; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Meigs, James B.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Taylor, Herman; Fox, Ervin] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Taylor, Herman] Jackson State Univ, Jackson, MS USA. [Taylor, Herman] Tougaloo Coll, Div Nat Sci, Tougaloo, MS USA. [Lyssenko, Valeriya; Groop, Leif] Lund Univ, Clin Res Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden. [Irgens, Henrik; Njolstad, Pal R.] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Burslem, Frank] Prescient Life Sci, Cardiovasc & Metab Dis Practice, London, England. [Johansson, Stefan] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Brosnan, M. Julia; Trimmer, Jeff K.; Rolph, Tim] Pfizer Inc, Cardiovasc & Metab Dis Res Unit, Cambridge, MA USA. [Newton-Cheh, Christopher; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Newton-Cheh, Christopher; O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Tuomi, Tiinamaija] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Tuomi, Tiinamaija] Univ Helsinki, Cent Hosp, Res Program Mol Med, Helsinki, Finland. [Molven, Anders] Univ Bergen, Dept Clin Med, Gade Lab Pathol, Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Cox, David R.] Pfizer Inc, Appl Quantitat Genotherapeut, San Francisco, CA USA. [Seidman, Christine E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Groop, Leif] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. RP Altshuler, D (reprint author), Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. EM altshuler@molbio.mgh.harvard.edu RI Altshuler, David/A-4476-2009; Johansson, Stefan/C-4394-2011; OI Altshuler, David/0000-0002-7250-4107; Johansson, Stefan/0000-0002-2298-7008; Tuomi, Tiinamaija/0000-0002-8306-6202 FU National Human Genome Research Institute of the US National Institutes of Health (NIH) [U54 HG003067]; Howard Hughes Medical Institute; Pfizer Inc.; NIH [5-T32-GM007748-33]; Fulbright Diabetes UK Fellowship [BDA 11/0004348]; Doris Duke Charitable Foundation [2006087]; National Institute of Diabetes and Digestive and Kidney Diseases grant [K24 DK080140]; NHLBI [N01-HC-95170, N01-HC95171, N01-HC-95172]; National Institute for Minority Health and Health Disparities; Norwegian Research Council; European Research Council FX We acknowledge the contribution of the participants of the Framingham and Jackson Heart Study, as well as the participants from the Malm Preventive Project, the Scania Diabetes Registry and the Botnia Study. This work was supported by grants from the National Human Genome Research Institute of the US National Institutes of Health (NIH) (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, E. Lander) and the Howard Hughes Medical Institute, as well as funding from Pfizer Inc. J. F. was supported in part by NIH training grant 5-T32-GM007748-33. N. L. B. was supported by a Fulbright Diabetes UK Fellowship (BDA 11/0004348). D. A. was supported by funding from the Doris Duke Charitable Foundation (2006087). J. M. acknowledges support from National Institute of Diabetes and Digestive and Kidney Diseases grant K24 DK080140. J. B. M. and J. C. F. acknowledge support from NIH grant R01 DK078616. A. G. B. and V. A. were supported by NIH Medical Scientist Training Program fellowship T32GM007753. J. G. S. and C. E. S. were supported by NIH RO1 2R01HL080494, the National Heart, Lung, and Blood Institute (NHLBI) and the LeDucq Foundation. The Jackson Heart Study is supported by contracts N01-HC-95170, N01-HC95171 and N01-HC-95172 from the NHLBI, the National Institute for Minority Health and Health Disparities and additional support from the National Institute of Biomedical Imaging and Bioengineering. The Framingham Heart Study was supported by contracts N01-HC-25195 and 6R01-NS 17950 from the NHLBI and genotyping services from Affymetrix, Inc. (contract N02-HL-6-4278 for the SNP Health Association Resource, SHARe, project). The Malm Preventive Project and the Scania Diabetes Registry were supported by a Swedish Research Council grant (Linne) to the Lund University Diabetes Centre. The Botnia study was supported by funding from the Sigrid Juselius Foundation and the Folkh lsan Research Foundation, as well as a European Research Council advanced research grant to L. G. (GA 269045). The MODY study was supported by grants from the KG Jebsen Foundation, the Norwegian Research Council, the University of Bergen, Helse Vest, Innovest and the European Research Council (AdG). NR 92 TC 37 Z9 37 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2013 VL 45 IS 11 BP 1380 EP + DI 10.1038/ng.2794 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 244JL UT WOS:000326384100021 PM 24097065 ER PT J AU Fauci, AS Folkers, GK Dieffenbach, CW AF Fauci, Anthony S. Folkers, Gregory K. Dieffenbach, Carl W. TI HIV-AIDS: much accomplished, much to do SO NATURE IMMUNOLOGY LA English DT Article ID ANTIRETROVIRAL THERAPY; RISK BEHAVIORS; INFECTION; PREVENTION AB As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal of an AIDS-free generation, researchers and clinicians must follow the dual pathway of optimizing the implementation of existing prevention and treatment interventions and discovering with basic and clinical research new and effective tools in both of these arenas. C1 [Fauci, Anthony S.; Folkers, Gregory K.; Dieffenbach, Carl W.] NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 25 TC 26 Z9 26 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2013 VL 14 IS 11 BP 1104 EP 1107 PG 4 WC Immunology SC Immunology GA 239KV UT WOS:000326023400003 PM 24145780 ER PT J AU Lee, YJ Holzapfel, KL Zhu, JF Jameson, SC Hogquist, KA AF Lee, You Jeong Holzapfel, Keli L. Zhu, Jinfang Jameson, Stephen C. Hogquist, Kristin A. TI Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells SO NATURE IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; CD1D-RESTRICTED NKT CELLS; AIRWAY HYPERREACTIVITY; CYTOKINE PRODUCTION; ZINC-FINGER; INNATE; RESPONSES; MICE; BET; ASTHMA AB Invariant natural killer T cells (iNKT cells) can produce copious amounts of interleukin 4 (IL-4) early during infection. However, indirect evidence suggests they may produce this immunomodulatory cytokine in the steady state. Through intracellular staining for transcription factors, we have defined three subsets of iNKT cells (NKT1, NKT2 and NKT17) that produced distinct cytokines; these represented diverse lineages and not developmental stages, as previously thought. These subsets exhibited substantial interstrain variation in numbers. In several mouse strains, including BALB/c, NKT2 cells were abundant and were stimulated by self ligands to produce IL-4. In those strains, steady-state IL-4 conditioned CD8(+) T cells to become 'memory-like', increased serum concentrations of immunoglobulin E (IgE) and caused dendritic cells to produce chemokines. Thus, iNKT cell-derived IL-4 altered immunological properties under normal steady-state conditions. C1 [Lee, You Jeong; Holzapfel, Keli L.; Jameson, Stephen C.; Hogquist, Kristin A.] Univ Minnesota, Dept Lab Med & Pathol, Dept Lab Med, Minneapolis, MN 55455 USA. [Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Hogquist, KA (reprint author), Univ Minnesota, Dept Lab Med & Pathol, Dept Lab Med, Minneapolis, MN 55455 USA. EM hogqu001@umn.edu RI Jameson, Stephen/D-9892-2013; Zhu, Jinfang/B-7574-2012; OI Hogquist, Kristin/0000-0001-9963-5687 FU US National Institute of Health, Division of Intramural Research, National Institute of Allergy and Infectious Diseases [R37-AI39560, RO1-AI075168, T32 HD060536]; US National Cancer Research Institute FX We thank J. Ding and S. Perry for technical support; M. Mohrs (Trudeau Institute) for KN2 mice on the B6 and BALB/c background; D. B. Sant'Angelo (Rutgers University) for Alexa Fluor 488-conjugated antibody to PLZF; M. Mohrs and M. Kronenberg for discussions; and S. Hamilton for critical review of the manuscript. Supported by the US National Institutes of Health (R37-AI39560 to K. A. H.; RO1-AI075168 to S. C. J.; T32 HD060536 to K. L. H.; and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, for J.Z.) and the Cancer Research Institute (Y.J.L.). NR 46 TC 132 Z9 132 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2013 VL 14 IS 11 BP 1146 EP U126 DI 10.1038/ni.2731 PG 10 WC Immunology SC Immunology GA 239KV UT WOS:000326023400011 PM 24097110 ER PT J AU Hu, GQ Tang, QS Sharma, S Yu, F Escobar, TM Muljo, SA Zhu, JF Zhao, KJ AF Hu, Gangqing Tang, Qingsong Sharma, Suveena Yu, Fang Escobar, Thelma M. Muljo, Stefan A. Zhu, Jinfang Zhao, Keji TI Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation SO NATURE IMMUNOLOGY LA English DT Article ID GENOME-WIDE IDENTIFICATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; INTEGRATIVE ANNOTATION; CUTTING EDGE; STEM-CELLS; REVEALS; SEQ; POPULATIONS; INTERFERON AB Although intergenic long noncoding RNAs (lincRNAs) have been linked to gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identified 1,524 lincRNA clusters in 42 T cell samples, from early T cell progenitors to terminally differentiated helper T cell subsets. Our analysis revealed highly dynamic and cell-specific expression patterns for lincRNAs during T cell differentiation. These lincRNAs were located in genomic regions enriched for genes that encode proteins with immunoregulatory functions. Many were bound and regulated by the key transcription factors T-bet, GATA-3, STAT4 and STAT6. We found that the lincRNA LincR-Ccr2-5'AS, together with GATA-3, was an essential component of a regulatory circuit in gene expression specific to the T(H)2 subset of helper T cells and was important for the migration of T(H)2 cells. C1 [Hu, Gangqing; Tang, Qingsong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Sharma, Suveena; Yu, Fang; Escobar, Thelma M.; Muljo, Stefan A.; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov; zhaok@nhlbi.nih.gov RI HU, GANGQING/K-5849-2012; Muljo, Stefan/F-5671-2015; Zhu, Jinfang/B-7574-2012 OI Muljo, Stefan/0000-0003-1013-446X; FU Division of Intramural Research of the NHLBI and NIAID (US National Institutes of Health) FX We thank the DNA Sequencing Core facility of the National Heart, Lung and Blood Institute (NHLBI) for sequencing the ChIP-Seq and RNA-Seq libraries; J. Edwards for most cell-sorting experiments; the flow cytometry core of NHLBI for some cell-sorting experiments and analysis; H. Cao for comments on the knockdown of lincRNA by shRNA; D. Northrup for critical reading and editing of the manuscript; H. Zhang for sharing experience with chemokines and chemokine receptors; P. Burr for RNA-Seq; and X. Zheng for sharing code for binomial tests. This study used the Biowulf Linux cluster of the US National Institutes of Health. Supported by the Division of Intramural Research of the NHLBI and NIAID (US National Institutes of Health). NR 50 TC 89 Z9 94 U1 7 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2013 VL 14 IS 11 BP 1190 EP U118 DI 10.1038/ni.2712 PG 11 WC Immunology SC Immunology GA 239KV UT WOS:000326023400016 PM 24056746 ER PT J AU Regard, JB Malhotra, D Gvozdenovic-Jeremic, J Josey, M Chen, M Weinstein, LS Lu, JM Shore, EM Kaplan, FS Yang, YZ AF Regard, Jean B. Malhotra, Deepti Gvozdenovic-Jeremic, Jelena Josey, Michelle Chen, Min Weinstein, Lee S. Lu, Jianming Shore, Eileen M. Kaplan, Frederick S. Yang, Yingzi TI Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification SO NATURE MEDICINE LA English DT Article ID PROTEIN-KINASE-A; SUPPRESSES OSTEOGENIC DIFFERENTIATION; MESENCHYMAL STEM-CELLS; STIMULATORY G-PROTEIN; BONE-FORMATION; OSTEOBLAST DIFFERENTIATION; IN-VIVO; CHONDROCYTE PROLIFERATION; PROMOTES PROLIFERATION; SKELETAL DEVELOPMENT AB Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that G alpha(s) restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes G alpha(s), Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-beta-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify G alpha(s) as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-beta-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation. C1 [Regard, Jean B.; Malhotra, Deepti; Gvozdenovic-Jeremic, Jelena; Josey, Michelle; Yang, Yingzi] NHGRI, NIH, Bethesda, MD 20892 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, NIH, Bethesda, MD 20892 USA. [Lu, Jianming] Codex BioSolut, Gaithersburg, MD USA. [Shore, Eileen M.; Kaplan, Frederick S.] Univ Penn, Perelman Sch Med, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Shore, Eileen M.] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kaplan, Frederick S.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Yang, YZ (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM jean.regard@novartis.com; yingzi@mail.nih.gov FU intramural research program of NHGRI at the US National Institutes of Health (NIH); intramural research program of NIDDK at the US National Institutes of Health (NIH); Progressive Osseous Heteroplasia Association; University of Pennsylvania Center for Research in FOP and Related Disorders; Penn Center for Musculoskeletal Disorders (NIH NIAMS) [P30-AR050950]; Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine; NIH NIAMS [R01-AR046831, R01-AR41916] FX We thank the entire Yang lab for stimulating discussions. We thank J. Fekecs and P. Andre for helping with the data illustration. The work in the Yang and Weinstein labs was supported by the intramural research programs of NHGRI and NIDDK at the US National Institutes of Health (NIH), respectively. We thank R. Caron for his work on the POH lesion histological analyses. The rabbit anti-Gli3 antibody was provided by S. Mackem (NIH NCI), and the dnPKA adenovirus was a gift from C.-M. Fan (Carnegie Institution for Science). The work in the Kaplan and Shore lab was supported by the Progressive Osseous Heteroplasia Association, the University of Pennsylvania Center for Research in FOP and Related Disorders, the Penn Center for Musculoskeletal Disorders (NIH NIAMS P30-AR050950), the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine and NIH NIAMS (R01-AR046831 and R01-AR41916). NR 73 TC 33 Z9 36 U1 4 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2013 VL 19 IS 11 BP 1505 EP + DI 10.1038/nm.3314 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 251IF UT WOS:000326920300028 PM 24076664 ER PT J AU Simmons, WK Rapuano, KM Kallman, SJ Ingeholm, JE Miller, B Gotts, SJ Avery, JA Hall, KD Martin, A AF Simmons, W. Kyle Rapuano, Kristina M. Kallman, Seth J. Ingeholm, John E. Miller, Bernard Gotts, Stephen J. Avery, Jason A. Hall, Kevin D. Martin, Alex TI Category-specific integration of homeostatic signals in caudal but not rostral human insula SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN AWARENESS; ACTIVATION; FEELINGS; NUCLEUS; FOODS; TASTE; BODY AB Prevailing theories hold that the insula is functionally organized along its caudal-to-rostral axis, with posterior regions coding lower-level sensory information and anterior regions coding higher-level stimulus significance relative to the body's homeostatic needs. Contrary to predictions of this model, the response of the taste-sensitive region of the caudal, but not rostral, insula to food images was directly related to the body's homeostatic state as indexed by levels of peripheral glucose. C1 [Simmons, W. Kyle; Avery, Jason A.] Laureate Inst Brain Res, Tulsa, OK USA. [Simmons, W. Kyle] Univ Tulsa, Fac Community Med, Tulsa, OK 74104 USA. [Simmons, W. Kyle; Rapuano, Kristina M.; Kallman, Seth J.; Ingeholm, John E.; Gotts, Stephen J.; Martin, Alex] NIHM, Lab Brain & Cognit, NIH, Bethesda, MD USA. [Miller, Bernard; Hall, Kevin D.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Avery, Jason A.] Univ Tulsa, Dept Biol Sci, Tulsa, OK 74104 USA. RP Simmons, WK (reprint author), Laureate Inst Brain Res, Tulsa, OK USA. EM wksimmons@laureateinstitute.org RI Simmons, William/K-8925-2015 OI Simmons, William/0000-0002-0399-9003 FU NIMH [K01MH096175-01]; NIDDK; Oklahoma Center for the Advancement of Science and Technology [OCAST HR10-141]; NARSAD; Oklahoma Tobacco Research Center; William K. Warren Foundation FX We would like to thank K. Burrows for help with data management and analysis of the high-sweetness and low-sweetness food pictures. This research supported by the Intramural Research Programs of the NIMH and the NIDDK, as well as by NIMH grant K01MH096175-01 to W.K.S., a grant from the Oklahoma Center for the Advancement of Science and Technology (OCAST HR10-141) to W.K.S., a NARSAD Young Investigator Award to W.K.S., a grant to W.K.S. from the Oklahoma Tobacco Research Center, and The William K. Warren Foundation. The study was conducted under NIH Clinical Study Protocol 09-DK-0081 (ClinicalTrials.gov ID NCT00846040). NR 16 TC 28 Z9 29 U1 0 U2 4 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 NOV PY 2013 VL 16 IS 11 BP 1551 EP 1552 DI 10.1038/nn.3535 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700011 PM 24077565 ER PT J AU Chittajallu, R Craig, MT McFarland, A Yuan, XQ Geffen, S Tricoire, L Erkkila, B Barron, SC Lopez, CM Liang, BJ Jeffries, BW Pelkey, KA McBain, CJ AF Chittajallu, Ramesh Craig, Michael T. McFarland, Ashley Yuan, Xiaoqing Geffen, Scott Tricoire, Ludovic Erkkila, Brian Barron, Sean C. Lopez, Carla M. Liang, Barry J. Jeffries, Brian W. Pelkey, Kenneth A. McBain, Chris J. TI Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT3AR expression SO NATURE NEUROSCIENCE LA English DT Article ID OSCILLATIONS IN-VITRO; STRATUM-ORIENS INTERNEURONS; CORTICAL INTERNEURONS; GABAERGIC INTERNEURONS; NETWORK OSCILLATIONS; RAT HIPPOCAMPUS; PERISOMATIC INHIBITION; RECEPTOR ACTIVATION; TRANSGENIC MICE; BASKET CELLS AB Forebrain circuits rely upon a relatively small but remarkably diverse population of GABAergic interneurons to bind and entrain large principal cell assemblies for network synchronization and rhythmogenesis. Despite the high degree of heterogeneity across cortical interneurons, members of a given subtype typically exhibit homogeneous developmental origins, neuromodulatory response profiles, morphological characteristics, neurochemical signatures and electrical features. Here we report a surprising divergence among hippocampal oriens-lacunosum moleculare (O-LM) projecting interneurons that have hitherto been considered a homogeneous cell population. Combined immunocytochemical, anatomical and electrophysiological interrogation of Htr3a-GFP and Nkx2-1-cre:RCE mice revealed that O-LM cells parse into a caudal ganglionic eminence-derived subpopulation expressing 5-HT3A receptors (5-HT(3A)Rs) and a medial ganglionic eminence-derived subpopulation lacking 5-HT(3A)Rs. These two cohorts differentially participate in network oscillations, with 5-HT3AR-containing O-LM cell recruitment dictated by serotonergic tone. Thus, members of a seemingly uniform interneuron population can exhibit unique circuit functions and neuromodulatory properties dictated by disparate developmental origins. C1 [Chittajallu, Ramesh; Craig, Michael T.; McFarland, Ashley; Yuan, Xiaoqing; Geffen, Scott; Tricoire, Ludovic; Erkkila, Brian; Barron, Sean C.; Lopez, Carla M.; Liang, Barry J.; Jeffries, Brian W.; Pelkey, Kenneth A.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD USA. RP Pelkey, KA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD USA. EM pelkeyk2@mail.nih.gov RI Craig, Michael/E-7070-2011 OI Craig, Michael/0000-0001-8481-6709 FU NICHD FX We thank D. Abebe for expert technical assistance. We are grateful to S. Anderson (University of Pennsylvania) and a Fishell (New York University) for providing the Nkx2-1-cre and the RCE reporter mouse lines, respectively. The GENSAT BAC-Cre driver line (Htr3a-NO152) mice were obtained from C. Gerfen (National Institute of Mental Health). We would also like to thank E. Mann (University of Oxford) for providing the code for the wavelet analyses. This work was supported by an NICHD intramural award to C.J.M. NR 50 TC 30 Z9 30 U1 0 U2 6 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 NOV PY 2013 VL 16 IS 11 BP 1598 EP 1607 DI 10.1038/nn.3538 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700017 PM 24097043 ER PT J AU Sarkar, C Chandra, G Peng, SY Zhang, ZJ Liu, AY Mukherjee, AB AF Sarkar, Chinmoy Chandra, Goutam Peng, Shiyong Zhang, Zhongjian Liu, Aiyi Mukherjee, Anil B. TI Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL SO NATURE NEUROSCIENCE LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; PALMITOYL-PROTEIN THIOESTERASE; ENZYME REPLACEMENT THERAPY; MOUSE MODEL; LYSOSOMAL STORAGE; HYDROXYLAMINE; ACTIVATION; EXPRESSION; BRAIN; NEURODEGENERATION AB Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disease (LSD) that has no effective treatment. It is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 deficiency impairs the cleavage of thioester linkage in palmitoylated proteins (constituents of ceroid), preventing degradation by lysosomal hydrolases. Consequently, accumulation of lysosomal ceroid leads to INCL. Thioester linkage is cleaved by nucleophilic attack. Hydroxylamine, a potent nucleophilic cellular metabolite, may have therapeutic potential for INCL, but its toxicity precludes clinical application. We found that a hydroxylamine derivative, N-(tert-Butyl) hydroxylamine (NtBuHA), was non-toxic, cleaved thioester linkage in palmitoylated proteins and mediated lysosomal ceroid depletion in cultured cells from INCL patients. In Ppt1(-/-) mice, which mimic INCL, NtBuHA crossed the blood-brain barrier, depleted lysosomal ceroid, suppressed neuronal apoptosis, slowed neurological deterioration and extended lifespan. Our findings provide a proof of concept that thioesterase-mimetic and antioxidant small molecules such as NtBuHA are potential drug targets for thioesterase deficiency diseases such as INCL. C1 [Sarkar, Chinmoy; Chandra, Goutam; Peng, Shiyong; Zhang, Zhongjian; Mukherjee, Anil B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Liu, Aiyi] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD USA. RP Mukherjee, AB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. EM mukherja@exchange.nih.gov RI Peng, Shiyong/D-6391-2014; OI Peng, Shiyong/0000-0003-0697-3674; Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank S.L. Hofmann (University of Texas Southwestern Medical Center) for the generous gift of Ppt1-/- mice and for a sample of recombinant human PPT1 enzyme that we used as a positive control. M. Sands (Washington University School of Medicine) provided a pair of C57 congenic Ppt1-/- mice that we used to establish our colony at the US National Institutes of Health. We thank S.W. Levin, J.Y. Chou and I. Owens for critical review of the manuscript and helpful suggestions. We also thank A. Bouchelion and A. Chen for editorial assistance. We thank L. Dye at the Microscopy and Imaging Core facility for his expert assistance in performing TEM of cultured lymphoblasts and mouse brain tissues. We are grateful to H.-S. fun for helping us with the FACS analysis. The mass spectrometric analyses for the detection of NtBuHA in brain tissues were performed in the laboratory of A.K. Cheema (Georgetown University School of Medicine). This research was supported in whole by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 49 TC 18 Z9 18 U1 0 U2 6 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 NOV PY 2013 VL 16 IS 11 BP 1608 EP 1617 DI 10.1038/nn.3526 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700018 PM 24056696 ER PT J AU Jia, JM Zhao, J Hu, ZH Lindberg, D Li, Z AF Jia, Jie-Min Zhao, Jun Hu, Zhonghua Lindberg, Daniel Li, Zheng TI Age-dependent regulation of synaptic connections by dopamine D2 receptors SO NATURE NEUROSCIENCE LA English DT Article ID DENDRITIC SPINE DENSITY; CORTICAL PYRAMIDAL NEURONS; ENTORHINAL CORTEX; ANTIPSYCHOTIC-DRUGS; PREFRONTAL CORTEX; SCHIZOPHRENIA; MECHANISMS; PHOSPHORYLATION; INHIBITION; PLASTICITY AB Dopamine D2 receptors (D2R) are G protein-coupled receptors that modulate synaptic transmission and are important for various brain functions, including learning and working memory. Abnormal D2R signaling has been implicated in psychiatric disorders such as schizophrenia. Here we report a new function of D2R in dendritic spine morphogenesis. Activation of D2R reduced spine number via GluN2B- and cAMP-dependent mechanisms in mice. Notably, this regulation occurred only during adolescence. During this period, D2R overactivation caused by mutations in the schizophrenia risk gene Dtnbp1 led to spine deficiency, dysconnectivity in the entorhinal-hippocampal circuit and impairment of spatial working memory. Notably, these defects could be ameliorated by D2R blockers administered during adolescence. Our findings suggest an age-dependent function of D2R in spine development, provide evidence that D2R dysfunction during adolescence impairs neuronal circuits and working memory, and indicate that adolescent interventions to prevent aberrant D2R activity protect against cognitive impairment. C1 [Jia, Jie-Min; Zhao, Jun; Hu, Zhonghua; Lindberg, Daniel; Li, Zheng] NIMH, Unit Synapse Dev & Plast, US NIH, Bethesda, MD 20892 USA. RP Li, Z (reprint author), NIMH, Unit Synapse Dev & Plast, US NIH, Bethesda, MD 20892 USA. EM lizheng2@mail.nih.gov RI Hu, Zhonghua/J-1169-2016; Jia, Jie-Min/O-1150-2013; Hu, Zhonghua/F-9493-2014; Li, Zheng/I-8016-2014 OI Hu, Zhonghua/0000-0002-0117-7081; Jia, Jie-Min/0000-0001-8446-3819; Li, Zheng/0000-0002-2978-2531 FU National Institute of Mental Health [ZIA MH002281] FX We thank H. Arnheiter (NINDS/NIH) for critical discussion of the manuscript and E.J. Sherman for editing the manuscript. This work was supported by the Intramural Research Program of the National Institute of Mental Health (ZIA MH002281 to Z.L.). NR 47 TC 21 Z9 21 U1 1 U2 22 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 NOV PY 2013 VL 16 IS 11 BP 1627 EP 1636 DI 10.1038/nn.3542 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700020 PM 24121738 ER PT J AU Lee, BR Ma, YY Huang, YHH Wang, XS Otaka, M Ishikawa, M Neumann, PA Graziane, NM Brown, TE Suska, A Guo, CY Lobo, MK Sesack, SR Wolf, ME Nestler, EJ Shaham, Y Schluter, OM Dong, Y AF Lee, Brian R. Ma, Yao-Ying Huang, Yanhua H. Wang, Xiusong Otaka, Mami Ishikawa, Masago Neumann, Peter A. Graziane, Nicholas M. Brown, Travis E. Suska, Anna Guo, Changyong Lobo, Mary Kay Sesack, Susan R. Wolf, Marina E. Nestler, Eric J. Shaham, Yavin Schlueter, Oliver M. Dong, Yan TI Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving SO NATURE NEUROSCIENCE LA English DT Article ID PERMEABLE AMPA RECEPTORS; NUCLEUS-ACCUMBENS; SYNAPTIC PLASTICITY; DRUG RELAPSE; REINSTATEMENT MODEL; WITHDRAWAL; EXPOSURE; SEEKING; SENSITIZATION; TRANSMISSION AB In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation-induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse-based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal. C1 [Lee, Brian R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. [Lee, Brian R.; Brown, Travis E.; Dong, Yan] Washington State Univ, Program Neurosci, Pullman, WA 99164 USA. [Ma, Yao-Ying; Otaka, Mami; Ishikawa, Masago; Neumann, Peter A.; Graziane, Nicholas M.; Guo, Changyong; Sesack, Susan R.; Dong, Yan] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Huang, Yanhua H.; Wang, Xiusong] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Suska, Anna; Schlueter, Oliver M.] European Neurosci Inst, Gottingen, Germany. [Lobo, Mary Kay; Nestler, Eric J.] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY USA. [Lobo, Mary Kay; Nestler, Eric J.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY USA. [Wolf, Marina E.] Rosalind Franklin Univ Med & Sci, Dept Neurosci, N Chicago, IL USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, US NIH, Baltimore, MD USA. RP Dong, Y (reprint author), Washington State Univ, Program Neurosci, Pullman, WA 99164 USA. EM yandong@pitt.edu RI shaham, yavin/G-1306-2014; dong, yan/J-2859-2014; Lobo, Mary Kay/K-7734-2015; Dong, Yan/A-4154-2016; Huang, Yanhua/P-1583-2015; Beroun, Anna/P-6322-2016; OI Lobo, Mary Kay/0000-0002-9419-2079; Dong, Yan/0000-0003-0016-9028; Huang, Yanhua/0000-0003-1770-0196; Beroun, Anna/0000-0003-4376-5241; Lee, Brian/0000-0002-3210-5638 FU National Institute on Drug Abuse [DA028020, DA029565, DA036303, DA030379, DA009621, DA029099, DA007359, DA014133, DA023206, DA031551, DA034856]; German Research Foundation through the Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain"; Gottingen University Medical School; Max Planck Society; [SCHL592/4] FX We thank B. Sorg, D. Dietz, R.L. Brown and H. Jansen for technical consultations. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse (Y.S.), extramural funds DA028020 (B.R.L.), DA029565 and DA036303 (Y.H.H.), DA030379 (M.E.W. and Y.D.), DA009621 and DA029099 (M.E.W.), DA007359 and DA014133 (E.J.N.), DA023206, DA031551 and DA034856 (Y.D.) from the National Institute on Drug Abuse, the German Research Foundation through the Cluster of Excellence "Nanoscale Microscopy and Molecular Physiology of the Brain" and grant SCHL592/4 (O.M.S.). The European Neuroscience Institute Gottingen is jointly funded by the Gottingen University Medical School and the Max Planck Society. NR 50 TC 74 Z9 74 U1 1 U2 22 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 NOV PY 2013 VL 16 IS 11 BP 1644 EP 1651 DI 10.1038/nn.3533 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700022 PM 24077564 ER PT J AU Justinova, Z Mascia, P Wu, HQ Secci, ME Redhi, GH Panlilio, LV Scherma, M Barnes, C Parashos, A Zara, T Fratta, W Solinas, M Pistis, M Bergman, J Kangas, BD Ferre, S Tanda, G Schwarcz, R Goldberg, SR AF Justinova, Zuzana Mascia, Paola Wu, Hui-Qiu Secci, Maria E. Redhi, Godfrey H. Panlilio, Leigh V. Scherma, Maria Barnes, Chanel Parashos, Alexandra Zara, Tamara Fratta, Walter Solinas, Marcell Pistis, Marco Bergman, Jack Kangas, Brian D. Ferre, Sergi Tanda, Gianluigi Schwarcz, Robert Goldberg, Steven R. TI Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid SO NATURE NEUROSCIENCE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; 3-MONOOXYGENASE INHIBITION; SYNAPTIC-TRANSMISSION; GLUTAMATE RELEASE; MAMMALIAN BRAIN; WORKING-MEMORY; BINDING-SITES; DOPAMINE AB In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (alpha 7nAChRs) modulate effects of Delta(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of alpha 7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of alpha 7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse. C1 [Justinova, Zuzana; Mascia, Paola; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Barnes, Chanel; Parashos, Alexandra; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Justinova, Zuzana; Wu, Hui-Qiu; Schwarcz, Robert] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Scherma, Maria; Zara, Tamara; Fratta, Walter; Pistis, Marco] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Monserrato, Italy. [Solinas, Marcell] INSERM, U1084, Expt & Clin Neurosci Lab, Neurobiol & Neuropharmacol Addict Grp, Poitiers, France. [Solinas, Marcell] Univ Poitiers, Poitiers, France. [Pistis, Marco] CNR, Neurosci Inst, Cagliari, Italy. [Bergman, Jack; Kangas, Brian D.] Harvard Univ, Sch Med, McLean Hosp, Belmont, MA 02178 USA. [Ferre, Sergi] NIDA, Integrat Neurobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Tanda, Gianluigi] NIDA, Psychobiol Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. EM sgoldber@mail.nih.gov RI Pistis, Marco/A-3773-2013; Ferre, Sergi/K-6115-2014; Justinova, Zuzana/A-9109-2011; Tanda, Gianluigi/B-3318-2009; Solinas, Marcello/M-3500-2016 OI Pistis, Marco/0000-0002-4622-3205; Ferre, Sergi/0000-0002-1747-1779; Justinova, Zuzana/0000-0001-5793-7484; Tanda, Gianluigi/0000-0001-9526-9878; Solinas, Marcello/0000-0002-0664-5964 FU National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services, NIDA Residential Research Support Services [N01 DA59909]; Italian Ministry of University and Scientific Research [DA023142, DA035974]; Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine; Regione Autonoma della Sardegna; European Social Fund [LR7 2007] FX We thank E. Thorndike for excellent technical assistance during the rodent studies. We thank I. Baum, S. Stevens and P. White for excellent veterinary assistance during the primate studies. This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health, Department of Health and Human Services, NIDA Residential Research Support Services Contract N01 DA59909 (principal investigator D. Kelly), by the Italian Ministry of University and Scientific Research, by DA023142 (J.B.) and DA035974 (B.D.K.) and by the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine. T.Z. was supported by a Grant from Regione Autonoma della Sardegna and by the European Social Fund, LR7 2007. NR 50 TC 19 Z9 19 U1 2 U2 12 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 NOV PY 2013 VL 16 IS 11 BP 1652 EP 1661 DI 10.1038/nn.3540 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 241YX UT WOS:000326205700023 PM 24121737 ER PT J AU Linehan, WM Srinivasan, R AF Linehan, W. Marston Srinivasan, Ramaprasad TI TARGETED THERAPIES Treating advanced kidney cancer-miles to go before we sleep SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID RENAL-CELL CARCINOMA AB A randomized phase III trial comparing pazopanib with sunitinib in patients with advanced clear cell renal cell carcinoma showed that although progression-free survival and overall survival were similar, pazopanib was better tolerated. Recent advances in genomics and metabolomics have provided novel insights that could be leveraged to improve therapy. C1 [Linehan, W. Marston; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, CRC Room 1W-5940, Bethesda, MD 20892 USA. EM wml@nih.gov FU Intramural NIH HHS [ZIA BC011038-06, ZIA BC011028-06] NR 10 TC 4 Z9 4 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 EI 1759-4782 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD NOV PY 2013 VL 10 IS 11 BP 614 EP 615 DI 10.1038/nrclinonc.2013.183 PG 2 WC Oncology SC Oncology GA 243NM UT WOS:000326323100005 PM 24129349 ER PT J AU Schetter, CD Schafer, P Lanzi, RG Clark-Kauffman, E Raju, TNK Hillemeier, MM AF Schetter, Christine Dunkel Schafer, Peter Lanzi, Robin Gaines Clark-Kauffman, Elizabeth Raju, Tonse N. K. Hillemeier, Marianne M. CA Community Child Hlth Network TI Shedding Light on the Mechanisms Underlying Health Disparities Through Community Participatory Methods: The Stress Pathway SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Review DE stress; health disparities; socioeconomic status (SES); ethnicity ID ADVERSE BIRTH OUTCOMES; PRENATAL PSYCHOSOCIAL PROFILE; INTIMATE PARTNER VIOLENCE; SOCIOECONOMIC-STATUS; PHYSICAL HEALTH; UNITED-STATES; LIFE EVENTS; PERCEIVED STRESS; PRETERM BIRTH; PSYCHOLOGICAL STRESS AB Health disparities are large and persistent gaps in the rates of disease and death between racial/ethnic and socioeconomic status subgroups in the population. Stress is a major pathway hypothesized to explain such disparities. The Eunice Kennedy Shriver National Institute of Child Health and Human Development formed a community/research collaborativethe Community Child Health Networkto investigate disparities in maternal and child health in five high-risk communities. Using community participation methods, we enrolled a large cohort of African American/Black, Latino/Hispanic, and non-Hispanic/White mothers and fathers of newborns at the time of birth and followed them over 2 years. A majority had household incomes near or below the federal poverty level. Home interviews yielded detailed information regarding multiple types of stress such as major life events and many forms of chronic stress including racism. Several forms of stress varied markedly by racial/ethnic group and income, with decreasing stress as income increased among Caucasians but not among African Americans; other forms of stress varied by race/ethnicity or poverty alone. We conclude that greater sophistication in studying the many forms of stress and community partnership is necessary to uncover the mechanisms underlying health disparities in poor and ethnic-minority families and to implement community health interventions. C1 [Schetter, Christine Dunkel] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Schafer, Peter] New York Acad Sci, New York, NY USA. [Lanzi, Robin Gaines] Univ Alabama Birmingham, Dept Hlth Behav, Birmingham, AL USA. [Clark-Kauffman, Elizabeth] North Shore Univ Hlth Syst, Sect Child & Family Hlth Studies, Evanston, IL USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Inst Hlth, Pregnancy & Perinatol Branch, Rockville, MD USA. [Hillemeier, Marianne M.] Penn State Univ, Dept Hlth Policy & Adm, University Pk, PA 16802 USA. RP Schetter, CD (reprint author), Univ Calif Los Angeles, Dept Psychol, 1285A Franz Hall, Los Angeles, CA 90095 USA. EM dunkel@psych.ucla.edu NR 117 TC 13 Z9 13 U1 11 U2 35 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 EI 1745-6924 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD NOV PY 2013 VL 8 IS 6 BP 613 EP 633 DI 10.1177/1745691613506016 PG 21 WC Psychology, Multidisciplinary SC Psychology GA 246KV UT WOS:000326537700002 ER PT J AU Petrov, MER Kim, Y Lauderdale, D Lewis, CE Reis, JP Carnethon, MR Knutson, K Glasser, SJ AF Petrov, Megan E. Ruiter Kim, Yongin Lauderdale, Diane Lewis, Cora E. Reis, Jared P. Carnethon, Mercedes R. Knutson, Kristen Glasser, Stephen J. TI Longitudinal Associations between Objective Sleep and Lipids: The CARDIA Study SO SLEEP LA English DT Article DE Sleep duration; sleep fragmentation; lipids; sleep quality; ethnicity; sex ID DENSITY-LIPOPROTEIN-CHOLESTEROL; CARDIOVASCULAR-DISEASE RISK; METABOLIC SYNDROME; BLOOD-PRESSURE; NATIONAL-HEALTH; FOLLOW-UP; DURATION; WOMEN; MORTALITY; HYPERTENSION AB Study Objective: To investigate the longitudinal relationships between actigraph-derived sleep duration, fragmentation, and lipid levels. Design and Setting: Longitudinal data from the Coronary Artery Risk Development in Young Adults Sleep Study (2003-05), an observational cohort at the Chicago site. Participants: There were 503 black and white adults, ages 32-51 years, with no prior history of cardiovascular disease. Interventions: N/A. Measurement and Results: Sleep duration and fragmentation were measured using 6 days of wrist actigraphy. Sleep quality was measured with the Pittsburgh Sleep Quality Index. The outcome variables, measured at 3 examinations over 10 years (Baseline [2000-01], 5-year [2005-06], and 10-year follow-up [2010-11]), were total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and TC/HDL ratio. The associations between each sleep parameter and 10-year change in lipids were analyzed with generalized estimating equation models adjusting for relevant confounders. After adjustment, each hour increase in sleep duration was significantly associated with higher TC (5.2 mg/dL, 95%CI: 1.7, 8.6) and LDL (3.4 mg/dL, 95%CI: 0.2, 6.6) in the total sample, a 1.1 mg/dL increase in TG (95%CI: 1.0, 1.1) among men, and a borderline significant greater odds for a TC/HDL ratio >= 5 among men (OR: 1.37, 95%CI: 0.99, 1.90). Overall, sleep fragmentation and sleep quality scores were not associated with change in lipids. Conclusions: Beyond relevant covariates, over a 10-year follow-up, longer objective sleep duration was longitudinally and significantly associated with a poorer lipid profile. Greater objective sleep fragmentation and self-reported poor sleep quality were not related to a poorer lipid profile. C1 [Petrov, Megan E. Ruiter] Arizona State Univ, Coll Nursing & Hlth Innovat, Phoenix, AZ 85004 USA. [Kim, Yongin; Lewis, Cora E.; Glasser, Stephen J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Lauderdale, Diane; Knutson, Kristen] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Reis, Jared P.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Carnethon, Mercedes R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Petrov, MER (reprint author), Arizona State Univ, Coll Nursing & Hlth Innovat, 500 N 3rd St, Phoenix, AZ 85004 USA. EM Megan.Petrov@asu.edu OI Knutson, Kristen/0000-0002-2751-6168 FU Novo Nordisk; AMGON; US Public Health Service [NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050]; National Heart, Lung, and Blood Institute [NO1-HC-95095]; National Institute on Aging [AG 11412] FX This was not an industry supported study. Poster presented at the Academy Health 2012 Annual Research Meeting, Orlando, FL, 6/25/2012. Dr. Petrov receives training support from AHRQ (5 T32 HS013852-09) and NCMHD (3 P60 MD000502-08S1). Dr. Lewis receives funding from Novo Nordisk. Dr. Glasser receives salary support from AMGON. The other authors have indicated no financial conflicts of interest. CARDIA is supported by US Public Health Service contracts NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050, and NO1-HC-95095 from the National Heart, Lung, and Blood Institute, and grant AG 11412 from the National Institute on Aging. Yongin Kim had full access to the data and is responsible for the data analyses presented. NR 46 TC 13 Z9 13 U1 0 U2 4 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD NOV 1 PY 2013 VL 36 IS 11 BP 1587 EP 1595 DI 10.5665/sleep.3104 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 246KW UT WOS:000326537800002 PM 24179290 ER PT J AU Endeshaw, Y Rice, TB Schwartz, AV Stone, KL Manini, TM Satterfield, S Cummings, S Harris, T Pahor, M AF Endeshaw, Yohannes Rice, Thomas B. Schwartz, Ann V. Stone, Katie L. Manini, Todd M. Satterfield, Suzanne Cummings, Steven Harris, Tamara Pahor, Marco CA Hlth ABC Study TI Snoring, Daytime Sleepiness, and Incident Cardiovascular Disease in The Health, Aging, and Body Composition Study SO SLEEP LA English DT Article DE Snoring; daytime sleepiness; cardiovascular disease ID CORONARY-HEART-DISEASE; 6-YEAR FOLLOW-UP; OLDER-ADULTS; RISK-FACTORS; APNEA; POPULATION; MORTALITY; HYPERTENSION; WOMEN; AGE AB Objectives: To examine the association between snoring and incident cardiovascular disease (CVD). Design, Settings, and Participants: This is a prospective study in which community dwelling older adults were evaluated at baseline, and followed up for an average of 9.9 years. Measurements: Data on snoring, daytime sleepiness, as well as demographic and clinical characteristics of study participants was collected at baseline, and participants were followed up every six months for an average of 9.9 years. Based on snoring and sleepiness status, 4 groups of participants were created: (1) No Snoring, No Sleepiness; (2) No Snoring, Sleepiness; (3) Snoring, No Sleepiness; (4) Snoring, Sleepiness. Incident CVD was defined as a diagnosis of myocardial infarction, angina pectoris, or congestive heart failure that resulted in overnight hospitalization during the follow-up period. Cox proportional hazard was used to estimate the risk of incident cardiovascular disease during follow-up by baseline snoring and sleepiness status. Results: A total of 2,320 participants with a mean age of 73.6 (2.9) years at baseline were included in the analysis. Fifty-two percent were women, and 58% were white. A total of 543 participants developed CVD events during the follow-up period. Participants who reported snoring associated with daytime sleepiness had significantly increased hazard ratio for CVD events (HR = 1.46 [1.03-2.08], P = 0.035) after adjusting for demographic and clinical confounding factors. Conclusion: The results suggest that self-reported snoring and daytime sleepiness status are associated with an increased risk of future cardiovascular disease among older adults. C1 [Endeshaw, Yohannes] Morehouse Sch Med, Dept Med, Atlanta, GA 30310 USA. [Rice, Thomas B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Stone, Katie L.; Cummings, Steven] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Manini, Todd M.; Pahor, Marco] Univ Florida, Coll Med, Dept Aging & Geriatr Res, Gainesville, FL USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Endeshaw, Y (reprint author), Morehouse Sch Med, Dept Med, Div Geriatr, 720 Westview Dr SW, Atlanta, GA 30310 USA. EM yendeshaw@msm.edu FU National Institute of Health (NIH), National Institute on Aging (NIA); NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR, Claude D. Pepper Older Americans Independence Center [R01-NR012459, P30 AG028740] FX This research was supported in part by the Intramural Research Program of the National Institute of Health (NIH), National Institute on Aging (NIA), by NIA contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, NINR grant R01-NR012459 and P30 AG028740 Claude D. Pepper Older Americans Independence Center. NR 50 TC 12 Z9 12 U1 0 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD NOV 1 PY 2013 VL 36 IS 11 BP 1737 EP 1745 DI 10.5665/sleep.3140 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 246KW UT WOS:000326537800020 PM 24179308 ER PT J AU Feng, Y Forsell, MNE Flynn, B Adams, W Lore, K Seder, R Wyatt, RT Hedestam, GBK AF Feng, Yu Forsell, Mattias N. E. Flynn, Barbara Adams, William Lore, Karin Seder, Robert Wyatt, Richard T. Hedestam, Gunilla B. Karlsson TI Chemical cross-linking of HIV-1 Env for direct TLR7/8 ligand conjugation compromises recognition of conserved antigenic determinants SO VIROLOGY LA English DT Article DE HIV-1 envelope glycoprotein; Cross-linker; Toll-like receptor ligand; Neutralizing antibody ID T-CELL RESPONSES; TOLL-LIKE RECEPTORS; PLASMACYTOID DENDRITIC CELLS; NAIVE B-CELLS; INNATE IMMUNITY; ANTIBODY-RESPONSES; NONHUMAN-PRIMATES; INFLUENZA VACCINE; HUMORAL IMMUNITY; ADJUVANTS AB Covalent conjugation of immune-stimulatory compounds to protein antigens is a potential means to self-adjuvant non-replicating subunit vaccines. Previously, it was demonstrated that covalent coupling of a Toll-like receptor (TLR) ligand to the exterior HIV-1 envelope glycoprotein, gp120, enhanced its immunogenicity. However, the consequences of chemical conjugation to gp120 on broadly neutralizing antibody (bNAb) epitopes were so far not examined. Here, we conjugated a TLR7/8 ligand to lysine residues on gp120 using NHS-PEO8-maleimide linkers and investigated if this affected Ab recognition of the CD4 binding site (CD4bs), a highly conserved target for bNAbs. We demonstrate that the recognition of the CD4bs was reduced following coupling, especially at a higher coupling ratio. These results have implications for the coupling of ligands to vaccine antigens where elicitation of humoral immune responses to specific neutralizing determinants is desired. (C) 2013 Elsevier Inc. All rights reserved. C1 [Feng, Yu; Forsell, Mattias N. E.; Flynn, Barbara; Seder, Robert; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Feng, Yu; Wyatt, Richard T.] Scripps Res Inst, IAVI Ctr Neutralizing Antibodies, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Adams, William; Lore, Karin] Karolinska Inst, Ctr Infect Med, SE-17177 Stockholm, Sweden. [Forsell, Mattias N. E.; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17177 Stockholm, Sweden. [Wyatt, Richard T.] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. RP Wyatt, RT (reprint author), Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. EM wyatt@scripps.edu; Gunilla.Karlsson.Hedestam@ki.se RI Feng, Yu/A-3396-2012 FU International AIDS Vaccine Initiative; Swedish International Development Agency/Department of Research Cooperation; Swedish Research Council; Vaccine Research Center; National Institutes of Health; Karolinska Institutet; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [108213-51-RKVA] FX We thank Christina Corbaci for assistance with the figures. This study was supported by grants from the International AIDS Vaccine Initiative (GKH and RW), the Swedish International Development Agency/Department of Research Cooperation (GKH), the Swedish Research Council (GKH), the intramural research program of the Vaccine Research Center, the National Institutes of Health (RW) and by Karolinska Institutet (GKH). MNEF is supported by amfAR Mathilde Krim Fellowship in Basic Biomedical Research # 108213-51-RKVA. NR 41 TC 4 Z9 4 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 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2013 VL 446 IS 1-2 BP 56 EP 65 DI 10.1016/j.virol.2013.07.028 PG 10 WC Virology SC Virology GA 236ZX UT WOS:000325839100007 PM 24074567 ER PT J AU Alexandre, KB Moore, PL Nonyane, M Gray, ES Ranchobe, N Chakauya, E McMahon, JB O'Keefe, BR Chikwamba, R Morris, L AF Alexandre, Kabamba B. Moore, Penny L. Nonyane, Molati Gray, Elin S. Ranchobe, Nthabeleng Chakauya, Ereck McMahon, James B. O'Keefe, Barry R. Chikwamba, Rachel Morris, Lynn TI Mechanisms of HIV-1 subtype C resistance to GRFT, CV-N and SVN SO VIROLOGY LA English DT Article DE Griffithsin; Cyanovirin-N; Scytovirin; HIV subtype C; Resistance; Entry inhibitor; Glycans; Single genome amplification; Microbicide ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN GP120; ENTRY INHIBITOR GRIFFITHSIN; CYANOVIRIN-N; ANTIBODY NEUTRALIZATION; CARBOHYDRATE-BINDING; LINKED GLYCOSYLATION; INACTIVATING PROTEIN; TYPE-1 STRAINS; PLANT-LECTINS AB We examined the ability of HIV-1 subtype C to develop resistance to the inhibitory lectins, griffithsin (GRFT), cyanovirin-N (CV-N) and scytovirin (SVN), which bind multiple mannose-rich glycans on gp120. Four primary HIV-1 strains cultured under escalating concentrations of these lectins became increasingly resistant tolerating 2 to 12 times their 50% inhibitory concentrations. Sequence analysis of gp120 showed that most had deletions of 1 to 5 mannose-rich glycans. Glycosylation sites at positions 230, 234, 241, 289 located in the C2 region and 339,392 and 448 in the C3-C4 region were affected. Furthermore, deletions and insertions of up to 5 amino acids in the V4 region were observed in 3 of the 4 isolates. These data suggest that loss of glycosylation sites on gp120 as well as rearrangement of glycans in V4 are mechanisms involved in HIV-1 subtype C escape from GRFT, CV-N and SVN. (C) 2013 Elsevier Inc. All rights reserved. C1 [Alexandre, Kabamba B.; Moore, Penny L.; Nonyane, Molati; Gray, Elin S.; Ranchobe, Nthabeleng; Morris, Lynn] Natl Inst Communicable Dis, Ctr HIV & STIs, ZA-2131 Johannesburg, South Africa. [Alexandre, Kabamba B.; Moore, Penny L.; Morris, Lynn] Univ Witwatersrand, Johannesburg, South Africa. [Chakauya, Ereck; Chikwamba, Rachel] CSIR, ZA-0001 Pretoria, South Africa. [McMahon, James B.; O'Keefe, Barry R.] NCI Frederick, Mol Targets Lab, Ctr Canc Res, Frederick, MD USA. RP Morris, L (reprint author), Natl Inst Communicable Dis, Ctr HIV & STIs, Private Bag X4, ZA-2131 Johannesburg, South Africa. EM lynnm@nicd.ac.za OI Moore, Penny/0000-0001-8719-4028; Gray, Elin/0000-0002-8613-3570 FU BioFISA program of NEPAD Agency/SANBio; Poliomyelitis Research Foundation; South African AIDS Vaccine Initiative (SAAVI); Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP); Fogarty International Center, NIH; NIH, National Cancer Institute, Center for Cancer Research; Wellcome Trust [089933/Z/09/Z] FX This work was funded by the BioFISA program of NEPAD Agency/SANBio under the microbicide project, the Poliomyelitis Research Foundation, the South African AIDS Vaccine Initiative (SAAVI) and a training fellowship to KBA from Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH. This research was also supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (B. O. & J. M.). Penny Moore is supported by the Wellcome Trust (Grant 089933/Z/09/Z). NR 54 TC 10 Z9 10 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 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2013 VL 446 IS 1-2 BP 66 EP 76 DI 10.1016/j.virol.2013.07.019 PG 11 WC Virology SC Virology GA 236ZX UT WOS:000325839100008 PM 24074568 ER PT J AU Lakdawala, SS Shih, AR Jayaraman, A Lamirande, EW Moore, I Paskel, M Sasisekharan, R Subbarao, K AF Lakdawala, Seema S. Shih, Angela R. Jayaraman, Akila Lamirande, Elaine W. Moore, Ian Paskel, Myeisha Sasisekharan, Ram Subbarao, Kanta TI Receptor specificity does not affect replication or virulence of the 2009 pandemic H1N1 influenza virus in mice and ferrets SO VIROLOGY LA English DT Article DE Influenza virus; Tissue tropism; Virulence; Receptor specificity; Replication ID BINDING PROPERTIES; RESPIRATORY-TRACT; CROSS-PROTECTION; CELL TROPISM; HUMAN AIRWAY; A VIRUSES; IN-VIVO; HEMAGGLUTININ; TRANSMISSION; ORIGIN AB Human influenza viruses predominantly bind alpha 2,6 linked sialic acid (SA) while avian viruses bind alpha 2,3 SA-containing complex glycans. Virulence and tissue tropism of influenza viruses have been ascribed to this binding preference. We generated 2009 pandemic H1N1 (pH1N1) viruses with either predominant alpha 2,3 or alpha 2,6 SA binding and evaluated these viruses in mice and ferrets. The alpha 2,3 pH1N1 virus had similar virulence in mice and replicated to similar titers in the respiratory tract of mice and ferrets as the alpha 2,6 and WT pH1N1 viruses. Immunohistochemical analysis determined that all viruses infected similar cell types in ferret lungs. There is increasing evidence that receptor specificity of influenza viruses is more complex than the binary model of alpha 2,6 and alpha 2,3 SA binding and our data suggest that influenza viruses use a wide range of SA moieties to infect host cells. Published by Elsevier Inc. C1 [Lakdawala, Seema S.; Shih, Angela R.; Lamirande, Elaine W.; Moore, Ian; Paskel, Myeisha; Subbarao, Kanta] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Infect Dis Lab, Bethesda, MD 20892 USA. [Jayaraman, Akila; Sasisekharan, Ram] MIT, Singapore MIT Alliance Res & Technol, Koch Inst Integrat Canc Res, Dept Biol Engn, Cambridge, MA USA. RP Sasisekharan, R (reprint author), MIT, Singapore MIT Alliance Res & Technol, Koch Inst Integrat Canc Res, Dept Biol Engn, Cambridge, MA USA. EM rams@MIT.edu; ksubbarao@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); National Institutes of Health [R37 GM057073-13]; Singapore-MIT Alliance for Research and Technology (SMART) FX We thank the Comparative Medical Branch of NIAID for technical assistance during the animal studies and members of the Subbarao lab for critical review of the manuscript. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and was funded in part by the National Institutes of Health (R37 GM057073-13 to RS) and in part by Singapore-MIT Alliance for Research and Technology (SMART to RS). The viruses generated in this manuscript could potentially alter the host range of the 2009 pandemic H1N1 influenza virus; therefore, our manuscript was reviewed by the NIH's Intramural Research Program's Committee on Dual Use Research of Concern (DURC). The committee concluded that the methods and results reported in our manuscript do not meet DURC criteria. NR 51 TC 9 Z9 10 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 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2013 VL 446 IS 1-2 BP 349 EP 356 DI 10.1016/j.virol.2013.08.011 PG 8 WC Virology SC Virology GA 236ZX UT WOS:000325839100039 PM 24074599 ER PT J AU Yu, L Takeda, K Markoff, L AF Yu, Li Takeda, Kazuyo Markoff, Lewis TI Protein-protein interactions among West Nile non-structural proteins and transmembrane complex formation in mammalian cells SO VIROLOGY LA English DT Article DE NS protein interactions; Transmembrane complex; Flavivirus replication complex ID DEPENDENT RNA-POLYMERASE; DENGUE-VIRUS TYPE-2; HEPATITIS-C VIRUS; FLAVIVIRUS KUNJIN; FLUORESCENCE COMPLEMENTATION; ENDOPLASMIC-RETICULUM; REPLICATION COMPLEX; SECONDARY STRUCTURE; LIVING CELLS; POLYCLONAL ANTISERA AB To study the membrane orientation of flavivirus non-structural proteins (NSPs) in the replication complex, the seven major West Nile (WN) NSPs were separately expressed in monkey cells, and their subcellular localization was investigated by imaging-based techniques. First, we observed by confocal microscopy that four small transmembrane proteins (TP) (NS2A, NS2B, NS4A, and NS4B) were located to the endoplasmic reticulum (ER), whereas the largest NSPs, NS1, NS3, and NS5 were not. We then analyzed the colocalization and the association of WN NSPs using the methods of confocal microscopy, fluorescence resonance energy transfer (FRET), and biologic fluorescence complementation (BiFC). Through these combined imaging techniques, protein-protein interactions (PPI) among WNNSPs were detected. Our data demonstrate that there are interactions between NS2A and NS4A, and interactions of NS2B with three other TPs (NS2A, NS4A, and NS4B) as well as the expected interaction with NS3. PPI between NS2A and NS4B or between NS4A and NS4B were not detected. By the criteria of these techniques, NS5 interacted only with NS3, and NS1 was not shown to be in close proximity with other NSPs. In addition, homo-oligomerization of some NSPs was observed and three-way interactions between NS2A, NS4A, and NA4B with NS2B-NS3 were also observed, respectively. Our results suggest that the four TPs are required for formation of transmembrane complex. NS2B protein seems to play a key role in bringing the TPs together on the ER membrane and in bridging the TPs with non-membrane-associated proteins (NS3 and NS5). Published by Elsevier Inc. C1 [Yu, Li; Markoff, Lewis] FDA, CBER, Microscopy & Imaging Core Facil, Off Vaccines Res & Review,Div Viral Prod,Lab Vect, Bethesda, MD USA. [Takeda, Kazuyo] FDA, CBER, Microscopy & Imaging Core Facil, Bethesda, MD USA. RP Yu, L (reprint author), Bg 29A,Room 1B18,NIH Campus,8800 Rockville Pike, Bethesda, MD 20892 USA. EM li.yu@fda.hhs.gov NR 78 TC 17 Z9 17 U1 3 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2013 VL 446 IS 1-2 BP 365 EP 377 DI 10.1016/j.virol.2013.08.006 PG 13 WC Virology SC Virology GA 236ZX UT WOS:000325839100041 PM 24074601 ER PT J AU Makrogiannis, S Caturegli, G Davatzikos, C Ferrucci, L AF Makrogiannis, Sokratis Caturegli, Giorgio Davatzikos, Christos Ferrucci, Luigi TI Computer-aided Assessment of Regional Abdominal Fat with Food Residue Removal in CT SO ACADEMIC RADIOLOGY LA English DT Article DE Body composition assessment; false positive reduction ID ADIPOSITY; QUANTIFICATION; REGISTRATION; ASSOCIATION; TOMOGRAPHY; NETWORKS; WAVELETS; IMAGES; HEALTH AB Rationale and Objectives: Separate quantification of abdominal subcutaneous and visceral fat regions is essential to understand the role of regional adiposity as risk factor in epidemiological studies. Fat quantification is often based on computed tomography (CT) because fat density is distinct from other tissue densities in the abdomen. However, the presence of intestinal food residues with densities similar to fat may reduce fat quantification accuracy. We introduce an abdominal fat quantification method in CT with interest in food residue removal. Materials and Methods: Total fat was identified in the feature space of Hounsfield units and divided into subcutaneous and visceral components using model-based segmentation. Regions of food residues were identified and removed from visceral fat using a machine learning method integrating intensity, texture, and spatial information. Cost-weighting and bagging techniques were investigated to address class imbalance. Results: We validated our automated food residue removal technique against semimanual quantifications. Our feature selection experiments indicated that joint intensity and texture features produce the highest classification accuracy at 95%. We explored generalization capability using k-fold cross-validation and receiver operating characteristic (ROC) analysis with variable k. Losses in accuracy and area under ROC curve between maximum and minimum k were limited to 0.1% and 0.3%. We validated tissue segmentation against reference semimanual delineations. The Dice similarity scores were as high as 93.1 for subcutaneous fat and 85.6 for visceral fat. Conclusions: Computer-aided regional abdominal fat quantification is a reliable computational tool for large-scale epidemiological studies. Our proposed intestinal food residue reduction scheme is an original contribution of this work. Validation experiments indicate very good accuracy and generalization capability. C1 [Makrogiannis, Sokratis; Caturegli, Giorgio; Ferrucci, Luigi] Natl Inst Hlth, Natl Inst Aging, Longitudinal Studies Sect, Baltimore, MD 21225 USA. [Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Makrogiannis, Sokratis] Delaware State Univ, Dept Math Sci, Dover, DE 19901 USA. RP Makrogiannis, S (reprint author), Natl Inst Hlth, Natl Inst Aging, Longitudinal Studies Sect, 3001 South Hanover St 5th Fl, Baltimore, MD 21225 USA. EM makrogianniss@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We also thank Dr. Ramona Ramachandran for producing reference masks of visceral fat and food residue regions. NR 30 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2013 VL 20 IS 11 BP 1413 EP 1421 DI 10.1016/j.acra.2013.08.007 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241AW UT WOS:000326139800012 PM 24119354 ER PT J AU Chuang, ML Leslie, RW Massaro, JM Manders, ES Fox, CS Hoffmann, U O'Donnell, CJ AF Chuang, Michael L. Leslie, Richard W. Massaro, Joseph M. Manders, Emily S. Fox, Caroline S. Hoffmann, Udo O'Donnell, Christopher J. TI Distribution of Abdominal Aortic Calcium by Computed Tomography: Impact of Analysis Method on Quantitative Calcium Score SO ACADEMIC RADIOLOGY LA English DT Article DE Abdominal aorta; calcium; population study; segment length; computed tomography ID CORONARY-ARTERY CALCIUM; HEART; ATHEROSCLEROSIS; CALCIFICATION; PREDICTOR; QUANTIFICATION; MORTALITY; COHORT; CT AB Rationale and Objectives: Abdominal aortic calcification (MC) can be quantified using computed tomography (CT), but imaging planes are prescribed based on bony landmarks, so that individual variation between the landmark and the aortoiliac junction can result in variable aortic coverage. In the Framingham CT substudy, we scanned a 15-cm (Z-direction) abdominal segment cranial to the Si vertebral body. We sought to determine the range and distribution of length of aorta scanned and the distribution of AAC within the abdominal aorta and to compare burden of AAC measured from fixed-length segments versus MC from all slices cranial to the aortoiliac bifurcation. Materials and Methods: MC was quantified by modified Agatston score (AS) in 100 Framingham Heart Study participants (60 13 years old, 51 men). We compared the AS measured from 5-cm and 8-cm segments with the AS(ALL) (total visualized aorta). Results: Of 100, 73 participants had MC >0. The total length of aorta imaged was >= 8 cm in 84% of participants. Qualitatively, 5-cm and 8-cm segments correctly identified 96% and 99%, respectively, of participants as having or not having MC. Quantitatively, AS(8cm) was within 20% of AS(ALL) in four-fifths and within 30% of AS(ALL) in nine-tenths of participant. AS(5cm) more severely underestimated AS(ALL). Conclusion: The use of 51 as the caudal imaging landmark in a 15-cm slab yields >= 8 cm aortic coverage in most adults. Both 5-cm and 8-cm analysis strategies are comparable to analyzing the total visualized abdominal aorta for prevalent MC, but only 8-cm segment analysis yields quantitatively similar measures of AAC. C1 [Chuang, Michael L.; Leslie, Richard W.; Massaro, Joseph M.; Manders, Emily S.; Fox, Caroline S.; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA 01702 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET & CT Program, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.; Hoffmann, Udo; O'Donnell, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP O'Donnell, CJ (reprint author), Natl Heart Lung & Blood Inst, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study [N01-HC-25195, N01-HC-38038]; NHLBI Division of Intramural Research FX From the National Heart, Lung, and Blood Institute, The Framingham Heart Study, 73 Mt Wayte Avenue, Suite No. 2, Framingham, MA 01702-5827 (M.L.C, R.W.L, J.M.M., E.S.M., C.S.F., C.J.O.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (J.M.M.); Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA (C.S.F.); Cardiac MR, PET and CT Program, Department of Radiology, Massachusetts General Hospital, Boston, MA (U.N.); Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA (C.J.O.); Harvard Medical School, Boston, MA (C.S.F., U.H., C.J.O.). Received April 2, 2013; accepted August 14, 2013. Source of funding: This project was supported by the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (contract Nos. N01-HC-25195 and N01-HC-38038). Dr O'Donnell is supported by the NHLBI Division of Intramural Research. There are no conflicts of interest. Address correspondence to: C.J.O. e-mail: odonnellc@nhlbi.nih.gov NR 17 TC 0 Z9 0 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 EI 1878-4046 J9 ACAD RADIOL JI Acad. Radiol. PD NOV PY 2013 VL 20 IS 11 BP 1422 EP 1428 DI 10.1016/j.acra.2013.08.008 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241AW UT WOS:000326139800013 PM 24119355 ER PT J AU Parham, DM Barr, FG AF Parham, David M. Barr, Frederic G. TI Classification of Rhabdomyosarcoma and Its Molecular Basis SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE rhabdomyosarcoma; classification systems; prognosis; genetic testing ID CHILDRENS ONCOLOGY GROUP; SPINDLE-CELL RHABDOMYOSARCOMA; TISSUE SARCOMA COMMITTEE; TUMOR ALVEOLAR RHABDOMYOSARCOMA; BECKWITH-WIEDEMANN-SYNDROME; POLYMERASE-CHAIN-REACTION; INTERGROUP RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; CHILDHOOD RHABDOMYOSARCOMA; FUSION STATUS AB Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, has traditionally been classified into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) for pediatric oncology practice. This review outlines the historical development of classification of childhood RMS and the challenges that have been associated with it, particularly problems with the diagnosis of solid variant ARMS and its distinction from ERMS. In addition to differences in clinical presentation and outcome, a number of genetic features underpin separation of ERMS from ARMS. Genetic differences associated with RMS subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS. Chimeric proteins encoded in most ARMS from the fusion of PAX3 or PAX7 with FOXO1 are expressed, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype. A sizeable minority of ARMS lacks these fusions and shares the clinical and biological features of ERMS. A battery of immunohistochemical tests may prove useful in separating ERMS from ARMS and fusion-positive ARMS from fusion-negative ARMS. Because of limitation of predicting outcome solely based on histologic classification, treatment protocols will begin to utilize fusion testing for stratification of affected patients into low-risk, intermediate-risk, and high-risk groups. C1 [Parham, David M.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Barr, Frederic G.] NCI, Lab Pathol, Bethesda, MD 20892 USA. RP Parham, DM (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, 940 Stanton L Young Blvd,BMSB451, Oklahoma City, OK 73104 USA. EM david-parham@ouhsc.edu FU Intramural Program of the National Cancer Institute; Children's Oncology Group, derived from National Cancer Institute [U10 CA98543] FX F.G.B. was supported by Intramural Program of the National Cancer Institute.; D.M.P. receives salary support from the Children's Oncology Group, derived from National Cancer Institute grant U10 CA98543. The other author has no conflicts of interest to disclose. NR 97 TC 36 Z9 39 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 EI 1533-4031 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD NOV PY 2013 VL 20 IS 6 BP 387 EP 397 DI 10.1097/PAP.0b013e3182a92d0d PG 11 WC Pathology SC Pathology GA 242WL UT WOS:000326275400003 PM 24113309 ER PT J AU Hartwell, TD Pequegnat, W Moore, JL Parker, CB Strader, LC Green, AM Quinn, TC Wasserheit, JN Klausner, JD AF Hartwell, Tyler D. Pequegnat, Willo Moore, Janet L. Parker, Corette B. Strader, Lisa C. Green, Annette M. Quinn, Thomas C. Wasserheit, Judith N. Klausner, Jeffrey D. CA NIMH Collaborative HIV STD Prevent TI The Utility of a Composite Biological Endpoint in HIV/STI Prevention Trials SO AIDS AND BEHAVIOR LA English DT Article DE Sexual behavior; Sexually transmitted diseases; HIV/STI prevention; Simulation of biological outcomes AB A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention. C1 [Hartwell, Tyler D.; Moore, Janet L.; Parker, Corette B.; Strader, Lisa C.; Green, Annette M.] Res Triangle Inst, Res Triangle Pk, NC 27709 USA. [Pequegnat, Willo] NIMH, Bethesda, MD 20892 USA. [Quinn, Thomas C.] Johns Hopkins Univ, Baltimore, MD USA. [Wasserheit, Judith N.] Univ Washington, Seattle, WA 98195 USA. [Klausner, Jeffrey D.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Pequegnat, W (reprint author), NIMH, 6001 Execut Blvd,Room 6111, Bethesda, MD 20892 USA. EM wpequegn@mail.nih.gov FU Intramural NIH HHS [ZIA AI000361-30]; NIMH NIH HHS [U10 MH061536] NR 14 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2013 VL 17 IS 9 BP 2893 EP 2901 DI 10.1007/s10461-013-0501-5 PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 240QW UT WOS:000326113100005 PM 23748863 ER PT J AU Hersch, RK Cook, RF Billings, DW Kaplan, S Murray, D Safren, S Goforth, J Spencer, J AF Hersch, Rebekah K. Cook, Royer F. Billings, Douglas W. Kaplan, Seth Murray, David Safren, Steven Goforth, Justin Spencer, Joy TI Test of a Web-Based Program to Improve Adherence to HIV Medications SO AIDS AND BEHAVIOR LA English DT Article DE Medication adherence; Web-based program; ART; Antiretroviral therapy ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; INJECTION-DRUG-USERS; DEPRESSION CBT-AD; SOCIETY-USA PANEL; ANTIRETROVIRAL MEDICATIONS; PROTEASE INHIBITORS; INCREASE ADHERENCE; HEALTH-PROMOTION; INTERVENTION AB We evaluated the effectiveness of a web-based version of the Life-Steps intervention combined with modules for stress reduction and mood management, designed to improve medication adherence among HIV infected individuals. 168 HIV+ adults were randomized into either the Life-Steps program or a waitlist control condition. All participants completed a baseline assessment and provided a 2-week electronic pill (MEMS) cap baseline reading. Follow up data collection was conducted at 3, 6 and 9 months. Patients in the web-based Life-Steps condition had significantly higher antiretroviral medication adherence rates than patients in the control group over the nine-month period as measured by the MEMS cap. In addition, analysis of viral load data indicated that the program also resulted in a significant decrease in viral load. These findings indicate that a web-based Life-Steps program can be a useful and implementable tool for helping patients living with HIV maintain medication adherence. C1 [Hersch, Rebekah K.; Cook, Royer F.; Billings, Douglas W.; Spencer, Joy] ISA Associates Inc, Alexandria, VA 22304 USA. [Kaplan, Seth] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Murray, David] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD USA. [Safren, Steven] Harvard Univ, Sch Med, Massachusettes Gen Hosp, Boston, MA USA. [Goforth, Justin] Whitman Walker Hlth, Washington, DC USA. RP Hersch, RK (reprint author), ISA Associates Inc, 201 North Union St,Suite 330, Alexandria, VA 22304 USA. EM rhersch@isagroup.com FU NIDA NIH HHS [5RC1DA028505, RC1 DA028505] NR 41 TC 9 Z9 9 U1 3 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2013 VL 17 IS 9 BP 2963 EP 2976 DI 10.1007/s10461-013-0535-8 PG 14 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 240QW UT WOS:000326113100012 PM 23760634 ER PT J AU Pecoraro, A Royer-Malvestuto, C Rosenwasser, B Moore, K Howell, A Ma, M Woody, GE AF Pecoraro, Anna Royer-Malvestuto, Charlotte Rosenwasser, Beth Moore, Kevin Howell, Allen Ma, Michelle Woody, George E. TI Factors contributing to dropping out from and returning to HIV treatment in an inner city primary care HIV clinic in the United States SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; AIDS; attrition; retention; engagement; substance abuse ID ANTIRETROVIRAL THERAPY; SUBSTANCE-ABUSE; INFECTION; RETENTION; PROGRAMS; BARRIERS; PATIENT AB Although advances in pharmacotherapy have enabled people living with HIV/AIDS to live longer, fuller lives, some leave medical care, resulting in sub-optimal treatment and increased health risk to themselves and others. Forty-one patients who dropped out of an urban, publically funded primary care HIV clinic were contacted and encouraged by outreach staff to return. Participants were interviewed within two weeks of returning, and themes associated with dropping out and returning were elicited and content analyzed. Dropping out was associated with drug/alcohol use, unstable housing/homelessness, psychiatric disorders, incarceration, problems with HIV medications, inability to accept the diagnosis, relocation, stigma, problems with the clinic, and forgetfulness. Returning was associated with health concerns, substance abuse treatment/recovery, stable housing, incarceration/release, positive feelings about the clinic, spirituality, and assistance from family/relocation. Because a large number of patients reported substance abuse, depression, and past suicide attempts. Clinic staff should assess substance use, depression, and suicidal ideation at each primary care visit and encourage patients to obtain substance abuse treatment and mental health care. Future interventions could include providing SBIRT and/or onsite mental health and substance abuse treatment, all of which may boost retention. C1 [Pecoraro, Anna; Royer-Malvestuto, Charlotte; Woody, George E.] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Pecoraro, Anna; Royer-Malvestuto, Charlotte; Woody, George E.] NIDA Clin Trials Network, Delaware Valley Node, Philadelphia, PA USA. [Rosenwasser, Beth; Moore, Kevin; Howell, Allen] Philadelphia FIGHT, Philadelphia, PA USA. [Rosenwasser, Beth] Temple Univ, Dept Educ, Philadelphia, PA 19122 USA. [Moore, Kevin] AIDS Care Grp, Philadelphia, PA USA. [Ma, Michelle] Univ Michigan, Sch Med, Philadelphia, PA USA. [Woody, George E.] Treatment Res Inst, Philadelphia, PA USA. RP Pecoraro, A (reprint author), Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. EM annp@mail.med.upenn.edu FU NIDA NIH HHS [KO5 DA-17009, P60 DA005186, U10 DA-13043] NR 17 TC 21 Z9 21 U1 1 U2 21 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 EI 1360-0451 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD NOV 1 PY 2013 VL 25 IS 11 BP 1399 EP 1406 DI 10.1080/09540121.2013.772273 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 244EW UT WOS:000326370900009 PM 23428205 ER PT J AU Marshall, L Cummins, J Spiegel, H Turpin, J Veronese, F Kashuba, A AF Marshall, Leslie Cummins, James Spiegel, Hans Turpin, James Veronese, Fulvia Kashuba, Angela CA HIV Prevention Pharmacology Best P TI Critical Need for Appropriate Mucosal Sample Collection to Determine Relational Animal Pharmacokinetic-Pharmacodynamic Models in HIV Prevention SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Letter ID HUMANIZED BLT MICE; TRANSMISSION; GENERATION; STRATEGIES; INFECTION C1 [Marshall, Leslie; Cummins, James; Turpin, James; Veronese, Fulvia] NIAID, Preclin Microbicide & Prevent Res Branch, Prevent Sci Program, DAIDS,NIH, Bethesda, MD 20892 USA. [Spiegel, Hans] HJF DAIDS, Bethesda, MD USA. [Kashuba, Angela] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. [Kashuba, Angela] Univ N Carolina, UNC Ctr AIDS Res, Chapel Hill, NC USA. RP Marshall, L (reprint author), NIAID, Preclin Microbicide & Prevent Res Branch, Prevent Sci Program, DAIDS,NIH, 6700B Rockledge Dr,Room 5224, Bethesda, MD 20892 USA. EM marshalllj@niaid.nih.gov NR 12 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP 1398 EP 1400 DI 10.1089/aid.2013.1501 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500499 PM 23909474 ER PT J AU Shapiro, SZ AF Shapiro, Stuart Z. TI HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMANIZED BLT MICE; TRANSMISSION; GENERATION; INFECTION AB This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's "Animal Rule" pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine. C1 NIAID, Vaccine Res Program, Div Aids, Bethesda, MD 20892 USA. RP Shapiro, SZ (reprint author), NIAID, Vaccine Res Program, Div Aids, 6700-B Rockledge Dr,Room 5146, Bethesda, MD 20892 USA. EM sshapiro@niaid.nih.gov NR 12 TC 1 Z9 1 U1 1 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP 1401 EP 1406 DI 10.1089/aid.2013.0142 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500500 PM 23379343 ER PT J AU Malaspina, A Collins, BS Dell, A Alter, G Onami, TM AF Malaspina, Angela Collins, Brenda S. Dell, Anne Alter, Galit Onami, Thandi M. TI Conference Report: "Functional Glycomics in HIV Type 1 Vaccine Design" Workshop Report, Bethesda, Maryland, April 30-May 1, 2012 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID RHESUS MACAQUES; VIRUS; PROTECTION; INFECTION; ANTIBODIES; SIVMAC251; RESPONSES; NEUTRALIZATION; INOCULATION; SIVSME660 AB A vital part of the renewed hope for a vaccine against the human immunodeficiency virus (HIV-1) is based on recent studies that have highlighted major sites of HIV-1 vulnerability that could be effectively targeted by a preventive vaccine. One of these potential vulnerabilities includes the dense cluster of carbohydrates surrounding HIV-1's envelope glycoproteins gp120 and gp41, typically referred to as the "glycan shield." Recent data from several laboratories have shown that glycans on the HIV-1 envelope form key epitopes for broadly neutralizing antibodies (bNAb). Moreover, HIV-1 envelope glycans play an important role in viral transmission, antigenicity, and immunogenicity. The recent availability of novel tools and technologies has now allowed investigators to leverage glycomic structure-function relationships in the design of candidate HIV-1 vaccines. Additionally, glycans modulate the immune response, playing an essential role in Fc receptor and complement activity. To promote cross-disciplinary collaboration and promote synergistic HIV-1- glycomics research, the National Institutes of Health (NIH) co-sponsored and convened a 1.5-day workshop entitled "Functional Glycomics in HIV-1 Vaccine Design." The meeting focused on the role of glycan interactions with neutralizing antibodies, the influence of immunoglobulin G (IgG) Fc receptor glycosylation, newly available glycomics technologies, and how new information on the role of glycans could be applied in HIV-1 immunogen design strategies. This report summarizes the discussions of this workshop. C1 [Malaspina, Angela] US Natl Inst Allergy & Infect Dis, Preclin Res & Dev Branch, Div Aids, Bethesda, MD USA. [Collins, Brenda S.] HJF DAIDS, Bethesda, MD USA. [Dell, Anne] Univ London Imperial Coll Sci Technol & Med, Div Mol Biosci, London, England. [Alter, Galit] Ragon Inst Massachusetts Gen Hosp,Massachusetts I, Charlestown, MA USA. [Onami, Thandi M.] US Natl Inst Allergy & Infect Dis, Vaccine Clin Res Branch, Div Aids, Bethesda, MD USA. RP Malaspina, A (reprint author), NIAID, DAIDS, VRP Preclin Res & Dev Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM amalaspina@niaid.nih.gov; thandi.onami@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C] FX The authors would like to thank all the speakers for their presentations and all the attendees for their participation in the discussions. This project has been funded in whole or in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272200800014C. NR 23 TC 0 Z9 1 U1 1 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP 1407 EP 1417 DI 10.1089/aid.2013.0102 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500501 PM 23767872 ER PT J AU Romano, J Kashuba, A Becker, S Cummins, J Turpin, J Veronese, F AF Romano, Joseph Kashuba, Angela Becker, Stephen Cummins, James Turpin, Jim Veronese, Fulvia CA Antiretroviral Pharmacology HIV TI Pharmacokinetics and Pharmacodynamics in HIV Prevention; Current Status and Future Directions: A Summary of the DAIDS and BMGF Sponsored Think Tank on Pharmacokinetics (PK)/Pharmacodynamics (PD) in HIV Prevention SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DEPENDENT CELLULAR CYTOTOXICITY; MONOCLONAL-ANTIBODY 2G12; N-LINKED GLYCAN; POTENT NEUTRALIZATION; ANTIGEN PRESENTATION; IMMUNE-RESPONSES; CONFORMATIONAL EPITOPE; BROAD NEUTRALIZATION; ANTIVIRAL ACTIVITY AB Thirty years after its beginning, the HIV/AIDS epidemic is still raging around the world. According to UNAIDS, in 2011 alone 1.7M deaths were attributable to AIDS, and 2.5M people were newly infected by the virus. Despite the success in treating HIV-infected people with potent antiretroviral drugs, preventing HIV infection is the key to ending the epidemic. Recently, the efficacy of topical and systemic antiviral chemoprophylaxis (i.e., pre-exposure prophylaxis or "PrEP"), using the same drugs used for HIV treatment, has been demonstrated in a number of clinical trials. However, results from other trials have been inconsistent, especially those evaluating PrEP in women. These inconsistencies may result from our incomplete understanding of pharmacokinetics (PK)/pharmacodynamics (PD) at the mucosal sites of sexual transmission: the male and female gastrointestinal and reproductive tracts. The drug concentrations used in these trials were derived from those used for treatment; however, we still do not know the relationship between the therapeutic and the preventive dose. This article presents the first comprehensive review of the available data in the HIV pharmacology field from animal models to human studies, and outlines gaps, challenges, and future directions. Addressing these pharmacological gaps and challenges will be critical in selecting and advancing future PrEP candidates and strategies with the greatest impact on the HIV epidemic. C1 [Romano, Joseph] NWJ Grp LLC, Wayne, PA USA. [Kashuba, Angela] Univ N Carolina, Chapel Hill, NC USA. [Becker, Stephen] BMGF, Seattle, WA USA. [Cummins, James; Turpin, Jim; Veronese, Fulvia] NIAID, PSP, DAIDS, NIH, Bethesda, MD 20892 USA. RP Veronese, F (reprint author), NIAID, PSP, DAIDS, NIH, 5th Floor,Room 5122 6700B Rockledge Dr, Bethesda, MD 20892 USA. EM fv10x@nih.gov FU NIAID/DAIDS CRMP [HHSN272201000001C] FX The Think Tank was funded via the NIAID/DAIDS CRMP contract (HHSN272201000001C). J.R. wrote the first draft of the manuscript and A.K. and F.V. coordinated the revised versions. All authors (including S.B., J.C., and J.T.) and Think Tank participants contributed to the final version of the manuscript and approved it. NR 82 TC 18 Z9 18 U1 2 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP 1418 EP 1427 DI 10.1089/aid.2013.0122 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500502 PM 23614610 ER PT J AU Ling, BH Rogers, L Johnson, AM Piatak, M Lifson, J Veazey, RS AF Ling, Binhua Rogers, Linda Johnson, Ann-Marie Piatak, Michael Lifson, Jeffrey Veazey, Ronald S. TI Effect of Combination Antiretroviral Therapy on Chinese Rhesus Macaques of Simian Immunodeficiency Virus Infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID TYPE-1 ENTRY INHIBITORS; HUMAN SERUM-ALBUMIN; HIV ENTRY; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODY; SEXUAL TRANSMISSION; CORE STRUCTURE; GP41; FUSION; MICROBICIDES AB Definitive treatment of HIV infection remains a critical but elusive goal, with persistence of residual virus even in the face of prolonged administration of suppressive combination antiretroviral treatment (cART) providing a source for recrudescent infection if treatment is stopped. Characterization of the residual virus and devising strategies to target it for eradication are key goals in HIV treatment research. Indian rhesus macaques (In-RM) infected with SIVmac have been widely used in such research. However, it has proven challenging to achieve and sustain clinically relevant levels of suppression (< 30 vRNA copies/ml plasma) with cART in such models. As ease of viral suppression by cART is related to pretreatment levels of viral replication, and levels of replication of SIVmac239/251 are lower in Chinese rhesus macaques (Ch-RM) than in In-RM, we evaluated cART administration to SIVmac-infected Ch-RM as a potential model for studies of residual virus and eradication strategies. Four SIVmac239-infected Ch-RM received cART including reverse transcriptase inhibitors PMPA/FTC and integrase inhibitor L-870812 daily for 8 weeks. Plasma viral loads were promptly reduced to < 30 copies/ml upon initiation of cART. Cell-associated SIV DNA levels in lymphocytes from the gut were also significantly reduced. Jejunal and colonic CCR5(+)CD4(+) mucosal memory T cells increased significantly; restoration of these cells was associated with reductions in immune activation. In conclusion, cART effectively suppressed viral replication to < 30 vRNA copies/ml in SIVmac239-infected Ch-RM, reducing immune activation and restoring mucosal immune cell populations. SIVmac239-infected Ch-RM may be a useful model for studying responses to cART and persistent tissue reservoirs and evaluating candidate eradication strategies to cure HIV infection. C1 [Ling, Binhua; Rogers, Linda; Johnson, Ann-Marie; Veazey, Ronald S.] Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Ling, Binhua] Tulane Univ, Sch Med, Dept Microbiol & Immunol, New Orleans, LA 70112 USA. [Piatak, Michael; Lifson, Jeffrey] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Veazey, Ronald S.] Tulane Univ, Sch Med, Dept Pathol, New Orleans, LA 70112 USA. RP Ling, BH (reprint author), Tulane Natl Primate Res Ctr, Div Comparat Pathol, 18703 3 Rivers Rd, Covington, LA 70433 USA. EM bling@tulane.edu FU NIAID [R01 AI093307-01A1]; Tulane Research Enhancement grant; National Center for Research Resources; Office of Research Infrastructure Programs (ORIP) of the National Institutes of Health [OD011104-51]; NCI/ NIH [HHSN261200800001E]; [R01 AI084793] FX We thank C. Lanclos and J. Bruhn of the immunology flow cytometry core laboratory, M. Duplantis and L. Li for tissue sample collection, and L. Doyle-Meyers and the animal care staff of the Department of Veterinary Medicine for their technical assistance. Research was supported by NIAID R01 AI093307-01A1 (BL), R01 AI084793 (RSV), a Tulane Research Enhancement grant (BL), and the National Center for Research Resources, and the Office of Research Infrastructure Programs (ORIP) of the National Institutes of Health through grant OD011104-51 and in part with federal funds from NCI/ NIH contract HHSN261200800001E. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the article. NR 30 TC 6 Z9 6 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP 1465 EP 1474 DI 10.1089/aid.2012.0378 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500508 PM 23387294 ER PT J AU Adamson, B Wakefield, S Flood, D Stoff, D Sopher, C Cook, R Pemberton, N Kublin, J Fuchs, J AF Adamson, B. Wakefield, S. Flood, D. Stoff, D. Sopher, C. Cook, R. Pemberton, N. Kublin, J. Fuchs, J. CA NIAID HIV Vaccine Trials Network TI HVTN Mentored Research Program for Black and Latino/a Medical Students Increases Intent to Pursue a Career in HIV/AIDS Vaccine Research SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Adamson, B.; Wakefield, S.; Flood, D.; Sopher, C.; Cook, R.; Pemberton, N.; Kublin, J.; NIAID HIV Vaccine Trials Network] HIV Vaccine Trials Network, Seattle, WA USA. [Stoff, D.] NIMH, Bethesda, MD 20892 USA. [Fuchs, J.] San Francisco Dept Publ Hlth, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A65 EP A65 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500163 ER PT J AU Bhiman, JN Doria-Rose, N Moore, PL Nonyane, M Karim, SSA Kwong, PD Mascola, JR Morris, L AF Bhiman, J. N. Doria-Rose, N. Moore, P. L. Nonyane, M. Karim, S. S. Abdool Kwong, P. D. Mascola, J. R. Morris, L. TI Interplay Between Broadly Cross-Neutralizing V2 Monoclonal Antibodies and Autologous Viral Evolution SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Bhiman, J. N.; Moore, P. L.; Nonyane, M.; Morris, L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. [Bhiman, J. N.; Moore, P. L.; Morris, L.] Univ Witwatersrand, Johannesburg, South Africa. [Doria-Rose, N.; Kwong, P. D.; Mascola, J. R.] NIAID, NIH, Bethesda, MD 20892 USA. [Karim, S. S. Abdool] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A12 EP A12 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500024 ER PT J AU Bonsignori, M Wiehe, K Lynch, RM Grimm, SK Kozink, DM Hwang, K Eudailey, JA Yang, G Ackerman, ME Kelsoe, G Liao, H Moody, MA Kepler, TB Montefiori, DC Mascola, JR Haynes, BF AF Bonsignori, M. Wiehe, K. Lynch, R. M. Grimm, S. K. Kozink, D. M. Hwang, K. Eudailey, J. A. Yang, G. Ackerman, M. E. Kelsoe, G. Liao, H. Moody, M. A. Kepler, T. B. Montefiori, D. C. Mascola, J. R. Haynes, B. F. TI Isolation and Characterization of an Autoreactive CD4bs Broad Neutralizing Antibody from a Chronic HIV-1 Controller with Systemic Lupus Erythematosus SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Bonsignori, M.; Wiehe, K.; Kozink, D. M.; Hwang, K.; Eudailey, J. A.; Yang, G.; Kelsoe, G.; Liao, H.; Moody, M. A.; Montefiori, D. C.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Lynch, R. M.; Mascola, J. R.] NIH, Bethesda, MD 20892 USA. [Grimm, S. K.; Ackerman, M. E.] Dartmouth Coll, Hanover, NH 03755 USA. [Kepler, T. B.] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A45 EP A46 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500109 ER PT J AU Caskey, M Trumpfheller, C Schlesinger, S Pollak, S Sinnenberg, L Pring, J Hurley, A Shimeliovich, I Sarma, P Yipp, B Mehandru, S Anandasabapathy, N Steinman, R Keler, T Koup, R Bailer, R Tomaras, G Sato, A AF Caskey, M. Trumpfheller, C. Schlesinger, S. Pollak, S. Sinnenberg, L. Pring, J. Hurley, A. Shimeliovich, I. Sarma, P. Yipp, B. Mehandru, S. Anandasabapathy, N. Steinman, R. Keler, T. Koup, R. Bailer, R. Tomaras, G. Sato, A. TI In Vivo Targeting of HIV Gag to Dendritic Cells Given with Poly ICLC Is Safe and Induces Durable CD4 T Cell and B Cell Responses in Healthy Volunteers SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Caskey, M.; Trumpfheller, C.; Schlesinger, S.; Pollak, S.; Sinnenberg, L.; Pring, J.; Hurley, A.; Shimeliovich, I.; Sarma, P.; Yipp, B.; Mehandru, S.; Anandasabapathy, N.; Steinman, R.] Rockefeller Univ, New York, NY 10021 USA. [Keler, T.] Celldex Therapeut, Phillipsburg, NJ USA. [Koup, R.] NIH, Bethesda, MD 20892 USA. [Bailer, R.] NIAID, Vaccine Immune T Cell & Antibody Lab, Bethesda, MD 20892 USA. [Tomaras, G.] Duke Univ, Durham, NC USA. [Sato, A.] Stat Ctr HIV AIDS Res, Seattle, WA USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A65 EP A65 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500162 ER PT J AU Chuang, G Zhang, B Lloyd, K Eudailey, J Blinn, J McKee, K Kwon, Y Mascola, JR Haynes, BF Georgiev, IS Kwong, PD AF Chuang, G. Zhang, B. Lloyd, K. Eudailey, J. Blinn, J. McKee, K. Kwon, Y. Mascola, J. R. Haynes, B. F. Georgiev, I. S. Kwong, P. D. TI Eliminating Autoreactivity of Variants of Antibody VRC07 by Glycan Masking SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Chuang, G.; Zhang, B.; McKee, K.; Kwon, Y.; Mascola, J. R.; Georgiev, I. S.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Lloyd, K.; Eudailey, J.; Blinn, J.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. RI Kwon, Young Do/A-6957-2010 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A55 EP A55 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500135 ER PT J AU Cicala, C AF Cicala, C. TI Inhibition of B Cell Function by HIV-1 Envelope: Role of Binding to Integrin alpha 4 beta 7 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Cicala, C.] NIAID, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A56 EP A56 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500138 ER PT J AU Connors, M Rogan, DC Kelly, EP Toulmin, SA Zimmerman, MG Migueles, SA AF Connors, M. Rogan, D. C. Kelly, E. P. Toulmin, S. A. Zimmerman, M. G. Migueles, S. A. TI Cytotoxic Capacity During a Recall Response Parallels Increases in Lytic Granule Contents of Virus-Specific CD8+T Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Connors, M.; Rogan, D. C.; Kelly, E. P.; Toulmin, S. A.; Zimmerman, M. G.; Migueles, S. A.] NIAID, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A135 EP A135 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500352 ER PT J AU De Rosa, SC Frahm, N Diaz, G Newling, P Morris, D Morgan, C Graham, B Swann, E Maenza, J Duerr, A McElrath, MJ AF De Rosa, S. C. Frahm, N. Diaz, G. Newling, P. Morris, D. Morgan, C. Graham, B. Swann, E. Maenza, J. Duerr, A. McElrath, M. J. TI No Increase in Activated T Cells and Limited Increase in Adenovirus-Specific T Cells in Colon and Rectal Mucosa Following HIV-1 DNA/rAd5 Immunization SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [De Rosa, S. C.; Frahm, N.; Diaz, G.; Newling, P.; Morris, D.; Morgan, C.; Maenza, J.; Duerr, A.; McElrath, M. J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Graham, B.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Swann, E.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A180 EP A181 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500472 ER PT J AU Deschamps, M Morgan, C Zorrilla, C Metch, B Donastorg, Y Joseph, P Swann, E Madenwald, T Escamilla, G Pape, JW AF Deschamps, M. Morgan, C. Zorrilla, C. Metch, B. Donastorg, Y. Joseph, P. Swann, E. Madenwald, T. Escamilla, G. Pape, J. W. CA H Protocol Team TI Feasibility of Enrolling Female Commercial Sex Workers at High Risk of HIV Infection for HIV Vaccine Trials in the Caribbean SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Deschamps, M.; Joseph, P.; Pape, J. W.] GHESKIO, Port Au Prince, Haiti. [Morgan, C.; Metch, B.; Madenwald, T.; Escamilla, G.; H Protocol Team] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Zorrilla, C.] Univ Puerto Rico, Sch Med, Maternal & Infant Studies Ctr CEMI, San Juan, PR 00936 USA. [Donastorg, Y.] Unidad Vacunas IDCP COIN DIGECITSS, Santo Domingo, Dominican Rep. [Swann, E.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A64 EP A64 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500159 ER PT J AU Doria-Rose, NA Moore, P Staupe, R Bhiman, J Ernandes, M Georgiev, I Bailer, R Louder, M O'Dell, S Mckee, K Crooks, E Schmidt, S Karim, SA Gorman, J Schramm, C Longo, N Pancera, M Rudicell, R Yang, Y Zhang, Z Zhu, J Binley, J Shapiro, L Kwong, P Morris, L Mascola, J AF Doria-Rose, N. A. Moore, P. Staupe, R. Bhiman, J. Ernandes, M. Georgiev, I. Bailer, R. Louder, M. O'Dell, S. Mckee, K. Crooks, E. Schmidt, S. Karim, S. Abdool Gorman, J. Schramm, C. Longo, N. Pancera, M. Rudicell, R. Yang, Y. Zhang, Z. Zhu, J. Binley, J. Shapiro, L. Kwong, P. Morris, L. Mascola, J. TI A Family of Broad and Highly Potent V1V2-Directed HIV-1 Neutralizing Antibodies with Long CDRH3s from a South African Seroconverter SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Doria-Rose, N. A.; Staupe, R.; Ernandes, M.; Georgiev, I.; Bailer, R.; Louder, M.; O'Dell, S.; Mckee, K.; Schmidt, S.; Gorman, J.; Longo, N.; Pancera, M.; Rudicell, R.; Yang, Y.; Zhu, J.; Kwong, P.; Mascola, J.] NIH, Bethesda, MD 20892 USA. [Moore, P.; Bhiman, J.; Morris, L.] Natl Inst Communicable Dis, Natl Hlth Lab Serv, Johannesburg, South Africa. [Crooks, E.; Binley, J.] Torrey Pines Inst, San Diego, CA USA. [Karim, S. Abdool] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. [Schramm, C.; Zhang, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A48 EP A48 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500115 ER PT J AU Enama, ME Novik, L Hendel, CS Holman, L Plummer, S Gordon, I Vasilenko, O Graham, BS Ledgerwood, JE AF Enama, M. E. Novik, L. Hendel, C. S. Holman, L. Plummer, S. Gordon, I. Vasilenko, O. Graham, B. S. Ledgerwood, J. E. TI Eligibility Assessments of Healthy Adults for Eleven HIV Vaccine Clinical Trials Conducted Through a Screening Protocol: 2002-2013 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Enama, M. E.; Novik, L.; Hendel, C. S.; Holman, L.; Plummer, S.; Gordon, I.; Vasilenko, O.; Graham, B. S.; Ledgerwood, J. E.] NIAID, VRC, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A72 EP A73 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500181 ER PT J AU Felber, BK Kulkarni, V Valentin, A Rosati, M Alicea, C Sardesai, NY Le Gall, S Mothe, B Brander, C Rolland, M Mullins, JI Pavlakis, GN AF Felber, B. K. Kulkarni, V. Valentin, A. Rosati, M. Alicea, C. Sardesai, N. Y. Le Gall, S. Mothe, B. Brander, C. Rolland, M. Mullins, J. I. Pavlakis, G. N. TI Altered Immunodominance Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Felber, B. K.; Kulkarni, V.; Valentin, A.; Rosati, M.; Alicea, C.; Pavlakis, G. N.] NCI, Frederick, MD 21701 USA. [Sardesai, N. Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Le Gall, S.] MIT & Harvard, Ragon Inst MGH, Cambridge, MA USA. [Mothe, B.; Brander, C.] Autonomous Univ Barcelona, IrsiCaixa AIDS Res Inst HIVACAT, Barcelona, Spain. [Rolland, M.; Mullins, J. I.] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A33 EP A33 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500075 ER PT J AU Francica, J Zhanhai, Z Schmidt, S Mascola, J Singh, M O'Hagan, D Martin, M Shapiro, L Seder, R AF Francica, J. Zhanhai, Z. Schmidt, S. Mascola, J. Singh, M. O'Hagan, D. Martin, M. Shapiro, L. Seder, R. TI Genetic Assessment of B Cell Responses Following Immunization with HIV Env Protein and Adjuvants or Pathogenic SHIV Infection in Non-human Primates SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Francica, J.; Schmidt, S.; Mascola, J.; Seder, R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Zhanhai, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. [Singh, M.; O'Hagan, D.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Martin, M.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A166 EP A167 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500436 ER PT J AU Frank, I Grunenberg, N Hural, J Edlesfsen, P DeCamp, A Allen, M Spearman, P Bar, K Kalams, S Baden, L Keefer, M Fuchs, J Novak, R Graham, B Enama, M Frahm, N AF Frank, I. Grunenberg, N. Hural, J. Edlesfsen, P. DeCamp, A. Allen, M. Spearman, P. Bar, K. Kalams, S. Baden, L. Keefer, M. Fuchs, J. Novak, R. Graham, B. Enama, M. Frahm, N. TI Enhanced HIV-Specific CD8+T Cell Responses Following Polytopic Administration of VRC rAd5 gag-pol/env A/B/C in HIV-Uninfected Healthy Adults SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Frank, I.; Bar, K.] Univ Penn, Philadelphia, PA 19104 USA. [Grunenberg, N.; Hural, J.; Edlesfsen, P.; DeCamp, A.; Frahm, N.] Univ Washington, Seattle, WA 98195 USA. [Allen, M.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Spearman, P.] Emory Univ, Atlanta, GA 30322 USA. [Kalams, S.] Vanderbilt Univ, Nashville, TN 37235 USA. [Baden, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Keefer, M.] Univ Rochester, Rochester, NY USA. [Fuchs, J.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Novak, R.] Univ Illinois, Chicago, IL USA. [Graham, B.; Enama, M.] Vaccine Res Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A63 EP A63 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500157 ER PT J AU Fuchs, JD Frank, I Elizaga, M Kochar, N Allen, M Frahm, N Carter, DK Li, S Edupuganti, S Kalams, S Sheets, R Pensiero, M Latham, T Egan, M Clarke, D Eldridge, J AF Fuchs, J. D. Frank, I. Elizaga, M. Kochar, N. Allen, M. Frahm, N. Carter, D. K. Li, S. Edupuganti, S. Kalams, S. Sheets, R. Pensiero, M. Latham, T. Egan, M. Clarke, D. Eldridge, J. TI A Recombinant Vesicular Stomatitis Virus (rVSV) HIV-1 Gag Vaccine Is Safe and Immunogenic in Healthy, HIV-1 Uninfected Phase I Trial Participants SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Fuchs, J. D.] San Francisco Dept Publ Hlth, San Francisco, WA USA. [Frank, I.] Univ Penn, Philadelphia, PA 19104 USA. [Elizaga, M.; Kochar, N.; Frahm, N.; Carter, D. K.; Li, S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Allen, M.; Sheets, R.; Pensiero, M.] NIAID, Bethesda, MD 20892 USA. [Edupuganti, S.] Emory Univ, Atlanta, GA 30322 USA. [Kalams, S.] Vanderbilt Univ, Nashville, TN 37235 USA. [Latham, T.; Egan, M.; Clarke, D.; Eldridge, J.] Profectus BioSci Inc, Tarrytown, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A74 EP A75 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500186 ER PT J AU Gao, F Bonsignori, M Liao, H Kumar, A Xia, S Cai, F Lu, X Kozink, DM Kwong, P Zhou, T Lynch, R Alam, SM Ferrari, G Kelsoe, G Sandrasegaram, G Shaw, GM Hahn, BH Montefiori, DC Kamanga, G Cohen, M Braber, P Korber, BT Mascola, JR Kepler, TB Haynes, BF AF Gao, F. Bonsignori, M. Liao, H. Kumar, A. Xia, S. Cai, F. Lu, X. Kozink, D. M. Kwong, P. Zhou, T. Lynch, R. Alam, S. M. Ferrari, G. Kelsoe, G. Sandrasegaram, G. Shaw, G. M. Hahn, B. H. Montefiori, D. C. Kamanga, G. Cohen, M. Braber, P. Korber, B. T. Mascola, J. R. Kepler, T. B. Haynes, B. F. TI Multiple Pathways of HIV-1 Autologous Neutralizing Antibodies Cooperate to Drive CD4 Binding Site Broadly Neutralizing Antibody Responses SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Gao, F.; Bonsignori, M.; Liao, H.; Kumar, A.; Xia, S.; Cai, F.; Lu, X.; Kozink, D. M.; Alam, S. M.; Ferrari, G.; Kelsoe, G.; Montefiori, D. C.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Kwong, P.; Zhou, T.; Lynch, R.; Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sandrasegaram, G.; Braber, P.; Korber, B. T.] Los Alamos Natl Lab, Los Alamos, NM USA. [Shaw, G. M.; Hahn, B. H.] Univ Penn, Philadelphia, PA 19104 USA. [Kamanga, G.; Cohen, M.] Univ N Carolina, Chapel Hill, NC USA. [Kepler, T. B.] Boston Univ, Boston, MA 02215 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A186 EP A186 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500485 ER PT J AU Georgiev, IS Rudicell, RS Saunders, KO Shi, W Kirys, T Mckee, K O'Dell, S Chuang, G Yang, Z Ofek, G Mascola, JR Nabel, GJ Kwong, PD AF Georgiev, I. S. Rudicell, R. S. Saunders, K. O. Shi, W. Kirys, T. Mckee, K. O'Dell, S. Chuang, G. Yang, Z. Ofek, G. Mascola, J. R. Nabel, G. J. Kwong, P. D. TI Antibodies VRC01 and 10E8 Require Minimal Somatic Framework Mutations to Achieve High Neutralization Breadth and Potency SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Georgiev, I. S.; Rudicell, R. S.; Saunders, K. O.; Shi, W.; Kirys, T.; Mckee, K.; O'Dell, S.; Chuang, G.; Yang, Z.; Ofek, G.; Mascola, J. R.; Nabel, G. J.; Kwong, P. D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A164 EP A165 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500430 ER PT J AU Gonzalez, N Lynch, RM McKee, K Yuste, E Mascola, JR Alcami, J AF Gonzalez, N. Lynch, R. M. McKee, K. Yuste, E. Mascola, J. R. Alcami, J. TI Characterization of Broadly Neutralizing Antibodies (bNAbs) to HIV-1 Present in a Cohort of Long Term Non-Progressors (LTNPs) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Gonzalez, N.; Alcami, J.] Inst Salud Carlos III, Ctr Nacl Microbiol, Madrid, Spain. [Lynch, R. M.; McKee, K.; Mascola, J. R.] NIH, Bethesda, MD 20892 USA. [Yuste, E.] Hosp Clin Barcelona, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A53 EP A53 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500130 ER PT J AU Gordon, SN Vaccari, M Doster, MN Liyanage, NP Pegu, P Schifanella, L Caccuri, F Keele, BF Foulds, KE Shen, X Tomaras, GD Montefiori, DC Roederer, M Ferrari, G Venzon, D Stablien, D Barouch, DH Felber, BK Pavlakis, GN Michael, NL Tartaglia, J Franchini, G AF Gordon, S. N. Vaccari, M. Doster, M. N. Liyanage, N. P. Pegu, P. Schifanella, L. Caccuri, F. Keele, B. F. Foulds, K. E. Shen, X. Tomaras, G. D. Montefiori, D. C. Roederer, M. Ferrari, G. Venzon, D. Stablien, D. Barouch, D. H. Felber, B. K. Pavlakis, G. N. Michael, N. L. Tartaglia, J. Franchini, G. TI Priming with Adenovirus26 Vaccines Affects ALVAC-SIV/gp120 Vaccine Efficacy Tested in a SIVmac251 Challenge Model Performed One-Month Post-Vaccination SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Gordon, S. N.; Vaccari, M.; Doster, M. N.; Liyanage, N. P.; Pegu, P.; Schifanella, L.; Caccuri, F.; Venzon, D.; Felber, B. K.; Pavlakis, G. N.; Franchini, G.] NCI, NIH, Bethesda, MD 20892 USA. [Keele, B. F.] NCI, SAIC Frederick, NIH, Frederick, MD 21701 USA. [Foulds, K. E.; Roederer, M.] NIAID, NIH, Bethesda, MD 20892 USA. [Shen, X.; Tomaras, G. D.] Duke Human Vaccine Inst, Durham, NC USA. [Montefiori, D. C.; Ferrari, G.] Duke Univ, Med Ctr, Durham, NC USA. [Stablien, D.] EMMES Corp, Rockville, MD USA. [Barouch, D. H.] Beth Israel Deaconess Med Ctr, Boston, MD USA. [Michael, N. L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Tartaglia, J.] Sanofi Pasteur, Swiftwater, PA USA. RI Tomaras, Georgia/J-5041-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A39 EP A39 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500092 ER PT J AU Gorman, J Doria-Rose, N Schramm, CA Moore, PL Pancera, M Yang, Y Staupe, RP Zhang, Z Georgiev, IS Bhiman, J Longo, NL Morris, L Shapiro, L Mascola, JR Kwong, PD AF Gorman, J. Doria-Rose, N. Schramm, C. A. Moore, P. L. Pancera, M. Yang, Y. Staupe, R. P. Zhang, Z. Georgiev, I. S. Bhiman, J. Longo, N. L. Morris, L. Shapiro, L. Mascola, J. R. Kwong, P. D. TI Structural Characterization of Potent, Longitudinally-Defined HIV-1 V1/V2-Directed Antibodies SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Gorman, J.; Doria-Rose, N.; Pancera, M.; Yang, Y.; Staupe, R. P.; Georgiev, I. S.; Longo, N. L.; Mascola, J. R.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Schramm, C. A.; Zhang, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. [Moore, P. L.; Bhiman, J.; Morris, L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A12 EP A12 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500023 ER PT J AU Hammer, S Sobieszczyk, M Janes, H Gilbert, P Karuna, S Grove, D Ramirez, S Bentley, C Anude, C Mulligan, M Koblin, B Buchbinder, S Keefer, M Hural, J McElrath, J Frahm, N Tomaras, G Graham, B Enama, M Broder, G Maynard, J Wakefield, S Holt, R DeJesus, E Frank, I Novak, R Martinez, A Kublin, J Corey, L AF Hammer, S. Sobieszczyk, M. Janes, H. Gilbert, P. Karuna, S. Grove, D. Ramirez, S. Bentley, C. Anude, C. Mulligan, M. Koblin, B. Buchbinder, S. Keefer, M. Hural, J. McElrath, J. Frahm, N. Tomaras, G. Graham, B. Enama, M. Broder, G. Maynard, J. Wakefield, S. Holt, R. DeJesus, E. Frank, I. Novak, R. Martinez, A. Kublin, J. Corey, L. CA HIV Vaccine Trials Network TI HVTN 505: Efficacy of a Multi-Gene DNA Prime/Recombinant Adeno 5 (rAd5) Vector Boost Vaccine in Men & Transgender Women (TGW) Who Have Sex with Men SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Hammer, S.; Sobieszczyk, M.; HIV Vaccine Trials Network] Columbia Univ, New York, NY USA. [Janes, H.; Gilbert, P.; Grove, D.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Karuna, S.; Ramirez, S.; Bentley, C.; Hural, J.; McElrath, J.; Frahm, N.; Broder, G.; Maynard, J.; Wakefield, S.; Holt, R.; Kublin, J.; Corey, L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Anude, C.; Martinez, A.] NIAID, DAIDS, Bethesda, MD 20892 USA. [Mulligan, M.] Emory Univ, Atlanta, GA 30322 USA. [Koblin, B.] New York Blood Ctr, New York, NY 10021 USA. [Buchbinder, S.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Keefer, M.] Univ Rochester, Rochester, NY USA. [Tomaras, G.] Duke Univ, Durham, NC USA. [Graham, B.; Enama, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [DeJesus, E.] Orlando Immunol Ctr, Orlando, FL USA. [Frank, I.] Univ Penn, Philadelphia, PA 19104 USA. [Novak, R.] Univ Illinois, Chicago, IL USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A172 EP A172 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500450 ER PT J AU Heeney, JL Wagner, R Esteban, M Jacobs, B Foulds, K Roederer, M Self, S Barnett, S Phogat, S Montefiori, D Tomaris, G Pantaleo, G AF Heeney, J. L. Wagner, R. Esteban, M. Jacobs, B. Foulds, K. Roederer, M. Self, S. Barnett, S. Phogat, S. Montefiori, D. Tomaris, G. Pantaleo, G. TI Rapid Appearance of Vaccine-Induced Potentially Protective Anti-Env Antibody Responses with Early Co-administration of gp120 with NYVAC or DNA SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Heeney, J. L.] Univ Cambridge, Cambridge, England. [Wagner, R.] Univ Regensburg, D-93053 Regensburg, Germany. [Esteban, M.] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. [Jacobs, B.] Arizona State Univ, Tempe, AZ USA. [Foulds, K.; Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Self, S.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Barnett, S.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Phogat, S.] Sanofi Pasteur, Swiftwater, PA USA. [Montefiori, D.; Tomaris, G.] Duke Univ, Med Ctr, Durham, NC USA. [Pantaleo, G.] CHU Vaudois, CH-1011 Lausanne, Switzerland. RI Pantaleo, Giuseppe/K-6163-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A162 EP A163 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500425 ER PT J AU Heeney, JL Jacobs, B Esteban, M Wagner, R Foulds, K Roederer, M Self, S Barnett, S Tartaglia, J Montefiori, D Tomaras, G Pantaleo, G AF Heeney, J. L. Jacobs, B. Esteban, M. Wagner, R. Foulds, K. Roederer, M. Self, S. Barnett, S. Tartaglia, J. Montefiori, D. Tomaras, G. Pantaleo, G. TI Increased HIV-1 Immunogenicity of Replication Competent NYVAC SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Heeney, J. L.] Univ Cambridge, Cambridge, England. [Jacobs, B.] Arizona State Univ, Tempe, AZ USA. [Esteban, M.] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. [Wagner, R.] Univ Regensburg, D-93053 Regensburg, Germany. [Foulds, K.; Roederer, M.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Self, S.] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Barnett, S.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Tartaglia, J.] Sanofi Pasteur, Swiftwater, PA USA. [Montefiori, D.] Univ Med Ctr, Durham, NC USA. [Tomaras, G.] Duke Univ, Med Ctr, Durham, NC USA. [Pantaleo, G.] CHU Vaudois, CH-1011 Lausanne, Switzerland. RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A160 EP A160 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500418 ER PT J AU Heit, A Schmitz, F Moore, M Gerdts, S Spearman, P Barnett, S Graham, B Robinson, H Astronomo, R Andersen-Nissen, E Frahm, N De Rosa, S McElrath, M AF Heit, A. Schmitz, F. Moore, M. Gerdts, S. Spearman, P. Barnett, S. Graham, B. Robinson, H. Astronomo, R. Andersen-Nissen, E. Frahm, N. De Rosa, S. McElrath, M. TI HVTN-Tested Candidate HIV Vaccines Induce Early, Antigen-Specific Plasmablast- and Tfh-like Responses in Peripheral Blood SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Heit, A.; Moore, M.; Gerdts, S.; Astronomo, R.; Andersen-Nissen, E.; Frahm, N.; De Rosa, S.; McElrath, M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schmitz, F.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Spearman, P.] Emory Univ, Sch Med, Atlanta, GA USA. [Barnett, S.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Graham, B.] NIH, Bethesda, MD 20892 USA. [Robinson, H.] GeoVax Inc, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A143 EP A144 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500375 ER PT J AU Hu, H Eller, M Zafar, S Currier, J Marovich, M Robb, M Kim, J Michael, N Ratto-Kim, S AF Hu, H. Eller, M. Zafar, S. Currier, J. Marovich, M. Robb, M. Kim, J. Michael, N. Ratto-Kim, S. TI Adenovirus 5 Hexon-Specific CD4 T Cells Are More Susceptible to HIV and Preferentially Depleted During Infection Compared to CMV-Specific CD4 T Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Hu, H.; Eller, M.; Zafar, S.; Currier, J.; Robb, M.; Kim, J.; Michael, N.; Ratto-Kim, S.] US MHRP, Silver Spring, MD USA. [Marovich, M.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A183 EP A183 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500479 ER PT J AU Hural, J Walsh, S Moodie, Z Frahm, N Gartland, A Friedrich, D Hertz, T Ahmed, H Wilck, M Morgan, C Swann, E Wang, H Manso, B Self, S Graham, B Jin, X AF Hural, J. Walsh, S. Moodie, Z. Frahm, N. Gartland, A. Friedrich, D. Hertz, T. Ahmed, H. Wilck, M. Morgan, C. Swann, E. Wang, H. Manso, B. Self, S. Graham, B. Jin, X. TI Vaccination with Heterologous HIV Envelope Sequences and Heterologous Adenovirus Vectors Increases T Cell Responses to Conserved Regions: HVTN 083 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Hural, J.; Moodie, Z.; Frahm, N.; Gartland, A.; Friedrich, D.; Hertz, T.; Ahmed, H.; Morgan, C.; Wang, H.; Manso, B.; Self, S.] HIV Vaccine Trials Network, Seattle, WA USA. [Walsh, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilck, M.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Swann, E.] NIAID, NIH, Bethesda, MD 20892 USA. [Graham, B.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Jin, X.] Univ Rochester, Rochester, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A172 EP A173 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500451 ER PT J AU Jensen, K Wilson, RL Piatak, M Lifson, JD Ranangathan, UD Jacobs, WR Fennelly, G Larsen, M Van Rompay, KK Kozlowski, PA Abel, K AF Jensen, K. Wilson, R. L. Piatak, M. Lifson, J. D. Ranangathan, U. D. Jacobs, W. R. Fennelly, G. Larsen, M. Van Rompay, K. K. Kozlowski, P. A. Abel, K. TI Vaccine-Induced Intestinal and Salivary IgA Correlates with Reduced SIV Viremia in Orally-Challenged Neonatal Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Wilson, R. L.; Kozlowski, P. A.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Piatak, M.; Lifson, J. D.] Frederick Natl Lab Canc Res, Frederick, MD USA. [Ranangathan, U. D.; Jacobs, W. R.; Fennelly, G.; Larsen, M.] Albert Einstein Coll Med, New York, NY USA. [Van Rompay, K. K.] Univ Calif Davis, CNPRC, Davis, CA USA. [Jensen, K.; Abel, K.] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A104 EP A104 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500265 ER PT J AU Joachim, A Munseri, P Nilsson, C Bakari, M Aboud, S Lyamuya, EF Moshiro, C Robb, M Marovich, M Earl, P Moss, B Buma, D Janabi, M Wahren, B Mhalu, F Ferrari, G Sandstrom, E Biberfeld, G AF Joachim, A. Munseri, P. Nilsson, C. Bakari, M. Aboud, S. Lyamuya, E. F. Moshiro, C. Robb, M. Marovich, M. Earl, P. Moss, B. Buma, D. Janabi, M. Wahren, B. Mhalu, F. Ferrari, G. Sandstrom, E. Biberfeld, G. TI A Late Third HIV-MVA Vaccination Boosted Strong and Potent Immune Responses in Tanzanian Volunteers Previously Immunized with HIV-DNA and HIV-MVA SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Joachim, A.; Munseri, P.] Muhimbili Univ Hlth & Allied Sci, Stockholm, Sweden. [Joachim, A.; Munseri, P.; Nilsson, C.] Karolinska Inst, Stockholm, Sweden. [Joachim, A.; Munseri, P.; Bakari, M.; Aboud, S.; Lyamuya, E. F.; Moshiro, C.; Biberfeld, G.] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Joachim, A.; Munseri, P.] Karolinska Inst, Dar Es Salaam, Tanzania. [Nilsson, C.] Swedish Inst communicable Dis Solna, Stockholm, Sweden. [Robb, M.; Marovich, M.] US MHRP, Silver Spring, MD USA. [Earl, P.; Moss, B.] NIAID, NIH, Bethesda, MD 20892 USA. [Buma, D.; Janabi, M.; Mhalu, F.] Muhimbili Natl Hosp, Dar Es Salaam, Tanzania. [Wahren, B.; Sandstrom, E.] Karolinska Inst, Stockholm, Sweden. [Ferrari, G.] Duke Univ, Med Ctr, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A174 EP A174 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500455 ER PT J AU Klatt, N Bosinger, S Heigele, A Lederman, M Juelg, B Camerini, D Torti, C Martin, J Deeks, S Sinclari, E Brenchley, J Paiardini, M Hecht, F Kirchhoff, F Hunt, P Silvestri, G AF Klatt, N. Bosinger, S. Heigele, A. Lederman, M. Juelg, B. Camerini, D. Torti, C. Martin, J. Deeks, S. Sinclari, E. Brenchley, J. Paiardini, M. Hecht, F. Kirchhoff, F. Hunt, P. Silvestri, G. TI Limited HIV Infection of Central Memory CD4+T Cells Is Associated with Lack of Progression in Viremic Individuals SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Klatt, N.] Univ Washington, Seattle, WA 98195 USA. [Bosinger, S.; Paiardini, M.; Silvestri, G.] Emory Univ, Atlanta, GA 30322 USA. [Heigele, A.; Kirchhoff, F.] Univ Ulm, Med Ctr, D-89069 Ulm, Germany. [Lederman, M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Juelg, B.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Camerini, D.] Univ Calif Irvine, Irvine, CA USA. [Torti, C.] Univ Brescia, Brescia, Italy. [Martin, J.; Deeks, S.; Sinclari, E.; Hecht, F.; Hunt, P.] UCSF Posit Hlth Program, San Francisco, CA USA. [Brenchley, J.] NIAID, NIH, LMM, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A128 EP A128 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500332 ER PT J AU Krebs, SJ Narpala, S Wheatley, A Slike, BM Eller, M Ratto-Kim, S Polonis, VR Kim, JH Robb, ML Marovich, MA Koup, RA Graham, BS Michael, NL McDermott, A AF Krebs, S. J. Narpala, S. Wheatley, A. Slike, B. M. Eller, M. Ratto-Kim, S. Polonis, V. R. Kim, J. H. Robb, M. L. Marovich, M. A. Koup, R. A. Graham, B. S. Michael, N. L. McDermott, A. TI Comparative Analysis of Binding Antibody Responses Elicited by a Cross-Section of Human HIV-1 Vaccine Clinical Trials SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Krebs, S. J.; Slike, B. M.; Eller, M.; Ratto-Kim, S.; Polonis, V. R.; Kim, J. H.; Robb, M. L.; Marovich, M. A.; Michael, N. L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Krebs, S. J.; Slike, B. M.; Eller, M.; Ratto-Kim, S.; Robb, M. L.] Henry M Jackson Fdn Adv Mil Med, Silver Spring, MD USA. [Narpala, S.; Wheatley, A.; Koup, R. A.; Graham, B. S.; McDermott, A.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A8 EP A9 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500014 ER PT J AU Kuwata, T Takaki, K Yoshimura, K Enomoto, I Wu, F Ourmanov, I Hirsch, VM Yokoyama, M Sato, H Matsushita, S AF Kuwata, T. Takaki, K. Yoshimura, K. Enomoto, I. Wu, F. Ourmanov, I. Hirsch, V. M. Yokoyama, M. Sato, H. Matsushita, S. TI Analysis of Env Regions Important for Binding and Resistance to B404, a Potent Neutralizing Antibody Against SIV SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Kuwata, T.; Takaki, K.; Enomoto, I.; Matsushita, S.] Kumamoto Univ, Kumamoto, Japan. [Wu, F.; Ourmanov, I.; Hirsch, V. M.] NIAID, LMM, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A57 EP A57 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500141 ER PT J AU Liang, F Sandgren, KJ Lindgren, G Thompson, EA Fausther-Bovendo, H O'Hagan, D Seubert, A De Gregorio, E Rao, S Sullivan, NJ Seder, RA Koup, RA Lore, K AF Liang, F. Sandgren, K. J. Lindgren, G. Thompson, E. A. Fausther-Bovendo, H. O'Hagan, D. Seubert, A. De Gregorio, E. Rao, S. Sullivan, N. J. Seder, R. A. Koup, R. A. Lore, K. TI Vaccine Adjuvants Induce Distinct Innate Immune Activation Profiles In Vivo SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Thompson, E. A.; Fausther-Bovendo, H.; Rao, S.; Sullivan, N. J.; Seder, R. A.; Koup, R. A.] NIH, Bethesda, MD 20892 USA. [O'Hagan, D.; Seubert, A.; De Gregorio, E.] Novartis Vaccines & Diagnost, Cambridge, MA USA. [Liang, F.; Sandgren, K. J.; Lindgren, G.; Lore, K.] Karolinska Inst, Stockholm, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A94 EP A94 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500239 ER PT J AU Lifson, JD Del Prete, GQ Moldt, B Keele, BF Estes, JD Oswald, K Fast, R Trubey, CM Smedley, J Burton, DR KewalRamani, V Piatak, M Bieniasz, P Hatziioannou, T AF Lifson, J. D. Del Prete, G. Q. Moldt, B. Keele, B. F. Estes, J. D. Oswald, K. Fast, R. Trubey, C. M. Smedley, J. Burton, D. R. KewalRamani, V. Piatak, M., Jr. Bieniasz, P. Hatziioannou, T. TI Novel R5 Tropic Founder Env SHIV for Nonhuman Primate Immunoprophylactic Studies SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Lifson, J. D.; Del Prete, G. Q.; Keele, B. F.; Estes, J. D.; Oswald, K.; Fast, R.; Trubey, C. M.; Smedley, J.; Piatak, M., Jr.] SAIC Frederick Inc, Frederick Natl Lab, Frederick, MD USA. [Moldt, B.; Burton, D. R.] Scripps Res Inst, La Jolla, CA 92037 USA. [KewalRamani, V.] NCI, Frederick, MD 21701 USA. [Bieniasz, P.; Hatziioannou, T.] Rockefeller Univ, New York, NY 10021 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A185 EP A186 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500484 ER PT J AU Liyanage, NP Gordon, SN Vaccari, M Pegu, P Doster, MN Tomaras, GD Venzon, D Stablien, D Tartaglia, J Barnett, SW Kim, JH Michael, NL Franchini, G AF Liyanage, N. P. Gordon, S. N. Vaccari, M. Pegu, P. Doster, M. N. Tomaras, G. D. Venzon, D. Stablien, D. Tartaglia, J. Barnett, S. W. Kim, J. H. Michael, N. L. Franchini, G. TI Alum and MF59, in Combination with ALVAC-SIV and Gp120 Vaccines Recruit Functionally Different NK Cells to the Gut of Vaccinated Rhesus Macaque SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Liyanage, N. P.; Gordon, S. N.; Vaccari, M.; Pegu, P.; Doster, M. N.; Franchini, G.] NCI, Bethesda, MD 20892 USA. [Tomaras, G. D.] Duke Human Vaccine Inst, Durham, NC USA. [Venzon, D.] NCI, NIH, Bethesda, MD 20892 USA. [Stablien, D.] EMMES Corp, Rockville, MD USA. [Tartaglia, J.] Sanofi Pasteur, Swiftwater, PA USA. [Barnett, S. W.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Kim, J. H.; Michael, N. L.] Walter Reed Army Inst Res, Silver Spring, MD USA. RI Tomaras, Georgia/J-5041-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A100 EP A100 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500255 ER PT J AU Lynch, RM Wong, P Wu, X Mascola, J AF Lynch, R. M. Wong, P. Wu, X. Mascola, J. TI Fitness Cost of Viral Escape from Broadly Neutralizing CD4-Binding Site Antibodies SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Lynch, R. M.; Wong, P.; Mascola, J.] NIH, Bethesda, MD 20892 USA. [Wu, X.] Aaron Diamond AIDS Res Ctr, New York, NY 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A62 EP A62 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500154 ER PT J AU Mackelprang, R Carrington, M Thomas, K Hughes, JP Baeten, JM Wald, A Farquhar, C Fife, K Campbell, MS Kapiga, S Mullins, JI Lingappa, JR AF Mackelprang, R. Carrington, M. Thomas, K. Hughes, J. P. Baeten, J. M. Wald, A. Farquhar, C. Fife, K. Campbell, M. S. Kapiga, S. Mullins, J. I. Lingappa, J. R. TI Host and Viral Factors Associated with HIV-1 RNA Set-Point Among HIV-1 Seroconverters from sub- Saharan Africa SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Mackelprang, R.; Thomas, K.; Hughes, J. P.; Baeten, J. M.; Wald, A.; Farquhar, C.; Campbell, M. S.; Kapiga, S.; Mullins, J. I.; Lingappa, J. R.] Univ Washington, Seattle, WA 98195 USA. [Carrington, M.] NCI, Frederick, MD 21701 USA. [Fife, K.] Indiana Univ, Bloomington, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A179 EP A179 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500468 ER PT J AU Mann, P Kosgei, J Sekiziyivu, A Sawe, F Maboko, L Kibuuka, H Tong, T Karasavva, N Robb, M Eller, L Ake, J Marovich, M Ngauy, V AF Mann, P. Kosgei, J. Sekiziyivu, A. Sawe, F. Maboko, L. Kibuuka, H. Tong, T. Karasavva, N. Robb, M. Eller, L. Ake, J. Marovich, M. Ngauy, V. TI Acceptability and Tolerability of Novel Mucosal Secretion Collection Methods in an HIV Vaccine Trial in East Africa SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Mann, P.; Maboko, L.] Natl Inst Med Res, Mbeya Med Res Ctr, Mbeya, Tanzania. [Kosgei, J.; Sawe, F.] Kenya Govt Med Res Ctr, Walter Reed Project, Kericho, Kenya. [Sekiziyivu, A.; Kibuuka, H.] Makerere Univ, Walter Reed Project, Kampala, Uganda. [Tong, T.; Robb, M.; Eller, L.; Ake, J.] US Mil HIV Res Program, Rockville, MD USA. [Karasavva, N.; Ngauy, V.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Marovich, M.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A142 EP A142 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500371 ER PT J AU Mason, R Welles, H Schmidt, S Chakrabarti, B Yang, Z Saunders, K Mascola, J Roederer, M AF Mason, R. Welles, H. Schmidt, S. Chakrabarti, B. Yang, Z. Saunders, K. Mascola, J. Roederer, M. TI Characterization of Antibodies Targeting the Receptor and Co-receptor Binding Region of SIV Envelope SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Mason, R.; Welles, H.; Schmidt, S.; Yang, Z.; Saunders, K.; Mascola, J.; Roederer, M.] NIAID, NIH, Bethesda, MD 20892 USA. [Chakrabarti, B.] Scripps Res Inst, La Jolla, CA 92037 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A37 EP A38 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500087 ER PT J AU Migueles, SA Zimmerman, MG Mendoza, D Toulmin, SA Kelly, EP Connors, M AF Migueles, S. A. Zimmerman, M. G. Mendoza, D. Toulmin, S. A. Kelly, E. P. Connors, M. TI Increased Cytotoxic Capacity of Immunodominant HIV-Specific CD8+T-Cell Responses Is Associated with Immune Control Regardless of HLA Type SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Migueles, S. A.; Zimmerman, M. G.; Mendoza, D.; Toulmin, S. A.; Kelly, E. P.; Connors, M.] NIAID, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A125 EP A125 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500323 ER PT J AU Murillo, PAM Sundling, C Feng, Y O'Dell, S Reimann, K Mascola, J Wyatt, R Hedestam, GBK AF Murillo, P. A. Martinez Sundling, C. Feng, Y. O'Dell, S. Reimann, K. Mascola, J. Wyatt, R. Hedestam, G. B. Karlsson TI Impact of TLR9 Stimulation on HIV-1 Env-Specific Immune Responses Elicited in Non-human Primates SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Murillo, P. A. Martinez; Sundling, C.; Hedestam, G. B. Karlsson] Karolinska Inst, Stockholm, Sweden. [Feng, Y.; Wyatt, R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [O'Dell, S.; Mascola, J.] NIH, Bethesda, MD 20892 USA. [Reimann, K.] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. RI Feng, Yu/A-3396-2012 NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A7 EP A7 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500011 ER PT J AU Navis, M Tran, K Li, Y Phad, G Sundling, C Wilson, R Soldemo, M McKee, K Mascola, J Wyatt, RT Hedestam, GBK AF Navis, M. Tran, K. Li, Y. Phad, G. Sundling, C. Wilson, R. Soldemo, M. McKee, K. Mascola, J. Wyatt, R. T. Hedestam, G. B. Karlsson TI Vaccine-Elicited CD4 Binding Site-Directed Antibodies Utilizing the Macaque Equivalent of the Human VH1-2 Heavy Chain Variable Gene Segment SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Navis, M.; Phad, G.; Sundling, C.; Soldemo, M.; Hedestam, G. B. Karlsson] Karolinska Inst, Stockholm, Sweden. [Tran, K.; Li, Y.; Wilson, R.; Wyatt, R. T.] Scripps Res Inst, La Jolla, CA 92037 USA. [McKee, K.; Mascola, J.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A41 EP A42 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500098 ER PT J AU Nawaz, F Cicala, C Schwing, C Wei, D Hiatt, J Jelicic, K Van Ryk, D Fauci, A Arthos, J AF Nawaz, F. Cicala, C. Schwing, C. Wei, D. Hiatt, J. Jelicic, K. Van Ryk, D. Fauci, A. Arthos, J. TI A Role for Glycosylation in HIV Transmission SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Nawaz, F.] NYU, New York, NY USA. [Cicala, C.; Schwing, C.; Wei, D.; Hiatt, J.; Jelicic, K.; Van Ryk, D.; Fauci, A.; Arthos, J.] NIAID, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A15 EP A16 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500033 ER PT J AU Ofek, G Zirkle, B Yang, Y McKee, K Zhu, Z Louder, MK Mascola, JR Dimitrov, DS Kwong, PD AF Ofek, G. Zirkle, B. Yang, Y. McKee, K. Zhu, Z. Louder, M. K. Mascola, J. R. Dimitrov, D. S. Kwong, P. D. TI Crystal Structure of the 2F5-like Antibody m66 in Complex with Its HIV-1 gp41 Epitope SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Ofek, G.; Zirkle, B.; Yang, Y.; McKee, K.; Louder, M. K.; Mascola, J. R.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Zhu, Z.; Dimitrov, D. S.] NCI, NIH, Frederick, MD 21701 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A52 EP A52 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500127 ER PT J AU Olvera, A Llano, A Rosati, M Perez-Alvarez, S Kulkarni, V Chowdhury, B Alicea, C Beach, RK Sardesai, NY Hanke, T Clotet, B Pavlakis, GN Felber, BK Brander, C Mothe, B AF Olvera, A. Llano, A. Rosati, M. Perez-Alvarez, S. Kulkarni, V. Chowdhury, B. Alicea, C. Beach, R. K. Sardesai, N. Y. Hanke, T. Clotet, B. Pavlakis, G. N. Felber, B. K. Brander, C. Mothe, B. TI DNA-MVA Prime-Boost Vaccine Eliciting T-Cell Specificities Associated with HIV-1 Control Is Highly Immunogenic in Mice and Breaks CTL Immunodominance SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Olvera, A.; Llano, A.; Perez-Alvarez, S.; Clotet, B.; Brander, C.; Mothe, B.] IrsiCaixa AIDS Res Inst HIVACAT, Badalona, Spain. [Olvera, A.; Clotet, B.; Brander, C.] Lluita Sida Hosp Germans Trias & Pujol, Badalona, Spain. [Rosati, M.; Kulkarni, V.; Chowdhury, B.; Alicea, C.; Beach, R. K.; Pavlakis, G. N.; Felber, B. K.] NCI, Frederick, MD 21701 USA. [Sardesai, N. Y.] Inovio Pharmaceut Biomed Corp, Blue Bell, PA USA. [Hanke, T.] Univ Oxford, Oxford OX1 2JD, England. [Clotet, B.; Brander, C.] Univ Autonoma Barcelona, Badalona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A15 EP A15 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500031 ER PT J AU Pancera, M Zhu, J O'Dell, S Yang, Y Zhang, B Changela, A McLellan, JS Wu, X Zhou, T Burton, DR Koff, WC Mascola, JR Kwong, PD AF Pancera, M. Zhu, J. O'Dell, S. Yang, Y. Zhang, B. Changela, A. McLellan, J. S. Wu, X. Zhou, T. Burton, D. R. Koff, W. C. Mascola, J. R. Kwong, P. D. TI Arginine-Scanning of PG16 Paratope Defines Quaternary Epitope SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Pancera, M.; Zhu, J.; O'Dell, S.; Yang, Y.; Zhang, B.; Changela, A.; McLellan, J. S.; Wu, X.; Zhou, T.; Burton, D. R.; Koff, W. C.; Mascola, J. R.; Kwong, P. D.] NIAID, NIH, VRC, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A59 EP A60 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500148 ER PT J AU Pavlakis, GN Jalah, R Li, J Valentin, A Rosati, M Patel, V Kulkarni, V Alicea, C Beach, RK Guan, Y Lifson, JD Hirsch, VM Venzon, D Broderick, KE Sardesai, NY Fouts, TR Pinter, A LaBranche, C Montefiori, DC Shen, S Tomaras, GD Felber, BK AF Pavlakis, G. N. Jalah, R. Li, J. Valentin, A. Rosati, M. Patel, V. Kulkarni, V. Alicea, C. Beach, R. Kelly Guan, Y. Lifson, J. D. Hirsch, V. M. Venzon, D. Broderick, K. E. Sardesai, N. Y. Fouts, T. R. Pinter, A. LaBranche, C. Montefiori, D. C. Shen, S. Tomaras, G. D. Felber, B. K. TI Optimization of Systemic and Mucosal Immune Responses to SIV and HIV-1 Antigens Using Different Protocols of DNA and Protein Immunization in Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Pavlakis, G. N.; Jalah, R.; Li, J.; Valentin, A.; Rosati, M.; Patel, V.; Kulkarni, V.; Alicea, C.; Beach, R. Kelly; Venzon, D.; Felber, B. K.] NCI, Frederick, MD 21701 USA. [Guan, Y.] Inst Human Virol, Baltimore, MD USA. [Lifson, J. D.] SAIC Frederick Inc, Frederick, MD USA. [Hirsch, V. M.] NIAID, Bethesda, MD 20892 USA. [Broderick, K. E.; Sardesai, N. Y.] Inovio Pharmaceut Inc, Blue Bell, PA USA. [Fouts, T. R.] Profectus BioSci Inc, Baltimore, MD USA. [Pinter, A.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [LaBranche, C.; Montefiori, D. C.; Shen, S.; Tomaras, G. D.] Duke Univ, Med Ctr, Durham, NC USA. RI Tomaras, Georgia/J-5041-2016; bebarta, vikhyat/K-3476-2015 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A19 EP A19 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500042 ER PT J AU Penaloza-MacMaster, P Wherry, EJ Barber, DL Teigler, JE Provine, NM Barouch, DH AF Penaloza-MacMaster, P. Wherry, E. J. Barber, D. L. Teigler, J. E. Provine, N. M. Barouch, D. H. TI Memory CD4 T Cells Provide Help Following Acute Viral Challenge, but Promote Lethal Immunopathology Following Chronic Viral Challenge SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Penaloza-MacMaster, P.; Teigler, J. E.; Provine, N. M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Wherry, E. J.] Univ Penn, Philadelphia, PA 19104 USA. [Barber, D. L.] NIAID, Bethesda, MD 20892 USA. [Barouch, D. H.] Ragon Inst MGH MIT & Harvard, Cambridge, MA 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A122 EP A122 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500316 ER PT J AU Phad, GE Sundling, C Zhang, Z Navis, M O'Dell, S Li, Y Wyatt, R Mascola, J Shapiro, L Hedestam, GBK AF Phad, G. E. Sundling, C. Zhang, Z. Navis, M. O'Dell, S. Li, Y. Wyatt, R. Mascola, J. Shapiro, L. Hedestam, G. B. Karlsson TI Genetic and Functional Characterization of Somatic Variants of Vaccine-Induced HIV-1 CD4bs-Directed Monoclonal Antibodies SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Phad, G. E.; Sundling, C.; Navis, M.; Hedestam, G. B. Karlsson] Karolinska Inst, Stockholm, Sweden. [Zhang, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. [O'Dell, S.; Mascola, J.] NIH, Bethesda, MD 20892 USA. [Li, Y.; Wyatt, R.] Scripps Res Inst, La Jolla, CA 92037 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A58 EP A58 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500144 ER PT J AU Redd, AD Ssemwanga, D Wendel, SK Ndembi, N Vandepitte, J Grosskurth, H Parry, CM Martens, C Bruno, D Porcella, SF Quinn, TC Kaleebu, P AF Redd, A. D. Ssemwanga, D. Wendel, S. K. Ndembi, N. Vandepitte, J. Grosskurth, H. Parry, C. M. Martens, C. Bruno, D. Porcella, S. F. Quinn, T. C. Kaleebu, P. TI Incidence of HIV-1 Superinfection Is Similar to Primary HIV-1 Incidence in a Cohort of Female Sex Workers in Uganda SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Redd, A. D.; Wendel, S. K.; Quinn, T. C.] NIAID, Immunoregulat Lab, NIH, Baltimore, MD USA. [Ssemwanga, D.; Vandepitte, J.; Parry, C. M.; Kaleebu, P.] MRC UVRI Uganda Res Unit AIDS, Entebbe, Uganda. [Ndembi, N.] Inst Human Virol, Abuja, Nigeria. [Grosskurth, H.] London Sch Hyg & Trop Med, London WC1, England. [Martens, C.; Bruno, D.; Porcella, S. F.] NIAID, Genom Unit, Res Technol Branch, Rocky Mt Labs,Div Intramural Res,NIH, Hamilton, MT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A77 EP A77 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500193 ER PT J AU Reddy, K Winkler, C Werner, L Mlisana, K Abdool Karim, S Ndung'u, T AF Reddy, K. Winkler, C. Werner, L. Mlisana, K. Abdool Karim, S. Ndung'u, T. TI APOBEC3G and-3F Induced Cytidine Deamination and Association with Viral Control in a Population with High Frequency of the APOBEC3G H186R Variant SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Reddy, K.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Durban, South Africa. [Winkler, C.] NCI, Frederick, MD 21701 USA. [Werner, L.; Mlisana, K.; Abdool Karim, S.; Ndung'u, T.] Univ KwaZulu Natal, CAPRISA, Durban, South Africa. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A91 EP A91 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500230 ER PT J AU Rolland, M Edlefsen, PT Gottardo, R Montefiori, DC Zolla-Pazner, S Moody, A Liao, LH Liu, P Tomaras, GD Haynes, BF Bailer, RT Koup, RA Mascola, JR Shen, X Korber, BT Tovanabutra, S Rerks-Ngarm, S Nitayaphan, S Pitisuttihum, P Kaewkungwal, J Robb, ML Michael, NL Mullins, JI Gilbert, PB Kim, JH AF Rolland, M. Edlefsen, P. T. Gottardo, R. Montefiori, D. C. Zolla-Pazner, S. Moody, A. Liao, L. H. Liu, P. Tomaras, G. D. Haynes, B. F. Bailer, R. T. Koup, R. A. Mascola, J. R. Shen, X. Korber, B. T. Tovanabutra, S. Rerks-Ngarm, S. Nitayaphan, S. Pitisuttihum, P. Kaewkungwal, J. Robb, M. L. Michael, N. L. Mullins, J. I. Gilbert, P. B. Kim, J. H. TI Genetic and Immunological Evidence for a Role of Env-V3 Antibodies in the RV144 Trial SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Rolland, M.; Tovanabutra, S.; Robb, M. L.; Michael, N. L.; Kim, J. H.] US MHRP, Silver Spring, MD USA. [Edlefsen, P. T.; Gottardo, R.; Gilbert, P. B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Montefiori, D. C.; Moody, A.; Liao, L. H.; Liu, P.; Tomaras, G. D.; Haynes, B. F.; Shen, X.] Duke Univ, Med Ctr, Raleigh, NC USA. [Zolla-Pazner, S.] NYU, New York, NY USA. [Bailer, R. T.; Koup, R. A.; Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Korber, B. T.] Los Alamos Natl Lab, Santa Fe, NM USA. [Rerks-Ngarm, S.] MOPH, Bangkok, Thailand. [Nitayaphan, S.] AFRIMS, Bangkok, Thailand. [Pitisuttihum, P.; Kaewkungwal, J.] Mahidol Univ, Bangkok 10700, Thailand. [Mullins, J. I.] Univ Washington, Seattle, WA 98195 USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 2 Z9 2 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A168 EP A168 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500440 ER PT J AU Rudicell, RS Pegu, A Ko, S Kwon, Y Georgiev, I Wu, X Zhu, J Chen, X Doria-Rose, N Zhou, T Yang, Y Zhang, B Todd, J O'Dell, S Louder, M Boyington, J Shi, W Yang, Z Haynes, BF Roederer, M Rao, S Kwong, PD Mascola, JR Nabel, GJ AF Rudicell, R. S. Pegu, A. Ko, S. Kwon, Y. Georgiev, I. Wu, X. Zhu, J. Chen, X. Doria-Rose, N. Zhou, T. Yang, Y. Zhang, B. Todd, J. O'Dell, S. Louder, M. Boyington, J. Shi, W. Yang, Z. Haynes, B. F. Roederer, M. Rao, S. Kwong, P. D. Mascola, J. R. Nabel, G. J. TI Engineering a Next Generation VRC01-Like Antibody with Improved In Vitro and In Vivo Function SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Rudicell, R. S.; Pegu, A.; Ko, S.; Kwon, Y.; Georgiev, I.; Chen, X.; Doria-Rose, N.; Zhou, T.; Yang, Y.; Zhang, B.; Todd, J.; O'Dell, S.; Louder, M.; Boyington, J.; Shi, W.; Yang, Z.; Roederer, M.; Rao, S.; Kwong, P. D.; Mascola, J. R.] NIAID, NIH, Bethesda, MD 20892 USA. [Wu, X.] Rockefeller Univ, New York, NY 10021 USA. [Zhu, J.] Scripps Res Inst, La Jolla, CA 92037 USA. [Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Nabel, G. J.] Sanofi, Cambridge, MA USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A48 EP A49 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500117 ER PT J AU Sastry, M Xu, L Bhattacharya, S Nabel, GJ Bewley, CA Kwong, PD AF Sastry, M. Xu, L. Bhattacharya, S. Nabel, G. J. Bewley, C. A. Kwong, P. D. TI Solution Structural Analysis of the Secondary Structure for HIV-1 gp120 Outer Domain by NMR Spectroscopy SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Sastry, M.; Xu, L.; Nabel, G. J.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. [Bhattacharya, S.] New York Struct Biol Ctr, New York, NY USA. [Bewley, C. A.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A27 EP A28 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500060 ER PT J AU Schifanella, L Gordon, S Vaccari, M Binello, N Caccuri, F Blackburn, M Fenizia, C Doster, M Pegu, P Liynage, N Shen, X Tomaras, G Rao, M Ferrari, G Venzon, D Stablien, D Barnett, S Tartaglia, J Franchini, G AF Schifanella, L. Gordon, S. Vaccari, M. Binello, N. Caccuri, F. Blackburn, M. Fenizia, C. Doster, M. Pegu, P. Liynage, N. Shen, X. Tomaras, G. Rao, M. Ferrari, G. Venzon, D. Stablien, D. Barnett, S. Tartaglia, J. Franchini, G. TI MF59 and ALUM, in Combination with an ALVAC-SIV/gp120 Vaccine, Induce Plasmablasts that Differ in the Expression of Homing Markers SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Schifanella, L.; Gordon, S.; Vaccari, M.; Binello, N.; Caccuri, F.; Blackburn, M.; Fenizia, C.; Doster, M.; Pegu, P.; Liynage, N.; Venzon, D.; Franchini, G.] NCI, NIH, Bethesda, MD 20892 USA. [Shen, X.; Tomaras, G.] Duke Human Vaccine Inst, Durham, NC USA. [Rao, M.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Ferrari, G.] Duke Univ, Med Ctr, Durham, NC USA. [Stablien, D.] EMMES Corp, Rockville, MD USA. [Barnett, S.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Tartaglia, J.] Sanofi Pasteur, Swiftwater, PA USA. RI Tomaras, Georgia/J-5041-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A13 EP A13 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500026 ER PT J AU Schramm, C Doria-Rose, NA Gorman, J Moore, PL Staupe, RP Zhang, Z Yang, Y Bhiman, J Georgiev, I Longo, NL Pancera, M Mullikin, JC Karim, SA Morris, L Kwong, PD Mascola, JR Shapiro, L AF Schramm, C. Doria-Rose, N. A. Gorman, J. Moore, P. L. Staupe, R. P. Zhang, Z. Yang, Y. Bhiman, J. Georgiev, I. Longo, N. L. Pancera, M. Mullikin, J. C. Karim, S. A. Morris, L. Kwong, P. D. Mascola, J. R. Shapiro, L. TI Long CDR H3 of a Broadly-Neutralizing Antibody Is Present at Recombination SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Schramm, C.; Zhang, Z.; Shapiro, L.] Columbia Univ, New York, NY USA. [Doria-Rose, N. A.; Gorman, J.; Staupe, R. P.; Yang, Y.; Georgiev, I.; Longo, N. L.; Pancera, M.; Kwong, P. D.; Mascola, J. R.] NIAID, NIH, Bethesda, MD 20892 USA. [Moore, P. L.; Bhiman, J.; Karim, S. A.; Morris, L.] Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa. [Mullikin, J. C.] 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A54 EP A54 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500133 ER PT J AU Shen, X Howington, R Park, H Sadagopal, S Kwa, S Cope, A Ding, S Bolton, D Roederer, M Amara, R Picker, L Seder, R McElrath, J Barnett, S Shattock, R Felber, B Pavlakis, G Pantaleo, G Montefiori, D Tomaras, G AF Shen, X. Howington, R. Park, H. Sadagopal, S. Kwa, S. Cope, A. Ding, S. Bolton, D. Roederer, M. Amara, R. Picker, L. Seder, R. McElrath, J. Barnett, S. Shattock, R. Felber, B. Pavlakis, G. Pantaleo, G. Montefiori, D. Tomaras, G. TI Vaccine Induced Epitope Specific Antibodies to the SIV Envelope Are Distinct from Those Induced to the HIV-1 Envelope SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Shen, X.; Howington, R.; Montefiori, D.; Tomaras, G.] Duke Univ, Durham, NC USA. [Park, H.; Picker, L.] Oregon Hlth & Sci Univ, Beaverton, OR USA. [Sadagopal, S.; Amara, R.] Emory Univ, Atlanta, GA 30322 USA. [Kwa, S.] GeoVax Inc, Smyrna, GA USA. [Cope, A.; Shattock, R.] Univ London Imperial Coll Sci Technol & Med, London, England. [Ding, S.] EuroVacc Fdn, Amsterdam, Netherlands. [Bolton, D.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Roederer, M.; Seder, R.] NIAID, NIH, Bethesda, MD 20892 USA. [McElrath, J.] Univ Washington, Seattle, WA 98195 USA. [Barnett, S.] Novartis Vaccines & Diagnost Inc, Cambridge, MA USA. [Felber, B.; Pavlakis, G.] NCI, Frederick, MD 21701 USA. [Pantaleo, G.] Univ Lausanne, Lausanne, Switzerland. RI Tomaras, Georgia/J-5041-2016; Pantaleo, Giuseppe/K-6163-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A10 EP A11 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500019 ER PT J AU Sirivichayakul, S Buranapraditkun, S Thantiworasit, P Rosati, M Felber, B Pitakpolrat, P Korber, B Ruxrungtham, K AF Sirivichayakul, S. Buranapraditkun, S. Thantiworasit, P. Rosati, M. Felber, B. Pitakpolrat, P. Korber, B. Ruxrungtham, K. TI Env-Specific Immunogenicity of Asian Mosaic HIV-1 Subtype AE/B gag/pol/env Combination and HIV-1 env Alone DNA Vaccine in BALB/c Mice SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Sirivichayakul, S.; Buranapraditkun, S.; Thantiworasit, P.; Pitakpolrat, P.; Ruxrungtham, K.] Chulalongkorn Univ, Bangkok, Thailand. [Rosati, M.; Felber, B.] NIH, Bethesda, MD 20892 USA. [Korber, B.] LANL, Los Alamos, NM 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A154 EP A154 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500402 ER PT J AU Srivatsan, S Zhou, T Zhu, J Yang, Y Du, X Zhang, B Kwong, PD AF Srivatsan, S. Zhou, T. Zhu, J. Yang, Y. Du, X. Zhang, B. Kwong, P. D. TI Characterization of Scaffolded PGT128-Specific V3-Glycopeptides for Use as HIV-1 Immunogens SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Srivatsan, S.; Zhou, T.; Zhu, J.; Yang, Y.; Du, X.; Zhang, B.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A27 EP A27 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500059 ER PT J AU Sunshine, J Kim, M Carlson, J Heckerman, D Migueles, S McElrath, J Mullins, JI Frahm, N AF Sunshine, J. Kim, M. Carlson, J. Heckerman, D. Migueles, S. McElrath, J. Mullins, J. I. Frahm, N. TI Extensive Yet Ineffective Gag Epitope Variant Recognition Observed in HIV-Progressors SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Sunshine, J.; Kim, M.; Mullins, J. I.] Univ Washington, Seattle, WA 98195 USA. [Carlson, J.; Heckerman, D.] Microsoft Res, Los Angeles, CA USA. [Migueles, S.] NIH, Bethesda, MD 20892 USA. [McElrath, J.; Frahm, N.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A127 EP A127 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500330 ER PT J AU Vaccari, M Gordon, SN Doster, M Liynage, N Pegu, P Schifanella, L Keele, BF Shen, X Tomaras, GD Rao, M Montefiori, DC Ferrari, G Foulds, K Roederer, M Venzon, D Stablein, DM Kim, JH Michael, NL Phogat, S Barnett, SW Tartaglia, J Franchini, G AF Vaccari, M. Gordon, S. N. Doster, M. Liynage, N. Pegu, P. Schifanella, L. Keele, B. F. Shen, X. Tomaras, G. D. Rao, M. Montefiori, D. C. Ferrari, G. Foulds, K. Roederer, M. Venzon, D. Stablein, D. M. Kim, J. H. Michael, N. L. Phogat, S. Barnett, S. W. Tartaglia, J. Franchini, G. TI Protection from SIVmac251 Acquisition by an ALVAC/SIV/gp120 Regimen Is Not Improved by the Increase of Anti-Envelope Antibodies and T Cell Responses SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Vaccari, M.; Gordon, S. N.; Doster, M.; Liynage, N.; Pegu, P.; Schifanella, L.; Venzon, D.; Franchini, G.] NCI, NIH, Bethesda, MD 20892 USA. [Keele, B. F.] Natl Canc Inst, SAIC Frederick, Frederick, MD USA. [Shen, X.; Tomaras, G. D.] Duke Human Vaccine Inst, Durham, NC USA. [Rao, M.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Montefiori, D. C.; Ferrari, G.] Duke Univ, Med Ctr, Durham, NC USA. [Foulds, K.; Roederer, M.] NIH, Bethesda, MD 20892 USA. [Stablein, D. M.] EMMES Corp, Rockville, MD USA. [Kim, J. H.; Michael, N. L.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Phogat, S.; Tartaglia, J.] Sanofi Pasteur, Swiftwater, PA USA. [Barnett, S. W.] Novartis Vaccines & Diagnost, Cambridge, MA USA. RI Tomaras, Georgia/J-5041-2016 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A34 EP A34 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500078 ER PT J AU Virnik, K Hockenbury, M Ni, Y Beren, J Kulkarni, V Rosati, M Alicea, C Pavlakis, GN Felber, BK Berkower, I AF Virnik, K. Hockenbury, M. Ni, Y. Beren, J. Kulkarni, V. Rosati, M. Alicea, C. Pavlakis, G. N. Felber, B. K. Berkower, I. TI HIV and SIV Vaccine Antigens Expressed by Live Attenuated Rubella Vectors Elicit Durable Immunity in Rhesus Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Virnik, K.; Hockenbury, M.; Ni, Y.; Beren, J.; Berkower, I.] FDA, Bethesda, MD USA. [Kulkarni, V.; Rosati, M.; Alicea, C.; Pavlakis, G. N.; Felber, B. K.] NCI, Frederick, MD 21701 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A36 EP A36 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500082 ER PT J AU Wang, Y Sundling, C Dai, K Wilson, R O'Dell, S Zhu, J Xiao, Y Mascola, JR Hedestam, GBK Wyatt, RT Li, Y AF Wang, Y. Sundling, C. Dai, K. Wilson, R. O'Dell, S. Zhu, J. Xiao, Y. Mascola, J. R. Hedestam, G. B. Karlsson Wyatt, R. T. Li, Y. TI Vaccine-Elicited B Cell Responses Against the HIV-1 Primary Receptor Binding Site SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Sundling, C.; Hedestam, G. B. Karlsson] Karolinska Inst, Stockholm, Sweden. [Wang, Y.; Dai, K.; Wilson, R.; Zhu, J.; Wyatt, R. T.; Li, Y.] Scripps Res Inst, La Jolla, CA 92037 USA. [O'Dell, S.; Mascola, J. R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Xiao, Y.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A170 EP A170 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500444 ER PT J AU Wieczorek, L Krebs, S Kalyanaraman, V Whitney, S Matyas, GR Rao, M Alving, CR Tong, T Molnar, S Wesberry, M Chenine, AL Tovanabutra, S Sanders-Buell, E Slike, B Alam, S Liao, H Haynes, BF Williams, C Zolla-Pazner, S Moscoso, C Cheng, H Hoelscher, M Maboko, L Michael, N Robb, ML VanCott, T Marovich, M Polonis, V AF Wieczorek, L. Krebs, S. Kalyanaraman, V. Whitney, S. Matyas, G. R. Rao, M. Alving, C. R. Tong, T. Molnar, S. Wesberry, M. Chenine, A. Laurence Tovanabutra, S. Sanders-Buell, E. Slike, B. Alam, S. Liao, H. Haynes, B. F. Williams, C. Zolla-Pazner, S. Moscoso, C. Cheng, H. Hoelscher, M. Maboko, L. Michael, N. Robb, M. L. VanCott, T. Marovich, M. Polonis, V. TI Comparable Antigenicity and Immunogenicity of Multimeric Forms of a Novel, Acute HIV-1 Subtype C Gp145 Envelope for Clinical Development SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Wieczorek, L.; Krebs, S.; Matyas, G. R.; Rao, M.; Alving, C. R.; Tong, T.; Molnar, S.; Wesberry, M.; Chenine, A. Laurence; Tovanabutra, S.; Sanders-Buell, E.; Slike, B.; Michael, N.; Robb, M. L.; Polonis, V.] Walter Reed Army Inst Res, Silver Spring, MD USA. [Wieczorek, L.; Krebs, S.; Tong, T.; Molnar, S.; Wesberry, M.; Chenine, A. Laurence; Tovanabutra, S.; Sanders-Buell, E.; Slike, B.; Robb, M. L.] Henry M Jackson Fdn, Silver Spring, MD USA. [Kalyanaraman, V.; Whitney, S.; VanCott, T.] Adv Biosci Labs Inc, Rockville, MD USA. [Matyas, G. R.; Rao, M.; Alving, C. R.; Michael, N.; Marovich, M.; Polonis, V.] US Mil HIV Res Program, Silver Spring, MD USA. [Alam, S.; Liao, H.; Haynes, B. F.] Duke Univ, Durham, NC USA. [Williams, C.; Zolla-Pazner, S.] Vet Affairs New York Harbor Healthcare Syst, New York, NY USA. [Williams, C.; Zolla-Pazner, S.] NYU, Sch Med, New York, NY USA. [Moscoso, C.; Cheng, H.] Univ Calif Davis, Davis, CA 95616 USA. [Hoelscher, M.; Maboko, L.] Mbeya Med Res Project, Munich, Germany. [Hoelscher, M.; Maboko, L.] Univ Munich, Munich, Germany. [Marovich, M.] NIH DAIDS, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A30 EP A30 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500066 ER PT J AU Williams, WB Jones, K Liu, P Trama, AM Seaton, K Moody, MA Vandergrift, N Wiehe, K Liao, H Montefiori, DC Ochsenbauer, C Kappes, J Hammer, SM Mascola, J Koup, R Corey, L Nabel, G Gilbert, P Morgan, CA Churchyard, G Maenza, J Baden, LR Keefer, M Graham, BS Tomaras, GD Haynes, BF AF Williams, W. B. Jones, K. Liu, P. Trama, A. M. Seaton, K. Moody, M. A. Vandergrift, N. Wiehe, K. Liao, H. Montefiori, D. C. Ochsenbauer, C. Kappes, J. Hammer, S. M. Mascola, J. Koup, R. Corey, L. Nabel, G. Gilbert, P. Morgan, C. A. Churchyard, G. Maenza, J. Baden, L. R. Keefer, M. Graham, B. S. Tomaras, G. D. Haynes, B. F. TI Antibody Repertoire Induced by the Multiclade (Env A, B, C) HIV-1 DNA Prime, rAd5 Boost VRC Vaccine SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Williams, W. B.; Jones, K.; Liu, P.; Trama, A. M.; Seaton, K.; Moody, M. A.; Vandergrift, N.; Wiehe, K.; Liao, H.; Montefiori, D. C.; Tomaras, G. D.; Haynes, B. F.] Duke Univ, Med Ctr, Durham, NC USA. [Ochsenbauer, C.; Kappes, J.] Univ Alabama Birmingham, Birmingham, AL USA. [Hammer, S. M.] Columbia Univ, Med Ctr, New York, NY USA. [Mascola, J.; Koup, R.; Nabel, G.; Graham, B. S.] NIAID, NIH, Bethesda, MD 20892 USA. [Corey, L.; Maenza, J.] Univ Washington, Seattle, WA 98195 USA. [Gilbert, P.; Morgan, C. A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Churchyard, G.] Aurum Inst, Johannesburg, South Africa. [Baden, L. R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Keefer, M.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RI Tomaras, Georgia/J-5041-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A9 EP A9 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500015 ER PT J AU Yang, Y Kwong, PD AF Yang, Y. Kwong, P. D. TI Microplate-Formatted Mammalian Protein Expression for Dissection and Improvement of Antibodies and Immunogens SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Yang, Y.; Kwong, P. D.] NIAID, 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A43 EP A43 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500103 ER PT J AU Zhang, B Kwon, Y Rudicell, RS McKee, K Zhang, Z Wu, X Mullikin, JC Shapiro, L Mascola, JR Kwong, PD AF Zhang, B. Kwon, Y. Rudicell, R. S. McKee, K. Zhang, Z. Wu, X. Mullikin, J. C. Shapiro, L. Mascola, J. R. Kwong, P. D. CA NISC Comparative Sequencing TI Improving HIV-1-Neutralizing Antibodies Through Use of Somatic Variants Identified by Next Generation Sequencing SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Zhang, B.; Kwon, Y.; Rudicell, R. S.; McKee, K.; Wu, X.; Mullikin, J. C.; Mascola, J. R.; Kwong, P. D.] NIH, Bethesda, MD 20892 USA. [Zhang, Z.; NISC Comparative Sequencing] Columbia Univ, New York, NY USA. RI Kwon, Young Do/A-6957-2010 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A45 EP A45 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500108 ER PT J AU Zhou, T Chen, L Lynch, R Wu, X Srivatsan, S Moquin, S Yang, Y Zhang, B Mascola, JR Kwong, PD AF Zhou, T. Chen, L. Lynch, R. Wu, X. Srivatsan, S. Moquin, S. Yang, Y. Zhang, B. Mascola, J. R. Kwong, P. D. TI Modalities of Broad and Potent Antibody Neutralization at the CD4-Binding Site on HIV-1 gp120 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Zhou, T.; Chen, L.; Lynch, R.; Wu, X.; Srivatsan, S.; Moquin, S.; Yang, Y.; Zhang, B.; Mascola, J. R.; Kwong, P. D.] NIAID, NIH, Bethesda, MD 20892 USA. RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 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 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A41 EP A41 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500097 ER PT J AU Zinszner, H Voronin, Y Allen, M Busch, M Fruth, U Golding, H Khurana, S Mulenga, J Peel, S Schito, M Fast, P AF Zinszner, H. Voronin, Y. Allen, M. Busch, M. Fruth, U. Golding, H. Khurana, S. Mulenga, J. Peel, S. Schito, M. Fast, P. TI Vaccine-Induced Antibodies: Impact for HIV Diagnosis, Clinical Trial Participants and Public Health SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT Conference on AIDS Vaccine CY OCT 07-10, 2013 CL Barcelona, SPAIN C1 [Zinszner, H.; Voronin, Y.] Global HIV Vaccine Enterprise, New York, NY USA. [Allen, M.] NIAID, NIH, Bethesda, MD 20892 USA. [Busch, M.] Blood Syst Res Inst, San Francisco, CA USA. [Fruth, U.] WHO, CH-1211 Geneva, Switzerland. [Golding, H.; Khurana, S.] US FDA, Bethesda, MD 20014 USA. [Mulenga, J.] Natl Blood Transfus Serv, Lusaka, Zambia. [Peel, S.; Schito, M.] US MHRP, Bethesda, MD USA. [Fast, P.] IAVI, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2013 VL 29 IS 11 SI SI BP A182 EP A182 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 239PI UT WOS:000326037500476 ER PT J AU Gurvich, EM Kenna, GA Leggio, L AF Gurvich, Eugenia M. Kenna, George A. Leggio, Lorenzo TI Use of Novel Technology-Based Techniques to Improve Alcohol-Related Outcomes in Clinical Trials SO ALCOHOL AND ALCOHOLISM LA English DT Review ID INTERACTIVE VOICE RESPONSE; ECOLOGICAL MOMENTARY ASSESSMENT; TIMELINE FOLLOW-BACK; MEDICATION COMPLIANCE; ANTIRETROVIRAL THERAPY; CONTINGENCY-MANAGEMENT; MONITORING-SYSTEM; DRINKING BEHAVIOR; ASSESSMENT EMA; ADHERENCE AB With a better understanding of the biologic basis of alcohol dependence and the considerable financial burden of alcohol abuse and dependence, the number of alcohol-related clinical pharmacotherapy trials has been on the rise. Subsequently, the potential to find efficacious treatments is more promising. Unfortunately, alcohol-related trials face a number of challenges, as a result of the difficulties that arise from traditional and outdated methods to collect data and ensure medication adherence. Novel technology-based assessments, such as ecological momentary assessment, interactive voice response, transdermal sensor and medication-event monitoring system provide a prospective solution-albeit not without possible concerns-to the difficulties faced in alcohol-related clinical trials. Clinical trials are meant to define the efficacy of the treatment and to determine an effective and safe dosage. However, due to lack of adherence a drug could inappropriately or mistakenly be judged as ineffective for treating a specific disorder. The described technologies may be important tools to prevent false negatives in validating drug efficacy, to provide consistency in clinical trials and to improve available data regarding the study of pharmacotherapies for alcohol dependence. C1 [Gurvich, Eugenia M.] Brown Univ, Sch Engn, Biomed Engn Undergrad Program, Providence, RI 02912 USA. [Kenna, George A.] Brown Univ, Sch Engn, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Leggio, L (reprint author), NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, 10 Ctr Dr 10CRC 15330 MSC 1108,Room 1-5429, Bethesda, MD 20892 USA. EM lorenzo.leggio@nih.gov RI Leggio, Lorenzo/M-2972-2016 FU Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA); Intramural Research Program of the National Institute on Drug Abuse (NIDA) FX Dr Leggio's research is supported by the Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Intramural Research Program of the National Institute on Drug Abuse (NIDA). NR 78 TC 10 Z9 10 U1 3 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 EI 1464-3502 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD NOV-DEC PY 2013 VL 48 IS 6 BP 712 EP 719 DI 10.1093/alcalc/agt134 PG 8 WC Substance Abuse SC Substance Abuse GA 239AJ UT WOS:000325993500014 PM 23955872 ER PT J AU Khan, H Kalogeropoulos, AP Georgiopoulou, VV Newman, AB Harris, TB Rodondi, N Bauer, DC Kritchevsky, SB Butler, J AF Khan, Hassan Kalogeropoulos, Andreas P. Georgiopoulou, Vasiliki V. Newman, Anne B. Harris, Tamara B. Rodondi, Nicolas Bauer, Douglas C. Kritchevsky, Stephen B. Butler, Javed TI Frailty and risk for heart failure in older adults: The health, aging, and body composition study SO AMERICAN HEART JOURNAL LA English DT Article ID LOWER-EXTREMITY PERFORMANCE; CARDIOVASCULAR-DISEASE; PHYSICAL FRAILTY; CONTROLLED TRIAL; EXERCISE; MORTALITY; ASSOCIATION; DISABILITY; PREDICTION; LEVEL AB Objective The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. Background Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. Methods We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. Results Mean age of participants was 74 +/- 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). Conclusions Frailty is independently associated with risk of HF in older adults. C1 [Khan, Hassan] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Kalogeropoulos, Andreas P.; Georgiopoulou, Vasiliki V.; Butler, Javed] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol & Med, Pittsburgh, PA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Lausanne Hosp, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Winston Salem, NC USA. RP Butler, J (reprint author), Emory Univ Hosp, 1462 Clifton Rd,Suite 504, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Kalogeropoulos, Andreas/A-9494-2009; Newman, Anne/C-6408-2013 OI Kalogeropoulos, Andreas/0000-0002-1284-429X; Newman, Anne/0000-0002-0106-1150 FU Intramural NIH HHS [Z01 AG007390-03] NR 38 TC 25 Z9 26 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD NOV PY 2013 VL 166 IS 5 BP 887 EP 894 DI 10.1016/j.ahj.2013.07.032 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 242IS UT WOS:000326233500015 PM 24176445 ER PT J AU Sysko, R Devlin, MJ Schebendach, J Tanofsky-Kraff, M Zimmerli, E Korner, J Yanovski, JA Zitsman, JL Walsh, BT AF Sysko, Robyn Devlin, Michael J. Schebendach, Janet Tanofsky-Kraff, Marian Zimmerli, Ellen Korner, Judith Yanovski, Jack A. Zitsman, Jeffrey L. Walsh, B. Timothy TI Hormonal responses and test meal intake among obese teenagers before and after laparoscopic adjustable gastric banding SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID PLASMA GHRELIN; ENERGY-INTAKE; WEIGHT-LOSS; ANOREXIA-NERVOSA; PUBERTAL CHANGES; ADOLESCENTS; VARIETY; SURGERY; BYPASS; PREDICTORS AB Background: Relatively little is known about changes in eating behavior or hormonal responses to food after bariatric surgery in adolescents. Objective: This study compared eating behavior and hormones among adolescents in a bariatric surgery program with those in nonoverweight control adolescents and evaluated changes before and after laparoscopic adjustable gastric banding (LAGB). Design: Fasting leptin, peptide YY (PYY), and ghrelin concentrations were obtained, and postprandial ghrelin and PYY area under the curve (AUC) were assessed after a single-item breakfast. Intake from an ad libitum lunchtime multi-item meal was measured. Results: Compared with controls (n = 9), all presurgical candidates (n = 20) had significantly greater fasting leptin, lower fasting ghrelin, and lower AUC ghrelin but similar PYY and AUC PYY. Preoperative candidates did not differ from controls in total energy consumed during the test meal. Postoperatively, among the 11 participants with data both before and after surgery, BMI (in kg/m(2)) decreased by 3.5 (P<0.001), significantly less energy was consumed in the test meal, and a smaller number of foods were selected. AUC ghrelin and PYY did not significantly change before or after LAGB. Conclusions: Few significant short-term changes were observed in appetitive hormones after LAGB. It is unclear whether objective measures of eating behavior will prove useful in evaluating the impact of bariatric surgery on outcomes. This trial was registered at clinicaltrials. gov as CT00764127. C1 [Sysko, Robyn; Devlin, Michael J.; Schebendach, Janet; Zimmerli, Ellen; Walsh, B. Timothy] New York State Psychiat Inst & Hosp, Columbia Ctr Eating Disorders, Div Clin Therapeut, New York, NY 10032 USA. [Sysko, Robyn; Devlin, Michael J.; Schebendach, Janet; Zimmerli, Ellen; Walsh, B. Timothy] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Tanofsky-Kraff, Marian] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Growth & Obes, Bethesda, MD USA. [Korner, Judith] Columbia Univ, Dept Med, New York, NY USA. [Zitsman, Jeffrey L.] Columbia Univ, Med Ctr, Ctr Adolescent Bariatr Surg, Dept Surg,Div Pediat Surg, New York, NY USA. RP Sysko, R (reprint author), New York State Psychiat Inst & Hosp, Columbia Ctr Eating Disorders, Unit 98, 1051 Riverside Dr, New York, NY 10032 USA. EM syskor@nyspi.columbia.edu OI Yanovski, Jack/0000-0001-8542-1637 FU National Institute of Diabetes and Digestive and Kidney Diseases [R21 DK074503, DK088532-01A1]; Intramural Research Program of the NIH [Z1A-HD-00641] FX Supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R21 DK074503 (to BTW) and DK088532-01A1 (to RS); and the Intramural Research Program of the NIH (Z1A-HD-00641; JAY). NR 34 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2013 VL 98 IS 5 BP 1151 EP 1161 DI 10.3945/ajcn.113.061762 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 239XJ UT WOS:000326059000003 PM 23985807 ER PT J AU Lam, TK Freedman, ND Fan, JH Qiao, YL Dawsey, SM Taylor, PR Abnet, CC AF Lam, Tram Kim Freedman, Neal D. Fan, Jin-Hu Qiao, You-Lin Dawsey, Sanford M. Taylor, Philip R. Abnet, Christian C. TI Prediagnostic plasma vitamin C and risk of gastric adenocarcinoma and esophageal squamous cell carcinoma in a Chinese population SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID HELICOBACTER-PYLORI INFECTION; NUTRITION INTERVENTION TRIAL; GENERAL-POPULATION; CANCER INCIDENCE; ASCORBIC-ACID; FOLLOW-UP; SERUM MICRONUTRIENTS; RANDOMIZED-TRIAL; MORTALITY; SUPPLEMENTATION AB Background: China has some of the highest incidence rates for gastric adenocarcinoma (GA) and esophageal squamous cell carcinoma (ESCC) in the world. Prospective studies suggested that vitamin C may reduce risks; however, associations are unclear because of limited sample size. Objective: The objective was to examine the relation between prediagnostic plasma vitamin C and the risk of GA and ESCC. Design: A case-cohort study was used to assess the association between prediagnostic plasma vitamin C and incidence of GA (n = 467) and ESCC (n = 618) in the General Population Nutrition Intervention Trial. With the use of multivariate Cox proportional hazards models, we estimated the HRs and 95% CIs. We also conducted a meta-analysis of the literature up to 1 October 2012 on the relation between circulating vitamin C and gastric cancer incidence. Two cohort studies and the current study were included to assess the body of evidence. Results: For GA, each 20-mu mol/L increase in plasma vitamin C was associated with a 14% decrease in risk (HR: 0.86; 95% CI: 0.76, 0.96). Compared with individuals with low plasma vitamin C concentrations (<= 28 mu mol/L), those with normal concentrations (>28 mu mol/L) had a 27% reduced risk of GA (HR: 0.73; 95% CI: 0.56, 0.94). No association between vitamin C concentrations and ESCC was seen. Meta-analysis showed that the risk of incident GA among those with the highest concentration of plasma vitamin C was 31% lower (random-effects-pooled-odds ratio 0.69; 95% CI: 0.54, 0.89) than those in the lowest category. Conclusion: Our data provide evidence that higher circulating vitamin C was associated with a reduced risk of incident GA, but no association was seen for ESCC. C1 [Lam, Tram Kim; Taylor, Philip R.] NCI, Div Canc Epidemiol & Genet, NIH, Genet Epidemiol Branch, Rockville, MD USA. [Freedman, Neal D.; Dawsey, Sanford M.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Nutr Epidemiol Branch, Rockville, MD USA. [Lam, Tram Kim] NCI, Div Canc Epidemiol & Genet, NIH, Div Canc Control & Populat Sci,Epidemiol & Genom, Rockville, MD USA. [Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. [Fan, Jin-Hu; Qiao, You-Lin] Peking Union Med Coll, Beijing 100021, Peoples R China. RP Lam, TK (reprint author), 9609 Med Ctr Dr,4E125, Rockville, MD 20850 USA. EM lamt@mail.nih.gov; qiaoy@cicams.ac.cn RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Supported by the Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 46 TC 13 Z9 13 U1 0 U2 10 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2013 VL 98 IS 5 BP 1289 EP 1297 DI 10.3945/ajcn.113.061267 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 239XJ UT WOS:000326059000018 PM 24025629 ER PT J AU Turkbey, B Fotin, SV Huang, RJ Yin, Y Daar, D Aras, O Bernardo, M Garvey, BE Weaver, J Haldankar, H Muradyan, N Merino, MJ Pinto, PA Periaswamy, S Choyke, PL AF Turkbey, Baris Fotin, Sergei V. Huang, Robert J. Yin, Yin Daar, Dagane Aras, Omer Bernardo, Marcelino Garvey, Brian E. Weaver, Juanita Haldankar, Hrishikesh Muradyan, Naira Merino, Maria J. Pinto, Peter A. Periaswamy, Senthil Choyke, Peter L. TI Fully Automated Prostate Segmentation on MRI: Comparison With Manual Segmentation Methods and Specimen Volumes SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE fully automated segmentation; MRI; prostate; segmentation; volume ID TRANSRECTAL ULTRASONOGRAPHY; RADICAL PROSTATECTOMY; ANTIGEN DENSITY; GLAND VOLUME; CANCER; ACCURACY; BIOPSY; IMAGES; ULTRASOUND; PREDICT AB OBJECTIVE. The objective of our study was to compare calculated prostate volumes derived from tridimensional MR measurements (ellipsoid formula), manual segmentation, and a fully automated segmentation system as validated by actual prostatectomy specimens. MATERIALS AND METHODS. Ninety-eight consecutive patients (median age, 60.6 years; median prostate-specific antigen [PSA] value, 6.85 ng/mL) underwent triplane T2-weighted MRI on a 3-T magnet with an endorectal coil while undergoing diagnostic workup for prostate cancer. Prostate volume estimates were determined using the formula for ellipsoid volume based on tridimensional measurements, manual segmentation of triplane MRI, and automated segmentation based on normalized gradient fields cross-correlation and graph-search refinement. Estimates of prostate volume based on ellipsoid volume, manual segmentation, and automated segmentation were compared with prostatectomy specimen volumes. Prostate volume estimates were compared using the Pearson correlation coefficient and linear regression analysis. The Dice similarity coefficient was used to quantify spatial agreement between manual segmentation and automated segmentation. RESULTS. The Pearson correlation coefficient revealed strong positive correlation between prostatectomy specimen volume and prostate volume estimates derived from manual segmentation (R = 0.89-0.91, p < 0.0001) and automated segmentation (R = 0.88-0.91, p < 0.0001). No difference was observed between manual segmentation and automated segmentation. Mean partial and full Dice similarity coefficients of 0.92 and 0.89, respectively, were achieved for axial automated segmentation. CONCLUSION. Prostate volume estimates obtained with a fully automated 3D segmentation tool based on normalized gradient fields cross-correlation and graph-search refinement can yield highly accurate prostate volume estimates in a clinically relevant time of 10 seconds. This tool will assist in developing a broad range of applications including routine prostate volume estimations, image registration, biopsy guidance, and decision support systems. C1 [Turkbey, Baris; Huang, Robert J.; Daar, Dagane; Aras, Omer; Bernardo, Marcelino; Garvey, Brian E.; Weaver, Juanita; Choyke, Peter L.] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Fotin, Sergei V.; Yin, Yin; Haldankar, Hrishikesh; Muradyan, Naira; Periaswamy, Senthil] iCAD Inc, Nashua, NH USA. [Merino, Maria J.] NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, NIH, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Rm B69, Bethesda, MD 20892 USA. EM pchoyke@mail.nih.gov NR 28 TC 4 Z9 4 U1 0 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD NOV PY 2013 VL 201 IS 5 BP W720 EP W729 DI 10.2214/AJR.12.9712 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 240LO UT WOS:000326097900009 PM 24147502 ER PT J AU Golding, A Hasni, S Illei, G Shevach, EM AF Golding, Amit Hasni, Sarfaraz Illei, Gabor Shevach, Ethan M. TI The Percentage of FoxP3+Helios + Treg Cells Correlates Positively With Disease Activity in Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; REGULATORY T-CELLS; REVISED CRITERIA; FOXP3 EXPRESSION; DISEASE-ACTIVITY; CLASSIFICATION; PHENOTYPE AB ObjectiveTo assess the use of Helios in combination with FoxP3 as a superior method for identifying non-cytokine-producing human Treg cells in patients with systemic lupus erythematosus (SLE) and to determine if FoxP3+Helios+ Treg cells are maintained at normal levels in patients with clinically active disease. MethodsPeripheral blood mononuclear cells (PBMCs) were purified from the blood of healthy volunteer donors and from 52 consecutive patients with SLE of varying clinical activity (Systemic Lupus Erythematosus Disease Activity Index scores of 0, 2-4, and 5). PBMCs (either fresh or after 4 hours of stimulation for cytokine production) were then analyzed by flow cytometry for the expression of cell surface markers (CD4, CD25, CD127, and CD45RA) and transcription factors (FoxP3 and Helios), as well as for the production of cytokines (interleukin-2 and interferon-). ResultsFoxP3+Helios+ Treg cells were found to be non-cytokine producing in both SLE patients and healthy controls. Patients with clinically active SLE had higher percentages of FoxP3+Helios+ Treg cells than did patients with inactive SLE or healthy controls. When corrected for the total CD4 cell count, the absolute numbers of FoxP3+Helios+ Treg cells in patients with moderately-to-highly active SLE were normal. ConclusionPrevious reports of a deficiency in Treg cell number or function in SLE are limited by their use of CD25, either alone or in combination with other markers, to identify human Treg cells. Helios in combination with FoxP3 is a superior method for detecting all non-cytokine-producing Treg cells, irrespective of CD25 or CD45RA expression. Using this method, we showed that FoxP3+Helios+ Treg cell numbers are not reduced in patients with clinically active SLE. C1 [Shevach, Ethan M.] NIAID, NIH, Bethesda, MD 20892 USA. [Hasni, Sarfaraz] NIAMSD, NIH, Bethesda, MD 20892 USA. [Illei, Gabor] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Golding, A (reprint author), Univ Maryland, Sch Med, Div Rheumatol & Clin Immunol, 10 South Pine St,MSTF Bldg 8-34, Baltimore, MD 21201 USA. EM agolding@medicine.umaryland.edu OI Golding, Amit/0000-0003-3659-6654 FU NIH (Intramural Research Programs of the National Institute of Allergy and Infectious Diseases); NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases); NIH (National Institute of Dental and Craniofacial Research) FX Supported by the NIH (Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute of Dental and Craniofacial Research). NR 29 TC 28 Z9 29 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 EI 1529-0131 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD NOV PY 2013 VL 65 IS 11 BP 2898 EP 2906 DI 10.1002/art.38119 PG 9 WC Rheumatology SC Rheumatology GA 241AG UT WOS:000326138200019 PM 23925905 ER PT J AU Moran, ME Hulshoff Pol, H Gogtay, N AF Moran, Marcel E. Hulshoff Pol, Hilleke Gogtay, Nitin TI A family affair: brain abnormalities in siblings of patients with schizophrenia SO BRAIN LA English DT Review DE schizophrenia; imaging; grey matter; endophenotype ID CHILDHOOD-ONSET SCHIZOPHRENIA; DIZYGOTIC TWINS DISCORDANT; VOXEL-BASED MORPHOMETRY; GRAY-MATTER DEFICITS; NONPSYCHOTIC SIBLINGS; HEALTHY SIBLINGS; UNAFFECTED SIBLINGS; HIPPOCAMPAL VOLUME; WHITE-MATTER; INTERMEDIATE-PHENOTYPE AB Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development. C1 [Moran, Marcel E.; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20814 USA. [Hulshoff Pol, Hilleke] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. RP Moran, ME (reprint author), NIMH, Child Psychiat Branch Bldg 10,10 Ctr Dr,RM 3N202, Bethesda, MD 20814 USA. EM marcel.moran@nih.gov RI Hulshoff Pol, Hilleke/B-4795-2014; Gogtay, Nitin/A-3035-2008 OI Hulshoff Pol, Hilleke/0000-0002-2038-5281; FU Intramural Research Program (IRP) at the National Institute of Mental Health in Bethesda, MD FX The present research was funded by the Intramural Research Program (IRP) at the National Institute of Mental Health in Bethesda, MD. NR 87 TC 21 Z9 21 U1 5 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD NOV PY 2013 VL 136 BP 3215 EP 3226 DI 10.1093/brain/awt116 PN 11 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 243BQ UT WOS:000326291800009 PM 23698280 ER PT J AU Gallea, C Popa, T Hubsch, C Valabregue, R Brochard, V Kundu, P Schmitt, B Bardinet, E Bertasi, E Flamand-Roze, C Alexandre, N Delmaire, C Meneret, A Depienne, C Poupon, C Hertz-Pannier, L Cincotta, M Vidailhet, M Lehericy, S Meunier, S Roze, E AF Gallea, Cecile Popa, Traian Hubsch, Cecile Valabregue, Romain Brochard, Vanessa Kundu, Prantik Schmitt, Benoit Bardinet, Eric Bertasi, Eric Flamand-Roze, Constance Alexandre, Nicolas Delmaire, Christine Meneret, Aurelie Depienne, Christel Poupon, Cyril Hertz-Pannier, Lucie Cincotta, Massimo Vidailhet, Marie Lehericy, Stephane Meunier, Sabine Roze, Emmanuel TI RAD51 deficiency disrupts the corticospinal lateralization of motor control SO BRAIN LA English DT Article DE motor disorders; genetics; corticospinal pathways; transcallosal inhibition; movement coordination ID CONGENITAL MIRROR MOVEMENTS; LINKED KALLMANNS-SYNDROME; TRANSCRANIAL MAGNETIC STIMULATION; INTERHEMISPHERIC INHIBITION; GENETIC-HETEROGENEITY; CORTICAL POTENTIALS; CORPUS-CALLOSUM; DCC MUTATION; CORTEX; PROJECTIONS AB Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 +/- 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 +/- 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system. C1 [Gallea, Cecile; Popa, Traian; Valabregue, Romain; Bardinet, Eric; Bertasi, Eric; Alexandre, Nicolas; Lehericy, Stephane] Ctr Neuroimagerie Rech CENIR, Inst Cerveau & Moelle Epiniere ICM, F-75651 Paris 13, France. [Gallea, Cecile; Popa, Traian; Hubsch, Cecile; Meneret, Aurelie; Depienne, Christel; Vidailhet, Marie; Lehericy, Stephane; Meunier, Sabine; Roze, Emmanuel] Univ Paris 06, CNRS UMR 7225, Ctr Rech, Inserm U975,UMR S975,Inst Cerveau & Moelle Epinie, Paris, France. [Hubsch, Cecile; Meneret, Aurelie; Vidailhet, Marie; Roze, Emmanuel] Grp Hosp Pitie Salpetriere, AP HP, Dept Neurol, Paris, France. [Brochard, Vanessa] AP HP, INSERM, Ctr Invest Clin 9503, Paris, France. [Kundu, Prantik] NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. [Schmitt, Benoit] CEA, I2BM, Lab Imagerie & Spect RMN, Gif Sur Yvette, France. [Flamand-Roze, Constance] Hop Bicetre, AP HP, Serv Neurol, Paris, France. [Delmaire, Christine] CHRU Lille, Dept Neuroradiol, F-59037 Lille, France. [Hertz-Pannier, Lucie] CEA, I2BM, Lab Rech Biomed, Neurospin, Gif Sur Yvette, France. [Cincotta, Massimo] Azienda Sanitaria Firenze, Unita Operat Neurol, Osped San Giovanni di Dio, I-50124 Florence, Italy. RP Gallea, C (reprint author), Hop La Pitie Salpetriere, Inst Cerveau & Moelle, Ctr Neuroimagerie Rech CENIR, 47-83 Blvd Hop, F-75651 Paris 13, France. EM cecile.gallea.icm@gmail.com RI meunier, sabine/G-7622-2014; Popa, Traian/B-7691-2016 OI meunier, sabine/0000-0002-6167-4602; Popa, Traian/0000-0003-1160-4830 FU Fondation pour la Recherche Medicale (FRM); AP-HP; CNRS from 'COSSEC-INSERM'; IHU-A-ICM [ANR-10-IAIHU-06]; IPSEN FX The authors would like to thank the Fondation pour la Recherche Medicale (FRM, grant to C.G., programme 'Espoir de la recherche', financement 'Post-doctorat en France'), AP-HP and CNRS ('Poste d'Accueil' for E.R., and funding to E.R. from 'COSSEC-INSERM') for their funding support and the IHU-A-ICM for their financial contribution and logistic support ('Investissement d'avenir' program, ANR-10-IAIHU-06). This work was also supported by Djilali Mehri and by an unrestricted grant from IPSEN. NR 69 TC 17 Z9 17 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 EI 1460-2156 J9 BRAIN JI Brain PD NOV PY 2013 VL 136 BP 3333 EP 3346 DI 10.1093/brain/awt258 PN 11 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 243BQ UT WOS:000326291800017 PM 24056534 ER PT J AU Kobrinsky, B Joseph, SO Muggia, F Liebes, L Beric, A Malankar, A Ivy, P Hochster, H AF Kobrinsky, B. Joseph, S. O. Muggia, F. Liebes, L. Beric, A. Malankar, A. Ivy, P. Hochster, H. TI A phase I and pharmacokinetic study of oxaliplatin and bortezomib: activity, but dose-limiting neurotoxicity SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Proteasome inhibitor; Bortezomib; Oxaliplatin; Neurotoxicity; Ataxia; Sensory neuropathy; Oxaliplatin pharmacokinetics ID PROTEASOME INHIBITOR BORTEZOMIB; METASTATIC COLORECTAL-CANCER; PHARMACODYNAMIC END-POINTS; SOLID TUMORS; TRIAL; 5-FLUOROURACIL; NEUROPATHY AB The potential synergy of modulating platinum-induced DNA damage by combining the proteasome inhibitor bortezomib with oxaliplatin was studied in patients with solid tumors, with special attention to avoidance of cumulative neurotoxicity (NT). In a 3 + 3 dose escalation design, patients received bortezomib at 1.0-1.5 mg/m(2) on days 1 and 4 and oxaliplatin at 60-85 mg/m(2) on day 1 of a 14-day cycle. NT assessments were performed at the start of every two cycles. Oxaliplatin pharmacokinetics (PK) were determined pre- and post-bortezomib. Thirty patients were enrolled with 25 (11 men, 14 women) fully evaluable for NT assessments at cycle 2. The median age was 56 years (range 35-74 years); median number of cycles received 2 (range 1-10). At dose levels 2-5 (B 1.3 mg/m(2)), patients manifested NT grades 3 and 4 at a median 3.4 cycles (range 2-9 cycles): 3 had ataxia (one also with sensory neuropathy or neurogenic hypotension, respectively) and 3 had just sensory neuropathy. A 6th dose-level reducing bortezomib to 1.0 mg/m(2) with oxaliplatin 85 mg/m(2)) was explored and no NT or dose limiting toxicities were noted among 7 evaluable patients (5 receiving two or more cycles). Four patients experienced a partial response-one with platinum-resistant ovarian cancer, another with gastroesophageal cancer, another with ampulla of Vater carcinoma, and a patient with cholangiocarcinoma. PK studies at dose levels 1 and 2 showed greater mean ultrafiltrable platinum when oxaliplatin was dosed after bortezomib. Bortezomib 1.0 mg/m(2) x 2 every 14 days combines safely with oxaliplatin. At higher doses, cumulative NT (i.e., cerebellar signs and sensory neuropathy) occurs at an accelerated pace perhaps from a PK interaction. C1 [Kobrinsky, B.; Joseph, S. O.; Muggia, F.; Liebes, L.] NYU, Sch Med, Div Hematol & Oncol, New York, NY 10016 USA. [Beric, A.] NYU, Sch Med, Dept Neurol, New York, NY 10016 USA. [Malankar, A.] NYU, Clin Trials Off, Inst Canc, New York, NY 10016 USA. [Ivy, P.] NCI, Bethesda, MD 20892 USA. [Hochster, H.] Yale Univ, Sch Med, Div Med Oncol, New Haven, CT USA. RP Muggia, F (reprint author), NYU, Sch Med, Div Hematol & Oncol, 550 1st Ave,OBV C&D Bldg Rm 556, New York, NY 10016 USA. EM Franco.Muggia@nyumc.org OI Beric, Aleksandar/0000-0003-4177-2632; Muggia, Franco/0000-0003-0703-9146 NR 19 TC 3 Z9 4 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2013 VL 72 IS 5 BP 1073 EP 1078 DI 10.1007/s00280-013-2295-6 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 240MJ UT WOS:000326100400014 PM 24048674 ER PT J AU Cho, H Lee, YS Kim, J Chung, JY Kim, JH AF Cho, Hanbyoul Lee, You Sun Kim, Julie Chung, Joon-Yong Kim, Jae-Hoon TI Overexpression of Glucose Transporter-1 (GLUT-1) Predicts Poor Prognosis in Epithelial Ovarian Cancer SO CANCER INVESTIGATION LA English DT Article DE GLUT-1; Ovarian cancer; Microarray; Biomarker; Immunohistochemistry ID GLUCOSE-TRANSPORTER; EXPRESSION; CARCINOMA; SURVIVAL; ANGIOGENESIS; CELLS AB Illumina microarray was used to identify differentially expressed genes in three epithelial ovarian cancer (EOC) cells. To validate themicroarray data, mRNA and protein level of glucose transporter-1 (GLUT-1) was examined. GLUT-1 had an EOC/normal cells ratio of 5.51 based on microarray. Real-time PCR and immunohistochemistry demonstrated that GLUT-1 expression was significantly increased in EOC (p=.029 and p<.001, respectively). On survival analysis, GLUT-1 overexpression (HR= 4.80, p=.027) and lymph nodemetastases (HR= 8.35, p=.016) conferred a significantly worse overall survival. In conclusion, GLUT-1 expression is remarkably upregulated in EOC and predicts a poor overall survival. C1 [Cho, Hanbyoul; Lee, You Sun; Kim, Julie; Kim, Jae-Hoon] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Kim, Julie; Chung, Joon-Yong] NCI, Appl Mol Pathol Lab, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, JH (reprint author), Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, 146-92 Dogok Dong, Seoul 135720, South Korea. EM jaehoonkim@yuhs.ac OI Chung, Joon-Yong/0000-0001-5041-5982 FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0005230, 2011-0010286, 2011-0007146]; Yonsei University College of Medicine [3-2010-0072, 6-2011-0073] FX This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286, and 2011-0007146) and faculty research grants from Yonsei University College of Medicine for 2010 and 2011 (3-2010-0072 and 6-2011-0073). NR 24 TC 15 Z9 15 U1 2 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0735-7907 EI 1532-4192 J9 CANCER INVEST JI Cancer Invest. PD NOV PY 2013 VL 31 IS 9 BP 607 EP 615 DI 10.3109/07357907.2013.849722 PG 9 WC Oncology SC Oncology GA 244HC UT WOS:000326377300007 PM 24164300 ER PT J AU Kim, J Kim, Y Tae, J Yeom, M Moon, B Huang, XP Roth, BL Lee, K Rhim, H Choo, IH Chong, Y Keum, G Nam, G Choo, H AF Kim, Jeeyeon Kim, Youngjae Tae, Jinsung Yeom, Miyoung Moon, Bongjin Huang, Xi-Ping Roth, Bryan L. Lee, Kangho Rhim, Hyewhon Choo, Il Han Chong, Youhoon Keum, Gyochang Nam, Ghilsoo Choo, Hyunah TI Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists SO CHEMMEDCHEM LA English DT Article DE antagonists; biaryls; aryl piperazines; receptors; structure-activity relationships ID SEROTONIN RECEPTOR; MOLECULAR-CLONING; HIGH-AFFINITY; SPINAL 5-HT7; LIGANDS; SELECTIVITY; AGONIST; DERIVATIVES; INHIBITION; ACTIVATION AB The 5-HT7 receptor (5-HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7R. Among the synthesized compounds, 1-([2-methoxy-(1,1-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7R (pK(i)=7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7R over other serotonin receptor subtypes, such as 5-HT1R, 5-HT2R, 5-HT3R, and 5-HT6R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. C1 [Kim, Jeeyeon; Kim, Youngjae; Yeom, Miyoung; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah] Korea Inst Sci & Technol, Ctr Neuromed, Seoul 136791, South Korea. [Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung] Yonsei Univ, Dept Chem, Seoul 120749, South Korea. [Yeom, Miyoung; Moon, Bongjin] Sogang Univ, Dept Chem, Seoul 121742, South Korea. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. [Lee, Kangho; Rhim, Hyewhon] Korea Inst Sci & Technol, Ctr Neurosci, Seoul 136791, South Korea. [Lee, Kangho; Rhim, Hyewhon] Univ Sci & Technol, Dept Neurosci, Taejon 305350, South Korea. [Choo, Il Han] Chosun Univ, Sch Med, Kwangju 501759, South Korea. [Chong, Youhoon] Konkuk Univ, Dept Biosci & Biotechnol, Seoul 143701, South Korea. [Choo, Hyunah] Univ Sci & Technol, Dept Biol Chem, Taejon 305350, South Korea. RP Nam, G (reprint author), Korea Inst Sci & Technol, Ctr Neuromed, Seongbuk gu, Seoul 136791, South Korea. EM gsnam@kist.re.kr; hchoo@kist.re.kr RI Keum, Gyochang/E-7492-2013; Roth, Bryan/F-3928-2010 OI Keum, Gyochang/0000-0001-8767-8022; FU US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]; National Research Foundation of Korea (NRF); Korean Ministry of Education, Science and Technology: the Basic Science Research Program [NRF-2013-R1A1A2A10009907]; Priority Research Centers Program [2012-0006686]; Korea Institute of Science and Technology (KIST) Institutional Program [2E23770] FX Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (contract: HHSN-271-2008-00025-C). This research was supported by two programs of the National Research Foundation of Korea (NRF) funded by the Korean Ministry of Education, Science and Technology: the Basic Science Research Program (NRF-2013-R1A1A2A10009907) and the Priority Research Centers Program (2012-0006686). Additional funding was provided by the Korea Institute of Science and Technology (KIST) Institutional Program (2E23770). NR 42 TC 4 Z9 4 U1 0 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD NOV PY 2013 VL 8 IS 11 BP 1855 EP 1864 DI 10.1002/cmdc.201300240 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 241RP UT WOS:000326185500016 PM 24039134 ER PT J AU Enoch, MA AF Enoch, Mary-Anne TI Genetic Influences on the Development of Alcoholism SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Alcohol use disorders; ALDH2; ADH1B; GABRA2; GABRG1; AUTS2; SGIP1; 5-HTTLPR; HTR2B; HTR3B; HTR3A; CRHR1; MAOA; CHD13; Childhood trauma; Gene-environment interactions; Flushing response; Addictions array; GWAS; Exome sequencing; RNA-Seq; GSA; COGA; NESARC; Pharmacogenetics ID GENOME-WIDE ASSOCIATION; NATIONAL EPIDEMIOLOGIC SURVEY; MU-OPIOID RECEPTOR; DRUG-DEPENDENCE; USE DISORDERS; LINKAGE DISEQUILIBRIUM; METABOLIZING GENES; JEWISH POPULATION; CANDIDATE GENES; FAMILY-HISTORY AB Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive. The strongest findings are with genes encoding alcohol metabolizing enzymes. A few candidate genes such as GABRA2 have shown robust associations with alcoholism. Moreover, it has become apparent that variants in stress-related genes such as CRHR1, may only confer risk in individuals exposed to trauma, particularly in early life. Over the past decade there have been tremendous advances in large scale SNP genotyping technologies allowing for genomewide associations studies (GWAS). As a result, it is now recognized that genetic risk for alcoholism is likely to be due to common variants in very many genes, each of small effect, although rare variants with large effects might also play a role. This has resulted in a paradigm shift away from gene centric studies toward analyses of gene interactions and gene networks within biologically relevant pathways. C1 [Enoch, Mary-Anne] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Enoch, Mary-Anne] NIAAA, NIH, DICBR, LNG, Bethesda, MD 20892 USA. RP Enoch, MA (reprint author), NIAAA, NIH, DICBR, LNG, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@niaaa.nih.gov FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 82 TC 19 Z9 20 U1 10 U2 55 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD NOV PY 2013 VL 15 IS 11 AR 412 DI 10.1007/s11920-013-0412-1 PG 9 WC Psychiatry SC Psychiatry GA 241SG UT WOS:000326187300009 PM 24091936 ER PT J AU Hong, CW Nam, AS Keller, HR Ligons, DL Park, JY Yoon, HW Park, JJ Luckey, MA Park, JH AF Hong, Changwan Nam, Anna S. Keller, Hilary R. Ligons, Davinna L. Park, Joo-Young Yoon, Hee-Won Park, Joseph J. Luckey, Megan A. Park, Jung-Hyun TI Interleukin-6 expands homeostatic space for peripheral T cells SO CYTOKINE LA English DT Article DE Apoptosis; Cytokine; Survival; Proliferation; Thymus ID MYELIN OLIGODENDROCYTE GLYCOPROTEIN; TRANSGENIC MICE; IN-VIVO; GROWTH-FACTOR; AUTOIMMUNE ENCEPHALOMYELITIS; IL-6-DEFICIENT MICE; RECEPTOR EXPRESSION; SIGNAL TRANSDUCER; FAMILY CYTOKINES; UP-REGULATION AB T cell homeostasis and survival is dependent on interleukin-7 (IL-7). Immune activation, however, downregulates IL-7 receptor expression on T cells so that T cell survival during activation must be maintained independently of IL-7. The pro-inflammatory cytokine IL-6 shares common signaling pathways with IL-7 and can promote T cell survival in vitro. But whether IL-6 promotes T cell survival and homeostasis in vivo is not clear. Notably, IL-6 overexpression results in massive plasmacytosis and autoimmunity so that an IL-6 effect on in vivo T cell survival has remained untested. To overcome this limitation, here we generated IL-6 transgenic mice on an immunoglobulin heavy chain (IgH) deficient background which rendered them B cell deficient. Notably, such IgH(KO)IL6(Tg) mice were free of any signs of inflammation or autoimmunity and remained healthy throughout the course of analysis. In these mice, we found that IL-6 overexpression significantly increased peripheral T cell numbers, but importantly without increasing thymopoiesis. Moreover, IL-6 signaled T cells maintained their naive phenotype and did not express activation/memory markers, suggesting that increased T cell numbers were due to increased T cell survival and not because of expansion of activated T cells. Mechanistically, we found that IL-6 signaling induced expression of pro-survival factors Mcl-1 and Pim-1/-2 but not Bcl-2. Thus, IL-6 is a T cell homeostatic cytokine that expands T cell space and can maintain the naive T cell pool. Published by Elsevier Ltd. C1 [Hong, Changwan; Nam, Anna S.; Keller, Hilary R.; Ligons, Davinna L.; Park, Joo-Young; Yoon, Hee-Won; Park, Joseph J.; Luckey, Megan A.; Park, Jung-Hyun] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Nam, Anna S.] Univ Missouri, Sch Med, Columbia, MO 65201 USA. [Nam, Anna S.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Park, JH (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 5B17,10 Ctr Dr, Bethesda, MD 20892 USA. EM parkhy@mail.nih.gov RI Park, Jung Hyun /B-5712-2015; Davis, Megan/F-5339-2015; OI Park, Jung Hyun /0000-0002-9547-9055; Park, Joseph/0000-0003-1311-5416 FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Drs. A. Singer and R. Etzensperger for critical review of this manuscript. We thank Drs. Wayne Chu and Phil Lucas for providing us reagents and protocol for performing TREC assays. This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 65 TC 3 Z9 3 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD NOV PY 2013 VL 64 IS 2 BP 532 EP 540 DI 10.1016/j.cyto.2013.08.001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 242QT UT WOS:000326257800010 PM 23988623 ER PT J AU Collette, NM Yee, CS Murugesh, D Sebastian, A Taher, L Gale, NW Economides, AN Harland, RM Loots, GG AF Collette, Nicole M. Yee, Cristal S. Murugesh, Deepa Sebastian, Aimy Taher, Leila Gale, Nicholas W. Economides, Aris N. Harland, Richard M. Loots, Gabriela G. TI Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner SO DEVELOPMENTAL BIOLOGY LA English DT Article DE WNT signaling; Sost; Sclerostin; Sostdc1; Shh; Limb formation; Polydactyly; syndactyly ID BONE MORPHOGENETIC PROTEIN; BMP ANTAGONIST; POLARIZING ACTIVITY; TARGETED DELETION; WNT/BETA-CATENIN; SONIC-HEDGEHOG; GENE-1 USAG-1; PROBE LEVEL; SCLEROSTIN; MOUSE AB WNT signaling is critical in most aspects of skeletal development and homeostasis, and antagonists of WNT signaling are emerging as key regulatory proteins with great promise as therapeutic agents for bone disorders. Here we show that Sost and its paralog Sostdc1 emerged through ancestral genome duplication and their expression patterns have diverged to delineate non-overlapping domains in most organ systems including musculoskeletal, cardiovascular, nervous, digestive, reproductive and respiratory. In the developing limb, Sost and Sostdc1 display dynamic expression patterns with Sost being restricted to the distal ectoderm and Sostdc1 to the proximal ectoderm and the mesenchyme. While Sostdc1(-/-) mice lack any obvious limb or skeletal defects, Sost(-/-) mice recapitulate the hand defects described for Sclerosteosis patients. However, elevated WNT signaling in Sost(-/-); Sostdc1(-/-) mice causes misregulation of SHH signaling, ectopic activation of Sox9 in the digit 1 field and preaxial polydactyly in a Gli1- and Gli3-dependent manner. In addition, we show that the syndactyly documented in Sclerosteosis is present in both Sost(-/-) and Sost(-/-); Sostdc1(-/-) mice, and is driven by misregulation of Fgf8 in the AER, a region lacking Sost and Sostdc1 expression. This study highlights the complexity of WNT signaling in skeletal biology and disease and emphasizes how redundant mechanism and non-cell autonomous effects can synergize to unveil new intricate phenotypes caused by elevated WNT signaling. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Collette, Nicole M.; Yee, Cristal S.; Murugesh, Deepa; Sebastian, Aimy; Loots, Gabriela G.] Lawrence Livermore Natl Lab, Biol & Biotechnol Div, Livermore, CA 94550 USA. [Yee, Cristal S.; Sebastian, Aimy; Loots, Gabriela G.] Univ Calif, Sch Nat Sci, Merced, CA USA. [Taher, Leila] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Taher, Leila] Univ Rostock, Inst Biostat & Informat Med & Ageing Res, D-18055 Rostock, Germany. [Gale, Nicholas W.; Economides, Aris N.] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Harland, Richard M.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Loots, GG (reprint author), Lawrence Livermore Natl Lab, Biol & Biotechnol Div, 7000 East Ave,L-452, Livermore, CA 94550 USA. EM loots1@llnl.gov OI Economides, Aris/0000-0002-6508-8942; Sebastian, Aimy/0000-0002-7822-7040 FU National Institutes of Health (NIH) Knock-Out Mouse Program (KOMP); NIH [HD47853, DK075730]; U.S. Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344]; NIH, NLM FX We would like to thank the National Institutes of Health (NIH) Knock-Out Mouse Program (KOMP) and Regeneron for providing the Sost and Sostdc1 knockout mice. NMC, CV, DM and GGL were supported by NIH Grant HD47853 and DK075730. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. LT was supported by the Intramural Research Program of the NIH, NLM. NR 72 TC 9 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 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD NOV 1 PY 2013 VL 383 IS 1 BP 90 EP 105 DI 10.1016/j.ydbio.2013.08.015 PG 16 WC Developmental Biology SC Developmental Biology GA 239WX UT WOS:000326057800011 PM 23994639 ER PT J AU Werner, JM Abdalla, A Gara, N Ghany, MG Rehermann, B AF Werner, Jens M. Abdalla, Adil Gara, Naveen Ghany, Marc G. Rehermann, Barbara TI The Hepatitis B Vaccine Protects Re-Exposed Health Care Workers, But Does Not Provide Sterilizing Immunity SO GASTROENTEROLOGY LA English DT Article DE Immunization; Immune Response; T Cell; Virus ID SURFACE-ANTIGEN; RESPONSES; ANTIBODY; BOOSTER; IMMUNOGENICITY; RECOVERY; EFFICACY; DECADES AB BACKGROUND & AIMS: Infection with hepatitis B virus (HBV) can be prevented by vaccination with HB surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for health care workers who were vaccinated as adults. METHODS: We investigated the immune mechanisms (antibody and T-cell responses) of long-term protection by the HBV vaccine in 90 health care workers with or without occupational exposure to HBV, 10-28 years after vaccination. RESULTS: Fifty-nine of 90 health care workers (65%) had levels of antibodies to HBs antigen above the cut-off (> 12 mIU/mL) and 30 of 90 (33%) had HBs-specific T cells that produced interferon-gamma. Titers of antibodies to HBs antigen correlated with numbers of HBs-specific interferon-gamma-producing T cells, but not with time after vaccination. Although occupational exposure to HBV after vaccination did not induce antibodies to the HBV core protein (HBcore), the standard biomarker for HBV infection, CD4(+) and CD8(+) T cells against HBcore and polymerase antigens were detected. Similar numbers of HBcore- and polymerase-specific CD4(+) and CD8(+) T cells were detected in health care workers with occupational exposure to HBV and in patients who acquired immunity via HBV infection. Most of the HBcore- and polymerase-specific T cells were CD45RO(+) CCR7(-)CD127(-) effector memory cells in exposed health care workers and in patients with acquired immunity. In contrast, most of the vaccine-induced HBs-specific T cells were CD45RO(-)CCR7(-)CD127(-) terminally differentiated cells. CONCLUSIONS: HBs antigen vaccine-induced immunity protects against future infection but does not provide sterilizing immunity, as evidenced by HBcore- and polymerase-specific CD8(+) T cells in vaccinated health care workers with occupational exposure to HBV. The presence of HBcore- and HBV polymerase-specific T-cell responses is a more sensitive indicator of HBV exposure than detection of HBcore-specific antibodies. C1 [Werner, Jens M.; Rehermann, Barbara] NIDDK, Immunol Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Werner, Jens M.; Abdalla, Adil; Gara, Naveen; Ghany, Marc G.; Rehermann, Barbara] NIDDK, Liver Dis Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,US Dept HHS, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM Rehermann@nih.gov OI Werner, Jens/0000-0001-7156-4370 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program; Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany [We-4675/1-1] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program. JMW was supported by grant We-4675/1-1 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany. NR 21 TC 15 Z9 16 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD NOV PY 2013 VL 145 IS 5 BP 1026 EP 1034 DI 10.1053/j.gastro.2013.07.044 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 238UV UT WOS:000325977600029 PM 23916846 ER PT J AU McDonald, CL AF McDonald, Cheryl L. TI Dr. Sonia Skarlatos and the National Heart, Lung, and Blood Institute Translational Research and Resource Programs SO HUMAN GENE THERAPY LA English DT Review ID LEFT-VENTRICULAR FUNCTION; CELL THERAPY RESEARCH; ACUTE MYOCARDIAL-INFARCTION; MARROW MONONUCLEAR-CELLS; RESEARCH NETWORK CCTRN; GENE-THERAPY; RANDOMIZED-TRIAL; DELIVERY; DISEASES; NHLBI AB Sonia I. Skarlatos, PhD (September 28, 1953-August 6, 2013), was the deputy director of the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI). This article reviews her work in establishing, leading, or facilitating extramural translational research programs supported by the NHLBI, specifically focusing on her work as a consistent advocate for the advancement of gene and cell therapies. C1 [McDonald, Cheryl L.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP McDonald, CL (reprint author), 6701 Rockledge Dr Room 8114,MSC 7940, Bethesda, MD 20892 USA. EM mcdonalc@nhlbi.nih.gov NR 17 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD NOV 1 PY 2013 VL 24 IS 11 BP 899 EP 905 DI 10.1089/hum.2013.2511 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 241QZ UT WOS:000326183700003 PM 24164237 ER PT J AU Grassi, MFR Olavarria, VN Kruschewsky, RD Yamano, Y Jacobson, S Taylor, GP Martin, F Galvao-Castro, B AF Rios Grassi, Maria Fernanda Olavarria, Viviana Nilla Kruschewsky, Ramon de Almeida Yamano, Yoshihisa Jacobson, Steven Taylor, Graham P. Martin, Fabiola Galvao-Castro, Bernardo TI Utility of HTLV proviral load quantification in diagnosis of HTLV-1-associated myelopathy requires international standardization SO JOURNAL OF CLINICAL VIROLOGY LA English DT Article DE HTLV-1; Proviral load; HAM/TSP; Cut-off value; Diagnosis ID LYMPHOTROPIC VIRUS TYPE-1; SPASTIC PARAPARESIS HAM/TSP; VIRAL LOAD; ASYMPTOMATIC CARRIERS; PERIPHERAL-BLOOD; INFECTION; CRITERIA; DISEASE; MARKER; ASSAYS C1 [Rios Grassi, Maria Fernanda; Galvao-Castro, Bernardo] Fundacao Oswaldo Cruz, Goncalo Moniz Ctr, Adv Lab Publ Hlth, Salvador, BA, Brazil. [Rios Grassi, Maria Fernanda; Olavarria, Viviana Nilla; Kruschewsky, Ramon de Almeida; Galvao-Castro, Bernardo] Bahiana Sch Med & Publ Hlth EBMSP, Salvador, BA, Brazil. [Yamano, Yoshihisa] St Marianna Univ, Sch Med, Inst Med Sci, Dept Rare Dis Res, Kawasaki, Kanagawa, Japan. [Jacobson, Steven] NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. [Taylor, Graham P.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Infect Dis Sect, London, England. [Martin, Fabiola] Univ York, Hull & York Med Sch, Dept Biol, Ctr Immunol & Infect, York YO10 5DD, N Yorkshire, England. RP Grassi, MFR (reprint author), Fundacao Oswaldo Cruz Bahia FIOCRUZ, Goncalo Moniz Ctr, Adv Lab Publ Hlth, Rua Waldemar Falcao 121, BR-40296710 Salvador, BA, Brazil. EM grassi@bahia.fiocruz.br; vini_olavarria@hotmail.com; ramonkruschewsky@bahiana.edu.br; yyamano@marianna-u.ac.jp; jacobsons@ninds.nih.gov; g.p.taylor@imperial.ac.uk; fabiola.martin@hyms.ac.uk; bgalvao@bahiana.edu.br FU Fundacao de Amparo a Pesquisa da Bahia (FAPESB) FX Fundacao de Amparo a Pesquisa da Bahia (FAPESB). NR 17 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1386-6532 EI 1873-5967 J9 J CLIN VIROL JI J. Clin. Virol. PD NOV PY 2013 VL 58 IS 3 BP 584 EP 586 DI 10.1016/j.jcv.2013.09.003 PG 3 WC Virology SC Virology GA 241OK UT WOS:000326176400017 PM 24095029 ER PT J AU Acquavella, N Fojo, T AF Acquavella, Nicolas Fojo, Tito TI Renal Cell Carcinoma: Trying but Failing to Improve the Only Curative Therapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Editorial Material ID PHASE-III TRIAL; RECOMBINANT INTERLEUKIN-2 THERAPY; ENDOTHELIAL GROWTH-FACTOR; HIGH-DOSE INTERLEUKIN-2; METASTATIC MELANOMA; ADOPTIVE IMMUNOTHERAPY; COMPLETE RESPONSES; INTERFERON-ALPHA; DOUBLE-BLIND; CANCER C1 [Acquavella, Nicolas; Fojo, Tito] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Ctr Canc Res, NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM acquavellapesn@mail.nih.gov; fojot@mail.nih.gov NR 38 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 EI 1537-4513 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2013 VL 36 IS 9 BP 459 EP 461 DI 10.1097/CJI.0000000000000002 PG 3 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 242WH UT WOS:000326275000001 PM 24145356 ER PT J AU Mazzetto-Betti, KC Leoni, RF Pontes-Neto, OM Sturzbecher, MJ Santos, AC Leite, JP Silva, AC de Araujo, DB AF Mazzetto-Betti, Kelley C. Leoni, Renata F. Pontes-Neto, Octavio M. Sturzbecher, Marcio J. Santos, Antonio C. Leite, Joao P. Silva, Afonso C. de Araujo, Draulio B. TI Quantification of BOLD fMRI Parameters to Infer Cerebrovascular Reactivity of the Middle Cerebral Artery SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE BOLD; fMRI; hypercapnia; cerebrovascular reactivity; auditory stimulus; middle cerebral artery ID LEVEL-DEPENDENT MRI; FUNCTIONAL MRI; BLOOD-FLOW; HYPERCAPNIA; BRAIN; REPRODUCIBILITY; STIMULATION; DISEASE; STROKE; MODEL AB PurposeTo quantify the amplitude and temporal aspects of the blood oxygenation level-dependent (BOLD) response to an auditory stimulus during normocapnia and hypercapnia in healthy subjects in order to establish which BOLD parameters are best suited to infer the cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA) territory. Materials and MethodsTwenty healthy volunteers (mean age: 23.6 3.7 years, 11 women) were subjected to a functional paradigm composed of five epochs of auditory stimulus (3 sec) intercalated by six intervals of rest (21 sec). Two levels of hypercapnia were achieved by a combination of air and CO2 while the end-tidal CO2 (ETCO2) was continually measured. An autoregressive method was applied to analyze four parameters of the BOLD signal: onset-time, time-to-peak, full-width-at-half-maximum (FWHM), and amplitude. ResultsBOLD onset time (P < 0.001) and full-width at half-maximum (FWHM) (P < 0.05) increased linearly, while BOLD amplitude decreased (P < 0.001) linearly with increasing levels of hypercapnia. Test-retest for reproducibility in five subjects revealed excellent concordance for onset time and amplitude. ConclusionThe robust linear dependence of BOLD onset time, FWHM, and amplitude to hypercapnia suggest future application of this protocol in clinical studies aimed at evaluating CVR of the MCA territory. J. Magn. Reson. Imaging 2013;38:1203-1209. (c) 2012 Wiley Periodicals, Inc. C1 [Mazzetto-Betti, Kelley C.; Leoni, Renata F.; Pontes-Neto, Octavio M.; Sturzbecher, Marcio J.; Santos, Antonio C.; Leite, Joao P.; de Araujo, Draulio B.] Univ Sao Paulo, Dept Neurosci & Behav Sci, FMRP, BR-14049 Ribeirao Preto, Brazil. [Leoni, Renata F.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Sturzbecher, Marcio J.; de Araujo, Draulio B.] Univ Sao Paulo, Dept Phys, FFCLRP, BR-14049 Ribeirao Preto, Brazil. [de Araujo, Draulio B.] Univ Fed Rio Grande do Norte, Onofre Lopes Univ Hosp, BR-59072970 Natal, RN, Brazil. [de Araujo, Draulio B.] Univ Fed Rio Grande do Norte, Inst Brain, BR-59072970 Natal, RN, Brazil. RP de Araujo, DB (reprint author), Univ Fed Rio Grande do Norte, Inst Brain, R Nascimento Castro 2155, BR-59056450 Natal, RN, Brazil. EM draulio@neuro.ufrn.br RI Leite, Joao/B-9070-2012; Pontes-Neto, Octavio/G-4294-2012; Araujo, Draulio/I-6038-2012; OI Leite, Joao/0000-0003-0558-3519; Pontes-Neto, Octavio/0000-0003-0317-843X; Araujo, Draulio/0000-0002-6934-2485; Leoni, Renata/0000-0002-4568-0746 FU FAPESP [2009/08691-7]; NIH; CNPq; CAPES; NINDS FX Contract grant sponsor: FAPESP; Contract grant number: 2009/08691-7; Contract grant sponsor: Intramural Research Program of the NIH, NINDS (Alan P. Koretsky, Scientific Director), CNPq and CAPES. NR 20 TC 0 Z9 0 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD NOV PY 2013 VL 38 IS 5 BP 1203 EP 1209 DI 10.1002/jmri.23943 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 241DP UT WOS:000326146900025 PM 23188762 ER PT J AU Shah, S Lie, RK AF Shah, Seema Lie, Reidar K. TI Aiming at a moving target: research ethics in the context of evolving standards of care and prevention SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE Ethics Committees; Consultation; Research Ethics; Applied and Professional Ethics; Codes of; Position Statements on Professional Ethics; HIV Infection and AIDS ID INTERNATIONAL CONSENSUS OPINION; PRACTICE GUIDELINES; CLINICAL-TRIALS; THERAPY; DEBATE AB In rapidly evolving medical fields where the standard of care or prevention changes frequently, guidelines are increasingly likely to conflict with what participants receive in research. Although guidelines typically set the standard of care, there are some cases in which research can justifiably deviate from guidelines. When guidelines conflict with research, an ethical issue only arises if guidelines are rigorous and should be followed. Next, it is important that the cumulative evidence and the conclusions reached by the guidelines do not eliminate the need for further research. Even when guidelines are rigorous and the study still asks an important question, we argue that there may be good reasons for deviations in three cases: (1) when research poses no greater net risk than the standard of care; (2) when there is a continued need for additional evidence, for example, when subpopulations are not covered by the guidelines; and (3) less frequently, when clinical practice guidelines can be justified by the evidence, but practitioners disagree about the guidelines, and the guidelines are not consistently followed as a result. We suggest that procedural protections may be especially useful in deciding when studies in the third category can proceed. C1 [Shah, Seema] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Lie, Reidar K.] Univ Bergen, Dept Philosophy, Bergen, Norway. RP Shah, S (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM shahse@mail.nih.gov FU NIH Clinical Center; Division of AIDS at the National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH Clinical Center and by the Division of AIDS at the National Institute of Allergy and Infectious Diseases. NR 23 TC 1 Z9 1 U1 1 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD NOV PY 2013 VL 39 IS 11 BP 699 EP 702 DI 10.1136/medethics-2012-100502 PG 4 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 240HX UT WOS:000326087200011 PM 23322683 ER PT J AU Brim, RL Miller, FG AF Brim, Remy L. Miller, Franklin G. TI The potential benefit of the placebo effect in sham-controlled trials: implications for risk-benefit assessments and informed consent SO JOURNAL OF MEDICAL ETHICS LA English DT Article DE Research Ethics; Policy Guidelines; Inst; Review Boards; Review Cttes; Informed Consent ID PARKINSONS-DISEASE; DOPAMINE RELEASE; CLINICAL-TRIALS; SURGERY; EXPECTATION; ETHICS; PAIN; ACUPUNCTURE; ANALGESIA; OUTCOMES AB There has been considerable debate surrounding the ethics of sham-controlled trials of procedures and interventions. Critics argue that these trials are unethical because participants assigned to the control group have no prospect of benefit from the trial, yet they are exposed to all the risks of the sham intervention. However, the placebo effect associated with sham procedures can often be substantial and has been well documented in the scientific literature. We argue that, in light of the scientific evidence supporting the benefits of sham interventions for pain and Parkinson's disease that stem from the placebo effect, these sham-controlled trials should be considered as offering potential direct benefit to participants. If scientific evidence demonstrates the positive effect of placebo from sham interventions on other conditions, sham-controlled trials of interventions for the treatment of these conditions should be considered to have prospects of benefit as well. This potential benefit should be taken into account by research ethics committees in risk-benefit analyses, and be included in informed consent documents. C1 [Brim, Remy L.; Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM FMiller@cc.nih.gov FU National Institutes of Health Clinical Center FX This research was supported by the intramural research program of the National Institutes of Health Clinical Center. NR 27 TC 5 Z9 5 U1 1 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 EI 1473-4257 J9 J MED ETHICS JI J. Med. Ethics PD NOV PY 2013 VL 39 IS 11 BP 703 EP 707 DI 10.1136/medethics-2012-101045 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 240HX UT WOS:000326087200012 PM 23239742 ER PT J AU Plazinska, A Kolinski, M Wainer, IW Jozwiak, K AF Plazinska, Anita Kolinski, Michal Wainer, Irving W. Jozwiak, Krzysztof TI Molecular interactions between fenoterol stereoisomers and derivatives and the beta(2)-adrenergic receptor binding site studied by docking and molecular dynamics simulations SO JOURNAL OF MOLECULAR MODELING LA English DT Article DE beta(2) adrenergic receptor; GPCRs; Docking; Fenoterol; Molecular dynamics; Stereoisomers ID BETA-ADRENERGIC-RECEPTOR; PROTEIN-COUPLED RECEPTOR; HIGH-AFFINITY BINDING; STRUCTURE PREDICTION; BETA-2-ADRENERGIC RECEPTOR; CRYSTAL-STRUCTURE; PARTIAL AGONISTS; FIELD ANALYSIS; AMINO-ACID; ACTIVATION AB The beta(2) adrenergic receptor (beta(2)-AR) has become a model system for studying the ligand recognition process and mechanism of the G protein coupled receptors activation. In the present study stereoisomers of fenoterol and some of its derivatives (N = 94 molecules) were used as molecular probes to identify differences in stereo-recognition interactions between beta(2)-AR and structurally similar agonists. The present study aimed at determining the 3D molecular models of the fenoterol derivative-beta(2)-AR complexes. Molecular models of beta(2)-AR have been developed by using the crystal structure of the human beta(2)-AR T4 lysozyme fusion protein with bound (S)-carazolol (PDB ID: 2RH1) and more recently reported structure of a nanobody-stabilized active state of the beta(2)-AR with the bound full agonist BI-167107 (PDB ID: 3P0G). The docking procedure allowed us to study the similarities and differences in the recognition binding site(s) for tested ligands. The agonist molecules occupied the same binding region, between TM III, TM V, TM VI and TM VII. The residues identified by us during docking procedure (Ser203, Ser207, Asp113, Lys305, Asn312, Tyr308, Asp192) were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions. Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Furthermore, the molecular dynamics simulations were used to study the molecular mechanism of interaction between ligands ((R,R')- and (S,S')-fenoterol) and beta(2)-AR. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member. This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms. C1 [Plazinska, Anita; Kolinski, Michal; Jozwiak, Krzysztof] Med Univ Lublin, Lab Med Chem & Neuroengn, PL-20093 Lublin, Poland. [Kolinski, Michal] Polish Acad Sci, Mossakowski Med Res Ctr, Bioinformat Lab, PL-02106 Warsaw, Poland. [Wainer, Irving W.] NIA, Lab Clin Invest, Baltimore, MD 21224 USA. RP Jozwiak, K (reprint author), Med Univ Lublin, Lab Med Chem & Neuroengn, Ul Chodzki 4A, PL-20093 Lublin, Poland. EM krzysztof.jozwiak@umlub.pl OI Plazinska, Anita/0000-0002-3698-2574 FU Polish Ministry of Science and Higher Education [N N405 617238]; Foundation for Polish Science [TEAM 2009-4/5, FOCUS 4/2006] FX The work was supported by the Polish Ministry of Science and Higher Education (Grant no. N N405 617238), by the Foundation for Polish Science (TEAM 2009-4/5 and FOCUS 4/2006 programmes), and using the equipment purchased within the Project "The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases" within the Operational Program Development of Eastern Poland 2007- 2013, Priority Axis I Modern Economy, Operations I. 3 Innovation Promotion. The research was also supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging; by the National Institutes of Health National Institute on Aging [Contract N01-AG31009]. NR 43 TC 10 Z9 10 U1 0 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1610-2940 EI 0948-5023 J9 J MOL MODEL JI J. Mol. Model. PD NOV PY 2013 VL 19 IS 11 BP 4919 EP 4930 DI 10.1007/s00894-013-1981-y PG 12 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications SC Biochemistry & Molecular Biology; Biophysics; Chemistry; Computer Science GA 241UH UT WOS:000326193200032 PM 24043542 ER PT J AU Nicastro, HL Firestone, GL Bjeldanes, LF AF Nicastro, Holly L. Firestone, Gary L. Bjeldanes, Leonard F. TI 3,3 '-Diindolylmethane rapidly and selectively inhibits hepatocyte growth factor/c-Met signaling in breast cancer cells SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE 3,3 '-diindolylmethane; Akt; c-Met; Breast cancer ID TYROSINE KINASE; EPIDEMIOLOGIC EVIDENCE; BRASSICA VEGETABLES; PROSTATE-CANCER; KAPPA-B; EXPRESSION; ACTIVATION; APOPTOSIS; RECEPTOR; RISK AB 3,3'-Diindolylmethane (DIM), an indole derivative from vegetables of the Brassica genus, has antiproliferative activity in breast cancer cells. Part of this activity is thought to be due to DIM inhibition of Akt signaling, but an upstream mechanism of DIM-induced Akt inhibition has not been described. The goals of this study were to investigate the kinetics of inhibition of Akt by physiologically relevant concentrations of DIM and to identify an upstream factor that mediates this effect. Here we report that DIM (5-25 mu M) inhibited Akt activation from 30 min to 24 h in tumorigenic MDA-MB-231 cells but did not inhibit Ala activation in non-tumorigenic preneoplastic MCF10AT cells. DIM inhibited hepatocyte growth factor (HGF)-induced Akt activation by up to 46%, cell migration by 66% and cell proliferation by up to 54%, but did not inhibit induction of Akt by epidermal growth factor or insulin-like growth factor-1. DIM decreased phosphorylation of the HGF receptor, c-Met, at tyrosines 1234 and 1235, indicating decreased activation of the receptor. This decrease was reversed by pretreatment with inhibitors of p38 or calcineurin. Our results demonstrate the important role of HGF and c-Met in DIM's anti-proliferative effect on breast cancer cells and suggest that DIM could have preventive or clinical value as an inhibitor of c-Met signaling. (C) 2013 Elsevier Inc. All rights reserved. C1 [Nicastro, Holly L.; Bjeldanes, Leonard F.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Firestone, Gary L.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Nicastro, HL (reprint author), NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Rockville, MD 20852 USA. EM holly.nicastro@nih.gov FU National Institutes of Health [CA 69056]; California Breast Cancer Research Program [14GB-0142] FX Grant CA 69056 from the National Institutes of Health, fellowship support for H.L.N. from California Breast Cancer Research Program 14GB-0142. NR 42 TC 8 Z9 8 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 EI 1873-4847 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD NOV PY 2013 VL 24 IS 11 BP 1882 EP 1888 DI 10.1016/j.jnutbio.2013.05.004 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 241AV UT WOS:000326139700012 PM 23968581 ER PT J AU Maggio, M Cattabiani, C Lauretani, F Bandinelli, S De Vita, F Dall'Aglio, E Corsonello, A Lattanzio, F Paolisso, G Ferrucci, L Ceda, GP AF Maggio, Marcello Cattabiani, Chiara Lauretani, Fulvio Bandinelli, Stefania De Vita, Francesca Dall'Aglio, Elisabetta Corsonello, Andrea Lattanzio, Fabrizia Paolisso, Giuseppe Ferrucci, Luigi Ceda, Gian Paolo TI Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE IGF-1 bioactivity; IGF-binding proteins; Mortality; Older participants ID FACTOR-BINDING PROTEIN-1; ACUTE MYOCARDIAL-INFARCTION; IGF-I; NITRIC-OXIDE; ELDERLY-MEN; FACTOR AXIS; LIFE-SPAN; CARDIOVASCULAR MORTALITY; COLORECTAL-CANCER; RANCHO-BERNARDO AB The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age-and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population. C1 [Maggio, Marcello; Cattabiani, Chiara; De Vita, Francesca; Dall'Aglio, Elisabetta; Ceda, Gian Paolo] Univ Parma, Sect Geriatr, Dept Clin & Expt Med, I-43100 Parma, Italy. [Maggio, Marcello; Lauretani, Fulvio; Ceda, Gian Paolo] Univ Hosp Parma, Geriatr Rehabil Dept, Geriatr Unit, Parma, Italy. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Florence, Italy. [Corsonello, Andrea] INRCA, Unit Geriatr Pharmacoepidemiol, Cosenza, Italy. [Lattanzio, Fabrizia] INRCA Ancona, Sci Direct, Ancona, Italy. [Paolisso, Giuseppe] Univ Naples 2, Dept Geriatr & Metab Dis, Naples, Italy. [Ferrucci, Luigi] NIA, NIH, Baltimore, MD 21224 USA. RP Maggio, M (reprint author), Univ Parma, Sect Geriatr, Dept Clin & Expt Med, Via Gramsci 14, I-43100 Parma, Italy. EM marcellomaggio2001@yahoo.it RI Lauretani, Fulvio/K-5115-2016; OI Paolisso, Giuseppe/0000-0002-2137-455X; Lauretani, Fulvio/0000-0002-5287-9972; Ceda, Gian Paolo/0000-0002-9648-8295 FU Italian Ministry of Health [ICS 110.1/RS97.71, RF-2010-2312659]; U.S. National Institute on Aging [N01-AG-916413, N01-AG-821336]; Intramural Research Program of the U.S. National Institute on Aging [263 MD 916413, 263 MD 821336]; Emilia Romagna Region FX The InCHIANTI study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health, the U.S. National Institute on Aging (contracts N01-AG-916413 and N01-AG-821336), in part, the Intramural Research Program of the U.S. National Institute on Aging (contracts 263 MD 916413 and 263 MD 821336), and grant RF-2010-2312659 from the Italian Ministry of Health and Emilia Romagna Region. None of the sponsoring institutions interfered with the collection, analysis, presentation, or interpretation of the data reported here. NR 61 TC 4 Z9 4 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 EI 1758-535X J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD NOV PY 2013 VL 68 IS 11 BP 1342 EP 1350 DI 10.1093/gerona/glt045 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 239BP UT WOS:000325996800004 PM 23671288 ER PT J AU Rosso, AL Studenski, SA Chen, WG Aizenstein, HJ Alexander, NB Bennett, DA Black, SE Camicioli, R Carlson, MC Ferrucci, L Guralnik, JM Hausdorff, JM Kaye, J Launer, LJ Lipsitz, LA Verghese, J Rosano, C AF Rosso, Andrea L. Studenski, Stephanie A. Chen, Wen G. Aizenstein, Howard J. Alexander, Neil B. Bennett, David A. Black, Sandra E. Camicioli, Richard Carlson, Michelle C. Ferrucci, Luigi Guralnik, Jack M. Hausdorff, Jeffrey M. Kaye, Jeff Launer, Lenore J. Lipsitz, Lewis A. Verghese, Joe Rosano, Caterina TI Aging, the Central Nervous System, and Mobility SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Motor control; Central nervous system; Mobility ID FUNCTIONING OLDER-ADULTS; MILD COGNITIVE IMPAIRMENT; LOWER-EXTREMITY FUNCTION; GAIT SPEED; DUAL-TASK; EXECUTIVE FUNCTION; FALL RISK; BRAIN; DECLINE; WALKING AB Background. Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies. Methods. A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults. Results. Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches. Conclusions. In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations. C1 [Rosso, Andrea L.; Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Studenski, Stephanie A.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Chen, Wen G.] NIA, Div Neurosci, Bethesda, MD 20892 USA. [Aizenstein, Howard J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Alexander, Neil B.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Black, Sandra E.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Neurol, Dept Med, Toronto, ON M5S 1A1, Canada. [Camicioli, Richard] Univ Alberta, Dept Med, Div Neurol, Edmonton, AB T6G 2R3, Canada. [Carlson, Michelle C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Hausdorff, Jeffrey M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hausdorff, Jeffrey M.] Tel Aviv Sourasky Med Ctr, Dept Neurol, Tel Aviv, Israel. [Kaye, Jeff] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Lipsitz, Lewis A.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Lipsitz, Lewis A.] Hebrew Senior Life, Inst Aging Res, Boston, MA USA. [Lipsitz, Lewis A.] Harvard Univ, Sch Med, Boston, MA USA. [Verghese, Joe] Yeshiva Univ, Dept Neurol, Albert Einstein Coll Med, New York, NY 10033 USA. RP Rosano, C (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Aging & Populat Hlth, 130 North Bellefield St,Room 507, Pittsburgh, PA 15213 USA. EM rosanoc@edc.pitt.edu OI Rosso, Andrea/0000-0001-5890-9856; Black, Sandra/0000-0001-7093-8289; Kaye, Jeffrey/0000-0002-9971-3478; Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010; Camicioli, Richard/0000-0003-2977-8660 FU National Institute on Aging [U13-AG-041613-01, T32-AG-000181]; University of Pittsburgh Claude D. Pepper Older Americans Independence Center (National Institute on Aging) [P30-AG-024827] FX This work was supported by a co-operative conference grant (National Institute on Aging, U13-AG-041613-01), the University of Pittsburgh Claude D. Pepper Older Americans Independence Center (National Institute on Aging, P30-AG-024827), and a postdoctoral training grant (National Institute on Aging, T32-AG-000181). NR 57 TC 45 Z9 45 U1 4 U2 25 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 NOV PY 2013 VL 68 IS 11 BP 1379 EP 1386 DI 10.1093/gerona/glt089 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 239BP UT WOS:000325996800007 PM 23843270 ER PT J AU Sutin, AR Zonderman, AB Ferrucci, L Terracciano, A AF Sutin, Angelina R. Zonderman, Alan B. Ferrucci, Luigi Terracciano, Antonio TI Personality Traits and Chronic Disease: Implications for Adult Personality Development SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Disease burden; Illness; Openness; Personality change; Personality traits ID ALZHEIMER-DISEASE; LIFE-SPAN; OLD-AGE; HEALTH; CONSCIENTIOUSNESS; DEPRESSION; METAANALYSIS; IMPULSIVITY; PERSPECTIVE; IMPAIRMENT AB Objective. Personality traits have been associated with chronic disease. Less is known about the longitudinal relation between personality and disease and whether chronic disease is associated with changes in personality. Method. Participants from the Baltimore Longitudinal Study of Aging (N = 2,008) completed the Revised NEO Personality Inventory and a standard medical interview at regularly scheduled visits; the Charlson Comorbidity Index, a weighted sum of 19 serious diseases, was derived from this interview. Using data from 6,685 visits, we tested whether personality increased risk of disease and whether disease was associated with personality change. Results. Measured concurrently, neuroticism and conscientiousness were associated with greater disease burden. The impulsiveness facet of neuroticism was the strongest predictor of developing disease across the follow-up period: For every standard deviation increase in impulsiveness, there was a 26% increased risk of developing disease and a 36% increased risk of getting more ill. Personality traits changed only modestly with disease: As participants developed chronic illnesses, they became more conservative (decreased openness). Discussion. This research indicates that personality traits confer risk for disease, in part, through health-risk behaviors. These traits, however, were relatively resistant to the effect of serious disease. C1 [Sutin, Angelina R.] Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, Tallahassee, FL 32306 USA. [Sutin, Angelina R.; Terracciano, Antonio] NIA, NIH, Baltimore, MD 21224 USA. [Zonderman, Alan B.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Geriatr, Tallahassee, FL 32306 USA. RP Sutin, AR (reprint author), Florida State Univ, Coll Med, Dept Med Humanities & Social Sci, NIH,DHHS, 1115 W Call St, Tallahassee, FL 32306 USA. EM angelina.sutin@med.fsu.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was supported, in part, by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 58 TC 22 Z9 22 U1 4 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 EI 1758-5368 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2013 VL 68 IS 6 BP 912 EP 920 DI 10.1093/geronb/gbt036 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 240TQ UT WOS:000326120600007 PM 23685925 ER PT J AU Ginsberg, MD Palesch, YY Hill, MD Martin, RH Moy, CS Barsan, WG Waldman, BD Tamariz, D Ryckborst, KJ AF Ginsberg, Myron D. Palesch, Yuko Y. Hill, Michael D. Martin, Renee H. Moy, Claudia S. Barsan, William G. Waldman, Bonnie D. Tamariz, Diego Ryckborst, Karla J. CA ALIAS Neurological Emergencies Treatment TI High-dose albumin treatment for acute ischaemic stroke (ALIAS) part 2: a randomised, double-blind, phase 3, placebo-controlled trial SO LANCET NEUROLOGY LA English DT Article ID FOCAL CEREBRAL-ISCHEMIA; MARKED NEUROPROTECTIVE EFFICACY; TISSUE-PLASMINOGEN ACTIVATOR; LOCAL VASCULAR DYNAMICS; PLATELET-AGGREGATION; GLYCINE ANTAGONIST; SERUM-ALBUMIN; PILOT TRIAL; RAT MODEL; THERAPY AB Background In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome. Methods We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495. Findings 422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 0.96, 95% CI 0.84-1.10, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%. Interpretation Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome. C1 [Ginsberg, Myron D.; Tamariz, Diego] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33101 USA. [Palesch, Yuko Y.; Martin, Renee H.; Waldman, Bonnie D.] Med Univ S Carolina, Dept Publ Hlth Sci, Data Coordinat Unit, Charleston, SC 29425 USA. [Hill, Michael D.; Ryckborst, Karla J.] Univ Calgary, Dept Clin Neurosci, Calgary Stroke Program, Calgary, AB, Canada. [Hill, Michael D.; Ryckborst, Karla J.] Univ Calgary, Hotchkiss Brain Inst, Dept Community Hlth Serv, Dept Med,Dept Radiol, Calgary, AB, Canada. [Hill, Michael D.; Ryckborst, Karla J.] Foothills Prov Gen Hosp, Calgary, AB T2N 2T9, Canada. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, Off Clin Res, Bethesda, MD USA. [Barsan, William G.] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. RP Ginsberg, MD (reprint author), Univ Miami, Miller Sch Med, Dept Neurol D4 5, POB 016960, Miami, FL 33101 USA. EM mginsberg@med.miami.edu RI Hill, Michael/C-9073-2012 OI Hill, Michael/0000-0002-6269-1543 FU National Institute of Neurological Disorders and Stroke, US National Institutes of Health; Baxter Healthcare Corporation FX Funding National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation. NR 54 TC 44 Z9 48 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2013 VL 12 IS 11 BP 1049 EP 1058 DI 10.1016/S1474-4422(13)70223-0 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 239ZC UT WOS:000326063500007 PM 24076337 ER PT J AU Mukamal, KJ Wilk, JB Biggs, ML Jensen, MK Ix, JH Kizer, JR Tracy, RP Zieman, SJ Mozaffarian, D Psaty, BM Siscovick, DS Djousse, L AF Mukamal, Kenneth J. Wilk, Jemma B. Biggs, Mary L. Jensen, Majken K. Ix, Joachim H. Kizer, Jorge R. Tracy, Russell P. Zieman, Susan J. Mozaffarian, Dariush Psaty, Bruce M. Siscovick, David S. Djousse, Luc TI Common FABP4 Genetic Variants and Plasma Levels of Fatty Acid Binding Protein 4 in Older Adults SO LIPIDS LA English DT Article DE Fatty acid binding proteins; Metabolism; Genetics ID METABOLIC SYNDROME; DIABETES RISK; ASSOCIATION; LOCI; MICE; OBESITY; DESIGN AB We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p a parts per thousand currency sign 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels. C1 [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Wilk, Jemma B.; Djousse, Luc] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02120 USA. [Wilk, Jemma B.; Mozaffarian, Dariush; Djousse, Luc] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Biggs, Mary L.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Jensen, Majken K.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ix, Joachim H.] Univ Calif San Diego, Nephrol Sect, Vet Affairs San Diego Healthcare Syst, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Med, New York, NY USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Publ Hlth, New York, NY USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. [Zieman, Susan J.] NIA, NIH, Bethesda, MD 20892 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02120 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Ctr Geriatr Res Educ & Clin, Boston, MA USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr, Boston, MA USA. RP Wilk, JB (reprint author), Brigham & Womens Hosp, Dept Med, Div Aging, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM jemmawilk@gmail.com; ldjousse@partners.org RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU NHLBI [N01-HC-65226, HHSN268201200036C, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL094555, HL080295]; National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058] FX Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. The research reported in this article was supported by contracts HHSN268201200036C, 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, and grants HL094555 (to Drs. Djousse, Ix, Mukamal, Zieman, and Kizer) and HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. NR 20 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 EI 1558-9307 J9 LIPIDS JI Lipids PD NOV PY 2013 VL 48 IS 11 BP 1169 EP 1175 DI 10.1007/s11745-013-3838-7 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 239TD UT WOS:000326047500010 PM 24043587 ER PT J AU Wang, LD Bi, XL Song, X Pohl, NM Cheng, YL Zhou, YX Shears, S Ansong, E Xing, MT Wang, SM Xu, XC Huang, P Xu, LY Wang, L Fan, ZM Zhao, XK Dong, HL Meltzer, SJ Ding, I Yang, WC AF Wang, Li-Dong Bi, Xiuli Song, Xin Pohl, Nicole M. Cheng, Yulan Zhou, Yixing Shears, Stephen Ansong, Emmanuel Xing, Mengtao Wang, Shaomeng Xu, Xiao-Chun Huang, Peng Xu, Liyan Wang, Liang Fan, Zongmin Zhao, Xueke Dong, Huali Meltzer, Stephen J. Ding, Ivan Yang, Wancai TI A Sequence Variant in the Phospholipase C Epsilon C2 Domain Is Associated With Esophageal Carcinoma and Esophagitis SO MOLECULAR CARCINOGENESIS LA English DT Article DE phospholipase C epsilon; esophageal cancer; esophagitis ID SQUAMOUS-CELL CARCINOMA; CRUCIAL ROLE; DEPENDENT ACTIVATION; RAS; CANCER; RHO; INFLAMMATION; DISTINCT; GROWTH; PLCE1 AB A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCE) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCE and this SNP in esophageal carcinogenesis, we analyzed PLCE genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCE mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59-22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33-1.64 in low-incidence area; P=0.008). In conclusion, the PLCE gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCE mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction. (c) 2013 Wiley Periodicals, Inc. C1 [Wang, Li-Dong; Song, Xin; Wang, Liang; Zhao, Xueke; Ding, Ivan; Yang, Wancai] Xinxiang Med Univ, Dept Pathol, Xinxiang 453003, Peoples R China. [Wang, Li-Dong; Fan, Zongmin] Zhengzhou Univ, Henan Key Lab Esophageal Canc Res, Affiliated Hosp 1, Zhengzhou 450052, Peoples R China. [Bi, Xiuli; Pohl, Nicole M.; Ansong, Emmanuel; Xing, Mengtao; Yang, Wancai] Univ Illinois, Dept Pathol, Chicago, IL USA. [Bi, Xiuli] Liaoning Univ, Sch Life Sci, Shenyang 110036, Peoples R China. [Cheng, Yulan; Meltzer, Stephen J.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol, Baltimore, MD 21205 USA. [Zhou, Yixing; Shears, Stephen] NIEHS, Inositol Signaling Grp, NIH, Res Triangle Pk, NC 27709 USA. [Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Wang, Shaomeng] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Wang, Shaomeng] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Wang, Shaomeng] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. [Xu, Xiao-Chun] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Huang, Peng] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA. [Xu, Liyan] Shantou Univ Med Coll, Dept Pathol, Shantou, Peoples R China. [Wang, Liang] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Dong, Huali] Univ Illinois, Ctr Canc, Chicago, IL USA. RP Yang, WC (reprint author), Xinxiang Med Univ, Dept Pathol, Xinxiang 453003, Peoples R China. FU National Institutes of Health, USA [CA112081]; Xinxiang Medical University; China National Natural Science Foundation [30670956, 30971133, 91229115]; Program of Liaoning Excellent Talents in University (LETU) [LJQ2011002]; NIH/National Institute of Environmental Health Sciences; [CA146799]; [DK087454] FX Contract grant sponsor: National Institutes of Health, USA; Contract grant number: CA112081 (to W. Yang); Contract grant sponsor:; Contract grant number: CA146799 and DK087454 (to S.J. Meltzer); Contract grant sponsor: Xinxiang Medical University Key Scientific Program 2009-5; Contract grant sponsor: China National Natural Science Foundation; Contract grant numbers: 30670956; 30971133 (to L. D. Wang); 91229115 (to W. Yang); Contract grant sponsor: Program of Liaoning Excellent Talents in University (LETU); Contract grant number: LJQ2011002 (to X. Bi); Contract grant sponsor: Intramural Research Program of the NIH/National Institute of Environmental Health Sciences (to S. Shears). NR 26 TC 5 Z9 6 U1 3 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 EI 1098-2744 J9 MOL CARCINOGEN JI Mol. Carcinog. PD NOV PY 2013 VL 52 SU 1 SI SI BP 80 EP 86 DI 10.1002/mc.22016 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 242DR UT WOS:000326218100010 ER PT J AU Couce, ML Boveda, MD Garcia-Jimemez, C Balmaseda, E Vives, I Castineiras, DE Fernandez-Marmiesse, A Fraga, JM Mudd, SH Corrales, FJ AF Couce, Maria L. Dolores Boveda, M. Garcia-Jimemez, Concepcion Balmaseda, Elena Vives, Inmaculada Castineiras, Daisy E. Fernandez-Marmiesse, Ana Fraga, Jose M. Mudd, S. Harvey Corrales, Fernando J. TI Clinical and metabolic findings in patients with methionine adenosyltransferase I/III deficiency detected by newborn screening SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE S-adenosylmethionine; Homocysteine; Newborn screening; Persistent hypermethioninemia ID S-ADENOSYLMETHIONINE; PERSISTENT HYPERMETHIONINEMIA; INBORN-ERRORS; DEMYELINATION; PATHWAY AB Persistent hypermethioninemia due to mutations in the MAT1A gene is often found during newborn screening (NBS) for homocystinuria due to cystathionine beta-synthase deficiency, however, outcomes and optimal management for these patients are not well established. We carried out a multicenter study of MAT I/III-deficient patients detected by NBS in four of the Spanish regional NBS programs. Data evaluated during NBS and follow-up for 18 patients included methionine and total homocysteine levels, clinical presentation parameters, genotypes, and development quotients. The birth prevalence was 1:1:22,874. At detection 16 of the 18 patients exhibited elevations of plasma methionine above 60 mu mol/L (mean 99.9 +/- 38 mu mol/L) and the mean value in confirmation tests was 301 mu mol/L (91-899) mu mol/L. All patients were asymptomatic. In four patients with more markedly elevated plasma methionines (>450 mu mol/L) total homocysteine values were slightly elevated (about 20 mu mol/L). The average follow-up period was 3 years 7 months (range: 2-123 months). Most patients (83%) were heterozygous for the autosomal dominant Arg264His mutation and, with one exception, presented relatively low circulating methionine concentrations (<400 mu M). Additional mutations identified in patients with mean confirmatory plasma methionines above 400 mu M were Arg199Cys. Leu355Arg, and a novel mutation, Thr288Ala. During continued follow-up, the patients have been asymptomatic, and, to date, no therapeutic interventions have been utilized. Therefore, the currently available evidence shows that hypermethioninemia due to heterozygous MAT1A mutations such as Arg264His is a mild condition for which no treatment is necessary. (C) 2013 Elsevier Inc. All rights reserved. C1 [Couce, Maria L.] Univ Santiago de Compostela, Hosp Clin, Dept Pediat, Unit Diag & Treatment Congenital Metab Dis, Santiago De Compostela 15706, A Coruna, Spain. [Dolores Boveda, M.; Castineiras, Daisy E.; Fernandez-Marmiesse, Ana] Univ Santiago de Compostela, Hosp Clin, Metab Lab, Unit Diag & Treatment Congenital Metab Dis, Santiago De Compostela 15706, A Coruna, Spain. [Garcia-Jimemez, Concepcion] Hosp Miguel Servet, Serv Pediat, Metab Unit, Zaragoza, Spain. [Balmaseda, Elena] Complejo Hosp Univ Albacete, Serv Pediat, Metab Unit, Albacete, Spain. [Vives, Inmaculada] Hosp Univ Virgen de la Arrixaca, Serv Pediat, Metab Unit, Murcia, Spain. [Fraga, Jose M.] Univ Santiago, Hosp Clin, Dept Pediat, Unit Diag & Treatment Congenital Metab Dis, Santiago De Compostela 15706, A Coruna, Spain. [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. [Corrales, Fernando J.] Univ Navarra, Ctr Appl Med Res, Proteon Unit, Div Hepatol & Gene Therapy, E-31080 Pamplona, Spain. RP Couce, ML (reprint author), Univ Santiago de Compostela, Hosp Clin, Dept Pediat, Unit Diag & Treatment Congenital Metab Dis, A Choupana S-N, Santiago De Compostela 15706, A Coruna, Spain. EM maria.luz.couce.pico@sergas.es; maria.boveda.fontan@sergas.es; igarciaji@salud.aragon.es; elenabalmaseda@hotmail.com; vivesmas@hotmail.com; daisy.castineiras.ramos@sergas.es; amarmiesse@gmail.com; pdneonat@usc.es; muddh@mail.nih.gov; fjcoriz@gmail.com OI fraga, jose m/0000-0001-8897-3621 NR 22 TC 12 Z9 12 U1 0 U2 8 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 NOV PY 2013 VL 110 IS 3 BP 218 EP 221 DI 10.1016/j.ymgme.2013.08.003 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 239WZ UT WOS:000326058000004 PM 23993429 ER PT J AU Lee, YM Pan, CJ Koeberl, DD Mansfield, BC Chou, JY AF Lee, Young Mok Pan, Chi-Jiunn Koeberl, Dwight D. Mansfield, Brian C. Chou, Janice Y. TI The upstream enhancer elements of the G6PC promoter are critical for optimal G6PC expression in murine glycogen storage disease type Ia SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Glycogen storage disease type I; Glucose-6-phosphatase; Adeno-associated virus; Gene therapy ID GENE-THERAPY; ADENOASSOCIATED-VIRUS; AAV; VECTORS; LIVER; TRANSDUCTION; DEFICIENCY; MANAGEMENT; SERIES; MOUSE AB Glycogen storage disease type-la (GSD-Ia) patients deficient in glucose-6-phosphatase-alpha (G6Pase-alpha or G6PC) manifest impaired glucose homeostasis characterized by fasting hypoglycemia, growth retardation, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. Two efficacious recombinant adeno-associated virus pseudotype 2/8 (rAAV8) vectors expressing human G6Pase-alpha have been independently developed. One is a single-stranded vector containing a 2864-bp of the G6PC promoter/enhancer (rAAV8-GPE) and the other is a double-stranded vector containing a shorter 382-bp minimal G6PC promoter/enhancer (rAAV8-miGPE). To identify the best construct, a direct comparison of the rAAV8-GPE and the rAAV8-miGPE vectors was initiated to determine the best vector to take forward into clinical trials. We show that the rAAV8-GPE vector directed significantly higher levels of hepatic G6Pase-alpha expression, achieved greater reduction in hepatic glycogen accumulation, and led to a better toleration of fasting in GSD-Ia mice than the rAAV8-miGPE vector. Our results indicated that additional control elements in the rAAV8-GPE vector outweigh the gains from the double-stranded rAAV8-miGPE transduction efficiency, and that the rAAV8-GPE vector is the current choice for clinical translation in human GSD-Ia. Published by Elsevier Inc. C1 [Lee, Young Mok; Pan, Chi-Jiunn; Mansfield, Brian C.; Chou, Janice Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Koeberl, Dwight D.] Duke Univ, Med Ctr, Div Med Genet, Dept Pediat, Durham, NC 27710 USA. [Mansfield, Brian C.] Fdn Fighting Blindness, Columbia, MD 21046 USA. RP Chou, JY (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov OI Mansfield, Brian/0000-0002-8533-2789 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Children's Fund for Glycogen Storage Disease Research FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and The Children's Fund for Glycogen Storage Disease Research. NR 24 TC 6 Z9 6 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2013 VL 110 IS 3 BP 275 EP 280 DI 10.1016/j.ymgme.2013.06.014 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 239WZ UT WOS:000326058000013 PM 23856420 ER PT J AU Mashalidis, EH Sledz, P Lang, S Abell, C AF Mashalidis, Ellene H. Sledz, Pawel Lang, Steffen Abell, Chris TI A three-stage biophysical screening cascade for fragment-based drug discovery SO NATURE PROTOCOLS LA English DT Article ID ISOTHERMAL TITRATION CALORIMETRY; X-RAY CRYSTALLOGRAPHY; THERMAL SHIFT ASSAYS; PROTEIN-PROTEIN INTERACTIONS; LEAD DISCOVERY; KINASE INHIBITORS; NMR-SPECTROSCOPY; LIGAND-BINDING; LIBRARY DESIGN; FLUORESCENCE AB This protocol describes the screening of a library of low-molecular-weight compounds (fragments) using a series of biophysical ligand-binding assays. Fragment-based drug discovery (FBDD) has emerged as a successful method to design high-affinity ligands for biomacromolecules of therapeutic interest. It involves detecting relatively weak interactions between the fragments and a target macromolecule using sensitive biophysical techniques. These weak binders provide a starting point for the development of inhibitors with submicromolar affinity. Here we describe an efficient fragment screening cascade that can identify binding fragments (hits) within weeks. It is divided into three stages: (i) preliminary screening using differential scanning fluorimetry (DSF), (ii) validation by NMR spectroscopy and (iii) characterization of binding fragments by isothermal titration calorimetry (ITC) and X-ray crystallography. Although this protocol is readily applicable in academic settings because of its emphasis on low cost and medium-throughput early-stage screening technologies, the core principle of orthogonal validation makes it robust enough to meet the quality standards of an industrial laboratory. C1 [Mashalidis, Ellene H.; Sledz, Pawel; Lang, Steffen; Abell, Chris] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Mashalidis, Ellene H.] NIAID, NIH, Bethesda, MD 20892 USA. RP Abell, C (reprint author), Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England. EM ca26@cam.ac.uk FU Gates Cambridge Trust; St. Edmund's College; NIH, NIAID FX E.H.M. acknowledges the NIH-Cambridge Graduate Partnership Program and C. Barry (Tuberculosis Research Section, NIAID, NIH). P.S. thanks the Gates Cambridge Trust and St. Edmund's College for funding. S. L. thanks the German Academic Exchange Service (DAAD) and the Structural Genomics Consortium, Oxford. We thank G. Williams (Astex Pharmaceuticals) and all members of the Abell, Blundell, Hyvonen and Ciulli groups for useful discussions. This research was supported in part by the Intramural Research Program of the NIH, NIAID. NR 62 TC 32 Z9 32 U1 10 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD NOV PY 2013 VL 8 IS 11 BP 2309 EP 2324 DI 10.1038/nprot.2013.130 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 241JX UT WOS:000326164100015 PM 24157549 ER PT J AU Lazarevic, V Glimcher, LH Lord, GM AF Lazarevic, Vanja Glimcher, Laurie H. Lord, Graham M. TI T-bet: a bridge between innate and adaptive immunity SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID CHRONIC VIRAL-INFECTION; IFN-GAMMA PRODUCTION; TRANSCRIPTION FACTOR EOMESODERMIN; TH1 CELL-DIFFERENTIATION; PATHOGENIC T(H)17 CELLS; V-ALPHA-14I NKT CELLS; GENE-EXPRESSION; LYMPHOID-CELLS; INTERFERON-GAMMA; DENDRITIC CELLS AB Originally described over a decade ago as a T cell transcription factor regulating T helper 1 cell lineage commitment, T-bet is now recognized as having an important role in many cells of the adaptive and innate immune system. T-bet has a fundamental role in coordinating type 1 immune responses by controlling a network of genetic programmes that regulate the development of certain immune cells and the effector functions of others. Many of these transcriptional networks are conserved across innate and adaptive immune cells and these shared mechanisms highlight the biological functions that are regulated by T-bet. C1 [Lazarevic, Vanja] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Glimcher, Laurie H.] Weill Cornell Med Coll, New York, NY 10065 USA. [Lord, Graham M.] Kings Coll London, Dept Expt Immunobiol, London SE1 9RT, England. RP Glimcher, LH (reprint author), Weill Cornell Med Coll, New York, NY 10065 USA. EM lglimche@med.cornell.edu FU US National Institutes of Health [CA112663, PO1NSO38037]; Irvington Institute; Medical Research Council, UK [G0802068]; Wellcome Trust, UK, [WT088747MA]; British Heart Foundation, UK [PG/12/36/29444]; National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London, UK FX We would like to acknowledge support from grants awarded by the US National Institutes of Health (grants CA112663 and PO1NSO38037) to L. H. G.; the Irvington Institute to V. L.; and to G. M. L. the Medical Research Council, UK (grant G0802068), the Wellcome Trust, UK, (grant WT088747MA) and the British Heart Foundation, UK, (grant PG/12/36/29444). G. M. L. is also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London, UK. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. NR 107 TC 99 Z9 101 U1 2 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2013 VL 13 IS 11 BP 777 EP 789 DI 10.1038/nri3536 PG 13 WC Immunology SC Immunology GA 241HY UT WOS:000326158400008 PM 24113868 ER PT J AU Cocco, P Vermeulen, R Flore, V Nonne, T Campagna, M Purdue, M Blair, A Monnereau, A Orsi, L Clavel, J Becker, N de Sanjose, S Foretova, L Staines, A Maynadie, M Nieters, A Miligi, L 't Mannetje, A Kricker, A Brennan, P Boffetta, P Lan, Q Rothman, N AF Cocco, P. Vermeulen, R. Flore, V. Nonne, T. Campagna, M. Purdue, M. Blair, A. Monnereau, A. Orsi, L. Clavel, J. Becker, N. de Sanjose, S. Foretova, L. Staines, A. Maynadie, M. Nieters, A. Miligi, L. 't Mannetje, A. Kricker, A. Brennan, P. Boffetta, P. Lan, Q. Rothman, N. TI Occupational exposure to trichloroethylene and risk of non-Hodgkin lymphoma and its major subtypes: a pooled IinterLlymph analysis SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID EPIDEMIOLOGY CONSORTIUM INTERLYMPH; ORGANIC-SOLVENTS; CANCER INCIDENCE; WORKERS; METAANALYSIS; MORTALITY; NEOPLASMS; EPILYMPH; COHORT AB Objectives We evaluated the association between occupational exposure to trichloroethylene (TCE) and risk of non-Hodgkin lymphoma (NHL) in a pooled analysis of four international case-control studies. Methods Overall, the pooled study population included 3788 NHL cases and 4279 controls. Risk of NHL and its major subtypes associated with TCE exposure was calculated with unconditional logistic regression and polytomous regression analysis, adjusting by age, gender and study. Results Risk of follicular lymphoma (FL), but not NHL overall or other subtypes, increased by probability (p=0.02) and intensity level (p=0.04), and with the combined analysis of four exposure metrics assumed as independent (p=0.004). After restricting the analysis to the most likely exposed study subjects, risk of NHL overall, FL and chronic lymphocytic leukaemia (CLL) were elevated and increased by duration of exposure (p=0.009, p=0.04 and p=0.01, respectively) and with the combined analysis of duration, frequency and intensity of exposure (p=0.004, p=0.015 and p=0.005, respectively). Although based on small numbers of exposed, risk of all the major NHL subtypes, namely diffuse large B-cell lymphoma, FL and CLL, showed increases in risk ranging 2-3.2-fold in the highest category of exposure intensity. No significant heterogeneity in risk was detected by major NHL subtypes or by study. Conclusions Our pooled analysis apparently supports the hypothesis of an increase in risk of specific NHL subtypes associated with occupational exposure to TCE. C1 [Cocco, P.; Flore, V.; Nonne, T.; Campagna, M.] Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Occupat Hlth Sect, Monserrato, Italy. [Vermeulen, R.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Purdue, M.; Blair, A.; Lan, Q.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Monnereau, A.] Inst Bergonie, Ctr Reg Lutte Canc, Bordeaux, France. [Orsi, L.; Clavel, J.] INSERM, Villejuif, France. [Becker, N.] German Canc Res Ctr, Heidelberg, Germany. [de Sanjose, S.] Catalan Inst Oncol, Canc Epidemiol Res Program, Unit Infect & Canc, Barcelona, Spain. [de Sanjose, S.] Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Barcelona, Spain. [Foretova, L.] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Staines, A.] Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland. [Maynadie, M.] Dijon Univ Hosp, Dijon, France. [Nieters, A.] Univ Freiburg, Ctr Chron Immunodeficiency, D-79106 Freiburg, Germany. [Miligi, L.] ISPO Canc Prevent & Res Inst, Environm & Occupat Epidemiol Unit, Florence, Italy. ['t Mannetje, A.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Kricker, A.] Univ Sydney, Sydney Med Sch, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Brennan, P.] Int Agcy Res Canc, F-69372 Lyon, France. [Boffetta, P.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. RP Cocco, P (reprint author), Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Occupat Hlth Sect, SS 554, I-09042 Cagliari, Italy. EM coccop@medicina.unica.it RI de Sanjose Llongueras, Silvia/H-6339-2014; Monnereau, Alain/L-1249-2014; Campagna, Marcello/L-1011-2016; Clavel, Jacqueline/Q-2750-2016; Vermeulen, Roel/F-8037-2011 OI Monnereau, Alain/0000-0002-5056-1397; Campagna, Marcello/0000-0002-5277-8477; Clavel, Jacqueline/0000-0002-3616-7676; Vermeulen, Roel/0000-0003-4082-8163 FU Italian Ministry for Education, University and Research [2007WEJLZB, 20092ZELR2]; Italian Association for Cancer Research (AIRC) [11855]; US NIH, National Cancer Institute; Association pour la Recherche contre le Cancer; Fondation de France; AFSSET; European Commission [QLK4-CT-2000-00422, FP6-2003-FOOD-2-B, 023103]; Spanish Ministry of Health [04-0091, RCESP 09-10]; German Federal Office for Radiation Protection [StSch4261, StSch4420] FX The study was supported by grants of the Italian Ministry for Education, University and Research (PRIN 2007 prot. 2007WEJLZB; PRIN 2009 prot. 20092ZELR2); the Italian Association for Cancer Research (AIRC, Investigator Grant 11855); and the intramural research programme of the US NIH, National Cancer Institute; the Association pour la Recherche contre le Cancer; the Fondation de France; AFSSET; a donation from Faberge employees; the European Commission, 5th Framework Program, Quality of Life (grant No QLK4-CT-2000-00422); European Commission, 6th Framework Program, FP6-2003-FOOD-2-B (contract No 023103); the Spanish Ministry of Health (grant No 04-0091, RCESP 09-10); the German Federal Office for Radiation Protection (grants No StSch4261 and StSch4420). NR 35 TC 4 Z9 9 U1 1 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD NOV PY 2013 VL 70 IS 11 BP 795 EP 802 DI 10.1136/oemed-2013-101551 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 239TN UT WOS:000326048600009 PM 23881218 ER PT J AU Behrens, T Kendzia, B Treppmann, T Olsson, A Jockel, KH Gustavsson, P Pohlabeln, H Ahrens, W Bruske, I Wichmann, HE Merletti, F Mirabelli, D Richiardi, L Simonato, L Zaridze, D Szeszenia-Dabrowska, N Rudnai, P Lissowska, J Fabianova, E Tardon, A Field, J Dumitru, RS Bencko, V Foretova, L Janout, V Siemiatycki, J Parent, ME McLaughlin, J Demers, P Landi, MT Caporaso, N Kromhout, H Vermeulen, R Peters, S Benhamou, S Stucker, I Guida, F Consonni, D Bueno-de-Mesquita, B 't Mannetje, A Pearce, N Tse, LA Yu, ITS Plato, N Boffetta, P Straif, K Schuz, J Pesch, B Bruning, T AF Behrens, Thomas Kendzia, Benjamin Treppmann, Tabea Olsson, Ann Joeckel, Karl-Heinz Gustavsson, Per Pohlabeln, Hermann Ahrens, Wolfgang Brueske, Irene Wichmann, Hans-Erich Merletti, Franco Mirabelli, Dario Richiardi, Lorenzo Simonato, Lorenzo Zaridze, David Szeszenia-Dabrowska, Neonila Rudnai, Peter Lissowska, Jolanta Fabianova, Eleonora Tardon, Adonina Field, John Dumitru, Rodica Stanescu Bencko, Vladimir Foretova, Lenka Janout, Vladimir Siemiatycki, Jack Parent, Marie-Elise McLaughlin, John Demers, Paul Landi, Maria Teresa Caporaso, Neil Kromhout, Hans Vermeulen, Roel Peters, Susan Benhamou, Simone Stuecker, Isabelle Guida, Florence Consonni, Dario Bueno-de-Mesquita, Bas 't Mannetje, Andrea Pearce, Neil Tse, Lap Ah Yu, Ignatius Tak-sun Plato, Nils Boffetta, Paolo Straif, Kurt Schuez, Joachim Pesch, Beate Bruening, Thomas TI Lung cancer risk among bakers, pastry cooks and confectionary makers: the SYNERGY study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID OCCUPATION; CARCINOGENS; EXPOSURE; MEN AB Introduction Some studies have suggested increased lung cancer risks among bakers, however the results overall were inconsistent. The authors studied lung cancer risks among bakers and baking-related occupations in the SYNERGY pooled case-control database from 16 countries. Methods Occupation in a baking-related job was identified from the subjects' job histories. ORs adjusted for log(age), study centre, smoking behaviour and ever employment in a job with known exposure to occupational lung carcinogens were calculated by unconditional logistic regression. Findings were stratified by sex, histological subtype of lung cancer and smoking status. Results 19366 cases (15606 men) and 23670 control subjects (18528 men) were included. 473 cases (415 men, 58 women) and 501 controls (437 men, 64 women) had ever worked in baking or a related job. We did not observe an increased risk for men in baking (OR 1.01; 95% CI 0.86 to 1.18). No linear trends were observed for duration of employment. Some results suggested increased lung cancer risks for women, for example, for working as a baker for >30years and in never-smokers, but after exclusion of one study these increased risks disappeared. Discussion The findings from this study do not suggest increased lung cancer risks in baking-related professions. C1 [Behrens, Thomas; Kendzia, Benjamin; Treppmann, Tabea; Pesch, Beate; Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance IPA Inst, D-44789 Bochum, Germany. [Olsson, Ann; Straif, Kurt; Schuez, Joachim] Int Agcy Res Canc, F-69372 Lyon, France. [Olsson, Ann; Gustavsson, Per; Plato, Nils] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Joeckel, Karl-Heinz] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Pohlabeln, Hermann; Ahrens, Wolfgang] Leibniz Inst Prevent Res & Epidemiol BIPS GmbH, Bremen, Germany. [Ahrens, Wolfgang] Univ Bremen, Inst Stat, D-28359 Bremen, Germany. [Brueske, Irene; Wichmann, Hans-Erich] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Merletti, Franco; Mirabelli, Dario; Richiardi, Lorenzo] CPO Piemonte, Canc Epidemiol Unit, Turin, Italy. [Merletti, Franco; Mirabelli, Dario; Richiardi, Lorenzo] Univ Turin, Turin, Italy. [Simonato, Lorenzo] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Zaridze, David] Russian Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, Neonila] Nofer Inst Occupat Med, Lodz, Poland. [Rudnai, Peter] Natl Inst Environm Hlth, Budapest, Hungary. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Fabianova, Eleonora] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Tardon, Adonina] Univ Oviedo Ciber Epidemiol, CIBERESP, Mol Epidemiol Canc Unit, Oviedo, Spain. [Field, John] Univ Liverpool, Roy Castle Lung Canc Res Programme, Canc Res Ctr, Liverpool L69 3BX, Merseyside, England. [Dumitru, Rodica Stanescu] Natl Inst Publ Hlth, Bucharest, Romania. [Bencko, Vladimir] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Janout, Vladimir] Palacky Univ, Fac Med, CR-77147 Olomouc, Czech Republic. [Siemiatycki, Jack] Univ Montreal, Hosp Res Ctr CRCHUM, Montreal, PQ, Canada. [Siemiatycki, Jack] Univ Montreal, Sch Publ Hlth, Montreal, PQ, Canada. [Parent, Marie-Elise] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ, Canada. [McLaughlin, John; Demers, Paul] Occupat Canc Res Ctr, Can Care Ontario, Toronto, ON, Canada. [Landi, Maria Teresa; Caporaso, Neil] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kromhout, Hans; Vermeulen, Roel; Peters, Susan] Univ Utrecht, Inst Risk Assessment Sci, Environm Epidemiol Div, Utrecht, Netherlands. [Peters, Susan] Univ Western Australia, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Benhamou, Simone] INSERM, U946, Paris, France. [Stuecker, Isabelle; Guida, Florence] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, U1018, Environm Epidemiol Canc Team, F-94807 Villejuif, France. [Stuecker, Isabelle; Guida, Florence] Univ Paris Sud, UMRS 1018, F-94807 Villejuif, France. [Consonni, Dario] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Unit Epidemiol, Milan, Italy. [Bueno-de-Mesquita, Bas] Natl Inst Publ Hlth & Environm Protect, Ctr Nutr & Hlth, NL-3720 BA Bilthoven, Netherlands. ['t Mannetje, Andrea] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Pearce, Neil] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Tse, Lap Ah; Yu, Ignatius Tak-sun] Chinese Univ Hong Kong, Div Occupat & Environm Hlth, JC Sch Publ Hlth & Primary Care, Hong Kong, Hong Kong, Peoples R China. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Behrens, T (reprint author), Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance IPA Inst, Burkle de la Camp Pl 1, D-44789 Bochum, Germany. EM behrens@ipa-dguv.de; behrens@ipa-dguv.de RI Bruske, Irene/N-3125-2013; Yu, Ignatius Tak Sun/A-9936-2008; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; Bruning, Thomas/G-8120-2015; Consonni, Dario/K-7943-2016; Vermeulen, Roel/F-8037-2011; OI richiardi, lorenzo/0000-0003-0316-9402; Bruning, Thomas/0000-0001-9560-5464; Consonni, Dario/0000-0002-8935-3843; Vermeulen, Roel/0000-0003-4082-8163; Peters, Susan/0000-0001-5662-1971; Pearce, Neil/0000-0002-9938-7852; Lissowska, Jolanta/0000-0003-2695-5799; Field, John/0000-0003-3951-6365; Ahrens, Wolfgang/0000-0003-3777-570X FU German Social Accident Insurance [FP 271]; Canadian Institutes of Health Research; Guzzo-SRC Chair in Environment and Cancer; Fondation de France; German Federal Ministry of Education, Science, Research, and Technology; Ministry of Labour and Social Affairs; EC's INCO-COPERNICUS Program; Polish State Committee for Science Research; Roy Castle Foundation; NIH/NCI/DCEG Intramural Research Program, Lombardy Region; INAIL; European Union Nuclear Fission Safety Program; Italian Association for Cancer Research; Region Piedmont; Compagnia di San Paolo; Europe Against Cancer Program; Swedish Council for Work Life Research; Swedish EPA; University of Oviedo; European Regional Development Fund; State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]; CIBERESP; [FISS-PI060604] FX This study was supported by the German Social Accident Insurance, grant FP 271. Grant sponsors of the individual studies were the Canadian Institutes of Health Research and Guzzo-SRC Chair in Environment and Cancer, the Fondation de France, the German Federal Ministry of Education, Science, Research, and Technology and the Ministry of Labour and Social Affairs, the EC's INCO-COPERNICUS Program, the Polish State Committee for Science Research, the Roy Castle Foundation, the NIH/NCI/DCEG Intramural Research Program, Lombardy Region, INAIL and the European Union Nuclear Fission Safety Program, the Italian Association for Cancer Research, Region Piedmont, the Compagnia di San Paolo, the Europe Against Cancer Program, the Swedish Council for Work Life Research and the Swedish EPA, the University of Oviedo, the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101), CIBERESP and FISS-PI060604. NR 15 TC 2 Z9 2 U1 1 U2 13 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 EI 1470-7926 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD NOV PY 2013 VL 70 IS 11 BP 810 EP 814 DI 10.1136/oemed-2013-101469 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 239TN UT WOS:000326048600011 PM 23911873 ER PT J AU Wu, YW Hess, CP Singhal, NS Groden, C Toro, C AF Wu, Yvonne W. Hess, Christopher P. Singhal, Nilika S. Groden, Catherine Toro, Camila TI Idiopathic Basal Ganglia Calcifications: An Atypical Presentation of PKAN SO PEDIATRIC NEUROLOGY LA English DT Article DE basal ganglia; calcification; neurodegeneration; genetics; dystonia; Fahr disease; eye of the tiger; PANK2; PKAN; pantothenate kinase ID KINASE-ASSOCIATED NEURODEGENERATION; HALLERVORDEN-SPATZ-SYNDROME; THE-TIGER SIGN; PANK2 MUTATIONS; EYE; DISEASE AB BACKGROUND: We report a patient with pantothenate kinase associated neurodegeneration presenting as idiopathic basal ganglia calcifications, previously known as Fahr's disease. METHODS: A teenage girl presented with slowly progressive dystonia. Her brain magnetic resonance imaging scan revealed TI and T2 hypointensities in both globus pallidi, and no eye-of-the-tiger sign. Computed tomography showed dense globus pallidi calcifications. Metabolic evaluation was negative. The patient was diagnosed with idiopathic basal ganglia calcifications, a poorly understood syndrome of unknown cause. Whole exome sequencing was performed. RESULTS: The patient was found to have two mutations in the pantothenate kinase 2 (PANK2) gene that have been previously associated with pantothenate kinase associated neurodegeneration: a paternally inherited p.G521R and maternally inherited p.T528M. No deleterious changes were identified in genes associated with idiopathic basal ganglia calcifications or dystonia. CONCLUSIONS: Pantothenate kinase associated neurodegeneration should be considered in patients with idiopathic basal ganglia calcifications, especially when findings are confined to the globus pallidus. C1 [Wu, Yvonne W.; Singhal, Nilika S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Wu, Yvonne W.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Hess, Christopher P.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Groden, Catherine; Toro, Camila] NHGRI, NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. RP Wu, YW (reprint author), Univ Calif San Francisco, Dept Neurol, 350 Parnassus,Suite 609, San Francisco, CA 94143 USA. EM wuy@neuropeds.ucsf.edu OI Hess, Christopher/0000-0002-5132-5302 FU earch Program of the National Human Genome Research Institute and the National Institutes of Health (NIH) Common Fund [1R01 FD004103-01] FX Portions of this work were funded by the Intramural Research Program of the National Human Genome Research Institute and the National Institutes of Health (NIH) Common Fund (NIH Undiagnosed Diseases Program). Dr. Hess is a co-investigator on NIH 1R01 FD004103-01 Phase 2 Study of Deferiprone in the Treatment of NBIA. NR 15 TC 8 Z9 9 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD NOV PY 2013 VL 49 IS 5 BP 351 EP 354 DI 10.1016/j.pediatrneurol.2013.06.021 PG 4 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 242BK UT WOS:000326212200011 PM 23968566 ER PT J AU Imayama, I Alfano, CM Mason, C Wang, CC Duggan, C Campbell, KL Kong, A Foster-Schubert, KE Blackburn, GL Wang, CY McTiernan, A AF Imayama, Ikuyo Alfano, Catherine M. Mason, Caitlin Wang, Chiachi Duggan, Catherine Campbell, Kristin L. Kong, Angela Foster-Schubert, Karen E. Blackburn, George L. Wang, Ching-Yun McTiernan, Anne TI Weight and metabolic effects of dietary weight loss and exercise interventions in postmenopausal antidepressant medication users and non-users: A randomized controlled trial SO PREVENTIVE MEDICINE LA English DT Article DE Obesity; Weight loss intervention; Antidepressants; Diet; Exercise ID DIABETES PREVENTION PROGRAM; BINGE-EATING DISORDER; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; PHYSICAL-ACTIVITIES; MAJOR DEPRESSION; MEDICINE USE; WOMEN; RISK; HEALTH AB Objective. Antidepressants may attenuate the effects of diet and exercise programs. We compared adherence and changes in body measures and biomarkers of glucose metabolism and inflammation between antidepressant users and non-users in a 12-month randomized controlled trial. Methods. Overweight or obese, postmenopausal women were assigned to: diet (10% weight loss goal, N = 118); moderate-to-vigorous aerobic exercise (225 min/week, N = 117); diet + exercise (N = 117); and control (N = 87) in Seattle, WA 2005-2009. Women using antidepressants at baseline were classified as users (N = 109). ANCOVA and generalized estimating equation approaches, respectively, were used to compare adherence (exercise amount, diet session attendance, and changes in percent calorie intake from fat, cardiopulmonary fitness, and pedometer steps) and changes in body measures (weight, waist and percent body fat) and serum biomarkers (glucose, insulin, homeostasis assessment-insulin resistance, and high-sensitivity C-reactive protein) between users and non-users. An interaction term (intervention x antidepressant use) tested effect modification. Results. There were no differences in adherence except that diet session attendance was lower among users in the diet + exercise group (P < 0.05 vs. non-users). Changes in body measures and serum biomarkers did not differ by antidepressant use (Pinteraction > 0.05). Conclusion. Dietary weight loss and exercise improved body measures and biomarkers of glucose metabolism and inflammation independent of antidepressant use. (C) 2013 Elsevier Inc. All rights reserved. C1 [Imayama, Ikuyo; Mason, Caitlin; Wang, Chiachi; Duggan, Catherine; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Alfano, Catherine M.] NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. [Campbell, Kristin L.] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Kong, Angela] Univ Illinois, Canc Educ & Career Dev Program, Chicago, IL USA. [Foster-Schubert, Karen E.; McTiernan, Anne] Univ Washington, Sch Med, Seattle, WA USA. [Blackburn, George L.] Harvard Univ, Sch Med, Div Nutr, Boston, MA USA. [Wang, Ching-Yun; McTiernan, Anne] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Wang, Ching-Yun] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP McTiernan, A (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M4-B874,POB 19024, Seattle, WA USA. EM amctiern@fhcrc.org RI Duggan, Catherine/F-9414-2015 OI Duggan, Catherine/0000-0001-7369-4021 FU National Cancer Institute (NCI) [R01 CA105204-01A1, U54-CA116847]; National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) [61-7015]; Canadian Institutes of Health Research; NCI [R25CA094880, 2R25CA057699]; National Center for Research Resources [5KL2RR025015-03] FX The NEW trial was supported by R01 CA105204-01A1 and U54-CA116847 from the National Cancer Institute (NCI). Part of this study was conducted at the University of Washington, Clinical Nutrition Research Unit supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) 61-7015. While working on the trial, CMA was employed at the Ohio State University, and located to NCI following completion of her effort on the NEW trial. CM is and KC was supported by a fellowship from the Canadian Institutes of Health Research. AK was supported by NCI R25CA094880 at the time of this study and is currently supported by NCI 2R25CA057699. KEF is supported by 5KL2RR025015-03 from the National Center for Research Resources, a component of the National Institute of Health (NIH) and NIH Roadmap for Medical Research. These funding agencies had no role in the study design, data collection, data analysis and interpretation of the results, and writing of the article and decision to submit it for publication. NR 40 TC 3 Z9 3 U1 2 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD NOV PY 2013 VL 57 IS 5 BP 525 EP 532 DI 10.1016/j.ypmed.2013.07.006 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 239WV UT WOS:000326057600022 PM 23859929 ER PT J AU Taber, DR Chriqui, JF Perna, FM Powell, LM Slater, SJ Chaloupka, FJ AF Taber, Daniel R. Chriqui, Jamie F. Perna, Frank M. Powell, Lisa M. Slater, Sandy J. Chaloupka, Frank J. TI Association between state physical education (PE) requirements and PE participation, physical activity, and body mass index change SO PREVENTIVE MEDICINE LA English DT Article DE Physical education; Exercise; Nutrition; Obesity; Adolescent; Health policy; Schools ID CHILDREN; OBESITY; ADOLESCENTS; POLICIES; SCHOOLS; TRENDS; OVERWEIGHT; HEALTH; IMPACT; YOUTH AB Objective. To determine if state physical education (PE) laws are associated with student physical education attendance and physical activity (PA), and whether physical education and competitive food laws, in conjunction, are associated with lower BMI change. Method State laws regarding physical education time requirements and competitive foods in 2003 and 2006 were classified as strong, weak, or none, based on codified law ratings obtained from the Classification of Laws Associated with School Students. Laws were linked to student data on PE attendance and physical activity (8th grade, Spring 2007) and BMI change (5th-8th grade, 2004-2007), obtained from the Early Childhood Longitudinal Study (n = 5510 students in 40 states). Results. Girls reported 0.31 more days of activity (95% CI: 0.02, 0.61) and were more likely to attend physical education >= 3 days/week (74.1% versus 52.1%, difference = 22.0,95% CI: 2.1, 42.0) if they resided in states with strong physical education laws compared to no physical education laws. Weak physical education laws had modest associations with PE and activity, and there was no evidence that weak laws reduce BMI gain regardless of competitive food laws. Conclusion. Strong physical education laws with specific time requirements may increase physical education attendance and activity in girls. There is insufficient evidence that physical education laws reduce student weight gain. (C) 2013 Elsevier Inc. All rights reserved. C1 [Taber, Daniel R.; Chriqui, Jamie F.; Powell, Lisa M.; Slater, Sandy J.; Chaloupka, Frank J.] Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60608 USA. [Chriqui, Jamie F.] Univ Illinois, Dept Polit Sci, Chicago, IL 60607 USA. [Perna, Frank M.] Natl Canc Inst, Div Canc Control & Populat Sci, Rockville, MD 20850 USA. [Powell, Lisa M.; Slater, Sandy J.] Univ Illinois, Dept Hlth Policy & Adm, Chicago, IL 60612 USA. [Chaloupka, Frank J.] Univ Illinois, Dept Econ, Chicago, IL 60607 USA. RP Taber, DR (reprint author), Univ Texas Austin, Sch Publ Hlth, Austin Reg Campus,1616 Guadalupe,Suite 6-300, Austin, TX 78701 USA. EM Daniel.Taber@uth.tmc.edu; jchriqui@uic.edu; pernafm@mail.nih.gov; powelll@uic.edu; sslater@uic.edu; fjc@uic.edu FU Robert Wood Johnson Foundation; National Cancer Institute [HHSN261201000350P, HHSN261201100522P] FX Support for this study was provided by the Robert Wood Johnson Foundation to the Bridging the Gap Program at the University of Illinois at Chicago (PI: Frank Chaloupka) and contracts HHSN261201000350P and HHSN261201100522P from the National Cancer Institute to the University of Illinois at Chicago (PI: Jamie Chriqui). The views expressed herein are solely those of the authors and do not reflect the official views or positions of the Robert Wood Johnson Foundation; the National Cancer Institute; or the National Institutes of Health. NR 42 TC 12 Z9 12 U1 4 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 EI 1096-0260 J9 PREV MED JI Prev. Med. PD NOV PY 2013 VL 57 IS 5 BP 629 EP 633 DI 10.1016/j.ypmed.2013.08.018 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 239WV UT WOS:000326057600040 PM 23978523 ER PT J AU Mazor, KM Beard, RL Alexander, GL Arora, NK Firneno, C Gaglio, B Greene, SM Lemay, CA Robinson, BE Roblin, DW Walsh, K Street, RL Gallagher, TH AF Mazor, Kathleen M. Beard, Renee L. Alexander, Gwen L. Arora, Neeraj K. Firneno, Cassandra Gaglio, Bridget Greene, Sarah M. Lemay, Celeste A. Robinson, Brandi E. Roblin, Douglas W. Walsh, Kathleen Street, Richard L., Jr. Gallagher, Thomas H. TI Patients' and family members' views on patient-centered communication during cancer care SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; patient-centered communication; qualitative; interviews ID PHYSICIAN COMMUNICATION; PERSPECTIVES; PERCEPTIONS; QUALITY; TIME AB ObjectivesTo explore patients' and family members' views on communication during cancer care and to identify those aspects of clinician-patient communication which were most important to patients and family members. MethodsWe conducted a secondary data analysis of qualitative data from 137 patients with cancer and family members of patients with cancer. We used a modified version of the constant comparative method and coding paradigm of grounded theory. ResultsPatients want sensitive, caring clinicians who provide information that they need, when they need it, in a way that they can understand; who listen and respond to questions and concerns, and who attempt to understand the patient's experience. Effective information exchange and a positive interpersonal relationship with the clinician were of fundamental importance to patients and family members. These were interrelated; for instance, failure to provide information a patient needed could damage the relationship, whereas excellent listening could foster the relationship. Information exchange and relationship were also integral to decision-making, managing uncertainty, responding to emotions, and self-management. Clinicians who were responsive to patients' needs beyond the immediate medical encounter were valued. ConclusionsThe complexity of cancer care today suggests that efforts to improve communication must be multilevel, acknowledging and addressing patient, clinician, organizational and policy barriers, and facilitators. Measurement tools are needed to assess cancer patients' and family members' experiences with communication over the course of cancer care to provide meaningful, actionable feedback to those seeking to optimize their effectiveness in communicating with patients with cancer. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Mazor, Kathleen M.; Firneno, Cassandra; Lemay, Celeste A.] Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Reliant Med Grp,Fallon Community Hlth Plan, Worcester, MA 01605 USA. [Beard, Renee L.] Coll Holy Cross, Dept Sociol & Anthropol, Worcester, MA 01610 USA. [Alexander, Gwen L.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Arora, Neeraj K.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Gaglio, Bridget] Kaiser Permanente Midatlantic States, Res Inst, Midatlantic Permanente, Rockville, MD USA. [Greene, Sarah M.] Grp Hlth Cooperat Puget Sound, Seattle, WA USA. [Robinson, Brandi E.; Roblin, Douglas W.] Kaiser Permanente Georgia, Ctr Hlth Res, Atlanta, GA USA. [Walsh, Kathleen] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Walsh, Kathleen] Meyers Primary Care Inst, Worcester, MA USA. [Street, Richard L., Jr.] Texas A&M Univ, Dept Commun, College Stn, TX USA. [Gallagher, Thomas H.] Univ Washington, Seattle, WA 98195 USA. RP Mazor, KM (reprint author), Univ Massachusetts, Sch Med, Meyers Primary Care Inst, Reliant Med Grp,Fallon Community Hlth Plan, Worcester, MA 01605 USA. EM kathy.mazor@meyersprimary.org FU National Cancer Institute [P20CA137219, U19 CA79689]; HMO CRN pilot grant; University of Massachusetts Clinical and Translational Science Cente; National Center for Advancing Translational Sciences [8UL1TR000161] FX This study was conducted in the Cancer Communication Research Center, funded by the National Cancer Institute (P20CA137219). Original data collection was funded by this grant, and by a supplement (P20CA137219), by an HMO CRN pilot grant, also funded by the National Cancer Institute (U19 CA79689) and via funding from the University of Massachusetts Clinical and Translational Science Center, which is funded by the National Center for Advancing Translational Sciences (8UL1TR000161). NR 22 TC 21 Z9 21 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2013 VL 22 IS 11 BP 2487 EP 2495 DI 10.1002/pon.3317 PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 239MS UT WOS:000326030300011 PM 23780672 ER PT J AU Erdmann, RB Gartner, JG Leonard, WJ Ellison, CA AF Erdmann, R. B. Gartner, J. G. Leonard, W. J. Ellison, C. A. TI Lack of Functional TSLP Receptors Mitigates Th2 Polarization and the Establishment and Growth of 4T1 Primary Breast Tumours but has Different Effects on Tumour Quantities in the Lung and Brain SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; IGM(+) B-CELLS; CD4(+) T-CELLS; AIRWAY INFLAMMATION; IN-VITRO; CANCER PROGRESSION; DENDRITIC CELLS; EXPRESSION; BARRIER; MICE AB The 4T1 mammary carcinoma cell line produces TSLP. We had hypothesized that TSLP promotes the development of a permissive environment for the growth and metastasis of primary tumour and that this is associated with a Th2-polarized antitumour immune response. We found that, in Tslpr(-/-) mice, the mean tumour diameters were smaller from days 27 to 40, and relatively fewer tumour cells were present in the lung, compared with wild-type mice. Polarization of the Th2 cytokine profile was also diminished in Tslpr(-/-) mice. These findings confirmed those reported previously by others. Here, we further show that primary tumours are established less often in Tslpr(-/-) mice and that, unexpectedly, the relative number of tumour cells in the brain is greater in Tslpr(-/-) mice compared with wild-type mice. Findings from our cytotoxicity assays show that 4T1-directed lysis is undetectable in both WT and Tslpr(-/-) mice, ruling out the possibility that altered cytotoxic responses in Tslpr(-/-) mice are responsible for the differences we observed. In a human tissue microarray, positive staining for TSLP was seen in tumour cells from breast cancer tissue, but it was also seen in normal glandular epithelial cells from normal breast tissue, which has not been shown before. Thus, our findings provide new insight into the effects of TSLP in metastatic breast cancer. C1 [Erdmann, R. B.; Gartner, J. G.; Ellison, C. A.] Univ Manitoba, Dept Immunol, Fac Med, Winnipeg, MB R3E 3P5, Canada. [Gartner, J. G.; Ellison, C. A.] Univ Manitoba, Dept Pathol, Fac Med, Winnipeg, MB R3E 3P5, Canada. [Leonard, W. J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ellison, CA (reprint author), Univ Manitoba, Dept Pathol, Fac Med, 401 Brodie Ctr,727 McDermot Ave, Winnipeg, MB R3E 3P5, Canada. EM Cynthia.Ellison@med.umanitoba.ca FU CancerCare Manitoba Foundation FX This project was funded by an operating grant awarded to C. A. Ellison by the CancerCare Manitoba Foundation. We thank Ms. Sandra Troup and Michelle Parisien from the Manitoba Breast Tumor Bank for their expert assistance with the TMA experiments. We also thank Dr. John Wilkins for the use of his microplate reader in the chemiluminescence assays. NR 46 TC 7 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-9475 EI 1365-3083 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD NOV PY 2013 VL 78 IS 5 BP 408 EP 418 DI 10.1111/sji.12106 PG 11 WC Immunology SC Immunology GA 240EL UT WOS:000326077600003 PM 24033709 ER PT J AU Wurtz, RH AF Wurtz, Robert H. TI David H. Hubel (1926-2013) SO SCIENCE LA English DT Biographical-Item C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Wurtz, RH (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM bob@lsr.nei.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 1 PY 2013 VL 342 IS 6158 BP 572 EP 572 DI 10.1126/science.1247113 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 243RJ UT WOS:000326334300030 PM 24179213 ER PT J AU McLellan, JS Chen, M Joyce, MG Sastry, M Stewart-Jones, GBE Yang, YP Zhang, BS Chen, L Srivatsan, S Zheng, AQ Zhou, TQ Graepel, KW Kumar, A Moin, S Boyington, JC Chuang, GY Soto, C Baxa, U Bakker, AQ Spits, H Beaumont, T Zheng, ZZ Xia, NS Ko, SY Todd, JP Rao, S Graham, BS Kwong, PD AF McLellan, Jason S. Chen, Man Joyce, M. Gordon Sastry, Mallika Stewart-Jones, Guillaume B. E. Yang, Yongping Zhang, Baoshan Chen, Lei Srivatsan, Sanjay Zheng, Anqi Zhou, Tongqing Graepel, Kevin W. Kumar, Azad Moin, Syed Boyington, Jeffrey C. Chuang, Gwo-Yu Soto, Cinque Baxa, Ulrich Bakker, Arjen Q. Spits, Hergen Beaumont, Tim Zheng, Zizheng Xia, Ningshao Ko, Sung-Youl Todd, John-Paul Rao, Srinivas Graham, Barney S. Kwong, Peter D. TI Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus SO SCIENCE LA English DT Article ID B-CELL RECEPTORS; MONOCLONAL-ANTIBODY; NEUTRALIZING ANTIBODY; PROTEIN; EPITOPE; MOTAVIZUMAB; SCAFFOLD; GP120 AB Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site empty set, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site empty set when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site empty set-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold. C1 [McLellan, Jason S.; Chen, Man; Joyce, M. Gordon; Sastry, Mallika; Stewart-Jones, Guillaume B. E.; Yang, Yongping; Zhang, Baoshan; Chen, Lei; Srivatsan, Sanjay; Zheng, Anqi; Zhou, Tongqing; Graepel, Kevin W.; Kumar, Azad; Moin, Syed; Boyington, Jeffrey C.; Chuang, Gwo-Yu; Soto, Cinque; Ko, Sung-Youl; Todd, John-Paul; Rao, Srinivas; Graham, Barney S.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Baxa, Ulrich] SAIC Frederick Inc, Electron Microscope Lab, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Bakker, Arjen Q.; Spits, Hergen; Beaumont, Tim] AIMM Therapeut, Acad Med Ctr, NL-1105 BA Amsterdam, Netherlands. [Zheng, Zizheng; Xia, Ningshao] Xiamen Univ, Natl Inst Diagnost & Vaccine Dev Infect Dis, Xiamen 361005, Peoples R China. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bgraham@nih.gov; pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU National Institute of Allergy and Infectious Diseases; National Natural Science Foundation of China [81161120419, 812111615]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX We thank A. M. Salazar for poly-ICLC; J. Stuckey for assistance with figures; I. S. Georgiev and M. Pancera for assistance with immunogen design; G. J. Nabel, R. A. Seder, L. Shapiro, and members of the Structural Biology Section; Structural Bioinformatics Core Section; and Viral Pathogenesis Laboratory at the Vaccine Research Center for helpful comments; and J. Chrzas, J. Gonczy, U. Chinte, and staff at SER-CAT (Southeast Regional Collaborative Access Team) for help with x-ray diffraction data collection. The data presented in this manuscript are tabulated in the main paper and supplementary materials. Atomic coordinates and structure factors of the reported crystal structures have been deposited in the Protein Data Bank under accession codes 4MMQ to 4MMV. Support for this work was provided by the Intramural Research Program (National Institute of Allergy and Infectious Diseases) and the National Natural Science Foundation of China (81161120419 and 812111615). Use of insertion device 22 (SER-CAT) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. H. S. and T. B. are inventors on an international patent application describing the technology used to isolate D25 and AM22 (Means and methods for influencing the stability of antibody producing cells, WO2007067046A1). A. Q. B. and T. B. are inventors on international patent applications for antibody D25 (RSV-specific binding molecules and means for producing them, WO2008147196A2) and antibody AM22 (RSV-specific binding molecule, WO2011043643A1). J. S. M., M. G. J., B.Z., B. S. G., and P. D. K. are inventors on U. S. patent applications describing the use of prefusion-stabilized RSV F glycoproteins as vaccine antigens (Prefusion RSV F proteins and their use, 61/798,389 and 61/863,909). J. S. M., M. C., Z.Z., N.X., and B. S. G. are inventors on a Chinese patent application for antibody 5C4 and its epitope (Anti-RSV high neutralization antibody and the peptide can be used for prevention of RSV infection and related disease, 201310082338.1). Reagents from the NIH are subject to nonrestrictive materials transfer agreements. NR 33 TC 167 Z9 173 U1 37 U2 103 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD NOV 1 PY 2013 VL 342 IS 6158 BP 592 EP 598 DI 10.1126/science.1243283 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 243RJ UT WOS:000326334300041 PM 24179220 ER PT J AU Taieb, D Varoquaux, A Chen, CC Pacak, K AF Taieeb, David Varoquaux, Arthur Chen, Clara C. Pacak, Karel TI Current and Future Trends in the Anatomical and Functional Imaging of Head and Neck Paragangliomas SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; GLOMUS-JUGULARE TUMORS; SOMATOSTATIN RECEPTOR SUBTYPE-2; GAMMA-KNIFE RADIOSURGERY; GERMLINE MUTATIONS; SUCCINATE-DEHYDROGENASE; IN-111-PENTETREOTIDE SCINTIGRAPHY; OCTREOTIDE SCINTIGRAPHY; I-123-MIBG SPECT; MR-ANGIOGRAPHY AB Head and neck paragangliomas (HNPGLs) account for approximately 3% of all paragangliomas (PGLs). Most often, HNPGLs are benign, nonsecreting, and slowly progressing. The initial physical examination and biochemical diagnosis usually adds very little to the proper diagnosis of these tumors, and, therefore, radiologists and nuclear medicine physicians play a pivotal role in providing the initial diagnosis, the locoregional staging, and the plan for detecting potential multicentric or metastatic lesions. Based on several current studies, the most accurate use of HNPGL-specific initial and subsequent imaging modalities must be guided by the knowledge of genetics and the specifically measured biochemical profile of these tumors for the proper management of these patients. Thus, this short review article presents the application of the most up-to-date anatomical and functional imaging approaches to HNPGLs tightly linked to the clinical management of these patients. Based on the most recent studies, 18F-FDOPA PET/CT has been shown to be a useful addition to anatomical imaging in the preoperative localization and molecular assessment of HNPGLs. It is estimated that the frequency of metabolically active PGLs on 18F-FDOPA PET/CT in this region is higher than 90%. For patients with hereditary PGL syndromes, F-18-FDG-PET/CT should be reserved. Imaging of somatostatin receptors using Octreoscan or 68Ga-labeled somatostatin analogues plays an important role for selecting patients for targeted radiation therapy. This review also concludes that it is expected that in the near future, these patients will indeed benefit from new diagnostic approaches based on the identification of new targets by molecular profiling studies that will result in the development of novel PGL-specific radiopharamceuticals. Published by Elsevier Inc. C1 [Taieeb, David] Aix Marseille Univ, La Timone Univ Hosp, CERIMED, Dept Nucl Med, Marseille, France. [Varoquaux, Arthur] Aix Marseille Univ, La Timone Univ Hosp, Dept Radiol, Marseille, France. [Chen, Clara C.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Pacak, Karel] NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NIH, CRC, Eunice Kennedy Shriver NICHD, Bldg 10,Room 1E-3140,10 Ctr Dr MSC-1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke at the National Institutes of Health FX The authors would like to thank Victoria Martucci for her excellent technical assistance in the preparation of this manuscript. This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. NR 69 TC 8 Z9 8 U1 0 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD NOV PY 2013 VL 43 IS 6 BP 462 EP 473 DI 10.1053/j.semnuclmed.2013.06.005 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 239WY UT WOS:000326057900008 PM 24094713 ER PT J AU Coker-Appiah, DS White, SF Clanton, R Yang, JJ Martin, A Blair, RJR AF Coker-Appiah, Dionne S. White, Stuart F. Clanton, Roberta Yang, Jiongjong Martin, Alex Blair, R. J. R. TI Looming animate and inanimate threats: The response of the amygdala and periaqueductal gray SO SOCIAL NEUROSCIENCE LA English DT Article DE Amygdala; Animacy; Threat; Looming; Periaqueductal gray ID POSTTRAUMATIC-STRESS-DISORDER; FEAR; PREPAREDNESS; EXPRESSIONS; AGGRESSION; BEHAVIOR; STIMULI; PHOBIAS; HUMANS AB Looming stimuli are processed as threatening and activate basic neural defense systems. However, it is unclear how animacy information modulates this response. Participants (N=25) viewed threatening or neutral images that were either animate (animals) or inanimate (objects) and which either approached (loomed) or receded from the participant. The amygdala was responsive to emotional, animacy, and looming information (particularly to looming threats and looming animate stimuli). Periaqueductal gray was also sensitive to emotional information and particularly responsive to looming threats. The data are interpreted within category-specific models of the amygdala and temporal cortex. C1 [Coker-Appiah, Dionne S.; White, Stuart F.; Clanton, Roberta; Blair, R. J. R.] NIMH, Sect Affect Cognit Neurosci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Coker-Appiah, Dionne S.] Georgetown Univ, Dept Psychiat, Sch Med, Washington, DC 20007 USA. [Yang, Jiongjong] Peking Univ, Dept Psychol, Beijing 100871, Peoples R China. [Martin, Alex] NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Coker-Appiah, DS (reprint author), Georgetown Univ, Dept Psychiat, Sch Med, 2115 Wisconsin Ave,NW,Suite 120, Washington, DC 20007 USA. EM dms229@georgetown.edu FU National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08]; National Institutes of Health Combined Neuroscience Review Board [93-M-0170] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [grant no. 1-ZIA-MH002860-08]. Ethical approval for this study was granted by the National Institutes of Health Combined Neuroscience Review Board under protocol 93-M-0170. NR 32 TC 6 Z9 6 U1 1 U2 8 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 EI 1747-0927 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PD NOV 1 PY 2013 VL 8 IS 6 BP 621 EP 630 DI 10.1080/17470919.2013.839480 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 243YE UT WOS:000326353500008 PM 24066700 ER PT J AU Yan, YP Shin, S Jha, BS Liu, QY Sheng, JT Li, FH Zhan, M Davis, J Bharti, K Zeng, XM Rao, M Malik, N Vemuri, MC AF Yan, Yiping Shin, Soojung Jha, Balendu Shekhar Liu, Qiuyue Sheng, Jianting Li, Fuhai Zhan, Ming Davis, Janine Bharti, Kapil Zeng, Xianmin Rao, Mahendra Malik, Nasir Vemuri, Mohan C. TI Efficient and Rapid Derivation of Primitive Neural Stem Cells and Generation of Brain Subtype Neurons From Human Pluripotent Stem Cells SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Article DE Astrocytes; Cell culture; Neural stem cell; Neural induction; Neural differentiation; Oligodendrocytes; Neuron; Nestin ID IN-VITRO; DIFFERENTIATION; PRECURSORS; IDENTITY AB Human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, are unique cell sources for disease modeling, drug discovery screens, and cell therapy applications. The first step in producing neural lineages from hPSCs is the generation of neural stem cells (NSCs). Current methods of NSC derivation involve the time-consuming, labor-intensive steps of an embryoid body generation or coculture with stromal cell lines that result in low-efficiency derivation of NSCs. In this study, we report a highly efficient serum-free pluripotent stem cell neural induction medium that can induce hPSCs into primitive NSCs (pNSCs) in 7 days, obviating the need for time-consuming, laborious embryoid body generation or rosette picking. The pNSCs expressed the neural stem cell markers Pax6, Sox1, Sox2, and Nestin; were negative for Oct4; could be expanded for multiple passages; and could be differentiated into neurons, astrocytes, and oligodendrocytes, in addition to the brain region-specific neuronal subtypes GABAergic, dopaminergic, and motor neurons. Global gene expression of the transcripts of pNSCs was comparable to that of rosette-derived and human fetal-derived NSCs. This work demonstrates an efficient method to generate expandable pNSCs, which can be further differentiated into central nervous system neurons and glia with temporal, spatial, and positional cues of brain regional heterogeneity. This method of pNSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions. C1 [Yan, Yiping; Shin, Soojung; Vemuri, Mohan C.] Life Technol, Primary & Stem Cell Culture Syst, Frederick, MD 21704 USA. [Jha, Balendu Shekhar; Rao, Mahendra; Malik, Nasir] NIH, Natl Ctr Regenerat Med, Bethesda, MD 20892 USA. [Liu, Qiuyue; Zeng, Xianmin] Buck Inst Age Res, Novato, CA USA. [Sheng, Jianting; Li, Fuhai; Zhan, Ming] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Davis, Janine; Bharti, Kapil] NEI, Unit Ocular & Stem Cell Translat Res, NIH, Bethesda, MD 20892 USA. RP Vemuri, MC (reprint author), Life Technol, Primary & Stem Cell Syst, 7335 Execut Way, Frederick, MD 21704 USA. EM mohan.vemuri@lifetech.com OI Jha, Balendu Shekhar/0000-0002-6509-8171 NR 26 TC 22 Z9 22 U1 3 U2 16 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD NOV PY 2013 VL 2 IS 11 BP 862 EP 870 DI 10.5966/sctm.2013-0080 PG 9 WC Cell & Tissue Engineering SC Cell Biology GA 243JF UT WOS:000326312000013 PM 24113065 ER PT J AU O'Neill, SC Lipkus, IM Sanderson, SC Shepperd, J Docherty, S McBride, CM AF O'Neill, Suzanne C. Lipkus, Isaac M. Sanderson, Saskia C. Shepperd, James Docherty, Sharron McBride, Colleen M. TI Motivations for genetic testing for lung cancer risk among young smokers SO TOBACCO CONTROL LA English DT Article DE Motivations; primary prevention; genetic testing; GSTM1; prevention; cessation; addiction ID SMOKING-BEHAVIOR; UNITED-STATES; UNREALISTIC OPTIMISM; HEALTH; SUSCEPTIBILITY; PREVENTION AB Objective To examine why young people might want to undergo genetic susceptibility testing for lung cancer despite knowing that tested gene variants are associated with small increases in disease risk. Methods The authors used a mixed-method approach to evaluate motives for and against genetic testing and the association between these motivations and testing intentions in 128 college students who smoke. Results Exploratory factor analysis yielded four reliable factors: Test Scepticism, Test Optimism, Knowledge Enhancement and Smoking Optimism. Test Optimism and Knowledge Enhancement correlated positively with intentions to test in bivariate and multivariate analyses (ps<0.001). Test Scepticism correlated negatively with testing intentions in multivariate analyses (p<0.05). Open-ended questions assessing testing motivations generally replicated themes of the quantitative survey. Conclusion In addition to learning about health risks, young people may be motivated to seek genetic testing for reasons, such as gaining knowledge about new genetic technologies more broadly. C1 [O'Neill, Suzanne C.] Georgetown Univ, Canc Control Program, Washington, DC 20007 USA. [Lipkus, Isaac M.; Docherty, Sharron] Duke Univ, Sch Nursing, Durham, NC USA. [Sanderson, Saskia C.] Mt Sinai Sch Med, New York, NY USA. [Shepperd, James] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP O'Neill, SC (reprint author), Georgetown Univ, Canc Control Program, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM sco4@georgetown.edu FU National Cancer Institute [RO1 CA01846]; American Cancer Society [MRSG-10-110-01-CPPB] FX Support for this work was provided by the National Cancer Institute (Grant RO1 CA01846 to IML) and the American Cancer Society (Grant MRSG-10-110-01-CPPB to SCO). NR 35 TC 5 Z9 5 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 EI 1468-3318 J9 TOB CONTROL JI Tob. Control PD NOV PY 2013 VL 22 IS 6 BP 406 EP 411 DI 10.1136/tobaccocontrol-2011-050306 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 240OY UT WOS:000326107800014 PM 22744911 ER PT J AU Koh, C Turner, T Zhao, XC Minniti, CP Feld, JJ Simpson, J Demino, M Conrey, AK Jackson, MJ Seamon, C Kleiner, DE Kato, GJ Heller, T AF Koh, Christopher Turner, Tiffany Zhao, Xiongce Minniti, Caterina P. Feld, Jordan J. Simpson, Jennifer Demino, Mary Conrey, Anna K. Jackson, Mary J. Seamon, Catherine Kleiner, David E. Kato, Gregory J. Heller, Theo TI Liver stiffness increases acutely during sickle cell vaso-occlusive crisis SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CHRONIC HEPATITIS-C; TRANSIENT ELASTOGRAPHY; NONINVASIVE ASSESSMENT; PORTAL-HYPERTENSION; DISEASE; FIBROSIS; ANEMIA; HEPATOPATHY; HEMOCHROMATOSIS; CLASSIFICATION AB Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10-39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE. Twenty-three patients were evaluated (mean age=34.3 years, standard deviation=7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P=0.01) and TRV (P=0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P<0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (P=0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P=0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (P=0.0037) and TRV (P=0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P=0.041), lower albumin (P=0.046), hemoglobin/hematocrit (P<0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC. Am. J. Heamtol. 88:E250-E254, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Koh, Christopher; Turner, Tiffany; Feld, Jordan J.; Simpson, Jennifer; Demino, Mary; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Zhao, Xiongce] NIDDK, Off Director, NIH, Bethesda, MD 20892 USA. [Minniti, Caterina P.; Conrey, Anna K.; Jackson, Mary J.; Seamon, Catherine; Kato, Gregory J.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Koh, C (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B-16,10 Ctr Dr,MSC 1800, Bethesda, MD 20892 USA. EM Christopher.Koh@nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Kleiner, David/0000-0003-3442-4453 FU Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Cancer Institute FX Contract grant sponsor: Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute and the National Cancer Institute. NR 50 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2013 VL 88 IS 11 BP E250 EP E254 DI 10.1002/ajh.23532 PG 5 WC Hematology SC Hematology GA 239NX UT WOS:000326033600002 PM 23828202 ER PT J AU Padalkar, MV Spencer, RG Pleshko, N AF Padalkar, M. V. Spencer, R. G. Pleshko, N. TI Near Infrared Spectroscopic Evaluation of Water in Hyaline Cartilage SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Water; Cartilage; Near infrared (NIR) spectroscopy; Partial least squares (PLS) regression ID HUMAN ARTICULAR-CARTILAGE; FIBER-OPTIC PROBE; NIR SPECTROSCOPY; FISCHER,KARL TITRATION; DEGENERATIVE CARTILAGE; REFLECTANCE; OSTEOARTHRITIS; SKIN; RELAXATION; DIFFUSION AB In diseased conditions of cartilage such as osteoarthritis, there is typically an increase in water content from the average normal of 60-85% to greater than 90%. As cartilage has very little capability for self-repair, methods of early detection of degeneration are required, and assessment of water could prove to be a useful diagnostic method. Current assessment methods are either destructive, time consuming, or have limited sensitivity. Here, we investigated the hypotheses that non-destructive near infrared spectroscopy (NIRS) of articular cartilage can be used to differentiate between free and bound water, and to quantitatively assess water content. The absorbances centered at 5200 and 6890 cm(-1) were attributed to a combination of free and bound water, and to free water only, respectively. The integrated areas of both absorbance bands were found to correlate linearly with the absolute water content (R = 0.87 and 0.86) and with percent water content (R = 0.97 and 0.96) of the tissue. Partial least square models were also successfully developed and were used to predict water content, and percent free water. These data demonstrate that NIRS can be utilized to quantitatively determine water content in articular cartilage, and may aid in early detection of degenerative tissue changes in a laboratory setting, and with additional validations, possibly in a clinical setting. C1 [Padalkar, M. V.; Pleshko, N.] Temple Univ, Dept Bioengn, Philadelphia, PA 19122 USA. [Spencer, R. G.] NIA, NIH, Baltimore, MD 21224 USA. RP Pleshko, N (reprint author), Temple Univ, Dept Bioengn, Philadelphia, PA 19122 USA. EM npleshko@temple.edu FU NIH [AR056145, EB000744]; Intramural Research Program at NIA FX This study was supported by NIH AR056145 and EB000744 and the Intramural Research Program at NIA. NR 66 TC 16 Z9 16 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 EI 1573-9686 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD NOV PY 2013 VL 41 IS 11 BP 2426 EP 2436 DI 10.1007/s10439-013-0844-0 PG 11 WC Engineering, Biomedical SC Engineering GA 236CZ UT WOS:000325772900015 PM 23824216 ER PT J AU Williams, TH Gumm, JM Mendelson, TC AF Williams, Tory H. Gumm, Jennifer M. Mendelson, Tamra C. TI Sexual selection acting on a speciation trait in darters (Percidae: Etheostoma) SO BEHAVIORAL ECOLOGY LA English DT Article DE association preference; behavioral isolation; female choice; male nuptial color; model ID MALE-MALE COMPETITION; FEMALE MATE CHOICE; LAKE VICTORIA CICHLIDS; WING MELANIN PATTERN; MALE COLORATION; SPECIES RICHNESS; MATING PREFERENCES; REPRODUCTIVE ISOLATION; BEHAVIORAL ISOLATION; PIERIS-OCCIDENTALIS AB Despite theoretical support linking sexual selection for elaborate coloration and behavioral isolation, few empirical examples clearly demonstrate that the sexually dichromatic signals responsible for behavioral isolation between species are, or have been, subject to sexual selection within species. The present study investigates sexual selection on male nuptial coloration in Etheostoma barrenense, a darter species for which male color has been shown in a previous study to contribute to behavioral isolation from a sympatric congener. Through the use of motorized model fish, we demonstrate that female E. barrenense discriminate between the orange and red body hues of conspecific males and exhibit an association preference for orange over red models. Combined with the results from a previous study, these data provide evidence for a link between sexual selection and behavioral isolation and by extension for a role of sexual selection in speciation. A post hoc analysis of the colors modeled in darter visual space suggests that quantifying signal values as they are perceived, rather than expressed, provide a promising way of linking sexual selection and behavioral isolation. C1 [Williams, Tory H.] NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, Rockville, MD 20852 USA. [Gumm, Jennifer M.] Stephen F Austin State Univ, Dept Biol, Nacogdoches, TX 75962 USA. [Mendelson, Tamra C.] Univ Maryland Baltimore Cty, Dept Biol Sci, Baltimore, MD 21250 USA. RP Williams, TH (reprint author), NIAAA, Sect Model Synapt Syst, Lab Mol Physiol, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM tory.williams@nih.gov FU National Science Foundation [DEB-0718987] FX This research was partially funded by National Science Foundation grant DEB-0718987 to T.C.M. NR 82 TC 12 Z9 12 U1 3 U2 46 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1045-2249 EI 1465-7279 J9 BEHAV ECOL JI Behav. Ecol. PD NOV-DEC PY 2013 VL 24 IS 6 BP 1407 EP 1414 DI 10.1093/beheco/art080 PG 8 WC Behavioral Sciences; Biology; Ecology; Zoology SC Behavioral Sciences; Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Zoology GA 239BG UT WOS:000325995900018 ER PT J AU Largent, E Grady, C Miller, FG Wertheimer, A AF Largent, Emily Grady, Christine Miller, Franklin G. Wertheimer, Alan TI MISCONCEPTIONS ABOUT COERCION AND UNDUE INFLUENCE: REFLECTIONS ON THE VIEWS OF IRB MEMBERS SO BIOETHICS LA English DT Article DE coercion; undue influence; payment ID CONSENT AB Payment to recruit research subjects is a common practice but raises ethical concerns relating to the potential for coercion or undue influence. We conducted the first national study of IRB members and human subjects protection professionals to explore attitudes as to whether and why payment of research participants constitutes coercion or undue influence. Upon critical evaluation of the cogency of ethical concerns regarding payment, as reflected in our survey results, we found expansive or inconsistent views about coercion and undue influence that may interfere with valuable research. In particular, respondents appear to believe that coercion and undue influence lie on a continuum; by contrast, we argue that they are wholly distinct: whereas undue influence is a cognitive distortion relating to assessment of risks and benefits, coercion is a threat of harm. Because payment is an offer, rather than a threat, payment is never coercive. C1 [Largent, Emily; Miller, Franklin G.; Wertheimer, Alan] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Wertheimer, Alan] Univ Vermont, Burlington, VT 05405 USA. RP Wertheimer, A (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov NR 15 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-9702 EI 1467-8519 J9 BIOETHICS JI Bioethics PD NOV PY 2013 VL 27 IS 9 BP 500 EP 507 DI 10.1111/j.1467-8519.2012.01972.x PG 8 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 237KD UT WOS:000325867600005 PM 22493972 ER PT J AU Duan, Q Liu, EY Auer, PL Zhang, GS Lange, EM Jun, G Bizon, C Jiao, S Buyske, S Franceschini, N Carlson, CS Hsu, L Reiner, AP Peters, U Haessler, J Curtis, K Wassel, CL Robinson, JG Martin, LW Haiman, CA Le Marchand, L Matise, TC Hindorff, LA Crawford, DC Assimes, TL Kang, HM Heiss, G Jackson, RD Kooperberg, C Wilson, JG Abecasis, GR North, KE Nickerson, DA Lange, LA Li, Y AF Duan, Qing Liu, Eric Yi Auer, Paul L. Zhang, Guosheng Lange, Ethan M. Jun, Goo Bizon, Chris Jiao, Shuo Buyske, Steven Franceschini, Nora Carlson, Chris S. Hsu, Li Reiner, Alex P. Peters, Ulrike Haessler, Jeffrey Curtis, Keith Wassel, Christina L. Robinson, Jennifer G. Martin, Lisa W. Haiman, Christopher A. Le Marchand, Loic Matise, Tara C. Hindorff, Lucia A. Crawford, Dana C. Assimes, Themistocles L. Kang, Hyun Min Heiss, Gerardo Jackson, Rebecca D. Kooperberg, Charles Wilson, James G. Abecasis, Goncalo R. North, Kari E. Nickerson, Deborah A. Lange, Leslie A. Li, Yun TI Imputation of coding variants in African Americans: better performance using data from the exome sequencing project SO BIOINFORMATICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; RARE VARIANT; DESIGN; ATHEROSCLEROSIS; HAPLOTYPES; DEEP; LOCI; TOOL; MAP AB Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3-11.4% for coding variants with minor allele frequency 51%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2' s two-panel combination. C1 [Duan, Qing; Zhang, Guosheng; Lange, Ethan M.; Lange, Leslie A.; Li, Yun] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Liu, Eric Yi; Li, Yun] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Auer, Paul L.; Jiao, Shuo; Carlson, Chris S.; Hsu, Li; Reiner, Alex P.; Peters, Ulrike; Haessler, Jeffrey; Curtis, Keith; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Lange, Ethan M.; Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Jun, Goo; Kang, Hyun Min; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Jun, Goo; Kang, Hyun Min; Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Bizon, Chris] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27599 USA. [Buyske, Steven] Rutgers State Univ, Dept Stat, Piscataway, NJ 08854 USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Franceschini, Nora; Heiss, Gerardo; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Peters, Ulrike] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wassel, Christina L.] Univ Pittsburgh, Grad Sch Publ Hlth, Div Epidemiol, Pittsburgh, PA 15261 USA. [Robinson, Jennifer G.] Univ Iowa, Dept Epidemiol & Med, Iowa City, IA 52242 USA. [Martin, Lisa W.] George Washington Univ, Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20037 USA. [Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96813 USA. [Hindorff, Lucia A.] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA. [Crawford, Dana C.] Vanderbilt Univ, Ctr Human Genet Res, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Assimes, Themistocles L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Li, Y (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. EM yunli@med.unc.edu RI Liu, Eric Yi/B-6221-2016; Jun, Goo/M-5235-2016; Jun, Goo/F-1941-2017; OI Jun, Goo/0000-0003-0891-0204; Jun, Goo/0000-0003-0891-0204; Martin, Lisa Warsinger/0000-0003-4352-0914; Buyske, Steven/0000-0001-8539-5416 FU National Institutes of Health [R01HG006292, R01HG006703] FX National Institutes of Health (R01HG006292 and R01HG006703 to Y.L.). NR 40 TC 15 Z9 16 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 1 PY 2013 VL 29 IS 21 BP 2744 EP 2749 DI 10.1093/bioinformatics/btt477 PG 6 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 239BW UT WOS:000325997500011 PM 23956302 ER PT J AU Keyak, JH Sigurdsson, S Karlsdottir, GS Oskarsdottir, D Sigmarsdottir, A Kornak, J Harris, TB Sigurdsson, G Jonsson, BY Siggeirsdottir, K Eiriksdottir, G Gudnason, V Lang, TF AF Keyak, J. H. Sigurdsson, S. Karlsdottir, G. S. Oskarsdottir, D. Sigmarsdottir, A. Kornak, J. Harris, T. B. Sigurdsson, G. Jonsson, B. Y. Siggeirsdottir, K. Eiriksdottir, G. Gudnason, V. Lang, T. F. TI Effect of finite element model loading condition on fracture risk assessment in men and women: The AGES-Reykjavik study SO BONE LA English DT Article DE Hip fracture; Femur; Bone strength; Finite element analysis; Osteoporosis; Quantitative computed tomography ID PROXIMAL FEMORAL STRENGTH; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; CT-SCAN DATA; HIP FRACTURE; IMPACT DIRECTION; TRABECULAR BONE; FEMUR; PREDICTION; ASSOCIATION; DXA AB Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (F-PL), posterior (F-P) and lateral (F-L) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (F-Stance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p <= 0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between F-P and fracture in women fell short of statistical significance (p = 0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, F-PL was 424 N (11%) less in subjects with fractures than in controls (p = 0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD. (c) 2013 Elsevier Inc. All rights reserved. C1 [Keyak, J. H.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. [Keyak, J. H.] Univ Calif Irvine, Dept Biomed Engn, Irvine, CA 92697 USA. [Keyak, J. H.] Univ Calif Irvine, Dept Mech & Aerosp Engn, Irvine, CA 92717 USA. [Sigurdsson, S.; Karlsdottir, G. S.; Oskarsdottir, D.; Sigmarsdottir, A.; Sigurdsson, G.; Siggeirsdottir, K.; Eiriksdottir, G.; Gudnason, V.] Iceland Heart Assoc Res Inst, Kopavogur, Iceland. [Oskarsdottir, D.; Sigurdsson, G.; Gudnason, V.] Univ Iceland, Reykjavik, Iceland. [Kornak, J.; Lang, T. F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Kornak, J.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Sigurdsson, G.] Landspitalinn Univ Hosp, Reykjavik, Iceland. [Jonsson, B. Y.] Skane Univ Hosp, Dept Orthoped, Malmo, Sweden. RP Keyak, JH (reprint author), Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92697 USA. EM jhkeyak@uci.edu RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 FU NIH/NIA [R01AG028832]; NIH/NIAMS [R01AR46197]; NIH [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by NIH/NIA R01AG028832 and NIH/NIAMS R01AR46197. The Age, Gene/Environment Susceptibility Reykjavik Study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study was approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. NR 26 TC 17 Z9 19 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD NOV PY 2013 VL 57 IS 1 BP 18 EP 29 DI 10.1016/j.bone.2013.07.028 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 235TC UT WOS:000325742600003 PM 23907032 ER PT J AU Carballido-Gamio, J Harnish, R Saeed, I Streeper, T Sigurdsson, S Amin, S Atkinson, EJ Therneau, TM Siggeirsdottir, K Cheng, XG Melton, LJ Keyak, JH Gudnason, V Khosla, S Harris, TB Lang, TF AF Carballido-Gamio, Julio Harnish, Roy Saeed, Isra Streeper, Timothy Sigurdsson, Sigurdur Amin, Shreyasee Atkinson, Elizabeth J. Therneau, Terry M. Siggeirsdottir, Kristin Cheng, Xiaoguang Melton, L. Joseph, III Keyak, Joyce H. Gudnason, Vilmundur Khosla, Sundeep Harris, Tamara B. Lang, Thomas F. TI Structural patterns of the proximal femur in relation to age and hip fracture risk in women SO BONE LA English DT Article DE Osteoporosis; Proximal femur; Statistical parametric mapping; Tensor-based morphometry (TBM); Age; Fracture ID TENSOR-BASED MORPHOMETRY; VOXEL-BASED MORPHOMETRY; GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; FEMORAL-NECK; COMPUTED-TOMOGRAPHY; GROWTH-PATTERNS; HUMAN BRAIN; BONE; STRENGTH; GEOMETRY AB Fractures of the proximal femur are the most devastating outcome of osteoporosis. It is generally understood that age-related changes in hip structure confer increased risk, but there have been few explicit comparisons of such changes in healthy subjects to those with hip fracture. In this study, we used quantitative computed tomography and tensor-based morphometry (TBM) to identify three-dimensional internal structural patterns of the proximal femur associated with age and with incident hip fracture. A population-based cohort of 349 women representing a broad age range (21-97 years) was included in this study, along with a cohort of 222 older women (mean age 79 7 years) with (n = 74) and without (n = 148) incident hip fracture. Images were spatially normalized to a standardized space, and age- and fracture-specific morphometric features were identified based on statistical maps of shape features described as local changes of bone volume. Morphometric features were visualized as maps of local contractions and expansions, and significance was displayed as Student's t-test statistical maps. Significant age-related changes included local expansions of regions low in volumetric bone mineral density (vBMD) and local contractions of regions high in vBMD. Some significant fracture-related features resembled an accentuated aging process, including local expansion of the superior aspect of the trabecular bone compartment in the femoral neck, with contraction of the adjoining cortical bone. However, other features were observed only in the comparison of hip fracture subjects with age-matched controls including focal contractions of the cortical bone at the superior aspect of the femoral neck, the lateral cortical bone just inferior to the greater trochanter, and the anterior intertrochanteric region. Results of this study support the idea that the spatial distribution of morphometric features is relevant to age-related changes in bone and independent to fracture risk. In women, the identification by TBM of fracture-specific morphometric alterations of the proximal femur, in conjunction with vBMD and clinical risk factors, may improve hip fracture prediction. (C) 2013 Elsevier Inc. All rights reserved. C1 [Carballido-Gamio, Julio; Harnish, Roy; Saeed, Isra; Streeper, Timothy; Lang, Thomas F.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Sigurdsson, Sigurdur; Siggeirsdottir, Kristin; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Amin, Shreyasee; Melton, L. Joseph, III] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Amin, Shreyasee] Mayo Clin, Coll Med, Dept Internal Med, Div Rheumatol, Rochester, MN USA. [Atkinson, Elizabeth J.; Therneau, Terry M.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Cheng, Xiaoguang] Beijing Ji Shui Tan Hosp, Dept Radiol, Beijing, Peoples R China. [Melton, L. Joseph, III; Khosla, Sundeep] Mayo Clin, Coll Med, Dept Internal Med, Div Endocrinol Diabet Metab & Nutr, Rochester, MN USA. [Keyak, Joyce H.] Univ Calif Irvine, Dept Radiol Sci, Irvine, CA 92717 USA. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Lang, TF (reprint author), 185 Berry St,Suite 350, San Francisco, CA 94143 USA. EM Thomas.Lang@ucsf.edu RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Khosla, Sundeep/0000-0002-2936-4372; Lang, Thomas/0000-0002-3720-8038 FU NIH/NIA [R01AG028832, R01AG034676, UL1 TR000135]; NIH/NIAMS [R01AR46197, R01AR027065]; NIH/NIA Professional Services Contract [HHSN311200900345P]; NIH [N01-AG-12100]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by NIH/NIA R01AG028832, NIH/NIAMS R01AR46197, NIH/NIA Professional Services Contract HHSN311200900345P, NIH/NIAMS R01AR027065, and NIH/NIA R01AG034676 and UL1 TR000135 (Center for Translational Science Activities). The Age, Gene/Environment Susceptibility Reykjavik study is funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). NR 43 TC 11 Z9 11 U1 0 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD NOV PY 2013 VL 57 IS 1 BP 290 EP 299 DI 10.1016/j.bone.2013.08.017 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 235TC UT WOS:000325742600039 PM 23981658 ER PT J AU Kenworthy, L Wallace, GL Birn, R Milleville, SC Case, LK Bandettini, PA Martin, A AF Kenworthy, Lauren Wallace, Gregory L. Birn, Rasmus Milleville, Shawn C. Case, Laura K. Bandettini, Peter A. Martin, Alex TI Aberrant neural mediation of verbal fluency in autism spectrum disorders SO BRAIN AND COGNITION LA English DT Article DE Autism; Verbal fluency; fMRI; Executive function; Left inferior frontal gyrus ID HIGH-FUNCTIONING AUTISM; VENTROLATERAL PREFRONTAL CORTEX; FRONTAL-LOBE LESIONS; WORKING-MEMORY TASK; EXECUTIVE FUNCTIONS; REPETITIVE BEHAVIOR; BRAIN ACTIVATION; SENTENCE COMPREHENSION; ASPERGERS-DISORDER; COGNITIVE CONTROL AB Objective: Contrasts of verbal fluency and automatic speech provide an opportunity to evaluate the neural underpinnings of generativity and flexibility in autism spectrum disorders (ASD). Method: We used functional magnetic resonance imaging (fMRI) to contrast brain activity in high functioning ASD (n = 17, mean verbal IQ = 117) and neurotypical (NT; n = 20, mean verbal IQ = 112) adolescent and young adult males (12-23 years). Participants responded to three word generation conditions: automatic speech (reciting months), category fluency, and letter fluency. Results: Our paradigm closely mirrored behavioral fluency tasks by requiring overt, free recall word generation while controlling for differences in verbal output between the groups and systematically increasing the task demand. The ASD group showed reduced neural response compared to the NT participants during fluency tasks in multiple regions of left anterior and posterior cortices, and sub-cortical structures. Six of these regions fell in cortico-striatal circuits previously linked to repetitive behaviors (Langen, Durston, Kas, van Engeland, & Staal, 2011), and activity in two of them (putamen and thalamus) was negatively correlated with autism repetitive behavior symptoms in the ASD group. In addition, response in left inferior frontal gyrus was differentially modulated in the ASD, relative to the NT, group as a function of task demand. Conclusions: These data indicate a specific, atypical brain response in ASD to demanding generativity tasks that may have relevance to repetitive behavior symptoms in ASD as well as to difficulties generating original verbal responses. Published by Elsevier Inc. C1 [Kenworthy, Lauren; Wallace, Gregory L.; Birn, Rasmus; Milleville, Shawn C.; Case, Laura K.; Bandettini, Peter A.; Martin, Alex] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Rockville, MD 20850 USA. RP Kenworthy, L (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Room 4C104,MSC 1366, Bethesda, MD 20892 USA. EM lkenwort@cnmc.org; gregwallace@mail.nih.-gov; rbirn@wisc.edu; millevis@mail.nih.gov; lkcase@gmail.com; bandettp@mail.nih.gov; alexmar-tin@mail.nih.gov OI Case, Laura/0000-0003-3730-2451; Wallace, Gregory/0000-0003-0329-5054 FU National Institute of Mental Health, National Institutes of Health, Division of Intramural Research under National Institutes of Health [10-M-0027]; Guldelsky Family Foundation FX This study was supported by the National Institute of Mental Health, National Institutes of Health, Division of Intramural Research, and it was conducted under National Institutes of Health Clinical Study Protocol 10-M-0027 (ClinicalTrials.gov ID NCT01031407). In addition, Lauren Kenworthy received support from the Guldelsky Family Foundation. The authors thank the children and their families who participated in the investigation, Ben Yerys for valuable feedback regarding the manuscript, and Eunice Dixon for editorial assistance. NR 82 TC 7 Z9 7 U1 2 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD NOV PY 2013 VL 83 IS 2 BP 218 EP 226 DI 10.1016/j.bandc.2013.08.003 PG 9 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 235SI UT WOS:000325740600007 PM 24056237 ER PT J AU Lamm, C Pine, DS Fox, NA AF Lamm, C. Pine, D. S. Fox, N. A. TI Impact of negative affectively charged stimuli and response style on cognitive-control-related neural activation: An ERP study SO BRAIN AND COGNITION LA English DT Article DE Emotion; AX-CPT; Reactive control; Proactive control; N2; LORETA; Prefrontal neural activation ID EMOTION REGULATION; WORKING-MEMORY; MECHANISMS; CHILDREN; INTERFERENCE; PERFORMANCE AB The canonical AX-CPT task measures two forms of cognitive control: sustained goal-oriented control ("proactive" control) and transient changes in cognitive control following unexpected events ("reactive" control). We modified this task by adding negative and neutral International Affective Picture System (IAPS) pictures to assess the effects of negative emotion on these two forms of cognitive control. Proactive and reactive control styles were assessed based on measures of behavior and electrophysiology, including the N2 event-related potential component and source space activation (Low Resolution Tomography [LORETA]). We found slower reaction-times and greater DLPFC activation for negative relative to neutral stimuli. Additionally, we found that a proactive style of responding was related to less prefrontal activation (interpreted to reflect increased efficiency of processing) during actively maintained previously cued information and that a reactive style of responding was related to less prefrontal activation (interpreted to reflect increased efficiency of processing) during just-in-time environmentally triggered information. This pattern of results was evident in relatively neutral contexts, but in the face of negative emotion, these associations were not found, suggesting potential response style-by-emotion interaction effects on prefrontal neural activation. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lamm, C.] Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. [Pine, D. S.] NIMH, Intramural Res Program, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Fox, N. A.] Univ Maryland, Dept Human Dev & Quantitat Methodol, Child Dev Lab, Catonsville, MD 21228 USA. RP Lamm, C (reprint author), Univ New Orleans, Dept Psychol, New Orleans, LA 70148 USA. EM clamm@uno.edu FU National Institute of Mental Health [P50MH078105] FX The project described was supported by Grant Number P50MH078105 to Megan R. Gunnar from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. The authors also thank Anna Kresse for her dedication in collecting this data in a timely manner. NR 22 TC 4 Z9 4 U1 3 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD NOV PY 2013 VL 83 IS 2 BP 234 EP 243 DI 10.1016/j.bandc.2013.07.012 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 235SI UT WOS:000325740600009 PM 24021156 ER PT J AU Loga, F Domes, K Freichel, M Flockerzi, V Dietrich, A Birnbaumer, L Hofmann, F Wegener, JW AF Loga, Florian Domes, Katrin Freichel, Marc Flockerzi, Veit Dietrich, Alexander Birnbaumer, Lutz Hofmann, Franz Wegener, Joeg W. TI The role of cGMP/cGKI signalling and Trpc channels in regulation of vascular tone SO CARDIOVASCULAR RESEARCH LA English DT Article DE Phenylephrine; Smooth muscle; Relaxation; Nitric oxide; Endothelium ID RECEPTOR POTENTIAL CHANNELS; ARTERIAL SMOOTH-MUSCLE; NITRIC-OXIDE SYNTHASE; PROTEIN-KINASE-G; ENDOTHELIAL-CELLS; MICE; VASORELAXATION; INHIBITION; ACTIVATION; EXPRESSION AB Signalling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (Trpc) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signalling. We tested this concept by investigating the role of cGMP/cGKI signalling on vascular tone and peripheral resistance using Trpc6(/), Trpc3(/), Trpc3(/)/6(/), Trpc1(/)/3(/)/6(/), and SM-specific cGKI(/) (sm-cGKI(/)) mice. -Adrenergic stimulation induced similar contractions in L-NG-nitroarginine methyl ester (l-NAME)-treated aorta and comparably increased peripheral pressure in hind limbs from all mouse lines investigated. After -adrenergic stimulation, 8-Br-cGMP diminished similarly aortic tone and peripheral pressure in control, Trpc6(/), Trpc3(/), Trpc3(/)/6(/), and Trpc1(/)/3(/)/6(/) mice but not in sm-cGKI(/) mice. In untreated aorta, -adrenergic stimulation induced similar contractions in the aorta from control and Trpc3(/) mice but larger contractions in sm-cGKI(/), Trpc6(/), Trpc3(/)/6(/), and Trpc1(/)/3(/)/6(/) mice, indicating a functional link between cGKI and Trpc6 channels. Trpc3 channels were detected by immunocytochemistry in both isolated aortic smooth muscle cells (SMCs) and aortic endothelial cells (ECs), whereas Trpc6 channels were detected only in ECs. Phenylephrine-stimulated Ca-2 levels were similar in SMCs from control (Ctr) and Trpc6(/) mice. Carbachol-stimulated Ca-2 levels were reduced in ECs from Trpc6(/) mice. Stimulated Ca-2 levels were lowered by 8-Br-cGMP in Ctr but not in Trpc6(/) ECs. The results suggest that cGKI and Trpc1,3,6 channels are not functionally coupled in vascular SM. Deletion of Trpc6 channels impaired endothelial cGKI signalling and vasodilator tone in the aorta. C1 [Loga, Florian; Domes, Katrin; Hofmann, Franz; Wegener, Joeg W.] Tech Univ Munich, FOR923, Inst Pharmakol & Toxikol, D-80802 Munich, Germany. [Freichel, Marc] Heidelberg Univ, Pharmakol Inst, D-69120 Heidelberg, Germany. [Freichel, Marc; Flockerzi, Veit] Univ Saarland, Med Fak, D-66421 Homburg, Germany. [Dietrich, Alexander] Univ Munich, Walther Straub Inst Pharmakol & Toxikol, D-80539 Munich, Germany. [Birnbaumer, Lutz] NIEHS, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Wegener, JW (reprint author), Tech Univ Munich, FOR923, Inst Pharmakol & Toxikol, Biedersteiner Str 29, D-80802 Munich, Germany. EM joerg.wegener@mytum.de OI Dietrich, Alexander/0000-0002-1168-8707 FU Deutsche Forschungsgemeinschaft; Fond der Chemischen Industrie; Intramural Research Program of the NIH [Z01-ES-101684] FX The work was funded by grants from Deutsche Forschungsgemeinschaft, Fond der Chemischen Industrie, and by the Intramural Research Program of the NIH (Project Z01-ES-101684 to L.B.). NR 36 TC 8 Z9 9 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD NOV 1 PY 2013 VL 100 IS 2 BP 280 EP 287 DI 10.1093/cvr/cvt176 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 239IG UT WOS:000326015200014 PM 23832809 ER PT J AU Berger, VW Gudehithlu, SK AF Berger, Vance W. Gudehithlu, Sheila K. TI Re: Compalati E, Canonica GW. Efficacy and safety of rupatadine for allergic rhino-conjunctivitis: a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Curr Med Res Opin 2013 Jul 5. DOI: 10.1185/03007995.2013.837386. SO CURRENT MEDICAL RESEARCH AND OPINION LA English DT Letter ID 10 MG; RHINITIS C1 [Berger, Vance W.] NCI, Rockville, MD 20850 USA. [Berger, Vance W.; Gudehithlu, Sheila K.] Univ Maryland Baltimore Cty, Biometry Res Grp, Natl Canc Inst, Rockville, MD 20850 USA. [Gudehithlu, Sheila K.] Univ Illinois, Natl Canc Inst, Rockville, MD 20850 USA. RP Berger, VW (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vb78c@nih.gov NR 7 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-7995 EI 1473-4877 J9 CURR MED RES OPIN JI Curr. Med. Res. Opin. PD NOV PY 2013 VL 29 IS 11 BP 1553 EP 1554 DI 10.1185/03007995.2013.837386 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 237FD UT WOS:000325853100018 PM 23971648 ER PT J AU Grice, BA Mason, CC Weil, EJ Knowler, WC Pomeroy, J AF Grice, Brian A. Mason, Clinton C. Weil, E. Jennifer Knowler, William C. Pomeroy, Jeremy TI The relationship between insulin sensitivity and maximal oxygen uptake is confounded by method of adjustment for body composition SO DIABETES & VASCULAR DISEASE RESEARCH LA English DT Article DE VO(2)max; insulin sensitivity; ratio adjustment; maximal oxygen uptake; per-weight standard ID CARDIORESPIRATORY FITNESS; STATISTICAL CONSIDERATIONS; ASSOCIATION; OVERWEIGHT; GLUCOSE; FATNESS; ADULTS; WOMEN; MEN AB Background: The use of ratios for analyzing physiologic variables often creates spurious associations. Methods: Results of a euglycaemic clamp, a graded exercise test to measure maximal oxygen uptake (VO(2)max) and underwater weighing in 358 nondiabetic adults (166 women and 192 men) were used to compare the effects of weight standardization by division or by partial Spearman correlations on the association between VO(2)max and insulin sensitivity. Results: VO(2)max and insulin sensitivity were negatively correlated when VO(2)max was divided by weight. When partial Spearman correlations were used to adjust VO(2)max for body composition, the correlation between VO(2)max and insulin sensitivity was greatly diminished. Conclusions: Division of VO(2)max by weight does not adjust for weight, but it creates spurious associations between VO(2)max and insulin sensitivity. C1 [Grice, Brian A.; Weil, E. Jennifer; Knowler, William C.; Pomeroy, Jeremy] NIDDK, Phoenix, AZ 85014 USA. [Mason, Clinton C.] Huntsman Canc Inst, Salt Lake City, UT USA. RP Pomeroy, J (reprint author), NIDDK, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM Jeremy.pomeroy@nih.gov FU NIDDK Intramural Research Program FX This research was supported by the NIDDK Intramural Research Program. NR 17 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1479-1641 EI 1752-8984 J9 DIABETES VASC DIS RE JI Diabetes Vasc. Dis. Res. PD NOV PY 2013 VL 10 IS 6 BP 530 EP 535 DI 10.1177/1479164113501529 PG 6 WC Endocrinology & Metabolism; Peripheral Vascular Disease SC Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 236NH UT WOS:000325803800008 PM 24062163 ER PT J AU Young, WS AF Young, W. Scott TI Shedding Heat on Oxytocin SO ENDOCRINOLOGY LA English DT Editorial Material ID RECEPTOR-DEFICIENT MICE; SOCIAL RECOGNITION; AUTISM LOCI; GENOME-WIDE; PARTURITION; MOUSE; BEHAVIOR; IMPAIRS; SEARCH; GENES C1 NIMH, NIH, Dept Hlth & Human Serv, Sect Neural Gene Express, Bethesda, MD 20892 USA. RP Young, WS (reprint author), NIMH, NIH, Dept Hlth & Human Serv, Sect Neural Gene Express, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU NIMH NIH HHS [Z01 MH002498, Z01-MH-002498-24] NR 32 TC 0 Z9 0 U1 0 U2 12 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 3961 EP 3962 DI 10.1210/en.2013-1885 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200004 PM 24141993 ER PT J AU Pedram, A Razandi, M Korach, KS Narayanan, R Dalton, JT Levin, ER AF Pedram, Ali Razandi, Mahnaz Korach, Kenneth S. Narayanan, Ramesh Dalton, James T. Levin, Ellis R. TI ER beta Selective Agonist Inhibits Angiotensin-Induced Cardiovascular Pathology in Female Mice SO ENDOCRINOLOGY LA English DT Article ID ESTROGEN-RECEPTOR-BETA; LEFT-VENTRICULAR HYPERTROPHY; HORMONE REPLACEMENT THERAPY; HYPERTENSIVE HEART-DISEASE; CARDIAC-HYPERTROPHY; POSTMENOPAUSAL WOMEN; IN-VIVO; MYOCARDIAL-INFARCTION; TARGETED DISRUPTION; NATRIURETIC-PEPTIDE AB Cardiac hypertrophy in humans can progress to cardiac failure if the underlying impetus is poorly controlled. An important direct stimulator of hypertrophy and its progression is the angiotensin II (AngII) peptide. AngII also causes hypertension that indirectly contributes to cardiac hypertrophy. Others and we have shown that estrogens acting through the estrogen receptor (ER)-beta can inhibit AngII-induced or other forms of cardiac hypertrophy in mice. However, the proliferative effects of estrogen in breast and uterus that promote the development of malignancy preclude using the steroid to prevent cardiac disease progression. We therefore tested whether an ER beta selective agonist, beta-LGND2, can prevent hypertension and cardiac pathology in female mice. AngII infusion over 3 weeks significantly stimulated systolic and diastolic hypertension, cardiac hypertrophy, and cardiac fibrosis, all significantly prevented by beta-LGND2 in wild-type but not in ER beta genetically deleted mice. AngII stimulated the Akt kinase to phosphorylate and inhibit the glycogen synthase kinase-3 beta kinase, leading to GATA4 transcription factor activation and hypertrophic mRNA expression. As a novel mechanism, all these actions were opposed by estradiol and beta-LGND2. Our findings provide additional understanding of the antihypertrophic effects of ER beta and serve as an impetus to test specific receptor agonists in humans to prevent the worsening of cardiovascular disease. C1 [Razandi, Mahnaz; Levin, Ellis R.] Dept Vet Affairs Med Ctr, Div Endocrinol, Long Beach, CA 90822 USA. [Pedram, Ali; Levin, Ellis R.] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Levin, Ellis R.] Univ Calif Irvine, Dept Biochem, Irvine, CA 92717 USA. [Korach, Kenneth S.] NIEHS, Res Triangle Pk, NC 27709 USA. [Dalton, James T.] GTx Inc, Memphis, TN 38163 USA. RP Levin, ER (reprint author), Long Beach Vet Affairs Med Ctr, Med Serv I 111, 5901 East 7th St, Long Beach, CA 90822 USA. EM ellis.levin@va.gov OI dalton, James T/0000-0002-3915-7326; Korach, Kenneth/0000-0002-7765-418X FU Research Service of the Department of Veterans Affairs; National Institutes of Health [CA-10036] FX This work was supported by grants from the Research Service of the Department of Veterans Affairs and National Institutes of Health Grant CA-10036 (to E.R.L.). NR 53 TC 14 Z9 14 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 4352 EP 4364 DI 10.1210/en.2013-1358 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200043 PM 23970786 ER PT J AU Sun, GH Heimeier, RA Fu, LZ Hasebe, T Das, B Ishizuya-Oka, A Shi, YB AF Sun, Guihong Heimeier, Rachel A. Fu, Liezhen Hasebe, Takashi Das, Biswajit Ishizuya-Oka, Atsuko Shi, Yun-Bo TI Expression Profiling of Intestinal Tissues Implicates Tissue-Specific Genes and Pathways Essential for Thyroid Hormone-Induced Adult Stem Cell Development SO ENDOCRINOLOGY LA English DT Article ID XENOPUS-LAEVIS TADPOLES; AMPHIBIAN METAMORPHOSIS; CONNECTIVE-TISSUE; MICROARRAY DATA; POSTEMBRYONIC DEVELOPMENT; MATRIX-METALLOPROTEINASE; BIOLOGICAL PATHWAYS; TR-ALPHA; EPITHELIUM; TOOL AB The study of the epithelium during development in the vertebrate intestine touches upon many contemporary aspects of biology: to name a few, the formation of the adult stem cells (ASCs) essential for the life-long self-renewal and the balance of stem cell activity for renewal vs cancer development. Although extensive analyses have been carried out on the property and functions of the adult intestinal stem cells in mammals, little is known about their formation during development due to the difficulty of manipulating late-stage, uterus-enclosed embryos. The gastrointestinal tract of the amphibian Xenopus laevis is an excellent model system for the study of mammalian ASC formation, cell proliferation, and differentiation. During T-3-dependent amphibian metamorphosis, the digestive tract is extensively remodeled from the larval to the adult form for the adaptation of the amphibian from its aquatic herbivorous lifestyle to that of a terrestrial carnivorous frog. This involves de novo formation of ASCs that requires T-3 signaling in both the larval epithelium and nonepithelial tissues. To understand the underlying molecular mechanisms, we have characterized the gene expression profiles in the epithelium and nonepithelial tissues by using cDNA microarrays. Our results revealed that T-3 induces distinct tissue-specific gene regulation programs associated with the remodeling of the intestine, particularly the formation of the ASCs, and further suggested the existence of potentially many novel stem cell-associated genes, at least in the intestine during development. C1 [Sun, Guihong] Wuhan Univ, Sch Basic Med Sci, Wuhan 430072, Peoples R China. [Sun, Guihong; Heimeier, Rachel A.; Fu, Liezhen; Das, Biswajit; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. [Hasebe, Takashi; Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Kawasaki, Kanagawa 2110063, Japan. RP Shi, YB (reprint author), NICHHD, NIH, Lab Gene Regulat & Dev, Bldg 18T,Room 106,18 Library Dr,MSC 5431, Bethesda, MD 20892 USA. EM heimeier781@gmail.com; a-oka@nms.ac.jp; shi@helix.nih.gov FU intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health; Narishige Zoological Science Award FX This work was supported by the intramural Research Program of National Institute of Child Health and Human Development, National Institutes of Health, and in part by Narishige Zoological Science Award (to T.H.). NR 54 TC 11 Z9 11 U1 0 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 4396 EP 4407 DI 10.1210/en.2013-1432 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200047 PM 23970787 ER PT J AU Shimamura, M Nakahara, M Orim, F Kurashige, T Mitsutake, N Nakashima, M Kondo, S Yamada, M Taguchi, R Kimura, S Nagayama, Y AF Shimamura, Mika Nakahara, Mami Orim, Florence Kurashige, Tomomi Mitsutake, Norisato Nakashima, Masahiro Kondo, Shinji Yamada, Masanobu Taguchi, Ryo Kimura, Shioko Nagayama, Yuji TI Postnatal Expression of BRAF(V600E) Does Not Induce Thyroid Cancer in Mouse Models of Thyroid Papillary Carcinoma SO ENDOCRINOLOGY LA English DT Article ID RET/PTC1 ONCOGENE; TRANSGENIC MICE; THYROTROPIN RECEPTOR; TARGETED EXPRESSION; TUMOR INITIATION; PTEN LOSS; K-RAS; ACTIVATION; CELLS; BRAF AB The mutant BRAF (BRAF(V600E)) is the most common genetic alteration in papillary thyroid carcinomas (PTCs). The oncogenicity of this mutation has been shown by some genetically engineered mouse models. However, in these mice, BRAF(V600E) is expressed in all the thyroid cells from the fetal periods, and suppresses thyroid function, thereby leading to TSH elevation, which by itself promotes thyroid tumorigenesis. To overcome these problems, we exploited 2 different approaches, both of which allowed temporally and spatially restricted expression of BRAF(V600E) in the thyroid glands. First, we generated conditional transgenic mice harboring the loxP-neo(R)-loxP-BRAF(V600E)-internal ribosome entry site-green fluorescent protein sequence [Tg(LNL-BRAF(V600E))]. The double transgenic mice (LNL-BRAF(V600E); TPO-Cre) were derived from a high expressor line of Tg(LNL-BRAF(V600E)) mice and TPO-Cre mice; the latter expresses Cre DNA recombinase under the control of thyroid-specific thyroid peroxidase (TPO) promoter and developed PTC-like lesions in early life under normal serum TSH levels due to mosaic recombination. In contrast, injection of adenovirus expressing Cre under the control of another thyroid-specific thyroglobulin (Tg) promoter (Ad-TgP-Cre) into the thyroids of LNL-BRAF(V600E) mice did not induce tumor formation despite detection of BRAF(V600E) and pERK in a small fraction of thyroid cells. Second, postnatal expression of BRAF(V600E) in a small number of thyroid cells was also achieved by injecting the lentivirus expressing loxP-green fluorescent protein-loxP-BRAF(V600E) into the thyroids of TPO-Cre mice; however, no tumor development was again observed. These results suggest that BRAF(V600E) does not appear to induce PTC-like lesions when expressed in a fraction of thyroid cells postnatally under normal TSH concentrations. C1 [Shimamura, Mika; Nakahara, Mami; Kurashige, Tomomi; Nagayama, Yuji] Nagasaki Univ, Dept Mol Med, Atom Bomb Dis Inst, Nagasaki 8528523, Japan. [Orim, Florence; Mitsutake, Norisato] Nagasaki Univ, Dept Radiat Med Sci, Atom Bomb Dis Inst, Nagasaki 8528523, Japan. [Nakashima, Masahiro] Nagasaki Univ, Dept Tumor & Diagnost Pathol, Atom Bomb Dis Inst, Nagasaki 8528523, Japan. [Kondo, Shinji] Nagasaki Univ, Dept Clin Pharmacol, Grad Sch Biomed Sci, Nagasaki 8528521, Japan. [Yamada, Masanobu; Taguchi, Ryo] Gunma Univ, Dept Med & Mol Sci, Grad Sch Med, Maebashi, Gumma 3718511, Japan. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nagayama, Y (reprint author), Nagasaki Univ, Dept Mol Med, Atom Bomb Dis Inst, Grad Sch Biomed Sci, 1-12-4 Sakamoto, Nagasaki 8528523, Japan. EM nagayama@nagasaki-u.ac.jp OI Mitsutake, Norisato/0000-0002-2744-8046 FU Japan Society for the Promotion of Science; Japan Thyroid Association FX This study was supported, in part, by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science and by Japan Thyroid Association. NR 34 TC 8 Z9 8 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD NOV PY 2013 VL 154 IS 11 BP 4423 EP 4430 DI 10.1210/en.2013-1174 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238HI UT WOS:000325935200049 PM 23970782 ER PT J AU Dias, C McDonald, A Sincan, M Rupps, R Markello, T Salvarinova, R Santos, RF Menghrajani, K Ahaghotu, C Sutherland, DP Fortuno, ES Kollmann, TR Demos, M Friedman, JM Speert, DP Gahl, WA Boerkoel, CF AF Dias, Cristina McDonald, Allison Sincan, Murat Rupps, Rosemarie Markello, Thomas Salvarinova, Ramona Santos, Rui F. Menghrajani, Kamal Ahaghotu, Chidi Sutherland, Darren P. Fortuno, Edgardo S., III Kollmann, Tobias R. Demos, Michelle Friedman, Jan M. Speert, David P. Gahl, William A. Boerkoel, Cornelius F. TI Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE exome sequencing; neurodegeneration; cerebellar white matter; familial hemophagocytic lymphohistiocytosis; interleukin-1 beta ID FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; NERVOUS-SYSTEM INVOLVEMENT; MULTIPLE-SCLEROSIS; CNS INVOLVEMENT; PERFORIN GENE; CHILDREN; INFLAMMATION; FREQUENCY; SPECTRUM; DISEASE AB Inflammation is an important contributor to pediatric and adult neurodegeneration. Understanding the genetic determinants of neuroinflammation provides valuable insight into disease mechanism. We characterize a disorder of recurrent immune-mediated neurodegeneration. We report two sisters who presented with neurodegeneration triggered by infections. The proband, a previously healthy girl, presented at 22.5 months with ataxia and dysarthria following mild gastroenteritis. MRI at onset showed a symmetric signal abnormality of the cerebellar and peritrigonal white matter. Following a progressive course of partial remissions and relapses, she died at 5 years of age. Her older sister had a similar course following varicella infection, she died within 13 months. Both sisters had unremarkable routine laboratory testing, with exception of a transient mild cytopenia in the proband 19 months after presentation. Exome sequencing identified a biallelic perforin1 mutation (PRF1; p. R225W) previously associated with familial hemophagocytic lymphohistiocytosis (FHL). In contrast to FHL, these girls did not have hematopathology or cytokine overproduction. However, 3 years after disease onset, the proband had markedly deficient interleukin-1 beta (IL-1 beta) production. These observations extend the spectrum of disease associated with perforin mutations to immune-mediated neurodegeneration triggered by infection and possibly due to primary immunodeficiency. C1 [Dias, Cristina; Rupps, Rosemarie; Friedman, Jan M.; Boerkoel, Cornelius F.] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada. [Dias, Cristina; Rupps, Rosemarie; Friedman, Jan M.; Boerkoel, Cornelius F.] BC Childrens Hosp, Child & Family Res Inst, Vancouver, BC, Canada. [McDonald, Allison; Sutherland, Darren P.; Fortuno, Edgardo S., III; Kollmann, Tobias R.; Speert, David P.] Child & Family Res Inst, Ctr Understanding & Preventing Infect Children, Vancouver, BC, Canada. [McDonald, Allison; Sutherland, Darren P.; Fortuno, Edgardo S., III; Kollmann, Tobias R.; Speert, David P.] Univ British Columbia, Dept Pediat, Div Infect & Immunol Dis, Vancouver, BC V6H 3N1, Canada. [Sincan, Murat; Markello, Thomas; Menghrajani, Kamal; Ahaghotu, Chidi; Gahl, William A.; Boerkoel, Cornelius F.] NIH, Undiagnosed Dis Program, Off Rare Dis Res, Bethesda, MD 20892 USA. [Sincan, Murat; Markello, Thomas; Menghrajani, Kamal; Ahaghotu, Chidi; Gahl, William A.; Boerkoel, Cornelius F.] NHGRI, Bethesda, MD 20892 USA. [Rupps, Rosemarie] Rare Dis Fdn, Vancouver, BC, Canada. [Salvarinova, Ramona] Univ British Columbia, Dept Pediat, Div Biochem Dis, Vancouver, BC V6H 3N1, Canada. [Santos, Rui F.] BC Childrens Hosp, Dept Radiol, Vancouver, BC, Canada. [Santos, Rui F.] Univ British Columbia, Vancouver, BC V6H 3N1, Canada. [Demos, Michelle] Univ British Columbia, Dept Pediat, Div Neurol, Vancouver, BC V6H 3N1, Canada. RP Boerkoel, CF (reprint author), Univ British Columbia, Dept Med Genet, 4500 Oak St,C234, Vancouver, BC V6H 3N1, Canada. EM cornelius.boerkoel@nih.gov OI Friedman, Jan/0000-0002-7482-9570; Dias, Cristina/0000-0001-5411-4984 FU Intramural Research Program of the NHGRI; Rare Disease Foundation; Canadian Institutes for Health Research; Canadian Child Health Clinician Scientist Program; Child and Family Research Institute; University of British Columbia FX We are grateful to Dr Camilo Toro for manuscript review and critical analysis, and acknowledge Drs Patrick Tang and Rusang Tan for their collaboration. We would like to express a special thanks to the patients' family. This study was primarily funded by the Intramural Research Program of the NHGRI and in part by the Rare Disease Foundation. Funding was supplied by the Canadian Institutes for Health Research (DPS). DPS is the Sauder Family Professor of Pediatric Infectious Diseases. CD is supported by the Canadian Child Health Clinician Scientist Program and the Child and Family Research Institute. AM is supported by the University of British Columbia. NR 44 TC 5 Z9 5 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD NOV PY 2013 VL 21 IS 11 BP 1232 EP 1239 DI 10.1038/ejhg.2013.20 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 237IC UT WOS:000325861500010 PM 23443029 ER PT J AU Szu, SC AF Szu, Shousun Chen TI Development of Vi conjugate - a new generation of typhoid vaccine SO EXPERT REVIEW OF VACCINES LA English DT Review DE infants; typhoid fever; vaccine development; Vi conjugate; young children ID INFLUENZAE TYPE-B; CAPSULAR POLYSACCHARIDE CONJUGATE; 2-TO 4-YEAR-OLD CHILDREN; STANDARD REFERENCE SERUM; ENTERICA SEROVAR TYPHI; IGG ANTI-VI; SALMONELLA-TYPHI; HAEMOPHILUS-INFLUENZAE; MULTIDRUG-RESISTANT; STREPTOCOCCUS-PNEUMONIAE AB Typhoid fever remains to be a serious disease burden worldwide with an estimated annual incidence about 20 million. The licensed vaccines showed moderate protections and have multiple deficiencies. Most important of all, none of the licensed typhoid vaccines demonstrated protection for children under 5 years old. These limitations impeded successful implementation of typhoid vaccination programs. To improve immunogenicity Vi was conjugated to rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. Vi-rEPA showed higher and longer lasting anti-Vi IgG in adults and children than Vi alone in high endemic areas. In school-age children and adults, the immunity persisted more than 8 years. In a double-blind, placebo-controlled and randomized efficacy trial in 2- to 5-year-old children, Vi-rEPA conferred 89% protective efficacy against typhoid fever and the protection lasted at least 4 years. When given concomitantly with infant routine vaccines, Vi-rEPA was safe, immunogenic and showed no interference with the routine vaccines. Vi conjugate vaccine was also attempted and successfully demonstrated by several other laboratories and manufactures. Using either rEPA or different carrier proteins, such as diphtheria or tetanus toxoid, recombinant diphtheria toxin (CRM197), the Vi conjugates synthesized was significantly more immunogenic than Vi alone. Recently, two Vi-tetanus toxoid conjugates were licensed in India for all ages, starts as young as 3 month old. This new generation of typhoid vaccine opens up a new era for typhoid prevention and elimination. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20814 USA. RP Szu, SC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 9402 Wildoak Dr, Bethesda, MD 20814 USA. EM SzuNIH@gmail.com FU NIH; NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 99 TC 23 Z9 23 U1 2 U2 18 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 EI 1744-8395 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD NOV PY 2013 VL 12 IS 11 BP 1273 EP 1286 DI 10.1586/14760584.2013.845529 PG 14 WC Immunology SC Immunology GA 240OD UT WOS:000326105500007 PM 24156285 ER PT J AU Hutter, CM Mechanic, LE Chatterjee, N Kraft, P Gillanders, EM AF Hutter, Carolyn M. Mechanic, Leah E. Chatterjee, Nilanjan Kraft, Peter Gillanders, Elizabeth M. CA NCI Gene-Environm Think Tank TI Gene-Environment Interactions in Cancer Epidemiology: A National Cancer Institute Think Tank Report SO GENETIC EPIDEMIOLOGY LA English DT Review DE gene-environment interactions; complex phenotypes; genetic epidemiology ID GENOME-WIDE ASSOCIATION; SAMPLE-SIZE REQUIREMENTS; MULTIPLE SUSCEPTIBILITY LOCI; NAT2 SLOW ACETYLATION; BODY-MASS INDEX; BLADDER-CANCER; BREAST-CANCER; COMPLEX DISEASES; STATISTICAL INTERACTIONS; MOLECULAR EPIDEMIOLOGY AB Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G x E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a Gene-Environment Think Tank on January 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G x E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G x E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors. C1 [Hutter, Carolyn M.; Mechanic, Leah E.; Gillanders, Elizabeth M.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Hutter, CM (reprint author), NCI, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 4E232,MSC 9763, Bethesda, MD 20892 USA. EM huttercm@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P30 CA016672] NR 142 TC 27 Z9 27 U1 3 U2 40 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2013 VL 37 IS 7 BP 643 EP 657 DI 10.1002/gepi.21756 PG 15 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 238VW UT WOS:000325980600001 PM 24123198 ER PT J AU Fan, RZ Wang, YF Mills, JL Wilson, AF Bailey-Wilson, JE Xiong, MM AF Fan, Ruzong Wang, Yifan Mills, James L. Wilson, Alexander F. Bailey-Wilson, Joan E. Xiong, Momiao TI Functional Linear Models for Association Analysis of Quantitative Traits SO GENETIC EPIDEMIOLOGY LA English DT Article DE rare variants; common variants; association mapping; quantitative trait loci; complex traits; functional data analysis ID RARE VARIANTS; SEQUENCING ASSOCIATION; COMMON DISEASES; REGRESSION; TESTS; SIMILARITY; STRATEGIES AB Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study. C1 [Fan, Ruzong; Wang, Yifan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Mills, James L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD 20852 USA. [Wilson, Alexander F.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Xiong, Momiao] Univ Texas Houston, Human Genet Ctr, Houston, TX USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, 6100 Execut Blvd,Room 7B07J,MSC 7510, Rockville, MD 20852 USA. EM fanr@mail.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland FX We greatly thank the Trinity Students Study groups for letting us analyze the data and using it as an example. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland (Ruzong Fan, Yifan Wang, and James L. Mills). NR 49 TC 22 Z9 22 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD NOV PY 2013 VL 37 IS 7 BP 726 EP 742 DI 10.1002/gepi.21757 PG 17 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 238VW UT WOS:000325980600009 PM 24130119 ER PT J AU Dasgeb, B Kainerstorfer, J Mehregan, D Van Vreede, A Gandjbakhche, A AF Dasgeb, Bahar Kainerstorfer, Jana Mehregan, Darius Van Vreede, Anthony Gandjbakhche, Amir TI An introduction to primary skin imaging SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Review ID OPTICAL COHERENCE TOMOGRAPHY; REFLECTANCE CONFOCAL MICROSCOPY; IN-VIVO; MELANOCYTIC LESIONS; ULTRASOUND; MELANOMA; DIAGNOSIS; ULTRASONOGRAPHY; ELASTOGRAPHY; CRITERIA AB Dermatology is a field in which clinical examination is heavily relied upon for diagnosis. When required, a tissue biopsy may also be performed to confirm the diagnosis. Recent advances in imaging techniques have been applied to cutaneous lesions to improve diagnostic accuracy without the need for biopsy. These new imaging techniques are reviewed for their developing role in dermatology. C1 [Dasgeb, Bahar] Mem Sloan Kettering Canc Ctr, Dept Dermatol, New York, NY 10021 USA. [Mehregan, Darius; Van Vreede, Anthony] Wayne State Univ, Dept Dermatol, Detroit, MI USA. [Dasgeb, Bahar; Kainerstorfer, Jana; Gandjbakhche, Amir] NICHD, Analyt & Stochast Biomed Phys Sect, NIH, Bethesda, MD USA. [Mehregan, Darius] Pinkus Dermatopathol Labs, Monroe, MI USA. RP Van Vreede, A (reprint author), 5057 Woodward Ave 3101, Detroit, MI 48202 USA. EM avanvree@med.wayne.edu NR 49 TC 4 Z9 4 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0011-9059 EI 1365-4632 J9 INT J DERMATOL JI Int. J. Dermatol. PD NOV PY 2013 VL 52 IS 11 BP 1319 EP 1330 DI 10.1111/ijd.12048 PG 12 WC Dermatology SC Dermatology GA 239WP UT WOS:000326056900001 PM 23879559 ER PT J AU Fernando, J Faber, TW Pullen, NA Falanga, YT Kolawole, EM Oskeritzian, CA Barnstein, BO Bandara, G Li, GQ Schwartz, LB Spiegel, S Straus, DB Conrad, DH Bunting, KD Ryan, JJ AF Fernando, Josephine Faber, Travis W. Pullen, Nicholas A. Falanga, Yves T. Kolawole, Elizabeth Motunrayo Oskeritzian, Carole A. Barnstein, Brian O. Bandara, Geethani Li, Geqiang Schwartz, Lawrence B. Spiegel, Sarah Straus, David B. Conrad, Daniel H. Bunting, Kevin D. Ryan, John J. TI Genotype-Dependent Effects of TGF-beta 1 on Mast Cell Function: Targeting the Stat5 Pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; FC-EPSILON-RI; NECROSIS-FACTOR-ALPHA; TGF-BETA; CYTOKINE PRODUCTION; T-CELLS; ALLERGIC RESPONSES; SIGNAL TRANSDUCER; GENE-EXPRESSION; TRANSCRIPTION 5 AB We previously demonstrated that TGF-beta 1 suppresses IgE-mediated signaling in human and mouse mast cells in vitro, an effect that correlated with decreased expression of the high-affinity IgE receptor, Fc epsilon RI. The in vivo effects of TGF-beta 1 and the means by which it suppresses mast cells have been less clear. This study shows that TGF-beta 1 suppresses Fc epsilon RI and c-Kit expression in vivo. By examining changes in cytokine production concurrent with Fc epsilon RI expression, we found that TGF-beta 1 suppresses TNF production independent of Fc epsilon RI levels. Rather, IgE-mediated signaling was altered. TGF-beta 1 significantly reduced expression of Fyn and Stat5, proteins critical for cytokine induction. These changes may partly explain the effects of TGF-beta 1, because Stat5B overexpression blocked TGF-mediated suppression of IgE-induced cytokine production. We also found that Stat5B is required for mast cell migration toward stem cell factor, and that TGF-beta 1 reduced this migration. We found evidence that genetic background may alter TGF responses. TGF-beta 1 greatly reduced mast cell numbers in Th1-prone C57BL/6, but not Th2-prone 129/Sv mice. Furthermore, TGF-beta 1 did not suppress IgE-induced cytokine release and did increase c-Kit-mediated migration in 129/Sv mast cells. These data correlated with high basal Fyn and Stat5 expression in 129/Sv cells, which was not reduced by TGF-beta 1 treatment. Finally, primary human mast cell populations also showed variable sensitivity to TGF-beta 1-mediated changes in Stat5 and IgE-mediated IL-6 secretion. We propose that TGF-beta 1 regulates mast cell homeostasis, and that this feedback suppression may be dependent on genetic context, predisposing some individuals to atopic disease. C1 [Fernando, Josephine; Faber, Travis W.; Pullen, Nicholas A.; Falanga, Yves T.; Kolawole, Elizabeth Motunrayo; Barnstein, Brian O.; Straus, David B.; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Oskeritzian, Carole A.; Spiegel, Sarah] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Oskeritzian, Carole A.; Spiegel, Sarah] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Li, Geqiang] Harvard Univ, Boston Childrens Hosp, Boston, MA 02115 USA. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA. [Conrad, Daniel H.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Bunting, Kevin D.] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Dept Pediat, Atlanta, GA 30322 USA. [Bunting, Kevin D.] Emory Univ, Atlanta, GA 30322 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Box 842012, Richmond, VA 23284 USA. EM jjryan@vcu.edu FU National Institutes of Health [1R01AI59638, U19AI077435, 2R01DK059380, K01AR053186, 1R01AI095494] FX This work was supported by National Institutes of Health Grants 1R01AI59638 (to J.J.R.), U19AI077435 (to J.J.R., S. S., and D. H. C.), 2R01DK059380 (to K. D. B.), K01AR053186 (to C.A.O.), and 1R01AI095494 (to C.A.O.). NR 66 TC 8 Z9 8 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2013 VL 191 IS 9 BP 4505 EP 4513 DI 10.4049/jimmunol.1202723 PG 9 WC Immunology SC Immunology GA 238FS UT WOS:000325929000007 PM 24068671 ER PT J AU McPhee, CG Bubier, JA Sproule, TJ Park, G Steinbuck, MP Schott, WH Christianson, GJ Morse, HC Roopenian, DC AF McPhee, Caroline G. Bubier, Jason A. Sproule, Thomas J. Park, Giljun Steinbuck, Martin P. Schott, William H. Christianson, Gregory J. Morse, Herbert C., III Roopenian, Derry C. TI IL-21 Is a Double-Edged Sword in the Systemic Lupus Erythematosus-like Disease of BXSB.Yaa Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HELPER T-CELLS; GERMINAL CENTER RESPONSES; B-CELLS; BCL-6 EXPRESSION; MURINE LUPUS; YAA MICE; AUTOIMMUNITY; INTERLEUKIN-21; GENERATION; RECEPTOR AB The pleiotropic cytokine IL-21 is implicated in the pathogenesis of human systemic lupus erythematosus by polymorphisms in the molecule and its receptor (IL-21R). The systemic lupus erythematosus-like autoimmune disease of BXSB.Yaa mice is critically dependent on IL-21 signaling, providing a model for understanding IL-21/IL-21R signaling in lupus pathogenesis. In this study, we generated BXSB.Yaa mice selectively deficient in IL-21R on B cells, on all T cells, or on CD8(+) T cells alone and examined the effects on disease. We found that IL-21 signaling to B cells is essential for the development of all classical disease manifestations, but that IL-21 signaling also supports the expansion of central memory, CD8(+) suppressor cells and broadly represses the cytokine activity of CD4(+) T cells. These results indicate that IL-21 has both disease-promoting and disease-suppressive effects in the autoimmune disease of BXSB.Yaa mice. C1 [McPhee, Caroline G.; Bubier, Jason A.; Sproule, Thomas J.; Park, Giljun; Steinbuck, Martin P.; Schott, William H.; Christianson, Gregory J.; Roopenian, Derry C.] Jackson Lab, Bar Harbor, ME 04609 USA. [Morse, Herbert C., III] NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. RP Roopenian, DC (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM hmorse@niaid.nih.gov; dcr@jax.org OI Morse, Herbert/0000-0002-9331-3705; Bubier, Jason/0000-0001-5013-1234 FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases; Alliance for Lupus Research; National Institutes of Health; Arthritis Foundation FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (to H. C. M.) and by the Alliance for Lupus Research (to D. C. R.). C. G. M. was supported in part by a National Institutes of Health Training Grant. J.A.B. was supported by the Arthritis Foundation. NR 47 TC 19 Z9 19 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 NOV 1 PY 2013 VL 191 IS 9 BP 4581 EP 4588 DI 10.4049/jimmunol.1300439 PG 8 WC Immunology SC Immunology GA 238FS UT WOS:000325929000015 PM 24078696 ER PT J AU Raetz, M Kibardin, A Sturge, CR Pifer, R Li, HY Burstein, E Ozato, K Larin, S Yarovinsky, F AF Raetz, Megan Kibardin, Alexey Sturge, Carolyn R. Pifer, Reed Li, Haiying Burstein, Ezra Ozato, Keiko Larin, Sergey Yarovinsky, Felix TI Cooperation of TLR12 and TLR11 in the IRF8-Dependent IL-12 Response to Toxoplasma gondii Profilin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; CD8-ALPHA(+) DENDRITIC CELLS; SINGLE-STRANDED RNA; SUBCELLULAR-LOCALIZATION; INTRACELLULAR PARASITE; INTERFERON-GAMMA; CUTTING EDGE; INTERLEUKIN-12; RECOGNITION; RESISTANCE AB TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-kappa B, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii. C1 [Raetz, Megan; Sturge, Carolyn R.; Pifer, Reed; Yarovinsky, Felix] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA. [Kibardin, Alexey; Larin, Sergey] Russian Acad Sci, Inst Gene Biol, Gene Therapy Lab, Moscow 119334, Russia. [Li, Haiying; Burstein, Ezra] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Ozato, Keiko] NICHHD, NIH, Program Genom Differentiat, Bethesda, MD 20892 USA. [Larin, Sergey] Fed Res Ctr Pediat Hematol Oncol & Immunol, Moscow 117198, Russia. [Larin, Sergey] Moscow Inst Phys & Technol, Moscow 141700, Russia. RP Yarovinsky, F (reprint author), Univ Texas SW Med Ctr Dallas, Dept Immunol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Felix.Yarovinsky@UTSouthwestern.edu RI Burstein, Ezra/B-7247-2016 OI Burstein, Ezra/0000-0003-4341-6367 FU National Institutes of Health [A1-085263, AI079371]; Burroughs Wellcome Foundation FX This work was supported by National Institutes of Health Grants A1-085263 and AI079371 (to F. Y.), as well as by a Burroughs Wellcome Foundation Investigators in the Pathogenesis of Infectious Diseases award (to F.Y.). NR 52 TC 25 Z9 31 U1 1 U2 13 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2013 VL 191 IS 9 BP 4818 EP 4827 DI 10.4049/jimmunol.1301301 PG 10 WC Immunology SC Immunology GA 238FS UT WOS:000325929000038 PM 24078692 ER PT J AU Giddings, LA Newman, DJ AF Giddings, Lesley-Ann Newman, David J. TI Microbial natural products: molecular blueprints for antitumor drugs SO JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY LA English DT Review DE Microbial natural product; Microbial genome; Cancer drugs; Clinical trial ID HISTONE-DEACETYLASE INHIBITORS; PHASE-II TRIAL; TUNICATE ECTEINASCIDIA-TURBINATA; TRANSFORMED-CELL DIFFERENTIATION; MICROTUBULE-STABILIZING AGENTS; SALINOSPORAMIDE-A NPI-0052; BIOSYNTHETIC GENE CLUSTERS; MOLLUSK ELYSIA-RUFESCENS; KAHALALIDE-F; PROTEASOME INHIBITOR AB Microbes from two of the three domains of life, the Prokarya, and Eukarya, continue to serve as rich sources of structurally complex chemical scaffolds that have proven to be essential for the development of anticancer therapeutics. This review describes only a handful of exemplary natural products and their derivatives as well as those that have served as elegant blueprints for the development of novel synthetic structures that are either currently in use or in clinical or preclinical trials together with some of their earlier analogs in some cases whose failure to proceed aided in the derivation of later compounds. In every case, a microbe has been either identified as the producer of secondary metabolites or speculated to be involved in the production via symbiotic associations. Finally, rapidly evolving next-generation sequencing technologies have led to the increasing availability of microbial genomes. Relevant examples of genome mining and genetic manipulation are discussed, demonstrating that we have only barely scratched the surface with regards to harnessing the potential of microbes as sources of new pharmaceutical leads/agents or biological probes. C1 [Giddings, Lesley-Ann; Newman, David J.] Frederick Natl Lab Canc Res, Nat Prod Branch, Dev Therapeut Program, DCTD, Frederick, MD 21702 USA. RP Giddings, LA (reprint author), Frederick Natl Lab Canc Res, Nat Prod Branch, Dev Therapeut Program, DCTD, POB B, Frederick, MD 21702 USA. EM Lesley-Ann.Giddings@nih.gov; dn22a@nih.gov NR 243 TC 14 Z9 15 U1 4 U2 72 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1367-5435 EI 1476-5535 J9 J IND MICROBIOL BIOT JI J. Ind. Microbiol. Biotechnol. PD NOV PY 2013 VL 40 IS 11 BP 1181 EP 1210 DI 10.1007/s10295-013-1331-1 PG 30 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 237DG UT WOS:000325847800001 PM 23999966 ER PT J AU Chaemsaithong, P Romero, R Korzeniewski, SJ Schwartz, AG Stampalija, T Dong, Z Yeo, L Hernandez-Andrade, E Hassan, SS Chaiworapongsa, T AF Chaemsaithong, Piya Romero, Roberto Korzeniewski, Steven J. Schwartz, Alyse G. Stampalija, Tamara Dong, Zhong Yeo, Lami Hernandez-Andrade, Edgar Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI Soluble TRAIL in normal pregnancy and acute pyelonephritis: a potential explanation for the susceptibility of pregnant women to microbial products and infection SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Innate immunity; neutrophil apoptosis; non-pregnant; normal pregnancy; plasma; tumor necrosis factor-related apoptosis-inducing ligand ID APOPTOSIS-INDUCING LIGAND; INFLAMMATORY RESPONSE SYNDROME; POLYMORPHONUCLEAR NEUTROPHIL ACTIVATION; INTRAUTERINE GROWTH RESTRICTION; RESPIRATORY-DISTRESS SYNDROME; URINARY-TRACT INFECTIONS; FADD-DEPENDENT APOPTOSIS; NF-KAPPA-B; METABOLIC CHARACTERISTICS; DEATH DOMAIN AB Objective: Pregnancy is characterized by activation of the innate immune response demonstrated by phenotypic and metabolic changes in granulocytes and monocytes. This state of activation has been implicated in the pathophysiology of multiorgan dysfunction of pregnant women with acute viral or bacterial infection. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the mediators responsible for neutrophil apoptosis. Gene deletion of TRAIL results in delayed neutrophil apoptosis and resolution of inflammation after the administration of bacterial endotoxin. The aim of this study was to determine whether maternal plasma concentrations of the soluble form of TRAIL (sTRAIL) differ in women with uncomplicated pregnancy and those with acute pyelonephritis. Method: A cross-sectional study was conducted to include women in the following groups: (1) non-pregnant (n = 23); (2) uncomplicated pregnancies (n = 93) and (3) pregnancies with acute pyelonephritis (n = 23). Plasma concentrations of sTRAIL were determined by enzyme-linked immunoassay. Results: (1) Women with uncomplicated pregnancies had a lower mean plasma sTRAIL concentration (pg/mL) than non-pregnant women (31.5 +/- 10.1 versus 53.3 +/- 12.5; p<0.001); (2) plasma sTRAIL concentrations did not change as a function of gestational age (Pearson correlation = -0.1; p = 0.4); (3) the mean plasma sTRAIL concentration (pg/mL) was significantly lower in pregnant women with acute pyelonephritis than in those with uncomplicated pregnancies (20.5 +/- 6.6 versus 31.5 +/- 10.1; p<0.001) and (4) among patients with acute pyelonephritis, patients with bacteremia had a significantly lower mean plasma concentration of sTRAIL (pg/mL) than those without bacteremia (15.1 +/- 4.8 versus 24.7 +/- 4.6; p<0.001). Conclusion: Women with uncomplicated pregnancies are associated with a significantly lower mean maternal plasma concentration of sTRAIL than that observed in non-pregnant women. Moreover, a further decrease in plasma sTRAIL concentration was observed in pregnant women with acute pyelonephritis, and this could account, at least in part, for the exaggerated intravascular inflammatory response previously reported in pyelonephritis during pregnancy. C1 [Chaemsaithong, Piya; Romero, Roberto; Korzeniewski, Steven J.; Schwartz, Alyse G.; Stampalija, Tamara; Dong, Zhong; Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Chaemsaithong, Piya; Romero, Roberto; Korzeniewski, Steven J.; Schwartz, Alyse G.; Stampalija, Tamara; Dong, Zhong; Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Korzeniewski, Steven J.; Schwartz, Alyse G.; Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. [Stampalija, Tamara] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, IT, Italy. RP Romero, R (reprint author), Wayne State Univ, NICHD, DHHS, Perinatol Res Branch,Hutzel Womens Hosp,NIH, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov RI Stampalija, Tamara/K-4900-2014 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services [HHSN275201300006C] FX The authors report no declarations of interest. This project has been funded in whole or in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201300006C. NR 107 TC 2 Z9 3 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD NOV PY 2013 VL 26 IS 16 BP 1568 EP 1575 DI 10.3109/14767058.2013.783811 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 238YP UT WOS:000325988600002 PM 23480056 ER PT J AU Rahimi, Z Ahmadi, R Vaisi-Raygani, A Rahimi, Z Bahrehmand, F Parsian, A AF Rahimi, Zohreh Ahmadi, Reza Vaisi-Raygani, Asad Rahimi, Ziba Bahrehmand, Fariborz Parsian, Abbas TI Butyrylcholinesterase (BChE) activity is associated with the risk of preeclampsia: influence on lipid and lipoprotein metabolism and oxidative stress SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE AOPE genotype; BChE activity; MDA; preeclampsia; TAC ID SERUM BUTYRYLCHOLINESTERASE; WESTERN IRAN; ANTIOXIDANT STATUS; DIABETES-MELLITUS; PREGNANCY; WOMEN; ALLELES; PROFILE; PSEUDOCHOLINESTERASE; PEROXIDATION AB Objective: To determine the butyrylcholinesterase (BChE) activity and phenotypes in preeclampsia and its possible association with lipid and lipoprotein metabolism and oxidative stress in preeclamptic women. Methods: In a case-control study, 101 pregnant women with normal pregnancy and 198 women with preeclampsia from Western Iran were studied. The serum BChE activity and phenotypes were measured using spectrophotometric method. The apolipoprotein E (APOE) genotypes were identified using PCR-RFLP. The serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined by HPLC and commercial kits, respectively. Results: The BChE activity and the frequency of non-usual BChE phenotype in preeclamptic women were significantly lower and higher, respectively compared to controls. There was a higher BChE activity in the presence of APOE epsilon 3 epsilon 4 compared to epsilon 3 epsilon 3 genotype in preeclamptic women. In addition, there were significant positive correlations between BChE activity and the levels of low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, total cholesterol (TC) and TAC. However, there was a negative but significant correlation between BChE activity and MDA level. Conclusions: Our study for the first time indicated that BChE activity might be involved in the pathogenesis of preeclampsia through influence on lipid and lipoprotein metabolism and oxidative stress. C1 [Rahimi, Zohreh; Rahimi, Ziba] Kermanshah Univ Med Sci, Med Biol Res Ctr, Kermanshah, Iran. [Rahimi, Zohreh; Ahmadi, Reza; Vaisi-Raygani, Asad; Bahrehmand, Fariborz] Kermanshah Univ Med Sci, Sch Med, Dept Biochem, Kermanshah, Iran. [Parsian, Abbas] NIAAA, Div Neurosci & Behav, NIH, Rockville, MD 20852 USA. RP Rahimi, Z (reprint author), Sch Med, Med Biol Res Ctr, Daneshgah Ave, Kermanshah 6714869914, Iran. EM zrahimi@kums.ac.ir OI Rahimi, Zohreh/0000-0001-7589-3307; Vaisi-Raygani, Asad/0000-0002-3042-2832 FU Kermanshah University of Medical Sciences, Kermanshah, Iran FX This work was financially supported by a grant from Vice Chancellor for Research of Kermanshah University of Medical Sciences, Kermanshah, Iran. The authors report no declarations of interest. NR 29 TC 4 Z9 4 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD NOV PY 2013 VL 26 IS 16 BP 1590 EP 1594 DI 10.3109/14767058.2013.795534 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 238YP UT WOS:000325988600006 PM 23650977 ER PT J AU Harford, TC Chen, CM Saha, TD Smith, SM Ruan, WJ Grant, BE AF Harford, Thomas C. Chen, Chiung M. Saha, Tulshi D. Smith, Sharon M. Ruan, W. June Grant, Bridget E. TI DSM-IV personality disorders and associations with externalizing and internalizing disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE DSM-IV personality disorders; DSM-IV substance use disorders; DSM-IV mood and anxiety disorders; Epidemiology; Structural equation modeling ID COMMON MENTAL-DISORDERS; GENERAL-POPULATION SAMPLE; PSYCHIATRIC DIAGNOSTIC MODULES; INTERVIEW SCHEDULE AUDADIS; ENVIRONMENTAL RISK-FACTORS; SUBSTANCE USE DISORDERS; UNITED-STATES; III-R; HIERARCHICAL STRUCTURE; ANXIETY DISORDERS AB Background: Although associations between personality disorders and psychiatric disorders are well established in general population studies, their association with liability dimensions for externalizing and internalizing disorders has not been fully assessed. The purpose of this study is to examine associations between personality disorders (PDs) and lifetime externalizing and internalizing Axis I disorders. Methods: Data were obtained from the total sample of 34,653 respondents from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drawing on the literature, a 3-factor exploratory structural equation model was selected to simultaneously assess the measurement relations among DSM-IV Axis I substance use and mood and anxiety disorders and the structural relations between the latent internalizing externalizing dimensions and DSM-IV PDs, adjusting for gender, age, race/ethnicity, and marital status. Results: Antisocial, histrionic, and borderline PDs were strong predictors for the externalizing factor, while schizotypal, borderline, avoidant, and obsessive-compulsive PDs had significantly larger effects on the internalizing fear factor when compared to the internalizing misery factor. Paranoid, schizoid, narcissistic, and dependent PDs provided limited discrimination between and among the three factors. An overarching latent factor representing general personality dysfunction was significantly greater on the internalizing fear factor followed by the externalizing factor, and weakest for the internalizing misery factor. Conclusion: Personality disorders offer important opportunities for studies on the externalizing internalizing spectrum of common psychiatric disorders. Future studies based on panic, anxiety, and depressive symptoms may elucidate PD associations with the internalizing spectrum of disorders. Published by Elsevier Ltd. C1 [Harford, Thomas C.; Chen, Chiung M.] CSR Inc, Arlington, VA 22201 USA. [Saha, Tulshi D.; Smith, Sharon M.; Ruan, W. June; Grant, Bridget E.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Chen, CM (reprint author), CSR Inc, 2107 Wilson Blvd,Suite 1000, Arlington, VA 22201 USA. EM cchen@csrincorporated.com FU National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH); NIAAA [HHSN267200800023C] FX This research was supported in part by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), and by the Alcohol Epidemiologic Data System funded by NIAAA Contract No. HHSN267200800023C to CSR, Incorporated. NR 57 TC 5 Z9 5 U1 2 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2013 VL 47 IS 11 BP 1708 EP 1716 DI 10.1016/j.jpsychires.2013.07.016 PG 9 WC Psychiatry SC Psychiatry GA 237AW UT WOS:000325841600022 PM 23932575 ER PT J AU Hill, ER Koganti, S Zhi, J Megyola, C Freeman, AF Palendira, U Tangye, SG Farrell, PJ Bhaduri-McIntosha, S AF Hill, Erik R. Koganti, Siva Zhi, Jizu Megyola, Cynthia Freeman, Alexandra F. Palendira, Umaimainthan Tangye, Stuart G. Farrell, Paul J. Bhaduri-McIntosha, Sumita TI Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes SO JOURNAL OF VIROLOGY LA English DT Article ID HYPER-IGE SYNDROME; LYMPHOPROLIFERATIVE DISEASE; INFECTIOUS-MONONUCLEOSIS; GENE-EXPRESSION; STAT3; CELLS; CYCLE; REPLICATION; MUTATIONS; CANCER AB Lytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBV-infected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis. C1 [Hill, Erik R.; Koganti, Siva; Bhaduri-McIntosha, Sumita] SUNY Stony Brook, Dept Pediat, Div Infect Dis, Stony Brook, NY 11794 USA. [Hill, Erik R.; Koganti, Siva; Bhaduri-McIntosha, Sumita] SUNY Stony Brook, Stony Brook Childrens Hosp, Stony Brook, NY 11794 USA. [Zhi, Jizu] SUNY Stony Brook, Sch Med, Bioinformat Core Facil, Stony Brook, NY 11794 USA. [Megyola, Cynthia] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Freeman, Alexandra F.] NIH, Lab Clin Infect Dis, Immunopathogenesis Sect, Bethesda, MD 20892 USA. [Palendira, Umaimainthan; Tangye, Stuart G.] Garvan Inst Med Res, Program Immunol, Darlinghurst, NSW, Australia. [Palendira, Umaimainthan; Tangye, Stuart G.] Univ NSW, St Vincents Clin Sch, Sydney, NSW, Australia. [Farrell, Paul J.] Imperial Coll, Fac Med, Virol Sect, London, England. [Bhaduri-McIntosha, Sumita] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Hill, ER (reprint author), Campbell Univ Coll Pharm & Hlth Sci, Dept Publ Hlth, Buies Creek, NC USA. EM sumita.bhaduri-mcintosh@stonybrookmedicine.edu RI Tangye, Stuart/H-4023-2014; OI Farrell, Paul/0000-0002-6754-9351 FU National Health and Medical Research Council of Australia; New South Wales Cancer Council; Research Foundation for The State University of New York; [K08 AI062732]; [K12 HD001401]; [1UL1RR024139-02] FX This study was supported by grants K08 AI062732, K12 HD001401, and 1UL1RR024139-02 and funds from The Research Foundation for The State University of New York to S. B.-M and from the National Health and Medical Research Council of Australia and the New South Wales Cancer Council to S.G.T. NR 44 TC 14 Z9 16 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 21 BP 11438 EP 11446 DI 10.1128/JVI.01762-13 PG 9 WC Virology SC Virology GA 237IR UT WOS:000325863400011 PM 23966384 ER PT J AU Welbourn, S Dutta, SM Semmes, OJ Strebel, K AF Welbourn, Sarah Dutta, Sucharita M. Semmes, O. John Strebel, Klaus TI Restriction of Virus Infection but Not Catalytic dNTPase Activity Is Regulated by Phosphorylation of SAMHD1 SO JOURNAL OF VIROLOGY LA English DT Article ID AICARDI-GOUTIERES SYNDROME; CYCLIN-DEPENDENT KINASES; HUMAN DENDRITIC CELLS; CD4(+) T-CELLS; HIV-1 RESTRICTION; DEOXYNUCLEOSIDE TRIPHOSPHATES; PROTEIN; VPX; IDENTIFICATION; MACROPHAGES AB SAMHD1 is a host protein responsible, at least in part, for the inefficient infection of dendritic, myeloid, and resting T cells by HIV-1. Interestingly, HIV-2 and SIVsm viruses are able to counteract SAMHD1 by targeting it for proteasomal degradation using their Vpx proteins. It has been proposed that SAMHD1 is a dGTP-dependent deoxynucleoside triphosphohydrolase (dNT-Pase) that restricts HIV-1 by reducing cellular dNTP levels to below that required for reverse transcription. However, nothing is known about SAMHD1 posttranslational modifications and their potential role in regulating SAMHD1 function. We used P-32 labeling and immunoblotting with phospho-specific antibodies to identify SAMHD1 as a phosphoprotein. Several amino acids in SAMHD1 were identified to be sites of phosphorylation using direct mass spectrometry. Mutation of these residues to alanine to prevent phosphorylation or to glutamic acid to mimic phosphorylation had no effect on the nuclear localization of SAMHD1 or its sensitivity to Vpx-mediated degradation. Furthermore, neither alanine nor glutamic acid substitutions had a significant effect on SAMHD1 dNTPase activity in an in vitro assay. Interestingly, however, we found that a T592E mutation, mimicking constitutive phosphorylation at a main phosphorylation site, severely affected the ability of SAMHD1 to restrict HIV-1 in a U937 cell-based restriction assay. In contrast, a T592A mutant was still capable of restricting HIV-1. These results indicate that SAMHD1 phosphorylation may be a negative regulator of SAMHD1 restriction activity. This conclusion is supported by our finding that SAMHD1 is hyperphosphorylated in monocytoid THP-1 cells under nonrestrictive conditions. C1 [Welbourn, Sarah; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Dutta, Sucharita M.; Semmes, O. John] Eastern Virginia Med Sch, Leroy T Canoles Jr Canc Res Ctr, Norfolk, VA 23501 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases; Canadian Institutes of Health Research (C.I.H.R); NIH [CA76959] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases, to K.S. and by NIH grant CA76959 to O.J.S. We acknowledge the contribution of the George L. Wright Center for Biomedical Proteomics. S.W. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (C.I.H.R). NR 36 TC 57 Z9 57 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 21 BP 11516 EP 11524 DI 10.1128/JVI.01642-13 PG 9 WC Virology SC Virology GA 237IR UT WOS:000325863400018 PM 23966382 ER PT J AU Delviks-Frankenberry, K Paprotka, T Cingoz, O Wildt, S Hu, WS Coffin, JM Pathak, VK AF Delviks-Frankenberry, Krista Paprotka, Tobias Cingoez, Oya Wildt, Sheryl Hu, Wei-Shau Coffin, John M. Pathak, Vinay K. TI Generation of Multiple Replication-Competent Retroviruses through Recombination between PreXMRV-1 and PreXMRV-2 SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; CHRONIC-FATIGUE-SYNDROME; NUDE-MICE; INFECTIOUS RETROVIRUS; CELL-LINES; NIH SWISS; XMRV; CANCER; PCR; TUMORS AB We previously identified two novel endogenous murine leukemia virus proviruses, PreXMRV-1 and PreXMRV-2, and showed that they most likely recombined during xenograft passaging of a human prostate tumor in mice to generate xenotropic murine leukemia virus-related virus (XMRV). To determine the recombination potential of PreXMRV-1 and PreXMRV-2, we examined the generation of replication-competent retroviruses (RCRs) over time in a cell culture system. We observed that either virus alone was noninfectious and the RNA transcripts of the viruses were undetectable in the blood and spleen of nude mice that carry them. To determine their potential to generate RCRs through recombination, we transfected PreXMRV-1 and PreXMRV-2 into 293T cells and used the virus produced to infect fresh cells; the presence of reverse transcriptase activity at 10 days postinfection indicated the presence of RCRs. Population sequencing of proviral DNA indicated that all RCRs contained the gag and 5' half of pol from PreXMRV-2 and the long terminal repeat, 3' half of pol (including integrase), and env from PreXMRV-1. All crossovers were within sequences of at least 9 identical nucleotides, and crossovers within each of two selected recombination zones of 415 nucleotides (nt) in the 5' untranslated region and 982 nt in pol were required to generate RCRs. A recombinant with the same genotype as XMRV was not detected, and our analysis indicates that the probability of generating an identical RCR is vanishingly small. In addition, the studies indicate that the process of RCR formation is primarily driven by selection for viable cis and trans elements from the parental proviruses. C1 [Delviks-Frankenberry, Krista; Paprotka, Tobias; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Cingoez, Oya; Coffin, John M.] Tufts Univ, Genet Program, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. [Wildt, Sheryl] Harlan Labs, Indianapolis, IN USA. RP Pathak, VK (reprint author), NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM vinay.pathak@nih.gov RI Delviks-Frankenberry, Krista/M-4822-2013 FU Bench-to-Bedside Award from the National Cancer Institute [R37 CA 089441]; F. M. Kirby Foundation FX This work was supported in part by a Bench-to-Bedside Award to V.K.P. and grant R37 CA 089441 to J.M.C. from the National Cancer Institute. J.M.C. was a research professor of the American Cancer Society with support from the F. M. Kirby Foundation. NR 51 TC 5 Z9 5 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 21 BP 11525 EP 11537 DI 10.1128/JVI.01787-13 PG 13 WC Virology SC Virology GA 237IR UT WOS:000325863400019 PM 23966380 ER PT J AU Choi, YP Priola, SA AF Choi, Young Pyo Priola, Suzette A. TI A Specific Population of Abnormal Prion Protein Aggregates Is Preferentially Taken Up by Cells and Disaggregated in a Strain-Dependent Manner SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; CREUTZFELDT-JAKOB-DISEASE; IN-VITRO; DENDRITIC CELLS; CULTURED-CELLS; NEURONAL CELLS; POLYSACCHARIDE SCAFFOLD; SCRAPIE INFECTION; PRP ACCUMULATION; NUCLEIC-ACIDS AB Prion diseases are characterized by the conversion of the soluble protease-sensitive host-encoded prion protein (PrPC) into its aggregated, protease-resistant, and infectious isoform (PrPSc). One of the earliest events occurring in cells following exposure to an exogenous source of prions is the cellular uptake of PrPSc. It is unclear how the biochemical properties of PrPSc influence its uptake, although aggregate size is thought to be important. Here we show that for two different strains of mouse prions, one that infects cells (22L) and one that does not (87V), a fraction of PrPSc associated with distinct sedimentation properties is preferentially taken up by the cells. However, while the fraction of PrPSc and the kinetics of uptake were similar for both strains, PrPSc derived from the 87V strain was disaggregated more rapidly than that derived from 22L. The increased rate of PrPSc disaggregation did not correlate with either the conformational or aggregate stability of 87V PrPSc, both of which were greater than those of 22L PrPSc. Our data suggest that the kinetics of disaggregation of PrPSc following cellular uptake is independent of PrPSc stability but may be dependent upon some component of the PrPSc aggregate other than PrP. Rapid disaggregation of 87V PrPSc by the cell may contribute, at least in part, to the inability of 87V to infect cells in vitro. C1 [Choi, Young Pyo; Priola, Suzette A.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM spriola@niaid.nih.gov FU 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 55 TC 3 Z9 4 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 21 BP 11552 EP 11561 DI 10.1128/JVI.01484-13 PG 10 WC Virology SC Virology GA 237IR UT WOS:000325863400021 PM 23966386 ER PT J AU Hatch, SC Sardo, L Chen, JB Burdick, R Gorelick, R Fivash, MJ Pathak, VK Hu, WS AF Hatch, Steven C. Sardo, Luca Chen, Jianbo Burdick, Ryan Gorelick, Robert Fivash, Matthew J., Jr. Pathak, Vinay K. Hu, Wei-Shau TI Gag-Dependent Enrichment of HIV-1 RNA near the Uropod Membrane of Polarized T Cells SO JOURNAL OF VIROLOGY LA English DT Article ID VIROLOGICAL SYNAPSES; BINDING PROTEIN; LOCALIZATION; TRANSLATION; LYMPHOCYTE; MOTILITY; SPREAD; DOMAIN AB The enrichment of HIV-1 macromolecules at the uropod of polarized T cells can significantly promote virus assembly and cell-mediated infection. Using live-cell fluorescence microscopy, we demonstrate that full-length HIV-1 RNA is enriched at the uropod membrane; furthermore, the presence of HIV-1 Gag containing a functional nucleocapsid domain is necessary for this HIV-1 RNA enrichment. The results from these studies provide novel insights into the mechanism of HIV-1 replication in polarized T cells. C1 [Hatch, Steven C.; Sardo, Luca; Chen, Jianbo; Hu, Wei-Shau] NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Burdick, Ryan; Pathak, Vinay K.] NCI, Viral Mutat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Gorelick, Robert] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD USA. [Fivash, Matthew J., Jr.] Data Management Serv Inc, Frederick, MD USA. RP Hu, WS (reprint author), NCI, Viral Recombinat Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM Wei-Shau.Hu@nih.gov RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU Intramural AIDS Targeted Antiviral Program, NIH; Intramural Research Program of the Center for Cancer Research, NCI; NCI, NIH [HHSN261200800001E]; SAIC-Frederick, Inc. FX This work was funded in part by the Intramural AIDS Targeted Antiviral Program, NIH, and the Intramural Research Program of the Center for Cancer Research, NCI, and in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E with SAIC-Frederick, Inc. NR 26 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 21 BP 11912 EP 11915 DI 10.1128/JVI.01680-13 PG 4 WC Virology SC Virology GA 237IR UT WOS:000325863400053 PM 23966405 ER PT J AU Gao, F Gulay, SP Kasprzak, W Dinman, JD Shapiro, BA Simon, AE AF Gao, Feng Gulay, Suna P. Kasprzak, Wojciech Dinman, Jonathan D. Shapiro, Bruce A. Simon, Anne E. TI The Kissing-Loop T-Shaped Structure Translational Enhancer of Pea Enation Mosaic Virus Can Bind Simultaneously to Ribosomes and a 5 ' Proximal Hairpin SO JOURNAL OF VIROLOGY LA English DT Article ID CAP-INDEPENDENT TRANSLATION; TURNIP CRINKLE VIRUS; PLANT VIRAL RNAS; MESSENGER-RNA; INITIATION-FACTOR; STEM-LOOP; 3' UTR; ELEMENT; REPLICATION; PROTEIN AB The Pea enation mosaic virus (PEMV) 3 ' translational enhancer, known as the kissing-loop T-shaped structure (kl-TSS), binds to 40S subunits, 60S subunits, and 80S ribosomes, whereas the Turnip crinkle virus (TCV) TSS binds only to 60S subunits and 80S ribosomes. Using electrophoretic mobility gel shift assay (EMSA)-based competition assays, the kl-TSS was found to occupy a different site in the ribosome than the P-site-binding TCV TSS, suggesting that these two TSS employ different mechanisms for enhancing translation. The kl-TSS also engages in a stable, long-distance RNA-RNA kissing-loop interaction with a 12-bp 5 ' coding-region hairpin that does not alter the structure of the kl-TSS as revealed by molecular dynamics simulations. Addition of the kl-TSS in trans to a luciferase reporter construct containing either wild-type or mutant 5 ' and 3 ' PEMV sequences suppressed translation, suggesting that the kl-TSS is required in cis to function, and both ribosome-binding and RNA interaction activities of the kl-TSS contributed to translational inhibition. Addition of the kl-TSS was more detrimental for translation than an adjacent eIF4E-binding 3 ' translational enhancer known as the PTE, suggesting that the PTE may support the ribosome-binding function of the kl-TSS. Results of in-line RNA structure probing, ribosome filter binding, and high-throughput selective 2 '-hydroxyl acylation analyzed by primer extension (hSHAPE) of rRNAs within bound ribosomes suggest that kl-TSS binding to ribosomes and binding to the 5 ' hairpin are compatible activities. These results suggest a model whereby posttermination ribosomes/ribosomal subunits bind to the kl-TSS and are delivered to the 5 ' end of the genome via the associated RNA-RNA interaction, which enhances the rate of translation reinitiation. C1 [Gao, Feng; Gulay, Suna P.; Dinman, Jonathan D.; Simon, Anne E.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Kasprzak, Wojciech] SAIC Frederick Inc, Basic Sci Program, Ctr Canc Res Nanobiol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Shapiro, Bruce A.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. RP Shapiro, BA (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM shapirbr@mail.nih.gov; simona@umd.edu RI Gao, Feng/K-4403-2015; OI Dinman, Jonathan/0000-0002-2402-9698 FU U.S. Public Health Service [GM 061515-05A2/G120CD, GM 061515-07S1, GM 058859]; NSF [MCB 1157906]; Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN 261200800001]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research FX This work was supported by grants from the U.S. Public Health Service (GM 061515-05A2/G120CD and GM 061515-07S1) and the NSF (MCB 1157906) to A. E. S. and from the U.S. Public Health Service (GM 058859) to J.D.D. This publication was also funded in part by federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN 261200800001E to W.K. This research was additionally supported in part by a grant from the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, to B.A.S. NR 57 TC 9 Z9 9 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 11987 EP 12002 DI 10.1128/JVI.02005-13 PG 16 WC Virology SC Virology GA 237JJ UT WOS:000325865400003 PM 23986599 ER PT J AU Kerr, PJ Rogers, MB Fitch, A DePasse, JV Cattadori, IM Hudson, PJ Tscharke, DC Holmes, EC Ghedin, E AF Kerr, Peter J. Rogers, Matthew B. Fitch, Adam DePasse, Jay V. Cattadori, Isabella M. Hudson, Peter J. Tscharke, David C. Holmes, Edward C. Ghedin, Elodie TI Comparative Analysis of the Complete Genome Sequence of the California MSW Strain of Myxoma Virus Reveals Potential Host Adaptations SO JOURNAL OF VIROLOGY LA English DT Article ID RABBIT FIBROMA VIRUS; TUMORIGENIC POXVIRUSES; MAXIMUM-LIKELIHOOD; VIRULENCE; RECOMBINATION; REPLICATION; SUPEROXIDE; DISMUTASE; HOMOLOGS; CELLS AB Myxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right-hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits. C1 [Kerr, Peter J.] CSIRO Ecosyst Sci, Canberra, ACT, Australia. [Rogers, Matthew B.; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Rogers, Matthew B.; Fitch, Adam; DePasse, Jay V.; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA USA. [Cattadori, Isabella M.; Hudson, Peter J.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Tscharke, David C.] Australian Natl Univ, Res Sch Biol, Canberra, ACT, Australia. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ghedin, E (reprint author), Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. EM elg21@pitt.edu RI Tscharke, David/C-9133-2009; OI Tscharke, David/0000-0001-6825-9172; Holmes, Edward/0000-0001-9596-3552 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 AI093804]; NHMRC Australia Fellowship; ARC Future Fellowship FX This work was funded in part by grant R01 AI093804 from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. E.C.H. was supported by an NHMRC Australia Fellowship, and D.C.T. was supported by an ARC Future Fellowship. NR 45 TC 9 Z9 9 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12080 EP 12089 DI 10.1128/JVI.01923-13 PG 10 WC Virology SC Virology GA 237JJ UT WOS:000325865400010 PM 23986601 ER PT J AU Han, SJ Marshall, V Barsov, E Quinones, O Ray, A Labo, N Trivett, M Ott, D Renne, R Whitby, D AF Han, Soo-Jin Marshall, Vickie Barsov, Eugene Quinones, Octavio Ray, Alex Labo, Nazzarena Trivett, Matthew Ott, David Renne, Rolf Whitby, Denise TI Kaposi's Sarcoma-Associated Herpesvirus MicroRNA SingleNucleotide Polymorphisms Identified in Clinical Samples Can Affect MicroRNA Processing, Level of Expression, and Silencing Activity SO JOURNAL OF VIROLOGY LA English DT Article ID MULTICENTRIC CASTLEMAN-DISEASE; PRIMARY EFFUSION LYMPHOMA; LYTIC SWITCH PROTEIN; DNA-SEQUENCES; CELL-LINES; IN-VITRO; DROSHA; BIOGENESIS; TRANSCRIPTION; RECOGNITION AB Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs that can produce 25 KSHV mature microRNAs. We previously reported single-nucleotide polymorphisms (SNPs) in KSHV-encoded pre-microRNA and mature microRNA sequences from clinical samples (V. Marshall et al., J. Infect. Dis., 195:645-659, 2007). To determine whether microRNA SNPs affect pre-microRNA processing and, ultimately, mature microRNA expression levels, we performed a detailed comparative analysis of (i) mature microRNA expression levels, (ii) in vitro Drosha/Dicer processing, and (iii) RNA-induced silencing complex-dependent targeting of wild-type (wt) and variant microRNA genes. Expression of pairs of wt and variant pre-microRNAs from retroviral vectors and measurement of KSHV mature microRNA expression by real-time reverse transcription-PCR (RT-PCR) revealed differential expression levels that correlated with the presence of specific sequence polymorphisms. Measurement of KSHV mature microRNA expression in a panel of primary effusion lymphoma cell lines by real-time RT-PCR recapitulated some observed expression differences but suggested a more complex relationship between sequence differences and expression of mature microRNA. Furthermore, in vitro maturation assays demonstrated significant SNP-associated changes in Drosha/DGCR8 and/or Dicer processing. These data demonstrate that SNPs within KSHV-encoded pre-microRNAs are associated with differential microRNA expression levels. Given the multiple reports on the involvement of microRNAs in cancer, the biological significance of these phenotypic and genotypic variants merits further studies in patients with KSHV-associated malignancies. C1 [Han, Soo-Jin; Renne, Rolf] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Marshall, Vickie; Barsov, Eugene; Ray, Alex; Labo, Nazzarena; Trivett, Matthew; Ott, David; Whitby, Denise] SAIC Frederick, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Quinones, Octavio] Frederick Natl Lab Canc Res, Comp Serv, Frederick, MD USA. [Quinones, Octavio] Frederick Natl Lab Canc Res, Stat Serv, Frederick, MD USA. RP Whitby, D (reprint author), SAIC Frederick, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 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]; [RO1 119917-6] 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 and by RO1 119917-6 to R.R. NR 43 TC 10 Z9 10 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12237 EP 12248 DI 10.1128/JVI.01202-13 PG 12 WC Virology SC Virology GA 237JJ UT WOS:000325865400025 PM 24006441 ER PT J AU Maruri-Avidal, L Weisberg, AS Moss, B AF Maruri-Avidal, Liliana Weisberg, Andrea S. Moss, Bernard TI Direct Formation of Vaccinia Virus Membranes from the Endoplasmic Reticulum in the Absence of the Newly Characterized L2-Interacting Protein A30.5 SO JOURNAL OF VIROLOGY LA English DT Article ID GOLGI INTERMEDIATE COMPARTMENT; A17L ENVELOPE PROTEIN; VIRION MEMBRANE; IMMATURE VIRIONS; VIRAL MEMBRANES; CRESCENT PRECURSORS; APOPTOTIC MIMICRY; EXTERNAL SCAFFOLD; MATURE VIRIONS; CELL ENTRY AB Crescents consisting of a single lipoprotein membrane with an external protein scaffold comprise the initial structural elements of poxvirus morphogenesis. Crescents enlarge to form spherical immature virions, which enclose viroplasm consisting of proteins destined to form the cores of mature virions. Previous studies suggest that the L2 protein participates in the recruitment of endoplasmic reticulum (ER)-derived membranes to form immature virions within assembly sites of cytoplasmic factories. Here we show that L2 interacts with the previously uncharacterized 42-amino-acid A30.5 protein. An open reading frame similar in size to the one encoding A30.5 is at the same genome location in representatives of all chordopoxvirus genera. A30.5 has a putative transmembrane domain and colocalized with markers of the endoplasmic reticulum and with L2. By constructing a complementing cell line expressing A30.5, we isolated a deletion mutant virus that exhibits a defect in morphogenesis in normal cells. Large electron-dense cytoplasmic inclusions and clusters of scaffold protein-coated membranes that resemble crescents and immature virions devoid of viroplasm were seen in place of normal structures. Crescent-shaped membranes were continuous with the endoplasmic reticulum membrane and oriented with the convex scaffold protein-coated side facing the lumen, while clusters of completed spherical immature-virion-like forms were trapped within the expanded lumen. Immature-virion-like structures were more abundant in infected RK-13 cells than in BS-C-1 or HeLa cells, in which cytoplasmic inclusions were decorated with scaffold protein-coated membrane arcs. We suggest that the outer surface of the poxvirus virion is derived from the luminal side of the ER membrane. C1 [Maruri-Avidal, Liliana; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, NIAID, NIH FX The research was supported by the Division of Intramural Research, NIAID, NIH. NR 47 TC 14 Z9 14 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12313 EP 12326 DI 10.1128/JVI.02137-13 PG 14 WC Virology SC Virology GA 237JJ UT WOS:000325865400032 PM 24027302 ER PT J AU Tan, Y Guan, WD Lam, TTY Pan, SH Wu, SG Zhan, YQ Viboud, C Holmes, EC Yang, ZF AF Tan, Yi Guan, Wenda Lam, Tommy Tsan-Yuk Pan, Sihua Wu, Shiguan Zhan, Yangqing Viboud, Cecile Holmes, Edward C. Yang, Zifeng TI Differing Epidemiological Dynamics of Influenza B Virus Lineages in Guangzhou, Southern China, 2009-2010 SO JOURNAL OF VIROLOGY LA English DT Article ID EVOLUTIONARY PATTERN; MAXIMUM-LIKELIHOOD; GENETIC-CHARACTERIZATION; CLINICAL CHARACTERISTICS; SEASONAL INFLUENZA; A VIRUSES; COCIRCULATION; STRAINS; TAIWAN; HEMAGGLUTININS AB The epidemiological and evolutionary dynamics of the two cocirculating lineages of influenza B virus, Victoria and Yamagata, are poorly understood, especially in tropical or subtropical areas of Southeast Asia. We performed a phylogenetic analysis of the hemagglutinin (HA) and neuraminidase (NA) sequences of influenza B viruses isolated in Guangzhou, a southern Chinese city, during 2009 to 2010 and compared the demographic and clinical features of infected patients. We identified multiple viral introductions of Victoria strains from both Chinese and international sources, which formed two phylogenetically and antigenically distinct clades (Victoria 1 and 2), some of which persisted between seasons. We identified one dominant Yamagata introduction from outside China during 2009. Our phylogenetic analysis reveals the occurrence of reassortment events among the Victoria and Yamagata lineages and also within the Victoria lineage. We found no significant difference in clinical severity by influenza B lineage, with the exceptions that (i) the Yamagata lineage infected older people than either Victoria lineage and (ii) fewer upper respiratory tract infections were caused by the Victoria 2 than the Victoria 1 clade. Overall, our study reveals the complex epidemiological dynamics of different influenza B lineages within a single geographic locality and has implications for vaccination policy in southern China. C1 [Tan, Yi; Viboud, Cecile; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tan, Yi] Chinese Univ Hong Kong, Fac Med, Sch Publ Hlth & Primary Care, Stanley Ho Ctr Emerging Infect Dis, Hong Kong, Hong Kong, Peoples R China. [Guan, Wenda; Pan, Sihua; Wu, Shiguan; Zhan, Yangqing; Yang, Zifeng] Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. [Lam, Tommy Tsan-Yuk] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Yang, Zifeng] Macau Univ Sci & Technol, Fac Chinese Med, Macao, Peoples R China. RP Yang, ZF (reprint author), Guangzhou Med Univ, Affiliated Hosp 1, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. EM jeffyah@163.com RI Lam, Tommy Tsan-Yuk/D-4837-2012; OI Holmes, Edward/0000-0001-9596-3552 FU Combination Project of Guangdong Province from Guangdong Provincial Department of Science and Technology, China [2010B091000018]; National Science and Technology Pillar Program during the 12th Five-year Plan Period from Ministry of Science and Technology, China [2012BAI05B01]; Science Research Fund for Youth Scholar from First Affiliated Hospital of Guangzhou Medical School, China [201220-gyfyy]; Influenza Program of the Fogarty International Center, National Institutes of Health; Office of Global Affairs' International Influenza Unit, U.S. Department of Health and Human Services; NHMRC Australia FX This work was supported by a Combination Project of Guangdong Province from Guangdong Provincial Department of Science and Technology, China (grant no. 2010B091000018), The National Science and Technology Pillar Program during the 12th Five-year Plan Period from Ministry of Science and Technology, China (grant no. 2012BAI05B01), The Science Research Fund for Youth Scholar from First Affiliated Hospital of Guangzhou Medical School, China (grant no. 201220-gyfyy), and the Influenza Program of the Fogarty International Center, National Institutes of Health, which is funded by the Office of Global Affairs' International Influenza Unit, U.S. Department of Health and Human Services. E. C. H. is funded by an NHMRC Australia Fellowship. NR 53 TC 18 Z9 18 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12447 EP 12456 DI 10.1128/JVI.01039-13 PG 10 WC Virology SC Virology GA 237JJ UT WOS:000325865400044 PM 24027322 ER PT J AU Lubaki, NM Ilinykh, P Pietzsch, C Tigabu, B Freiberg, AN Koup, RA Bukreyev, A AF Lubaki, Ndongala M. Ilinykh, Philipp Pietzsch, Colette Tigabu, Bersabeh Freiberg, Alexander N. Koup, Richard A. Bukreyev, Alexander TI The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains vol(87, pg 7471, 2013) SO JOURNAL OF VIROLOGY LA English DT Correction C1 [Lubaki, Ndongala M.] Univ Texas Med Branch, Galveston Natl Lab, Dept Pathol, Galveston, TX 77555 USA. Univ Texas Med Branch, Galveston Natl Lab, Dept Microbiol & Immunol, Galveston, TX 77555 USA. NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lubaki, NM (reprint author), Univ Texas Med Branch, Galveston Natl Lab, Dept Pathol, Galveston, TX 77555 USA. NR 1 TC 0 Z9 0 U1 2 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2013 VL 87 IS 22 BP 12506 EP 12506 DI 10.1128/JVI.02496-13 PG 1 WC Virology SC Virology GA 237JJ UT WOS:000325865400053 ER PT J AU Saba, E Origoni, M Taccagni, G Ferrari, D Doglioni, C Nava, A Lisco, A Grivel, JC Margolis, L Poli, G AF Saba, E. Origoni, M. Taccagni, G. Ferrari, D. Doglioni, C. Nava, A. Lisco, A. Grivel, J-C Margolis, L. Poli, G. TI Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle SO MUCOSAL IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; FEMALE REPRODUCTIVE-TRACT; DC-SIGN; T-CELLS; RHESUS MACAQUES; INNATE IMMUNITY; GENITAL-TRACT; MACROPHAGES; TRANSMISSION; EXPRESSION AB Cervical tissue explants (CTEs) from 22 HIV-1 seronegative women were exposed to R5 HIV-1 ex vivo. Eight CTEs were productively infected in terms of HIV-1 p24(Gag) release in culture supernatants, whereas 14 were not. Nonetheless, both accumulation of HIV-1(gag) DNA and of p24(Gag)(+) CD4(+) Tcells and macrophages occurred in both productive and, at lower levels, in nonproductive CTEs. Nonproductive CTEs differed from productive CTEs for higher secretion of C-C motif chemokine ligand 3 (CCL3) and CCL5. A post-hoc analysis revealed that all productive CTEs were established from women in their secretory phase of the menstrual cycle, whereas nonproductive CTEs were derived from women either in their secretory (28%) or proliferative (36%) menstrual cycle phases or with an atrophic endometrium (36%). Thus, our results support the epidemiological observation that sexual HIV-1 transmission from males to women as well as from women to men is more efficient during their secretory phase of the menstrual cycle. C1 [Saba, E.; Nava, A.; Poli, G.] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. [Saba, E.; Origoni, M.; Poli, G.] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy. [Origoni, M.; Ferrari, D.] Ist Sci San Raffaele, Dept Obstet & Gynecol, I-20132 Milan, Italy. [Taccagni, G.; Doglioni, C.] Ist Sci San Raffaele, Dept Pathol, I-20132 Milan, Italy. [Lisco, A.; Grivel, J-C; Margolis, L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. RP Margolis, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD USA. EM margolis@helix.nih.gov; poli.guido@hsr.it OI ORIGONI, Massimo/0000-0001-6690-3606; DOGLIONI, Claudio/0000-0002-4969-5216 FU Cariplo Foundation, Milano, Italy; National Program of Research on HIV/AIDS of the Italian Ministry of Health [AIDS 40H77]; NICHD FX E. S. conducted this study as student of the Program of Basic and Applied Immunology, International PhD School in Molecular Medicine, San Raffaele University, Milan, Italy; E.S.'s PhD fellowship was supported by a grant of the Cariplo Foundation, Milano, Italy. This study was supported by the grant AIDS 40H77 of the National Program of Research on HIV/AIDS of the Italian Ministry of Health (to G. P.). The work of A. L., J-C.G., and L. M. was supported by the NICHD Intramural Program. We thank Elisa Vicenzi for helpful discussions. NR 50 TC 27 Z9 27 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 EI 1935-3456 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD NOV PY 2013 VL 6 IS 6 BP 1081 EP 1090 DI 10.1038/mi.2013.2 PG 10 WC Immunology SC Immunology GA 238BX UT WOS:000325916800003 PM 23385427 ER PT J AU Cruz, FC Koya, E Guez-Barber, DH Bossert, JM Lupica, CR Shaham, Y Hope, BT AF Cruz, Fabio C. Koya, Eisuke Guez-Barber, Danielle H. Bossert, Jennifer M. Lupica, Carl R. Shaham, Yavin Hope, Bruce T. TI New technologies for examining the role of neuronal ensembles in drug addiction and fear SO NATURE REVIEWS NEUROSCIENCE LA English DT Article ID NUCLEUS-ACCUMBENS NEURONS; STRESS-INDUCED REINSTATEMENT; PALATABLE FOOD SEEKING; CONTEXT-SPECIFIC SENSITIZATION; HIPPOCAMPAL PLACE CELLS; INDUCED GENE-REGULATION; IN-VIVO EXPERIENCE; FOS MESSENGER-RNA; PREFRONTAL CORTEX; SYNAPTIC PLASTICITY AB Correlational data suggest that learned associations are encoded within neuronal ensembles. However, it has been difficult to prove that neuronal ensembles mediate learned behaviours because traditional pharmacological and lesion methods, and even newer cell type-specific methods, affect both activated and non-activated neurons. In addition, previous studies on synaptic and molecular alterations induced by learning did not distinguish between behaviourally activated and non-activated neurons. Here, we describe three new approaches - Daun02 inactivation, FACS sorting of activated neurons and Fos-GFP transgenic rats - that have been used to selectively target and study activated neuronal ensembles in models of conditioned drug effects and relapse. We also describe two new tools - Fos-tTA transgenic mice and inactivation of CREB-overexpressing neurons - that have been used to study the role of neuronal ensembles in conditioned fear. C1 [Cruz, Fabio C.; Koya, Eisuke; Guez-Barber, Danielle H.; Bossert, Jennifer M.; Lupica, Carl R.; Shaham, Yavin; Hope, Bruce T.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hope, BT (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; shaham, yavin/G-1306-2014 OI Hope, Bruce/0000-0001-5804-7061; FU US National Institute on Drug Abuse, Intramural Research Program FX The writing of this article was supported by the US National Institute on Drug Abuse, Intramural Research Program. We thank the members of the Hope, Lupica and Shaham laboratories who contributed to the development and implementation of the new technologies described in this article. NR 144 TC 49 Z9 49 U1 6 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2013 VL 14 IS 11 BP 743 EP 754 DI 10.1038/nrn3597 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 238CS UT WOS:000325918900007 PM 24088811 ER PT J AU Blair, RJR AF Blair, R. James R. TI The neurobiology of psychopathic traits in youths SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID CALLOUS-UNEMOTIONAL TRAITS; DISRUPTIVE BEHAVIOR DISORDERS; VENTROMEDIAL PREFRONTAL CORTEX; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; POSTTRAUMATIC-STRESS-DISORDER; ONSET CONDUCT DISORDER; MATTER MICROSTRUCTURAL ABNORMALITIES; ANTISOCIAL PERSONALITY-DISORDERS; PROBABILISTIC RESPONSE REVERSAL; OPPOSITIONAL DEFIANT DISORDER AB Conduct disorder is a childhood behaviour disorder that is characterized by persistent aggressive or antisocial behaviour that disrupts the child's environment and impairs his or her functioning. A proportion of children with conduct disorder have psychopathic traits. Psychopathic traits consist of a callous-unemotional component and an impulsive-antisocial component, which are associated with two core impairments. The first is a reduced empathic response to the distress of other individuals, which primarily reflects reduced amygdala responsiveness to distress cues; the second is deficits in decision making and in reinforcement learning, which reflects dysfunction in the ventromedial prefrontal cortex and striatum. Genetic and prenatal factors contribute to the abnormal development of these neural systems, and social-environmental variables that affect motivation influence the probability that antisocial behaviour will be subsequently displayed. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM JamesBlair@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, USA [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, USA, under grant number 1-ZIA-MH002860-08. NR 247 TC 104 Z9 104 U1 53 U2 173 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2013 VL 14 IS 11 BP 786 EP 799 DI 10.1038/nrn3577 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 238CS UT WOS:000325918900010 PM 24105343 ER PT J AU Casey, BJ Craddock, N Cuthbert, BN Hyman, SE Lee, FS Ressler, KJ AF Casey, B. J. Craddock, Nick Cuthbert, Bruce N. Hyman, Steven E. Lee, Francis S. Ressler, Kerry J. TI DSM-5 and RDoC: progress in psychiatry research? SO NATURE REVIEWS NEUROSCIENCE LA English DT Editorial Material ID FUTURE AB Neuroscience studies into psychiatric disorders generally rely on disease definitions that are based on the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), the fifth edition of which (DSM-5) was released earlier this year. Designed as a purely diagnostic tool, the DSM considers different disorders as distinct entities. However, boundaries between disorders are often not as strict as the DSM suggests. To provide an alternative framework for research into psychiatric disorders, the US National Institute of Mental Health (NIMH) has recently introduced its Research Domain Criteria (RDoC) project. In the RDoC, five 'domains' each reflect a brain system in which functioning is impaired, to different degrees, in different psychiatric conditions. Nature Reviews Neuroscience asked six leading investigators for their thoughts on how DSM-5 and the RDoC will influence neuroscience research into psychiatric disorders. C1 [Casey, B. J.] Cornell Univ, Weill Med Coll, Dept Psychiat, Inst Dev Psychobiol, New York, NY 10065 USA. [Craddock, Nick] Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales. [Cuthbert, Bruce N.] NIMH, NIH, Bethesda, MD 20892 USA. [Hyman, Steven E.] MIT, Stanley Ctr Psychiat Res, Broad Inst, Cambridge, MA 02142 USA. [Hyman, Steven E.] Harvard Univ, Cambridge, MA 02142 USA. [Lee, Francis S.] Cornell Univ, Weill Cornell Med Coll, Dept Psychiat, New York, NY 10065 USA. [Lee, Francis S.] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10065 USA. [Ressler, Kerry J.] Emory Univ, Howard Hughes Med Inst, Atlanta, GA 30329 USA. [Ressler, Kerry J.] Emory Univ, Dept Psychiat & Behav Sci, Atlanta, GA 30329 USA. RP Casey, BJ (reprint author), Cornell Univ, Weill Med Coll, Dept Psychiat, Inst Dev Psychobiol, New York, NY 10065 USA. EM bjc2002@med.cornell.edu; craddockn@cardiff.ac.uk; bcuthber@mail.nih.gov; stevehy@broadinstitute.org; fslee@med.cornell.edu; kressle@emory.edu OI Ressler, Kerry/0000-0002-5158-1103 FU NIMH NIH HHS [P50 MH079513]; NINDS NIH HHS [R01 NS052819] NR 6 TC 74 Z9 78 U1 1 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X EI 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD NOV PY 2013 VL 14 IS 11 BP 810 EP 814 DI 10.1038/nrn3621 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 238CS UT WOS:000325918900012 PM 24135697 ER PT J AU Magnus, MC Stene, LC Haberg, SE Nafstad, P Stigum, H London, SJ Nystad, W AF Magnus, Maria C. Stene, Lars C. Haberg, Siri E. Nafstad, Per Stigum, Hein London, Stephanie J. Nystad, Wenche TI Prospective Study of Maternal Mid-pregnancy 25-hydroxyvitamin D Level and Early Childhood Respiratory Disorders SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE asthma; lower respiratory tract infection; pregnancy; vitamin D ID VITAMIN-D INTAKE; NORWEGIAN MOTHER; LUNG DEVELOPMENT; IMMUNE-SYSTEM; D DEFICIENCY; ASTHMA; RISK; CHILDREN; COHORT; INFECTION AB BackgroundStudies suggest that prenatal vitamin D status may be inversely associated with lower respiratory tract infections (LRTIs) early in life. Studies of prenatal vitamin D status and development of asthma have inconsistent findings. MethodsWe examined the associations of maternal mid-pregnancy 25-hydroxyvitamin D [25(OH)D] level with the frequency of LRTIs by 36 months and with current asthma at 36 months using the Norwegian Mother and Child Cohort Study. Maternal plasma 25(OH)D level was measured using liquid chromatography-tandem mass spectrometry. Respiratory disorders were evaluated by maternal report through questionnaires. LRTIs were analysed in a random sample of 1248 children. Asthma was analysed using a case-control design, including 489 cases and 1183 controls. Multivariable generalised linear models calculated adjusted measures of association. ResultsThe median gestational week of sample collection was 18 weeks (range 9, 35). The mean 25(OH)D level was 73.7nmol/L (standard deviation 23.7). Higher maternal mid-pregnancy 25(OH)D level was associated with a reduced risk of three or more LRTIs by 36 months vs. none, adjusted risk ratio 0.74 [95% confidence interval (CI): 0.58, 0.93] per 20nmol/L increase. Associations were similar when examining the frequency of LRTIs by 18 months, and the frequency of LRTIs between 18 and 36 months. Maternal mid-pregnancy 25(OH)D level was not significantly associated with current asthma at 36 months, adjusted odds ratio 0.91 [95% CI 0.81, 1.02] per 20nmol/L increase. ConclusionsHigher maternal mid-pregnancy 25(OH)D level was associated with a modestly reduced risk of recurrent LRTIs by 36 months, but was not associated with current asthma at 36 months. C1 [Magnus, Maria C.; Stene, Lars C.; Haberg, Siri E.; Nafstad, Per; Stigum, Hein; Nystad, Wenche] Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, N-0403 Oslo, Norway. [Nafstad, Per; Stigum, Hein] Univ Oslo, Dept Community Med, Fac Med, Oslo, Norway. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [London, Stephanie J.] NIEHS, Lab Resp Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Magnus, MC (reprint author), Norwegian Inst Publ Hlth, Dept Chron Dis, Div Epidemiol, POB 4404 Nydalen, N-0403 Oslo, Norway. EM maria.christine.magnus@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU NIH (NIH/NIEHS) [ZIAES049019]; NIH (NIH/NINDS) [1 UO1 NS 047537-01, 2 UO1 NS 047537-06A1]; Norwegian Research Council/FUGE [151918/S10]; Norwegian Extra-Foundation for Health and Rehabilitation [2011.2.0218] FX The Norwegian Mother and Child Cohort Study is supported by NIH (NIH/NIEHS project number ZIAES049019, NIH/NINDS grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1), in addition to a grant from the Norwegian Research Council/FUGE (grant number 151918/S10). The first author was further supported by a grant from the Norwegian Extra-Foundation for Health and Rehabilitation (grant number 2011.2.0218). The authors are grateful to all the families participating in the Norwegian Mother and Child Cohort Study. NR 39 TC 19 Z9 19 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2013 VL 27 IS 6 BP 532 EP 541 DI 10.1111/ppe.12080 PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 238WZ UT WOS:000325983800004 PM 24134527 ER PT J AU Nilsen, RM Suren, P Gunnes, N Alsaker, ER Bresnahan, M Hirtz, D Hornig, M Lie, KK Lipkin, WI Reichborn-Kjennerud, T Roth, C Schjolberg, S Smith, GD Susser, E Vollset, SE Oyen, AS Magnus, P Stoltenberg, C AF Nilsen, Roy M. Suren, Pal Gunnes, Nina Alsaker, Elin R. Bresnahan, Michaeline Hirtz, Deborah Hornig, Mady Lie, Kari Kveim Lipkin, W. Ian Reichborn-Kjennerud, Ted Roth, Christine Schjolberg, Synnve Smith, George Davey Susser, Ezra Vollset, Stein Emil Oyen, Anne-Siri Magnus, Per Stoltenberg, Camilla TI Analysis of Self-selection Bias in a Population-based Cohort Study of Autism Spectrum Disorders SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE Autism; cohort; Norway; pregnancy; selection bias ID FOLIC-ACID SUPPLEMENTS; PERINATAL RISK-FACTORS; INFANTILE-AUTISM; CHILDREN; PARTICIPATION; ASSOCIATION; PREVALENCE; REGISTRY; CHARGE; DELAY AB BackgroundThis study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). MethodsThe cohort sample (n=89836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n=507856). The children were born in 1999-2007, and seven prenatal and perinatal exposures were selected for analyses. ResultsASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. ConclusionsAssociations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study. C1 [Nilsen, Roy M.; Vollset, Stein Emil; Stoltenberg, Camilla] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5018 Bergen, Norway. [Reichborn-Kjennerud, Ted] Univ Oslo, Inst Psychiat, N-0316 Oslo, Norway. [Oyen, Anne-Siri] Lovisenberg Hosp, Nic Waals Inst, Oslo, Norway. [Bresnahan, Michaeline; Hornig, Mady; Lipkin, W. Ian; Susser, Ezra] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Hirtz, Deborah] NINDS, Bethesda, MD 20892 USA. [Smith, George Davey] Univ Bristol, MRC Integrat Epidemiol Unit IEU, Bristol, Avon, England. RP Nilsen, RM (reprint author), Univ Bergen, Dept Global Publ Hlth & Primary Care, Kalfarveien 31, N-5018 Bergen, Norway. EM roy.nilsen@uib.no RI Davey Smith, George/A-7407-2013 OI Davey Smith, George/0000-0002-1407-8314 FU Norwegian Ministry of Health and Care Services; Norwegian Ministry of Education and Research; Research Council of Norway/FUGE [151918]; National Institute of Neurological Disorders and Stroke (NIH/NINDS), Bethesda, MD, USA [NS47537]; National Institute of Environmental Health Sciences (NIH/NIEHS), Research Triangle Park, NC, USA [NO-ES-75558]; NINDS [NS47537]; Faculty of Medicine and Dentistry, University of Bergen, Norway FX The authors are indebted to Ane Johannessen for her valuable comments on previous versions of this manuscript. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services, the Norwegian Ministry of Education and Research, the Research Council of Norway/FUGE (grant 151918), the National Institute of Neurological Disorders and Stroke (NIH/NINDS), Bethesda, MD, USA [grant NS47537 (Lipkin)], and the National Institute of Environmental Health Sciences (NIH/NIEHS), Research Triangle Park, NC, USA (contract NO-ES-75558). The Autism Birth Cohort study is funded by the NINDS [grant NS47537 (Lipkin)]. The current work was supported by the Faculty of Medicine and Dentistry, University of Bergen, Norway. NR 30 TC 27 Z9 27 U1 3 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2013 VL 27 IS 6 BP 553 EP 563 DI 10.1111/ppe.12077 PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 238WZ UT WOS:000325983800006 PM 23919580 ER PT J AU Schisterman, EF Silver, RM Perkins, NJ Mumford, SL Whitcomb, BW Stanford, JB Lesher, LL Faraggi, D Wactawski-Wende, J Browne, RW Townsend, JM White, M Lynch, AM Galai, N AF Schisterman, Enrique F. Silver, Robert M. Perkins, Neil J. Mumford, Sunni L. Whitcomb, Brian W. Stanford, Joseph B. Lesher, Laurie L. Faraggi, David Wactawski-Wende, Jean Browne, Richard W. Townsend, Janet M. White, Mark Lynch, Anne M. Galai, Noya TI A Randomised Trial to Evaluate the Effects of Low-dose Aspirin in Gestation and Reproduction: Design and Baseline Characteristics SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE low-dose aspirin; conception; pregnancy; miscarriage; subfertility ID RECURRENT MISCARRIAGE; PREGNANCY; WOMEN; PREVENTION; HEPARIN; WEIGHT AB BackgroundLow-dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves livebirth rates in women with one to two prior losses. MethodsWe performed a multicentre, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006-12). Eligible women were aged 18-40 years actively trying to conceive, with one to two prior losses. Participants were randomised to receive daily LDA (81mg/day) or a matching placebo, and all were provided with daily 400-mcg folic acid. Follow-up continued for 6 menstrual cycles while attempting to conceive. For those who conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative livebirth rate over the trial period. ResultsThere were 1228 women randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86%more thanhigh school education), and employed (75%) with a household income >$100000 annually (40%). The characteristics of those in the treatment and placebo arms were well balanced. ConclusionsWe describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on livebirth and other pregnancy outcomes in these women. C1 [Schisterman, Enrique F.; Perkins, Neil J.; Mumford, Sunni L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Rockville, MD 20854 USA. [Silver, Robert M.; Stanford, Joseph B.; Lesher, Laurie L.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Stanford, Joseph B.] Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT USA. [Whitcomb, Brian W.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Browne, Richard W.] SUNY Buffalo, Dept Biotech & Clin Lab Sci, Buffalo, NY 14260 USA. [Townsend, Janet M.; White, Mark] Commonwealth Med Coll, Dept Family Community & Rural Hlth, Scranton, PA USA. [Lynch, Anne M.] Univ Colorado, Dept Obstet & Gynecol, Denver, CO 80202 USA. [Faraggi, David; Galai, Noya] Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,7B03, Rockville, MD 20854 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). We would like to especially thank the EAGeR participants for their extraordinary commitment to the study, all of the EAGeR investigators and staff who devoted their time and energy to the success of this trial, and the Data Safety and Monitoring Board members for ongoing oversight, constant support, and advice throughout the trial. NR 17 TC 19 Z9 19 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 EI 1365-3016 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD NOV PY 2013 VL 27 IS 6 BP 598 EP 609 DI 10.1111/ppe.12088 PG 12 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 238WZ UT WOS:000325983800010 PM 24118062 ER PT J AU Smith, SM Dart, RC Katz, NP Paillard, F Adams, EH Comer, SD Degroot, A Edwards, RR Haddox, JD Jaffe, JH Jones, CM Kleber, HD Kopecky, EA Markman, JD Montoya, ID O'Brien, C Roland, CL Stanton, M Strain, EC Vorsanger, G Wasan, AD Weiss, RD Turk, DC Dworkin, RH AF Smith, Shannon M. Dart, Richard C. Katz, Nathaniel P. Paillard, Florence Adams, Edgar H. Comer, Sandra D. Degroot, Aldemar Edwards, Robert R. Haddox, J. David Jaffe, Jerome H. Jones, Christopher M. Kleber, Herbert D. Kopecky, Ernest A. Markman, John D. Montoya, Ivan D. O'Brien, Charles Roland, Carl L. Stanton, Marsha Strain, Eric C. Vorsanger, Gary Wasan, Ajay D. Weiss, Roger D. Turk, Dennis C. Dworkin, Robert H. TI Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations SO PAIN LA English DT Review DE Classification; Clinical trials; Prescription drug abuse; Prescription drug misuse; Systematic review ID AMERICAN ASSOCIATION; ADVERSE EVENTS; OPIOID THERAPY; CHRONIC PAIN; ADDICTION; DEPENDENCE; DIVERSION; ADOLESCENTS AB As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Smith, Shannon M.; Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. [Dart, Richard C.] Univ Colorado, Sch Med, Denver, CO USA. [Dart, Richard C.] Denver Hlth, Rocky Mt Poison & Drug Ctr, Denver, CO USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.; Haddox, J. David] Tufts Univ, Boston, MA 02111 USA. [Paillard, Florence] Focus Biocom, Durango, CO USA. [Adams, Edgar H.] Covance Market Access, Gaithersburg, MD USA. [Comer, Sandra D.; Kleber, Herbert D.] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Degroot, Aldemar] Astellas Pharma Inc, Northbrook, IL USA. [Edwards, Robert R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Haddox, J. David] Purdue Pharma LP, Stamford, CT USA. [Jaffe, Jerome H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Jones, Christopher M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Kopecky, Ernest A.] Collegium Pharmaceut Inc, Canton, MA USA. [Markman, John D.] Univ Rochester, Dept Neurosurg, Rochester, NY USA. [Montoya, Ivan D.] NIDA, Bethesda, MD 20892 USA. [O'Brien, Charles] Univ Penn, Philadelphia, PA 19104 USA. [Roland, Carl L.] Pfizer Inc, Cary, NC USA. [Stanton, Marsha] Horizon Pharma Inc, Deerfield, IL USA. [Strain, Eric C.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Vorsanger, Gary] Janssen Sci Affairs LLC, Raritan, NJ USA. [Wasan, Ajay D.] Harvard Univ, Sch Med, Chestnut Hill, MA USA. [Weiss, Roger D.] Harvard Univ, Sch Med, Boston, MA USA. [Weiss, Roger D.] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02178 USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Dworkin, Robert H.] Univ Rochester, Sch Med & Dent, Ctr Human Expt Therapeut, Rochester, NY USA. RP Smith, SM (reprint author), Univ Rochester, Sch Med & Dent, Dept Anesthesiol, Rochester, NY 14627 USA. EM shannon1_smith@urmc.rochester.edu RI bebarta, vikhyat/K-3476-2015 FU U.S. Food and Drug Administration, the Centers for Disease Control and Prevention; ACTTION; U.S. Food and Drug Administration; National Institute on Drug Abuse [DA09236, DA031022, DA16759, K23 DA020681] FX The findings, conclusions, and recommendations contained in this report are those of the authors. No official endorsement by the U.S. Food and Drug Administration, the Centers for Disease Control and Prevention, or the pharmaceutical companies that provided unrestricted grants to support the activities of ACTTION should be inferred. Financial support for this study was provided by ACTTION, which has received research contracts, grants, or other revenue from the U.S. Food and Drug Administration, various pharmaceutical companies, and other sources. This work was also supported by Grants DA09236, DA031022, and DA16759 (to Sandra D. Comer), Grant K23 DA020681 (to Ajay D. Wasan), and Grant K24 DA022288 (to Roger D. Weiss) from the National Institute on Drug Abuse. NR 43 TC 54 Z9 54 U1 0 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2287 EP 2296 DI 10.1016/j.pain.2013.05.053 PG 10 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500010 PM 23792283 ER PT J AU O'Connor, AB Turk, DC Dworkin, RH Katz, NP Colucci, R Haythornthwaite, JA Klein, M O'Brien, C Posner, K Rappaport, BA Reisfield, G Adams, EH Balster, RL Bigelow, GE Burke, LB Comer, SD Cone, E Cowan, P Denisco, RA Farrar, JT Foltin, RW Haddox, JD Hertz, S Jay, GW Junor, R Kopecky, EA Leiderman, DB McDermott, MP Palmer, PP Raja, SN Rauschkolb, C Rowbotham, MC Sampaio, C Setnik, B Smith, SM Sokolowska, M Stauffer, JW Walsh, SL Zacny, JP AF O'Connor, Alec B. Turk, Dennis C. Dworkin, Robert H. Katz, Nathaniel P. Colucci, Robert Haythornthwaite, Jennifer A. Klein, Michael O'Brien, Charles Posner, Kelly Rappaport, Bob A. Reisfield, Gary Adams, Edgar H. Balster, Robert L. Bigelow, George E. Burke, Laurie B. Comer, Sandra D. Cone, Edward Cowan, Penney Denisco, Richard A. Farrar, John T. Foltin, Richard W. Haddox, J. David Hertz, Sharon Jay, Gary W. Junor, Roderick Kopecky, Ernest A. Leiderman, Deborah B. McDermott, Michael P. Palmer, Pamela P. Raja, Srinivasa N. Rauschkolb, Christine Rowbotham, Michael C. Sampaio, Cristina Setnik, Beatrice Smith, Shannon M. Sokolowska, Marta Stauffer, Joseph W. Walsh, Sharon L. Zacny, James P. TI Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations SO PAIN LA English DT Article DE Abuse; Abuse liability; Clinical trial; Opioids; Prescription drug abuse; Risk of abuse; Study design ID CHRONIC OPIOID THERAPY; CHRONIC NONCANCER PAIN; ABERRANT DRUG BEHAVIOR; CORE OUTCOME MEASURES; CROSS-VALIDATION; MISUSE MEASURE; UNITED-STATES; SOAPP-R; RISK; SCREENER AB Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [O'Connor, Alec B.] Univ Rochester, Dept Med, Rochester, NY USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Dworkin, Robert H.] Univ Rochester, Dept Anesthesiol, Rochester, NY USA. [Katz, Nathaniel P.] Analges Solut, Natick, MA USA. [Katz, Nathaniel P.] Tufts Univ, Sch Med, Dept Anesthesiol, Boston, MA 02111 USA. [Colucci, Robert] Colucci & Associates LLC, Newtown, CT USA. [Haythornthwaite, Jennifer A.; Bigelow, George E.; Cone, Edward] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Klein, Michael; Rappaport, Bob A.; Burke, Laurie B.; Hertz, Sharon] US FDA, Silver Spring, MD USA. [O'Brien, Charles] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Posner, Kelly; Comer, Sandra D.; Foltin, Richard W.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Ctr Suicide Risk Assessment, New York, NY USA. [Reisfield, Gary] Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32611 USA. [Adams, Edgar H.] Covance, Princeton, NJ USA. [Balster, Robert L.] Virginia Commonwealth Univ, Inst Drug & Alcohol Studies, Richmond, VA USA. [Cowan, Penney] Amer Chron Pain Assoc, Rocklin, CA USA. [Denisco, Richard A.] NIDA, Rockville, MD USA. [Farrar, John T.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Haddox, J. David] Purdue Pharma LP, Stamford, CT USA. [Haddox, J. David] Tufts Univ, Sch Med, Dept Publ Hlth & Community Med, Boston, MA 02111 USA. [Jay, Gary W.] Pfizer Inc, Ann Arbor, MI USA. [Junor, Roderick] Eisai Ltd, Woodcliff Lake, NJ USA. [Kopecky, Ernest A.] Endo Pharmaceut Inc, Chadds Ford, PA USA. [Leiderman, Deborah B.] CNS Drug Consulting LLC, Mclean, VA USA. [McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY USA. [Palmer, Pamela P.] AcelRx Pharmaceut Inc, Redwood City, CA USA. [Raja, Srinivasa N.] Johns Hopkins Univ, Baltimore Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21218 USA. [Rauschkolb, Christine] Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ USA. [Rowbotham, Michael C.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Sampaio, Cristina] Fac Med Lisbon, Clin Pharmacol & Therapeut Lab, Lisbon, Portugal. [Setnik, Beatrice; Smith, Shannon M.] King Pharmaceut Inc, Cary, NC USA. [Sokolowska, Marta] Grunenthal USA Inc, Bedminster, NJ USA. [Stauffer, Joseph W.] Durect Corp, Cupertino, CA USA. [Walsh, Sharon L.] Univ Kentucky, Ctr Drug & Alcohol Res, Dept Behav Sci, Lexington, KY 40506 USA. [Zacny, James P.] Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. RP Turk, DC (reprint author), Univ Washington, Dept Anesthesiol & Pain Med, Box 356540, Seattle, WA 98195 USA. EM turkdc@uw.edu OI Yang, Shuman/0000-0002-9638-0890 FU University of Rochester Office of Continuing Professional Education FX The views expressed in this article are those of the authors, none of whom have financial conflicts of interest related to the specific issues discussed herein. At the time of the consensus meeting on which this article is based, 9 of the authors were employed by one of the companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education to support the activities of IMMPACT, including the consensus meeting; these companies were AcelRx, Durect, Eisai, Endo, Grunenthal, Johnson & Johnson, King, Pfizer, and Purdue Pharma LP. No official endorsement by the U.S. Food and Drug Administration, U.S. National Institutes of Health, or the pharmaceutical companies that provided unrestricted grants to the University of Rochester Office of Continuing Professional Education should be inferred. NR 58 TC 14 Z9 14 U1 5 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2324 EP 2334 DI 10.1016/j.pain.2013.06.035 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500014 PM 24148704 ER PT J AU Slade, GD Smith, SB Zaykin, DV Tchivileva, IE Gibson, DG Yuryev, A Mazo, I Bair, E Fillingim, R Ohrbach, R Greenspan, J Maixner, W Diatchenko, L AF Slade, Gary D. Smith, Shad B. Zaykin, Dmitri V. Tchivileva, Inna E. Gibson, Dustin G. Yuryev, Anton Mazo, Ilya Bair, Eric Fillingim, Roger Ohrbach, Richard Greenspan, Joel Maixner, William Diatchenko, Luda TI Facial pain with localized and widespread manifestations: Separate pathways of vulnerability SO PAIN LA English DT Article DE Temporomandibular disorder; Human genetics; Serotonergic receptor; Case-control study ID EXPERIMENTALLY EVOKED PAIN; T-CELL INFILTRATION; COMBINING P-VALUES; TEMPOROMANDIBULAR DISORDERS; NEUROPATHIC PAIN; PALPATION TENDERNESS; SPINAL-CORD; SEROTONIN; OPPERA; RISK AB Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P = 0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P = 0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P = 1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P = 0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P = 1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background. (C) 2013 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved. C1 [Slade, Gary D.; Smith, Shad B.; Tchivileva, Inna E.; Gibson, Dustin G.; Bair, Eric; Maixner, William; Diatchenko, Luda] Univ N Carolina, Reg Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. [Slade, Gary D.] Univ N Carolina, Dept Dent Ecol, Chapel Hill, NC 27599 USA. [Slade, Gary D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Zaykin, Dmitri V.] NIEHS, Res Triangle Pk, NC 27709 USA. [Yuryev, Anton; Mazo, Ilya] Ariadne Diagnost LLC, Rockville, MD USA. [Fillingim, Roger] Univ Florida, Dept Community Dent & Behav Sci, Gainesville, FL USA. [Ohrbach, Richard] SUNY Buffalo, Dept Oral Diagnost Sci, Buffalo, NY 14260 USA. [Greenspan, Joel] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Slade, GD (reprint author), Univ N Carolina, Reg Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. EM gary_slade@dentistry.unc.edu RI Mazo, Ilya/G-6549-2014; OI Mazo, Ilya/0000-0002-8587-4895; Gibson, Dustin/0000-0002-9073-3376; Bair, Eric/0000-0001-8733-7869; Greenspan, Joel/0000-0003-4062-9797 FU National Institutes of Health, National Institutes of Dental and Cranial Research [RO1-DE16558, UO1-DE017018]; Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences FX This work was supported by the National Institutes of Health, National Institutes of Dental and Cranial Research (grant numbers RO1-DE16558 and UO1-DE017018 to L. D., G. S., W. M.). D.V.Z was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. We are grateful to investigators at OPPERA study sites for their contribution in directing data collection: Dr. Joel Greenspan, University of Maryland, Baltimore, MD; Mr. Charles Knott, Battelle Memorial Inc, Durham, NC. NR 50 TC 14 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2335 EP 2343 DI 10.1016/j.pain.2013.07.009 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500015 PM 23867732 ER PT J AU Ramsden, CE Faurot, KR Zamora, D Suchindran, CM MacIntosh, BA Gaylord, S Ringel, A Hibbeln, JR Feldstein, AE Mori, TA Barden, A Lynch, C Coble, R Mas, E Palsson, O Barrow, DA Mann, JD AF Ramsden, Christopher E. Faurot, Keturah R. Zamora, Daisy Suchindran, Chirayath M. MacIntosh, Beth A. Gaylord, Susan Ringel, Amit Hibbeln, Joseph R. Feldstein, Ariel E. Mori, Trevor A. Barden, Anne Lynch, Chanee Coble, Rebecca Mas, Emilie Palsson, Olafur Barrow, David A. Mann, J. Douglas TI Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial SO PAIN LA English DT Article DE Omega-3; Omega-6; Headache; Migraine; Clinical trial ID LINOLEIC-ACID; PSYCHOMETRIC PROPERTIES; INFLAMMATORY PAIN; PROSTAGLANDIN E-2; CHRONIC MIGRAINE; SPINAL-CORD; METABOLITES; PRODUCTS; PLACEBO; IMPACT AB Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs -2.1; P < 0.001) and the number of Headache Days per month (-8.8 vs -4.0; P = 0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (4.6 vs 1.2; P = 0.01) and the n-6 in HUFA score (21.0 vs 4.0%; P < 0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P < 0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P < 0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Ramsden, Christopher E.; Ringel, Amit; Hibbeln, Joseph R.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Ramsden, Christopher E.; Faurot, Keturah R.; Zamora, Daisy; Gaylord, Susan; Lynch, Chanee; Coble, Rebecca; Mann, J. Douglas] Univ N Carolina, Program Integrat Med, Dept Phys Med & Rehabil, Chapel Hill, NC 27515 USA. [Suchindran, Chirayath M.] Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. [MacIntosh, Beth A.] Univ N Carolina, North Carolina Translat Clin Sci Inst, Nutr Res & Metab Core, Chapel Hill, NC USA. [Feldstein, Ariel E.] Univ Calif San Diego, Dept Pediat Gastroenterol Hepatol & Nutr, San Diego, CA 92103 USA. [Mori, Trevor A.; Barden, Anne; Mas, Emilie] Univ Western Australia, Royal Perth Hosp, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Palsson, Olafur] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. [Barrow, David A.] Univ N Carolina, Sch Dent, Chapel Hill, NC USA. [Mann, J. Douglas] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. RP Ramsden, CE (reprint author), NIAAA, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chris.ramsden@nih.gov FU Mayday Fund; UNC Research Fellowship in Complementary and Alternative Medicine (National Center for Complementary and Alternative Medicine [NCCAM], National Institutes of Health [NIH]) [T32-AT003378]; North Carolina Clinical and Translational Sciences Institute (National Center for Research Resources [NCRR], NIH) [UL1RR025747]; UNC Nutrition Obesity Research Center, CHAI Core (National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], NIH) [DK056350]; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX The authors thank the patients who participated in the trial, and acknowledge the following individuals for their research assistance: Marjorie Busby for expertise with study design; Beth Fowler, Carol Carr, Regina McCoy, and Tim McCaskill for design and functionality of the study Website; Meg Mangan for 24-hour recall data collection and management; Jim Loewke and Duk Hyun for fatty acid analyses; and Sharon Majchrzak-Hong for data management support. This project was supported by the Mayday Fund (primary source); the UNC Research Fellowship in Complementary and Alternative Medicine (grant T32-AT003378, National Center for Complementary and Alternative Medicine [NCCAM], National Institutes of Health [NIH]); the North Carolina Clinical and Translational Sciences Institute (grant UL1RR025747, National Center for Research Resources [NCRR], NIH); the UNC Nutrition Obesity Research Center, CHAI Core (grant DK056350, National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK], NIH); and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 61 TC 41 Z9 41 U1 0 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2441 EP 2451 DI 10.1016/j.pain.2013.07.028 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500027 PM 23886520 ER PT J AU Colloca, L Klinger, R Flor, H Bingel, U AF Colloca, Luana Klinger, Regine Flor, Herta Bingel, Ulrike TI Pain beyond biology Response SO PAIN LA English DT Letter C1 [Colloca, Luana] NIMH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Klinger, Regine] Univ Hamburg, Dept Psychol, Outpatient Clin Behav Therapy, Hamburg, Germany. [Flor, Herta] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, Mannheim, Germany. [Bingel, Ulrike] Univ Duisburg Essen, Univ Hosp Essen, Dept Neurol, Essen, Germany. RP Colloca, L (reprint author), NIMH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov NR 8 TC 0 Z9 0 U1 1 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD NOV PY 2013 VL 154 IS 11 BP 2572 EP 2572 DI 10.1016/j.pain.2013.06.048 PG 1 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 238FG UT WOS:000325927500044 PM 23973360 ER PT J AU Little, MP AF Little, Mark P. TI A review of non-cancer effects, especially circulatory and ocular diseases SO RADIATION AND ENVIRONMENTAL BIOPHYSICS LA English DT Review DE Circulatory disease; Radiation; Heart disease; Stroke; Cataract; Central nervous system; Review ID ATOMIC-BOMB SURVIVORS; CORONARY-HEART-DISEASE; URANIUM MINERS COHORT; RATE GAMMA-RADIATION; TERM-FOLLOW-UP; IONIZING-RADIATION; CARDIOVASCULAR-DISEASES; CANCER INCIDENCE; DOSE-RESPONSE; MULTIMODEL INFERENCE AB There is a well-established association between high doses (> 5 Gy) of ionizing radiation exposure and damage to the heart and coronary arteries, although only recently have studies with high-quality individual dosimetry been conducted that would enable quantification of this risk adjusting for concomitant chemotherapy. The association between lower dose exposures and late occurring circulatory disease has only recently begun to emerge in the Japanese atomic bomb survivors and in various occupationally exposed cohorts and is still controversial. Excess relative risks per unit dose in moderate- and low-dose epidemiological studies are somewhat variable, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors. Radiation doses of 1 Gy or more are associated with increased risk of posterior subcapsular cataract. Accumulating evidence from the Japanese atomic bomb survivors, Chernobyl liquidators, US astronauts, and various other exposed groups suggests that cortical cataracts may also be associated with ionizing radiation, although there is little evidence that nuclear cataracts are radiogenic. The dose-response appears to be linear, although modest thresholds (of no more than about 0.6 Gy) cannot be ruled out. A variety of other non-malignant effects have been observed after moderate/low-dose exposure in various groups, in particular respiratory and digestive disease and central nervous system (and in particular neuro-cognitive) damage. However, because these are generally only observed in isolated groups, or because the evidence is excessively heterogeneous, these associations must be treated with caution. C1 NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, 9609 Med Ctr Dr MSC 9778, Bethesda, MD 20892 USA. EM mark.little@nih.gov FU Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The author is grateful for the detailed and helpful comments of Dr Alice Sigurdson and the two referees. NR 108 TC 25 Z9 30 U1 2 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-634X EI 1432-2099 J9 RADIAT ENVIRON BIOPH JI Radiat. Environ. Biophys. PD NOV PY 2013 VL 52 IS 4 BP 435 EP 449 DI 10.1007/s00411-013-0484-7 PG 15 WC Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Environmental Sciences & Ecology; Radiology, Nuclear Medicine & Medical Imaging GA 240DM UT WOS:000326074900002 PM 23903347 ER PT J AU Gonzalez, RG Furie, KL Goldmacher, GV Smith, WS Kamalian, S Payabvash, S Harris, GJ Halpern, EF Koroshetz, WJ Camargo, ECS Dillon, WP Lev, MH AF Gonzalez, R. Gilberto Furie, Karen L. Goldmacher, Gregory V. Smith, Wade S. Kamalian, Shervin Payabvash, Seyedmehdi Harris, Gordon J. Halpern, Elkan F. Koroshetz, Walter J. Camargo, Erica C. S. Dillon, William P. Lev, Michael H. TI Good Outcome Rate of 35% in IV-tPA-Treated Patients With Computed Tomography Angiography Confirmed Severe Anterior Circulation Occlusive Stroke SO STROKE LA English DT Article DE computed tomography angiography; ischemic stroke; thrombolysis; tissue plasminogen activator; treatment outcome ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; ENDOVASCULAR TREATMENT; TRIAL; ALTEPLASE; THERAPY; NINDS AB Background and Purpose To determine the effect of intravenous tissue plasminogen activator (IV-tPA) on outcomes in patients with severe major anterior circulation ischemic stroke. Methods Prospectively, 649 patients with acute stroke had admission National Institutes of Health stroke scale (NIHSS) scores, noncontrast computed tomography (CT), CT angiography (CTA), and 6-month outcome assessed using modified Rankin scale. IV-tPA treatment decisions were made before CTA, at the time of noncontrast CT scanning, as per routine clinical protocol. Severe symptoms were defined as NIHSS>10. Poor outcome was defined as modified Rankin scale >2. Major occlusions were identified on CTA. Univariate and multivariate stepwise-forward logistic regression analyses of the full cohort were performed. Results Of 649 patients, 188 (29%) patients presented with NIHSS>10, and 64 out of 188 (34%) patients received IV-tPA. Admission NIHSS, large artery occlusion, and IV-tPA all independently predicted good outcomes; however, a significant interaction existed between IV-tPA and occlusion (P<0.001). Of the patients who presented with NIHSS>10 with anterior circulation occlusion, twice the percentage had good outcomes if they received IV-tPA (17 out of 49 patients, 35%) than if they did not (13 out of 77 patients, 17%; P=0.031). The number needed to treat was 7 (95% confidence interval, 3-60). Conclusions IV-tPA treatment resulted in significantly better outcomes in patients with severely symptomatic stroke with major anterior circulation occlusions. The 35% good outcome rate was similar to rates found in endovascular therapy trials. Vascular imaging may help in patient selection and stratification for trials of IV-thrombolytic and endovascular therapies. C1 [Gonzalez, R. Gilberto; Furie, Karen L.; Goldmacher, Gregory V.; Kamalian, Shervin; Payabvash, Seyedmehdi; Harris, Gordon J.; Halpern, Elkan F.; Camargo, Erica C. S.; Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Goldmacher, Gregory V.] ICON Med Imaging Beacon Biosci, N Wales, PA USA. [Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Dillon, William P.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Payabvash, Seyedmehdi] Univ Minnesota, Dept Radiol, Minneapolis, MN 55455 USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. [Camargo, Erica C. S.] Boston Univ, Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Furie, Karen L.] Rhode Isl Hosp, Dept Neurol, Providence, RI USA. [Furie, Karen L.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Gonzalez, RG (reprint author), Massachusetts Gen Hosp, Dept Radiol, POB 9657, Boston, MA 02114 USA. EM rggonzalez@partners.org RI Demchuk, Andrew/E-1103-2012; Kamalian, Shervin/D-7667-2013 OI Demchuk, Andrew/0000-0002-4930-7789; Kamalian, Shervin/0000-0001-8962-4773 FU National Institutes of Health Agency for Health Care Policy and Research (AHCPR) [R01 HS11392-01A1] FX This work was supported by the National Institutes of Health Agency for Health Care Policy and Research (AHCPR), R01 HS11392-01A1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. NR 18 TC 15 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2013 VL 44 IS 11 BP 3109 EP 3113 DI 10.1161/STROKEAHA.113.001938 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 238YE UT WOS:000325987300040 PM 24003051 ER PT J AU Goldenberg, RL Farrow, V McClure, EM Reddy, UM Fretts, RC Schulkin, J AF Goldenberg, Robert L. Farrow, Victoria McClure, Elizabeth M. Reddy, Uma M. Fretts, Ruth C. Schulkin, Jay TI Stillbirth: Knowledge and Practice among US Obstetrician-Gynecologists SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE stillbirth; fetal death; obstetric practice; OBGYN knowledge ID RISK-FACTORS; FETAL DEATH; INCOME COUNTRIES; UNITED-STATES; MORTALITY; TRENDS; DISPARITIES; PREGNANCY; RATES; CARE AB Objective To determine knowledge of U.S. obstetrician-gynecologists (OBGYNs) and individual and institutional practices regarding stillbirth. Study Design We surveyed 1,000 members of the American College of Obstetricians and Gynecologists regarding their knowledge of risk factors and causes of stillbirth and self-rated performance in stillbirth management. Results Of the 499 who responded, 365 currently practiced obstetrics. Knowledge regarding epidemiology, risk factors, and effective interventions to reduce stillbirth was only fair. About 30% of respondents were unaware that preeclampsia, advanced maternal age, elevated -fetoprotein, multiple gestation, cigarette smoking, illicit drug use, and being postterm increased risk. Tests to identify stillbirth causes were not performed consistently. Forty-two percent of respondents did not review test results to determine cause. Most hospitals did not have protocols for stillbirth evaluation nor preprinted forms to obtain appropriate stillbirth tests. Stillbirth audits with feedback were rarely performed. Conclusions OBGYN knowledge and institutional practice regarding stillbirth could be substantially improved. Residency programs need improved education regarding stillbirth. Hospitals and their OBGYN departments should focus more on stillbirth through continuing education programs and grand rounds and develop stillbirth management protocols and standardized order sheets to appropriately evaluate stillbirths. Audits that evaluate cause of death and preventability with a feedback loop focused on improvement in care should be considered. C1 [Goldenberg, Robert L.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Farrow, Victoria; Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. [Farrow, Victoria] American Univ, Dept Psychol, Washington, DC 20016 USA. [McClure, Elizabeth M.] Res Triangle Inst, Durham, NC USA. [Reddy, Uma M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol & Pregnancy Branch, Washington, DC USA. [Fretts, Ruth C.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Goldenberg, RL (reprint author), Columbia Univ, Sch Med, Dept Obstet & Gynecol, 622 W 168th St,PH 16-66, New York, NY 10027 USA. EM rlg88@columbia.edu RI Guinan, Irazu/C-4498-2017 FU American College of Obstetricians and Gynecologists from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services [UA6MC19010]; DOE [DE-AC05-06OR23100] FX This research was funded by cooperative agreement UA6MC19010 with the American College of Obstetricians and Gynecologists from the Maternal and Child Health Bureau, Health Resources and Services Administration, Department of Health and Human Services. This research was performed under an appointment to the Department of Homeland Security (DHS) Scholarship and Fellowship Program, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy (DOE) and DHS. ORISE is managed by Oak Ridge Associated Universities (ORAU) under DOE contract number DE-AC05-06OR23100. All opinions expressed in this paper are the authors' and do not necessarily reflect the policies and views of DHS, DOE, or ORAU/ORISE. NR 32 TC 0 Z9 0 U1 0 U2 4 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 EI 1098-8785 J9 AM J PERINAT JI Am. J. Perinatol. PD NOV PY 2013 VL 30 IS 10 BP 812 EP 820 DI 10.1055/s-0032-1333407 PG 8 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 236LA UT WOS:000325796700003 ER PT J AU Qian, WJ Burke, TR AF Qian, Wen-Jian Burke, Terrence R., Jr. TI Design and synthesis of a reagent for solid-phase incorporation of the phosphothreonine mimetic (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) into peptides in a bio-reversible phosphonyl-bis-pivaloyloxymethyl (POM) prodrug form SO AMINO ACIDS LA English DT Article DE Phosphothreonine mimetic; Prodrug; Pmab; Solid-phase peptide synthesis; Signal transduction ID POLO-BOX DOMAIN; SIGNAL-TRANSDUCTION; SH2 DOMAIN; KINASE 1; POTENT; PHOSPHOSERINE; PHOSPHATES; LIGANDS; TARGET; TOOLS AB Reported herein are the synthesis and solid-phase peptide incorporation of N-Fmoc-(2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid bis-pivaloyloxymethyl phosphoryl ester [Fmoc-Pmab(POM)(2)-OH, 2] as a phosphatase-stable phosphothreonine (pThr) mimetic bearing orthogonal protection suitable for the synthesis of Pmab-containing peptides having bio-reversible protection of the phosphonic acid moiety. This represents the first report of a bio-reversibly protected pThr mimetic in a form suitable for facile solid-phase peptide synthesis. C1 [Qian, Wen-Jian; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,Natl Canc Inst Frederick,NIH, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res,Natl Canc Inst Frederick,NIH, Frederick, MD 21702 USA. EM burkete@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research, NCI-Frederick; National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick and the National Cancer Institute, National Institutes of Health. NR 28 TC 1 Z9 1 U1 1 U2 18 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0939-4451 EI 1438-2199 J9 AMINO ACIDS JI Amino Acids PD NOV PY 2013 VL 45 IS 5 BP 1143 EP 1148 DI 10.1007/s00726-013-1567-0 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 236QI UT WOS:000325813800011 PM 23907438 ER PT J AU Lim, P Dek, D Try, V Eastman, RT Chy, S Sreng, S Suon, S Mao, S Sopha, C Sam, B Ashley, EA Miotto, O Dondorp, AM White, NJ Su, XZ Char, MC Anderson, JM Amaratunga, C Menard, D Fairhurst, RM AF Lim, Pharath Dek, Dalin Try, Vorleak Eastman, Richard T. Chy, Sophy Sreng, Sokunthea Suon, Seila Mao, Sivanna Sopha, Chantha Sam, Baramey Ashley, Elizabeth A. Miotto, Olivo Dondorp, Arjen M. White, Nicholas J. Su, Xin-zhuan Char, Meng Chuor Anderson, Jennifer M. Amaratunga, Chanaki Menard, Didier Fairhurst, Rick M. TI Ex Vivo Susceptibility of Plasmodium falciparum to Antimalarial Drugs in Western, Northern, and Eastern Cambodia, 2011-2012: Association with Molecular Markers SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IN-VITRO; DIHYDROARTEMISININ-PIPERAQUINE; ARTEMETHER-LUMEFANTRINE; ARTEMISININ RESISTANCE; MEFLOQUINE COMBINATION; CHLOROQUINE RESISTANCE; CANDIDATE GENES; MALARIA; EFFICACY; ARTESUNATE AB In 2008, dihydroartemisinin (DHA)-piperaquine (PPQ) became the first-line treatment for uncomplicated Plasmodium falciparum malaria in western Cambodia. Recent reports of increased treatment failure rates after DHA-PPQ therapy in this region suggest that parasite resistance to DHA, PPQ, or both is now adversely affecting treatment. While artemisinin (ART) resistance is established in western Cambodia, there is no evidence of PPQ resistance. To monitor for resistance to PPQ and other antimalarials, we measured drug susceptibilities for parasites collected in 2011 and 2012 from Pursat, Preah Vihear, and Ratanakiri, in western, northern, and eastern Cambodia, respectively. Using a SYBR green I fluorescence assay, we calculated the ex vivo 50% inhibitory concentrations (IC(50)s) of 310 parasites to six antimalarials: chloroquine (CQ), mefloquine (MQ), quinine (QN), PPQ, artesunate (ATS), and DHA. Geometric mean IC50s (GMIC(50)s) for all drugs (except PPQ) were significantly higher in Pursat and Preah Vihear than in Ratanakiri (P <= 0.001). An increased copy number of P. falciparum mdr1 (pfmdr1), an MQ resistance marker, was more prevalent in Pursat and Preah Vihear than in Ratanakiri and was associated with higher GMIC(50)s for MQ, QN, ATS, and DHA. An increased copy number of a chromosome 5 region (X5r), a candidate PPQ resistance marker, was detected in Pursat but was not associated with reduced susceptibility to PPQ. The ex vivo IC50 and pfmdr1 copy number are important tools in the surveillance of multidrug-resistant (MDR) parasites in Cambodia. While MDR P. falciparum is prevalent in western and northern Cambodia, there is no evidence for PPQ resistance, suggesting that DHA-PPQ treatment failures result mainly from ART resistance. C1 [Lim, Pharath; Eastman, Richard T.; Su, Xin-zhuan; Anderson, Jennifer M.; Amaratunga, Chanaki; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Lim, Pharath; Dek, Dalin; Try, Vorleak; Sreng, Sokunthea; Suon, Seila; Char, Meng Chuor] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia. [Lim, Pharath; Chy, Sophy; Menard, Didier] Inst Pasteur Cambodge, Phnom Penh, Cambodia. [Mao, Sivanna] Sampov Meas Referral Hosp, Pursat, Cambodia. [Sopha, Chantha] Makara 16 Referral Hosp, Preah Vihear, Cambodia. [Sam, Baramey] Ratanakiri Referral Hosp, Ratanakiri, Cambodia. [Ashley, Elizabeth A.; Miotto, Olivo; Dondorp, Arjen M.; White, Nicholas J.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Ashley, Elizabeth A.; Dondorp, Arjen M.; White, Nicholas J.] Univ Oxford, Ctr Trop Med, Churchill Hosp, Oxford, England. [Miotto, Olivo] Univ Oxford, MRC Ctr Genom & Global Hlth, Oxford, England. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM rfairhurst@niaid.nih.gov RI Menard, Didier/O-3294-2013; OI Menard, Didier/0000-0003-1357-4495; Miotto, Olivo/0000-0001-8060-6771; Su, Xinzhuan/0000-0003-3246-3248 FU Wellcome Trust; Wellcome Trust Mahidol University-Oxford Tropical Medicine Research Programme; Intramural Research Program of the NIAID; NIH; Department for International Development, United Kingdom; Tracking Resistance Artemisinins Collaboration (TRAC) FX A.A., O.M., A.M.D., and N.J.W. are supported by the Wellcome Trust as part of the Wellcome Trust Mahidol University-Oxford Tropical Medicine Research Programme. This study was funded by the Intramural Research Program of the NIAID, NIH, and the Department for International Development, United Kingdom, as part of the Tracking Resistance Artemisinins Collaboration (TRAC). NR 35 TC 13 Z9 13 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2013 VL 57 IS 11 BP 5277 EP 5283 DI 10.1128/AAC.00687-13 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 235ZY UT WOS:000325764000012 PM 23939897 ER PT J AU Havens, PL Kiser, JJ Stephensen, CB Hazra, R Flynn, PM Wilson, CM Rutledge, B Bethel, J Pan, CG Woodhouse, LR Van Loan, MD Liu, N Lujan-Zilbermann, J Baker, A Kapogiannis, BG Gordon, CM Mulligan, K AF Havens, Peter L. Kiser, Jennifer J. Stephensen, Charles B. Hazra, Rohan Flynn, Patricia M. Wilson, Craig M. Rutledge, Brandy Bethel, James Pan, Cynthia G. Woodhouse, Leslie R. Van Loan, Marta D. Liu, Nancy Lujan-Zilbermann, Jorge Baker, Alyne Kapogiannis, Bill G. Gordon, Catherine M. Mulligan, Kathleen CA Adolescent Med Trials Network HIV TI Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency? SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HIV-INFECTED PATIENTS; OPTIMIZED BACKGROUND REGIMEN; PARATHYROID-HORMONE; ANTIRETROVIRAL THERAPY; TUBULAR DYSFUNCTION; ALKALINE-PHOSPHATASE; SALVAGE THERAPY; RENAL-FAILURE; CALCIUM; ADULTS AB Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D[1,25-OH(2) D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2) D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2) D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. C1 [Havens, Peter L.; Pan, Cynthia G.] Med Coll Wisconsin, Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53226 USA. [Kiser, Jennifer J.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO USA. [Stephensen, Charles B.; Woodhouse, Leslie R.; Van Loan, Marta D.] USDA ARS, Western Human Nutr Res Ctr, Davis, CA USA. [Hazra, Rohan; Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Flynn, Patricia M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Wilson, Craig M.] Univ Alabama Birmingham, Birmingham, AL USA. [Rutledge, Brandy; Bethel, James; Liu, Nancy] WESTAT Corp, Rockville, MD 20850 USA. [Lujan-Zilbermann, Jorge] Univ S Florida, Coll Med, Tampa, FL USA. [Baker, Alyne] Tulane Univ, New Orleans, LA 70118 USA. [Gordon, Catherine M.] Hasbro Childrens Hosp, Providence, RI USA. [Gordon, Catherine M.] Brown Univ, Providence, RI 02912 USA. [Mulligan, Kathleen] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Havens, PL (reprint author), Med Coll Wisconsin, Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53226 USA. EM phavens@mcw.edu; kathleen.mulligan@ucsf.edu FU General Clinical Research Center Program of the National Center for Research Resources; National Institutes of Health; Department of Health and Human Services; Children's National Medical Center [M01RR020359]; University of Pennsylvania/Children's Hospital of Philadelphia [NCRRUL1-RR-024134]; University of California at San Francisco [UL1-RR024131]; Seattle Children's Hospital [UL1-RR025014]; Texas Children's Hospital and Baylor College of Medicine [M01-RR00188]; Boston University Medical Center [UL1-RR02517]; SUNY-Stony Brook [M01-RR10710]; Louisiana Board of Regents RC/EEP [RC/EEP-06]; Adolescent Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01HD 040533, U01 HD 040474]; National Institutes on Drug Abuse; Mental Health; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [U01 A1068632] FX Eight of these sites utilized their General Clinical Research Center (GCRC)/Pediatric Clinical Research Center (PCRC) for the study; the centers were supported by grants from the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health, and Department of Health and Human Services under the following grant numbers: Children's National Medical Center, M01RR020359; University of Pennsylvania/Children's Hospital of Philadelphia, NCRRUL1-RR-024134; University of California at San Francisco, UL1-RR024131; Seattle Children's Hospital, UL1-RR025014; Texas Children's Hospital and Baylor College of Medicine, M01-RR00188; Boston University Medical Center, UL1-RR02517; and SUNY-Stony Brook, M01-RR10710. The Tulane University Health Sciences Center utilized its Clinical and Translational Research Center (CTRC) for the study; the center was supported in whole or in part by funds provided through the Louisiana Board of Regents RC/EEP (RC/EEP-06).; This work was supported by the Adolescent Trials Network for HIV/AIDS Interventions (ATN) from the National Institutes of Health (U01HD 040533 and U01 HD 040474] through the Eunice Kennedy Shriver National Institute of Child Health and Human Development [B. Kapogiannis]), with supplemental funding from the National Institutes on Drug Abuse (N. Borek) and Mental Health (P. Brouwers and S. Allison). The protocol was coendorsed by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group. Support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (U01 A1068632). The study was scientifically reviewed by the ATN's Therapeutic Leadership Group. Network, scientific, and logistical support was provided by the ATN Coordinating Center (C. Wilson and C. Partlow) at The University of Alabama at Birmingham. Network operations and analytic support was provided by the ATN Data and Operations Center at Westat, Inc. (J. Korelitz and B. Driver). NR 50 TC 18 Z9 18 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2013 VL 57 IS 11 BP 5619 EP 5628 DI 10.1128/AAC.01096-13 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 235ZY UT WOS:000325764000054 PM 24002093 ER PT J AU Natarajan, G Shankaran, S Laptook, AR Pappas, A Bann, CM McDonald, SA Das, A Higgins, RD Hintz, SR Vohr, BR AF Natarajan, Girija Shankaran, Seetha Laptook, Abbot R. Pappas, Athina Bann, Carla M. McDonald, Scott A. Das, Abhik Higgins, Rosemary D. Hintz, Susan R. Vohr, Betty R. CA Eunice Kennedy Shriver Natl Inst TI Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy SO ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION LA English DT Article DE Outcomes research; hypoxic-ischemic encephalopathy; apgar scores ID EMERGENCY CARDIOVASCULAR CARE; WHOLE-BODY HYPOTHERMIA; CEREBRAL-PALSY; CARDIOPULMONARY-RESUSCITATION; NEONATAL ENCEPHALOPATHY; THERAPEUTIC HYPOTHERMIA; TERM INFANTS; ASSOCIATION; COMPLICATIONS; CHILDREN AB Aim To determine the association between 10 min Apgar scores and 6-7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT). Methods Evaluations at 6-7years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre. Results In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0-3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0-3; there was no significant interaction between cooling and Apgar scores (p=0.26). Conclusions Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration. C1 [Natarajan, Girija; Shankaran, Seetha; Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Laptook, Abbot R.; Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Bann, Carla M.; McDonald, Scott A.] RTI Int, Social Stat & Environm Sci Unit, Res Triangle Pk, NC USA. [Das, Abhik] Social Stat & Environm Sci Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. RP Natarajan, G (reprint author), Childrens Hosp Michigan, Div Neonatol, Dept Pediat, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM gnatara@med.wayne.edu FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX The Neonatal Research Network's Whole-Body Hypothermia Trial and its 6-7 Year School-age Follow-up were provided grant support by the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Grant numbers are provided for each site above. Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating centre (DCC) for the network, which stored, managed and analysed the data for this study. On behalf of the NRN, Dr Abhik Das (DCC Principal Investigator) and Mr Scott A. McDonald (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. NR 27 TC 28 Z9 29 U1 0 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1359-2998 EI 1468-2052 J9 ARCH DIS CHILD-FETAL JI Arch. Dis. Child.-Fetal Neonatal Ed. PD NOV PY 2013 VL 98 IS 6 BP F473 EP F479 DI 10.1136/archdischild-2013-303692 PG 7 WC Pediatrics SC Pediatrics GA 233GN UT WOS:000325556000003 PM 23896791 ER PT J AU Fang, ZZ Krausz, KW Tanaka, N Li, F Qu, AJ Idle, JR Gonzalez, FJ AF Fang, Zhong-Ze Krausz, Kristopher W. Tanaka, Naoki Li, Fei Qu, Aijuan Idle, Jeffrey R. Gonzalez, Frank J. TI Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Trichloroethylene; Dichloroacetate; Trichloroacetate; PPAR alpha; Metabolomics; Toxicity ID ACTIVATED-RECEPTOR-ALPHA; LIVER-TUMOR-INDUCTION; BILE-ACID HOMEOSTASIS; PPAR-ALPHA; PROTEOMIC ANALYSIS; HEPATOCELLULAR-CARCINOMA; B6C3F1 MICE; WILD-TYPE; DICHLOROACETATE; SPECTROMETRY AB Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor alpha (PPAR alpha). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPAR alpha target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPAR alpha target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum. C1 [Fang, Zhong-Ze; Krausz, Kristopher W.; Tanaka, Naoki; Li, Fei; Qu, Aijuan; Idle, Jeffrey R.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov RI Li, Fei/F-6849-2013; OI Idle, Jeff/0000-0002-6143-1520 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 40 TC 14 Z9 15 U1 1 U2 29 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 EI 1432-0738 J9 ARCH TOXICOL JI Arch. Toxicol. PD NOV PY 2013 VL 87 IS 11 BP 1975 EP 1987 DI 10.1007/s00204-013-1053-1 PG 13 WC Toxicology SC Toxicology GA 235EW UT WOS:000325700300008 PM 23575800 ER PT J AU Reis, JP Launer, LJ Terry, JG Loria, CM Al Hazzouri, AZ Sidney, S Yaffe, K Jacobs, DR Whitlow, CT Zhu, N Carr, JJ AF Reis, Jared P. Launer, Lenore J. Terry, James G. Loria, Catherine M. Al Hazzouri, Adina Zeki Sidney, Stephen Yaffe, Kristine Jacobs, David R., Jr. Whitlow, Christopher T. Zhu, Na Carr, J. Jeffrey TI Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: The CARDIA study SO ATHEROSCLEROSIS LA English DT Article DE Atherosclerosis; Cognition; Subclinical disease; Risk factors ID CORONARY-ARTERY CALCIUM; DIABETES-MELLITUS; BLOOD-PRESSURE; DEMENTIA; ASSOCIATION; IMPAIRMENT; MIDLIFE; HEALTH; RISK AB Objective: Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults. Methods: This cross-sectional study included 2510 black and white adults (age: 43-55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010-11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory). Results: A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p < 0.05). Conclusions: In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging. Published by Elsevier Ireland Ltd. C1 [Reis, Jared P.; Loria, Catherine M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Terry, James G.; Whitlow, Christopher T.; Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [Al Hazzouri, Adina Zeki; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Sidney, Stephen] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Jacobs, David R., Jr.; Zhu, Na] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. RP Reis, JP (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10197, Bethesda, MD 20892 USA. EM reisjp@mail.nih.gov RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU National Heart, Lung, and Blood Institute [N01-HC95095, N01-HC48047, N01-HC48050, N01-HC48049, N01-HC48048, R01-HL098445] FX The Coronary Risk Development in Young Adults Study is conducted and supported by the National Heart, Lung, and Blood Institute (N01-HC95095, N01-HC48047, N01-HC48050, N01-HC48049, N01-HC48048, R01-HL098445). NR 29 TC 13 Z9 13 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD NOV PY 2013 VL 231 IS 1 BP 72 EP 77 DI 10.1016/j.atherosclerosis.2013.08.038 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 235XH UT WOS:000325755300014 PM 24125414 ER PT J AU Xia, D Esser, L Tang, WK Zhou, F Zhou, YH Yu, LD Yu, CA AF Xia, Di Esser, Lothar Tang, Wai-Kwan Zhou, Fei Zhou, Yihui Yu, Linda Yu, Chang-An TI Structural analysis of cytochrome bc(1) complexes: Implications to the mechanism of function SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Review DE Cytochrome bc(1) complex; Bifurcated electron flow; Mechanism of ubiquinol oxidation; Crystal structure; Control of ISP domain movement ID IRON-SULFUR PROTEIN; YEAST SACCHAROMYCES-CEREVISIAE; QUINOL OXIDATION SITE; MITOCHONDRIAL PROCESSING PEPTIDASE; BACTERIUM RHODOBACTER-SPHAEROIDES; ELECTRON-TRANSFER REACTIONS; BOVINE HEART-MITOCHONDRIA; WATER-SOLUBLE FRAGMENT; X-RAY-STRUCTURE; C REDUCTASE AB The cytochrome bc(1) complex (bc(1)) is the mid-segment of the cellular respiratory chain of mitochondria and many aerobic prokaryotic organisms: it is also part of the photosynthetic apparatus of non-oxygenic purple bacteria. The bc(1) complex catalyzes the reaction of transferring electrons from the low potential substrate ubiquinol to high potential cytochrome c. Concomitantly, bc(1) translocates protons across the membrane, contributing to the proton-motive force essential for a variety of cellular activities such as ATP synthesis. Structural investigations of bc(1) have been exceedingly successful, yielding atomic resolution structures of bc(1) from various organisms and trapped in different reaction intermediates. These structures have confirmed and unified results of decades of experiments and have contributed to our understanding of the mechanism of bc(1) functions as well as its inactivation by respiratory inhibitors. This article is part of a Special Issue entitled: Respiratory complex III and related bc complexes. Published by Elsevier B.V. C1 [Xia, Di; Esser, Lothar; Tang, Wai-Kwan; Zhou, Fei; Zhou, Yihui] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Yu, Linda; Yu, Chang-An] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Xia, D (reprint author), 37 Convent Dr Bldg 37,Room 2122C, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; NIH [GM 30721] FX We thank George Leiman for editorial assistance during the preparation of this manuscript This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and in part from an NIH grant (GM 30721) to CAY. NR 112 TC 27 Z9 28 U1 2 U2 41 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD NOV-DEC PY 2013 VL 1827 IS 11-12 SI SI BP 1278 EP 1294 DI 10.1016/j.bbabio.2012.11.008 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 232RA UT WOS:000325510500003 PM 23201476 ER PT J AU Dibrova, DV Cherepanov, DA Galperin, MY Skulachev, VP Mulkidjanian, AY AF Dibrova, Daria V. Cherepanov, Dmitry A. Galperin, Michael Y. Skulachev, Vladimir P. Mulkidjanian, Armen Y. TI Evolution of cytochrome bc complexes: From membrane-anchored dehydrogenases of ancient bacteria to triggers of apoptosis in vertebrates SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Review DE Bioenergetics, molecular evolution, ubiquinol: cytochrome c oxidoreductase; ubiquinone; plastoquinone; cytochrome c; cardiolipin, cell death, photosynthesis, apoptosome ID TARGETED PLASTOQUINONE DERIVATIVES; PURPLE PHOTOSYNTHETIC BACTERIA; TRANSMEMBRANE PROTON-TRANSFER; INNER MITOCHONDRIAL-MEMBRANE; ANAEROBIC AMMONIUM OXIDATION; UNIVERSAL COMMON ANCESTOR; OXYGEN SPECIES GENERATION; IRON-SULFUR PROTEIN; ACTIVATED Q-CYCLE; X-RAY-STRUCTURE AB This review traces the evolution of the cytochrome bc complexes from their early spread among prokaryotic lineages and up to the mitochondrial cytochrome bc(1) complex (complex III) and its role in apoptosis. The results of phylogenomic analysis suggest that the bacterial cytochrome b(6)f-type complexes with short cytochromes b were the ancient form that preceded in evolution the cytochrome bc(1)-type complexes with long cytochromes b. The common ancestor of the b(6)f-type and the bc(1)-type complexes probably resembled the b(6)f-type complexes found in Heliobacteriaceae and in some Planctomycetes. Lateral transfers of cytochrome bc operons could account for the several instances of acquisition of different types of bacterial cytochrome bc complexes by archaea. The gradual oxygenation of the atmosphere could be the key evolutionary factor that has driven further divergence and spread of the cytochrome bc complexes. On the one hand, oxygen could be used as a very efficient terminal electron acceptor. On the other hand, auto-oxidation of the components of the bc complex results in the generation of reactive oxygen species (ROS), which necessitated diverse adaptations of the b(6)f-type and bc(1)-type complexes, as well as other, functionally coupled proteins. A detailed scenario of the gradual involvement of the cardiolipin-containing mitochondrial cytochrome bc(1) complex into the intrinsic apoptotic pathway is proposed, where the functioning of the complex as an apoptotic trigger is viewed as a way to accelerate the elimination of the cells with irreparably damaged, ROS-producing mitochondria. This article is part of a Special Issue entitled: Respiratory complex III and related bc complexes. (C) 2013 Elsevier B.V. All rights reserved. C1 [Dibrova, Daria V.; Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Dibrova, Daria V.; Skulachev, Vladimir P.; Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, Sch Bioengn & Bioinformat, Moscow 119992, Russia. [Dibrova, Daria V.] Moscow MV Lomonosov State Univ, Inst Mitoengn, Moscow 119992, Russia. [Cherepanov, Dmitry A.] RAS, AN Frumkin Electrochem Inst, Moscow 119991, Russia. [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Skulachev, Vladimir P.; Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119991, Russia. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. EM amulkid@uos.de RI Mulkidjanian, Armen/J-8086-2013; Cherepanov, Dmitry/R-8391-2016; OI Mulkidjanian, Armen/0000-0001-5844-3064; Galperin, Michael/0000-0002-2265-5572 FU Deutsche Forschungsgemeinschaft [DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1]; COST Action of the EU [CM0902]; Russian Government [02.740.11.5228]; Deutscher Akademischer Austausch Dienst; Russian Foundation for Basic Research [RFBR 0-04-91331]; Intramural Research Program of the NIH at the National Library of Medicine FX Very useful discussions with Drs. D. Frishman, E.V. Koonin, K.S. Makarova and Y.I. Wolf are greatly appreciated. Of a particularly value for us was the suggestion of Dr. A.V. Bogachev on the emergence of first high-potential electron acceptors in the framework of biogenic photosynthesis. We are grateful to an anonymous Reviewer for pointing out the binding of the cn heme in the b6f-type complexes by the CXGG motif. This study was supported by the Mitoengineering Institute, Moscow, Russia and grants from the Deutsche Forschungsgemeinschaft (DFG-Mu-1285/1-10, DFG-436-RUS 113/963/0-1), the COST Action CM0902 of the EU and the Russian Government ( 02.740.11.5228) to A.Y.M., from the Deutscher Akademischer Austausch Dienst to D.V.D. and from the Russian Foundation for Basic Research (RFBR 0-04-91331) to V.P.S. M.Y.G is supported by the Intramural Research Program of the NIH at the National Library of Medicine. NR 238 TC 33 Z9 34 U1 3 U2 44 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 EI 0006-3002 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD NOV-DEC PY 2013 VL 1827 IS 11-12 SI SI BP 1407 EP 1427 DI 10.1016/j.bbabio.2013.07.006 PG 21 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 232RA UT WOS:000325510500014 PM 23871937 ER PT J AU Suarez, C Welsch, S Chlanda, P Hagen, W Hoppe, S Kolovou, A Pagnier, I Raoult, D Locker, JK AF Suarez, Cristina Welsch, Sonja Chlanda, Petr Hagen, Wim Hoppe, Simone Kolovou, Androniki Pagnier, Isabelle Raoult, Didier Locker, Jacomine Krijnse TI Open membranes are the precursors for assembly of large DNA viruses SO CELLULAR MICROBIOLOGY LA English DT Article ID VACCINIA VIRUS; INTERMEDIATE COMPARTMENT; ENDOPLASMIC-RETICULUM; GIANT MIMIVIRUS; NONENVELOPED VIRUSES; MELTING-POT; AMEBAS; MICROORGANISMS; MORPHOGENESIS; PENETRATION AB Nucleo cytoplasmic large DNA viruses (NCLDVs) are a group of double-stranded DNA viruses that replicate their DNA partly or entirely in the cytoplasm in association with viral factories (VFs). They share about 50 genes suggesting that they are derived from a common ancestor. Using transmission electron microscopy (TEM) and electron tomography (ET) we showed that the NCLDV vaccinia virus (VACV) acquires its membrane from open membrane intermediates, derived from the ER. These open membranes contribute to the formation of a single open membrane of the immature virion, shaped into a sphere by the assembly of the viral scaffold protein on its convex side. We now compare VACV with the NCLDV Mimivirus by TEM and ET and show that the latter also acquires its membrane from open membrane intermediates that accumulate at the periphery of the cytoplasmic VF. In analogy to VACV this membrane is shaped by the assembly of a layer on the convexside of its membrane, likely representing the Mimivirus capsid protein. By quantitative ET we show for both viruses that the open membrane intermediates of assembly adopt an open-eight' conformation with a characteristic diameter of 90nm for Mimi- and 50nm for VACV. We discuss these results with respect to the common ancestry of NCLDVs and propose a hypothesis on the possible origin of this unusual membrane biogenesis. C1 [Suarez, Cristina; Hoppe, Simone; Kolovou, Androniki; Locker, Jacomine Krijnse] Heidelberg Univ, Electron Microscopy Core Facil, D-69120 Heidelberg, Germany. [Suarez, Cristina; Hoppe, Simone; Kolovou, Androniki; Locker, Jacomine Krijnse] Heidelberg Univ, Dept Infect Dis, D-69120 Heidelberg, Germany. [Welsch, Sonja; Hagen, Wim] European Mol Biol Lab, Struct & Computat Biol Program, D-69120 Heidelberg, Germany. [Chlanda, Petr] NICHHD, NIH, Bethesda, MD 20892 USA. [Pagnier, Isabelle; Raoult, Didier] Aix Marseille Univ, URMITE, UMR CNRS 7278, IRD 198,INSERM 1095,Fac Med, Marseille, France. RP Locker, JK (reprint author), Heidelberg Univ, Electron Microscopy Core Facil, Neuenheimer Feld 267, D-69120 Heidelberg, Germany. EM jacomine.krijnse@bioquant.uni-heidelberg.de OI Pagnier, Isabelle/0000-0002-1724-3450 FU priority programme SPP1175 of the German scientific research foundation (DFG); cluster of excellence CellNetworks FX This work was funded by the priority programme SPP1175 of the German scientific research foundation (DFG). We also thank the electron microscopy core facility of the Heidelberg university and their staff for technical as well as the cluster of excellence CellNetworks for financial support. NR 40 TC 13 Z9 13 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD NOV PY 2013 VL 15 IS 11 BP 1883 EP 1895 DI 10.1111/cmi.12156 PG 13 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 233CD UT WOS:000325541700008 PM 23751082 ER PT J AU Inouchi, M Matsumoto, R Taki, J Kikuchi, T Mitsueda-Ono, T Mikuni, N Wheaton, L Hallett, M Fukuyama, H Shibasaki, H Takahashi, R Ikeda, A AF Inouchi, Morito Matsumoto, Riki Taki, Junya Kikuchi, Takayuki Mitsueda-Ono, Takahiro Mikuni, Nobuhiro Wheaton, Lewis Hallett, Mark Fukuyama, Hidenao Shibasaki, Hiroshi Takahashi, Ryosuke Ikeda, Akio TI Role of posterior parietal cortex in reaching movements in humans: Clinical implication for 'optic ataxia' SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Bereitschaftspotential; Cortical electrical stimulation; Optic ataxia; Posterior parietal cortex; Reaching ID TRANSCRANIAL MAGNETIC STIMULATION; POSITRON-EMISSION-TOMOGRAPHY; SUPPLEMENTARY MOTOR AREA; FUNCTIONAL-ANATOMY; FRONTAL-CORTEX; HUMAN BRAIN; PARIETOOCCIPITAL CORTEX; EFFECTOR INFORMATION; VOLUNTARY MOVEMENTS; ONLINE ADJUSTMENTS AB Objective: To clarify the spatio-temporal profile of cortical activity related to reaching movement in the posterior parietal cortex (PPC) in humans. Methods: Four patients with intractable partial epilepsy who underwent subdural electrode implantation were studied as a part of pre-surgical evaluation. We investigated the Bereitschaftspotential (BP) associated with reaching and correlated the findings with the effect of electrical stimulation of the same cortical area. Results: BPs specific for reaching, as compared with BPs for simple movements by the hand or arm contralateral to the implanted hemisphere, were recognized in all patients, mainly around the intraparietal sulcus (IPS), the superior parietal lobule (SPL) and the precuneus. BPs near the IPS had the earlier onset than BPs in the SPL. Electrical stimulation of a part of the PPC, where the reach-specific BPs were recorded, selectively impaired reaching. Conclusions: Intracranial BP recording and cortical electrical stimulation delineated human reach-related areas in the PPC. Significance: The present study for the first time by direct cortical recording in humans demonstrates that parts of the cortices around the IPS and SPL play a crucial role in visually-guided reaching. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Inouchi, Morito; Matsumoto, Riki; Mitsueda-Ono, Takahiro; Shibasaki, Hiroshi; Takahashi, Ryosuke; Ikeda, Akio] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068507, Japan. [Taki, Junya; Kikuchi, Takayuki; Mikuni, Nobuhiro] Kyoto Univ, Grad Sch Med, Dept Neurosurg, Kyoto 6068507, Japan. [Fukuyama, Hidenao] Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto 6068507, Japan. [Taki, Junya] Tenri Hosp, Dept Neurosurg, Tenri, Nara 632, Japan. [Mitsueda-Ono, Takahiro] Otsu Red Cross Hosp, Dept Neurol, Otsu, Shiga, Japan. [Mikuni, Nobuhiro] Sapporo Med Univ, Dept Neurosurg, Sapporo, Hokkaido, Japan. [Wheaton, Lewis] Georgia Inst Technol, Sch Appl Physiol, Atlanta, GA 30332 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Ikeda, A (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, 54 Shogoin Kawaharacho, Kyoto 6068507, Japan. EM akio@kuhp.kyoto-u.ac.jp RI Matsumoto, Riki/I-8397-2016; OI Matsumoto, Riki/0000-0003-3985-9210; Ikeda, Akio/0000-0002-0790-2598; Wheaton, Lewis/0000-0003-0771-0294 FU Research Grant for Nervous and Mental Disorders from the Ministry of Health and Welfare [22A-6]; Research Grant from the Japan Epilepsy Research Foundation FX This work was supported by The Research Grant for Nervous and Mental Disorders (22A-6) from the Ministry of Health and Welfare, The Research Grant from the Japan Epilepsy Research Foundation (2009-2010) and Grants-in-Aid for Scientific Research NR 79 TC 3 Z9 3 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD NOV PY 2013 VL 124 IS 11 BP 2230 EP 2241 DI 10.1016/j.clinph.2013.05.011 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 236FE UT WOS:000325779800021 PM 23831168 ER PT J AU Berger, VW AF Berger, Vance W. TI CORR Insights(A (R)): Have Levels of Evidence Improved the Quality of Orthopaedic Research? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material ID RANDOMIZED CLINICAL-TRIALS; SELECTION C1 NCI, Canc Prevent Div, Rockville, MD 20850 USA. RP Berger, VW (reprint author), NCI, Canc Prevent Div, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM vb78c@nih.gov NR 8 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD NOV PY 2013 VL 471 IS 11 BP 3687 EP 3688 DI 10.1007/s11999-013-3203-4 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 231ND UT WOS:000325422700045 PM 23904248 ER PT J AU Osman, J Galli, S Hanafy, M Tang, X Ahmed, A AF Osman, J. Galli, S. Hanafy, M. Tang, X. Ahmed, A. TI Identification of novel biomarkers in neuroblastoma associated with the risk for bone marrow metastasis: a pilot study SO CLINICAL & TRANSLATIONAL ONCOLOGY LA English DT Article DE Neuroblastoma; Nestin; XIAP; VEGF; Immunohistochemistry ID ENDOTHELIAL GROWTH-FACTOR; ANGIOGENIC FACTORS; NESTIN EXPRESSION; GENE-EXPRESSION; CELLS; TUMORS; PROGRESSION; INHIBITOR; APOPTOSIS; PATHWAYS AB Neuroblastoma is a common pediatric neoplasm with variable histopathological features that carry an inherent risk of developing distant metastases, in particular bone marrow metastasis. Nestin, X-linked inhibitor of apoptosis (XIAP) and vascular growth factors (VEGF) are biomarkers that are implicated in the tumorigenesis of various cancers. We studied the expression of these biomarkers in neuroblastoma, in relation to bone marrow (BM) metastasis and other histologic parameters. Patients with neuroblastoma included seven with BM metastasis and 12 with non-metastatic tumors. Slides from the primary tumors were immunostained with antibodies against nestin, XIAP, VEGF-A, VEGF-B, VEGF-D, VEGF-R1, and VEGF-R2. Immunostaining results were evaluated by two pathologists, graded and statistically correlated with the risk of developing BM metastasis. Nestin was expressed in 16/19 cases with no significant difference between patients with BM metastasis and those without BM metastasis. XIAP was identified in 18/19 tumor cases; the staining density was significantly lower in patients with bone marrow metastasis and those with unfavorable histology. VEGF-R1, VEGF-R2, and VEGF-B were expressed while VEGF-A and VEGF-D were not. Significantly, higher expression of VEGF-B was noted in patients with BM metastasis. Expression of VEGF-B and XIAP in neuroblastoma may play a role in the development of bone marrow metastasis. Given the limited number of patients in this study, a larger cohort is needed to validate these findings. C1 [Osman, J.; Hanafy, M.; Tang, X.] Arkansas Childrens Hosp, Dept Pathol, Little Rock, AR 72202 USA. [Galli, S.] NCI, NIH, Bethesda, MD 20892 USA. [Ahmed, A.] Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA. RP Ahmed, A (reprint author), Childrens Mercy Hosp & Clin, 2401 Gillham Rd, Kansas City, MO 64108 USA. EM aahmed@cmh.edu OI Ahmed, Atif/0000-0002-8791-5785 NR 27 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1699-048X EI 1699-3055 J9 CLIN TRANSL ONCOL JI Clin. Transl. Oncol. PD NOV PY 2013 VL 15 IS 11 BP 953 EP 958 DI 10.1007/s12094-013-1030-4 PG 6 WC Oncology SC Oncology GA 235BQ UT WOS:000325690100014 PM 23553333 ER PT J AU Tumaini, B Lee, DW Lin, TS Castiello, L Stroncek, DF Mackall, C Wayne, A Sabatino, M AF Tumaini, Barbara Lee, Daniel W. Lin, Tasha Castiello, Luciano Stroncek, David F. Mackall, Crystal Wayne, Alan Sabatino, Marianna TI Simplified process for the production of anti-CD19-CAR-engineered T cells SO CYTOTHERAPY LA English DT Article DE adoptive cellular immunotherapy; CD19 antigen; genetic engineering; genetic transduction; precursor cell lymphoblastic leukemia-lymphoma ID CHIMERIC-ANTIGEN-RECEPTOR; RETROVIRAL GENE MARKING; METASTATIC MELANOMA; CANCER REGRESSION; ANTITUMOR LYMPHOCYTES; CD19 ANTIGEN; THERAPY; ANTIBODY; IMMUNOTHERAPY; LYMPHOMA AB Background aims. Adoptive immunotherapy with the use of chimeric antigen receptor (CAR)-engineered T cells specific for CD 19 has shown promising results for the treatment of B-cell lymphomas and leukemia. This therapy involves the transduction of autologous T cells with a viral vector and the subsequent cell expansion. We describe a new, simplified method to produce anti-CD 19-CAR T cells. Methods. T cells were isolated from peripheral blood mononuclear cell (PBMC) with anti-CD3/anti-CD28 paramagnetic beads. After 2 days, the T cells were added to culture bags pre-treated with RetroNectin and loaded with the retroviral anti-CD 19 CAR vector. The cells, beads and vector were incubated for 24 h, and a second transduction was then performed. No spinoculation was used. Cells were then expanded for an additional 9 days. Results. The method was validated through the use of two PBMC products from a patient with B-cell chronic lymphoblastic leukemia and one PBMC product from a healthy subject. The two PBMC products from the patient with B-cell chronic lymphoblastic leukemia contained 11.4% and 12.9% T cells. The manufacturing process led to final products highly enriched in T cells with a mean CD3+ cell content of 98%, a mean expansion of 10.6-fold and a mean transduction efficiency of 68%. Similar results were obtained from the PBMCs of the first four patients with acute lymphoblastic leukemia treated at our institution. Conclusions. We developed a simplified, semi-closed system for the initial selection, activation, transduction and expansion of T cells with the use of anti-CD3/anti-CD28 beads and bags to produce autologous anti-CD19 CAR transduced T cells to support an ongoing clinical trial. C1 [Tumaini, Barbara; Castiello, Luciano; Stroncek, David F.; Sabatino, Marianna] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Lee, Daniel W.; Lin, Tasha; Mackall, Crystal; Wayne, Alan] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Sabatino, M (reprint author), NIH, Dept Transfus Med, Cell Proc Sect, 10 Ctr Dr MSC 1288,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM sabatinom@cc.nih.gov RI Castiello, Luciano/K-8616-2016 OI Castiello, Luciano/0000-0001-7146-3158 FU Intramural Research Program of the National Institutes of Health, Clinical Center; National Cancer Institute FX The authors would like to thank Dr Steven A. Rosenberg for providing clinical grade vector. This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center and National Cancer Institute. NR 29 TC 15 Z9 16 U1 0 U2 17 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD NOV PY 2013 VL 15 IS 11 BP 1406 EP 1415 DI 10.1016/j.jcyt.2013.06.003 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 235PI UT WOS:000325732800010 PM 23992830 ER PT J AU Koulaouzidis, A Karargyris, A Rondonotti, E Noble, CL Douglas, S Alexandridis, E Zahid, AM Bathgate, AJ Trimble, KC Plevris, JN AF Koulaouzidis, Anastasios Karargyris, Alexandros Rondonotti, Emanuele Noble, Colin L. Douglas, Sarah Alexandridis, Efstratios Zahid, Ali M. Bathgate, Andrew J. Trimble, Ken C. Plevris, John N. TI Three-dimensional representation software as image enhancement tool in small-bowel capsule endoscopy: A feasibility study SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Capsule endoscopy; Enhancement; Feasibility; Inflammatory; Polyps; Reconstruction; Small bowel; Software; Three-dimensional; Vascular ID VIRTUAL CHROMOENDOSCOPY; RECONSTRUCTION; SHAPE; LESIONS AB Background: Three-dimensional imaging in capsule endoscopy is not currently feasible due to hardware limitations. However, software algorithms that enable three-dimensional reconstruction in capsule endoscopy are available. Methods: Feasibility study. A phantom was designed to test the accuracy of three-dimensional reconstruction. Thereafter, 192 small-bowel capsule endoscopy images (of vascular: 50; inflammatory: 73; protruding structures: 69) were reviewed with the aid of a purpose-built three-dimensional reconstruction software. Seven endoscopists rated visualisation improved or non-improved. Subgroup analyses performed for diagnostic category, diagnosis, image surface morphology and colour and SBCE equipment used (PillCam (R) vs. MiroCam (R)). Results: Overall, phantom experiments showed that the three-dimensional reconstruction software was accurate at 90% of red, 70% of yellow and 45% of white phantom models. Enhanced visualisation for 56% of vascular, 23% of inflammatory and <10% of protruding structures was noted (P = 0.007, 0.172 and 0.008, respectively). Furthermore, three-dimensional software application enhanced 53.7% of red, 21.8% of white, 17.3% of red and white, and 9.2% of images of lesions with colour similar to that of the surrounding mucosa, P < 0.0001. Conclusions: Application of a three-dimensional reconstruction software in capsule endoscopy leads to image enhancement for a significant proportion of vascular, but less so for inflammatory and protruding lesions. Until optics technology allows hardware-enabled three-dimensional reconstruction, it seems a plausible alternative. Crown Copyright (C) 2013 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. All rights reserved. C1 [Koulaouzidis, Anastasios; Douglas, Sarah; Alexandridis, Efstratios; Zahid, Ali M.; Bathgate, Andrew J.; Trimble, Ken C.; Plevris, John N.] Royal Infirm, Ctr Liver & Digest Disorders, Edinburgh EH16 4SA, Midlothian, Scotland. [Karargyris, Alexandros] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Rondonotti, Emanuele] Osped Valduce, Gastroenterol Unit, Como, Italy. [Noble, Colin L.] Western Gen Hosp, Gastrointestinal Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Plevris, John N.] Univ Edinburgh, Sch Med, Edinburgh, Midlothian, Scotland. RP Koulaouzidis, A (reprint author), Royal Infirm, Endoscopy Unit, 51 Little France Crescent,Old Dalkeith Rd, Edinburgh EH16 4SA, Midlothian, Scotland. EM akoulaouzidis@hotmail.com FU Given Imaging Ltd., Germany; Fujinong FX Dr A. Koulaouzidis has received research support from Given Imaging Ltd., Germany (Given (R) Imaging-ESGE Research Grant 2011), unrelated though to the present work.; Dr E. Alexandridis has received research support from Fujinong, unrelated to present work. NR 24 TC 12 Z9 12 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD NOV PY 2013 VL 45 IS 11 BP 909 EP 914 DI 10.1016/j.dld.2013.05.013 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 233YE UT WOS:000325604700009 PM 23849802 ER PT J AU Chowell, G Viboud, C AF Chowell, Gerardo Viboud, Cecile TI Lessons Learned from Case Fatality Risk Estimates of 2009 Pandemic Influenza SO EPIDEMIOLOGY LA English DT Editorial Material ID A H1N1 VIRUS; CIRCULATION; INFECTION; MORTALITY; SEVERITY; A/H1N1 C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, 900 S Cady Mall,Rm 233, Tempe, AZ 85287 USA. EM gchowell@asu.edu FU Intramural NIH HHS [Z99 TW999999] NR 17 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2013 VL 24 IS 6 BP 842 EP 844 DI 10.1097/01.ede.0000434434.52506.bc PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 232YH UT WOS:000325530100007 PM 24076991 ER PT J AU Li, D Longnecker, MP Dunson, DB AF Li, Daniel Longnecker, Matthew P. Dunson, David B. TI Lipid Adjustment for Chemical Exposures Accounting for Concomitant Variables SO EPIDEMIOLOGY LA English DT Article ID ADIPOSE-TISSUE; BREAST-CANCER; HUMAN HEALTH; HUMAN-SERUM; POLYCHLORINATED-BIPHENYLS; ORGANOCHLORINE COMPOUNDS; PCB CONGENERS; CORD-BLOOD; WOMEN; RISK AB Background: Some environmental chemical exposures are lipophilic and need to be adjusted by serum lipid levels before data analyses. There are currently various strategies that attempt to account for this problem, but all have their drawbacks. To address such concerns, we propose a new method that uses Box-Cox transformations and a simple Bayesian hierarchical model to adjust for lipophilic chemical exposures. Methods: We compared our Box-Cox method to existing methods. We ran simulation studies in which increasing levels of lipid-adjusted chemical exposure did and did not increase the odds of having a disease, and we looked at both single-exposure and multiple-exposure cases. We also analyzed an epidemiology dataset that examined the effects of various chemical exposure on the risk of birth defects. Results: Compared with existing methods, our Box-Cox method produced unbiased estimates, good coverage, similar power, and lower type I error rates. This was the case in both single- and multiple-exposure simulation studies. Results from analysis of the birth-defect data differed from results using existing methods. Conclusion: Our Box-Cox method is a novel and intuitive way to account for the lipophilic nature of certain chemical exposures. It addresses some of the problems with existing methods, is easily extendable to multiple exposures, and can be used in any analysis that involves concomitant variables. C1 [Li, Daniel; Dunson, David B.] Duke Univ, Dept Stat Sci, Durham, NC 27708 USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), Duke Univ, Box 90251, Durham, NC 27708 USA. EM dunson@stat.duke.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health [R01 ES 017240]; NIEHS FX This research was supported by grant R01 ES 017240 from the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health and supported in part by intramural funds from NIEHS. NR 26 TC 5 Z9 5 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2013 VL 24 IS 6 BP 921 EP 928 DI 10.1097/EDE.0b013e3182a671e4 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 232YH UT WOS:000325530100018 PM 24051893 ER PT J AU Hoover, RN Fraumeni, JF AF Hoover, Robert N. Fraumeni, Joseph F., Jr. TI A Conversation with Joseph F. Fraumeni, Jr. SO EPIDEMIOLOGY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; CANCER SUSCEPTIBILITY LOCI; LUNG-CANCER; FAMILIAL SYNDROME; BREAST-CANCER; NEOPLASMS; ANIRIDIA; SARCOMAS; SMOKING; TUMOR C1 [Hoover, Robert N.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Hoover, RN (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7E-584 MSC 9773, Bethesda, MD USA. EM hooverr@mail.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD NOV PY 2013 VL 24 IS 6 BP 929 EP 933 DI 10.1097/EDE.0b013e3182a56987 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 232YH UT WOS:000325530100019 ER PT J AU Siddiqui, MM Rais-Bahrami, S Truong, H Stamatakis, L Vourganti, S Nix, J Hoang, AN Walton-Diaz, A Shuch, B Weintraub, M Kruecker, J Amalou, H Turkbey, B Merino, MJ Choyke, PL Wood, BJ Pinto, PA AF Siddiqui, M. Minhaj Rais-Bahrami, Soroush Hong Truong Stamatakis, Lambros Vourganti, Srinivas Nix, Jeffrey Hoang, Anthony N. Walton-Diaz, Annerleim Shuch, Brian Weintraub, Michael Kruecker, Jochen Amalou, Hayet Turkbey, Baris Merino, Maria J. Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI Magnetic Resonance Imaging/Ultrasound-Fusion Biopsy Significantly Upgrades Prostate Cancer Versus Systematic 12-core Transrectal Ultrasound Biopsy SO EUROPEAN UROLOGY LA English DT Article DE Image-guided biopsy; Targeted biopsy; Magnetic resonance imaging; Prostate cancer; Prostatic neoplasms/diagnosis; Prostatic neoplasms/pathology; Prostatic neoplasms/; ultrasonography ID GLEASON SCORE; ACCURACY AB Background: Gleason scores from standard, 12-core prostate biopsies are upgraded historically in 25-33% of patients. Multiparametric prostate magnetic resonance imaging (MP-MRI) with ultrasound (US)-targeted fusion biopsy may better sample the true gland pathology. Objective: The rate of Gleason score upgrading from an MRI/US-fusion-guided prostate-biopsy platform is compared with a standard 12-core biopsy regimen alone. Design, setting, and participants: There were 582 subjects enrolled from August 2007 through August 2012 in a prospective trial comparing systematic, extended 12-core transrectal ultrasound biopsies to targeted MRI/US-fusion-guided prostate biopsies performed during the same biopsy session. Outcome measurements and statistical analysis: The highest Gleason score from each biopsy method was compared. Interventions: An MRI/US-fusion-guided platform with electromagnetic tracking was used for the performance of the fusion-guided biopsies. Results and limitations: A diagnosis of prostate cancer (PCa) was made in 315 (54%) of the patients. Addition of targeted biopsy led to Gleason upgrading in 81 (32%) cases. Targeted biopsy detected 67% more Gleason >= 4 + 3 tumors than 12-core biopsy alone and missed 36% of Gleason <= 3 + 4 tumors, thus mitigating the detection of lower-grade disease. Conversely, 12-core biopsy led to upgrading in 67 (26%) cases over targeted biopsy alone but only detected 8% more Gleason >= 4 + 3 tumors. On multivariate analysis, MP-MRI suspicion was associated with Gleason score upgrading in the targeted lesions (p < 0.001). The main limitation of this study was that definitive pathology from radical prostatectomy was not available. Conclusions: MRI/US-fusion-guided biopsy upgrades and detects PCa of higher Gleason score in 32% of patients compared with traditional 12-core biopsy alone. Targeted biopsy technique preferentially detects higher-grade PCa while missing lower-grade tumors. (C) 2013 Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Siddiqui, M. Minhaj; Rais-Bahrami, Soroush; Hong Truong; Stamatakis, Lambros; Vourganti, Srinivas; Nix, Jeffrey; Hoang, Anthony N.; Walton-Diaz, Annerleim; Shuch, Brian; Weintraub, Michael; Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Amalou, Hayet; Wood, Bradford J.; Pinto, Peter A.] NCI, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Kruecker, Jochen] Philips Res North Amer, Briarcliff Manor, NY USA. [Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1210,Bldg 10,CRC Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research; NIH; Pfizer Inc; Leona M. and Harry B. Helmsley Charitable Trust; Howard Hughes Medical Institute FX This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. This research was also made possible through the 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 Web site at http://www.fnih.org/work/programs-development/medical-research-scholars- program. NR 16 TC 183 Z9 188 U1 3 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD NOV PY 2013 VL 64 IS 5 BP 713 EP 719 DI 10.1016/j.eururo.2013.05.059 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 232FT UT WOS:000325478100011 PM 23787357 ER PT J AU Addolorato, G Mirijello, A Leggio, L AF Addolorato, Giovanni Mirijello, Antonio Leggio, Lorenzo TI Alcohol addiction: toward a patient-oriented pharmacological treatment SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Editorial Material DE alcohol use disorder; drug treatment ID DEPENDENT PATIENTS; NALTREXONE RESPONSE; CONTROLLED-TRIAL; DOUBLE-BLIND; BACLOFEN; SAFETY; ONDANSETRON; ABSTINENCE; EFFICACY AB Very few medications (i.e., disulfiram, naltrexone and acamprosate) are approved for the treatment of alcoholism and their effects are suboptimal. The development of new effective and safe pharmacological agents to treat alcoholic patients is crucial, together with the need to identify predictors of outcomes in different subsets of patients. C1 [Addolorato, Giovanni; Mirijello, Antonio] Univ Cattolica Sacro Cuore, Dept Internal Med, Gemelli Hosp, I-00168 Rome, Italy. [Leggio, Lorenzo] NIAAA, Sect Clin Psychoneuroendocrinol & Neuropsychophar, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. [Leggio, Lorenzo] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Leggio, Lorenzo] Brown Univ, Dept Behav & Social Sci, Providence, RI 02912 USA. RP Addolorato, G (reprint author), Univ Cattolica Sacro Cuore, Dept Internal Med, I-00168 Rome, Italy. EM g.addolorato@rm.unicatt.it RI Leggio, Lorenzo/M-2972-2016; Mirijello, Antonio/C-4103-2017; OI Mirijello, Antonio/0000-0003-3932-3803; Addolorato, Giovanni/0000-0002-1522-9946 FU Intramural NIH HHS [Z99 AA999999] NR 14 TC 6 Z9 6 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD NOV PY 2013 VL 14 IS 16 BP 2157 EP 2160 DI 10.1517/14656566.2013.834047 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 232UZ UT WOS:000325521200001 PM 23984836 ER PT J AU Aliaga, L Lai, C Yu, J Chub, N Shim, H Sun, LX Xie, CS Yang, WJ Lin, X O'Donovan, MJ Cai, HB AF Aliaga, Leonardo Lai, Chen Yu, Jia Chub, Nikolai Shim, Hoon Sun, Lixin Xie, Chengsong Yang, Wan-Jou Lin, Xian O'Donovan, Michael J. Cai, Huaibin TI Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons SO HUMAN MOLECULAR GENETICS LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; CEREBRAL-CORTEX; EPH RECEPTORS; MICE; STRESS; DEGENERATION; MUTANT; CORD; ER; AGGREGATION AB The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings provide new pathophysiological mechanisms of P56S VAPB that differentially affect the function and survival of CSMNs and SMNs in ALS8. C1 [Aliaga, Leonardo; Lai, Chen; Yu, Jia; Shim, Hoon; Sun, Lixin; Xie, Chengsong; Yang, Wan-Jou; Lin, Xian; Cai, Huaibin] NIA, Transgen Sect, Neurogenet Lab, Bethesda, MD 20892 USA. [Chub, Nikolai; O'Donovan, Michael J.] NINDS, Dev Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. RP Cai, HB (reprint author), NIA, Transgen Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI Yu, Jia/J-2792-2014; o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 FU National Institute on Aging [AG000943]; National Institute of Neurological Disorders and Stroke at NIH FX This work was supported in part by the intramural research programs of National Institute on Aging (AG000943, H. C.) and National Institute of Neurological Disorders and Stroke at NIH. L. A. was an Howard Hugh Medical Institute Scholar. NR 36 TC 17 Z9 17 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2013 VL 22 IS 21 BP 4293 EP 4305 DI 10.1093/hmg/ddt279 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 236CN UT WOS:000325771500005 PM 23771029 ER PT J AU Bian, L Traurig, M Hanson, RL Marinelarena, A Kobes, S Muller, YL Malhotra, A Huang, K Perez, J Gale, A Knowler, WC Bogardus, C Baier, LJ AF Bian, Li Traurig, Michael Hanson, Robert L. Marinelarena, Alejandra Kobes, Sayuko Muller, Yunhua L. Malhotra, Alka Huang, Ke Perez, Jessica Gale, Alex Knowler, William C. Bogardus, Clifton Baier, Leslie J. TI MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECENT SEGMENTAL DUPLICATIONS; NONOBESE PIMA-INDIANS; LARGE GENE LISTS; ADIPOCYTE DIFFERENTIATION; HUMAN-GENOME; INCREASED EXPRESSION; FEEDING-BEHAVIOR; FOOD-INTAKE; OBESITY; KINASE AB To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P 6.7 10(7) and 8.1 10(7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P 10(2)10(5)), and the combined P-values across both American Indians and Caucasian were P 10(4)10(9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation. C1 NIDDK, Diabet Mol Genet Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85004 USA. RP Baier, LJ (reprint author), NIDDK, Diabet Mol Genet Sect, NIH, 455 North 5th St, Phoenix, AZ 85004 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; NIDDK, NIH FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Funding to pay the Open Access publication charges for this article was provided by The Intramural Program of NIDDK, NIH. NR 51 TC 9 Z9 9 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2013 VL 22 IS 21 BP 4438 EP 4449 DI 10.1093/hmg/ddt291 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 236CN UT WOS:000325771500018 PM 23825110 ER PT J AU Gonzalez-Perez, M Marino-Ramirez, L Parra-Lopez, CA Murcia, MI Marquina, B Mata-Espinoza, D Rodriguez-Miguez, Y Baay-Guzman, GJ Huerta-Yepez, S Hernandez-Pando, R AF Gonzalez-Perez, Monica Marino-Ramirez, Leonardo Parra-Lopez, Carlos Alberto Murcia, Martha Isabel Marquina, Brenda Mata-Espinoza, Dulce Rodriguez-Miguez, Yadira Baay-Guzman, Guillermina J. Huerta-Yepez, Sara Hernandez-Pando, Rogelio TI Virulence and Immune Response Induced by Mycobacterium avium Complex Strains in a Model of Progressive Pulmonary Tuberculosis and Subcutaneous Infection in BALB/c Mice SO INFECTION AND IMMUNITY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NON-HIV PATIENTS; NONTUBERCULOUS MYCOBACTERIA; MURINE MODEL; SP-NOV.; IDENTIFICATION; PATHOGENESIS; COLOMBIENSE; MACROPHAGES; DISEASE AB The genus Mycobacterium comprises more than 150 species, including important pathogens for humans which cause major public health problems. The vast majority of efforts to understand the genus have been addressed in studies with Mycobacterium tuberculosis. The biological differentiation between M. tuberculosis and nontuberculous mycobacteria (NTM) is important because there are distinctions in the sources of infection, treatments, and the course of disease. Likewise, the importance of studying NTM is not only due to its clinical significance but also due to the mechanisms by which some species are pathogenic while others are not. Mycobacterium avium complex (MAC) is the most important group of NTM opportunistic pathogens, since it is the second largest medical complex in the genus after the M. tuberculosis complex. Here, we evaluated the virulence and immune response of M. avium subsp. avium and Mycobacterium colombiense, using experimental models of progressive pulmonary tuberculosis and subcutaneous infection in BALB/c mice. Mice infected intratracheally with a high dose of MAC strains showed high expression of tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase with rapid bacillus elimination and numerous granulomas, but without lung consolidation during late infection in coexistence with high expression of anti-inflammatory cytokines. In contrast, subcutaneous infection showed high production of the proinflammatory cytokines TNF-alpha and gamma interferon with relatively low production of anti-inflammatory cytokines such as interleukin-10 (IL-10) or IL-4, which efficiently eliminate the bacilli but maintain extensive inflammation and fibrosis. Thus, MAC infection evokes different immune and inflammatory responses depending on the MAC species and affected tissue. C1 [Gonzalez-Perez, Monica; Marino-Ramirez, Leonardo; Parra-Lopez, Carlos Alberto; Murcia, Martha Isabel] Univ Nacl Colombia, Sch Med, Dept Microbiol, Bogota, Colombia. [Gonzalez-Perez, Monica; Marquina, Brenda; Mata-Espinoza, Dulce; Rodriguez-Miguez, Yadira; Hernandez-Pando, Rogelio] Natl Inst Med Sci & Nutr, Dept Pathol, Expt Pathol Sect, Mexico City, DF, Mexico. [Marino-Ramirez, Leonardo] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Gonzalez-Perez, Monica; Marino-Ramirez, Leonardo] PanAmer Bioinformat Inst, Santa Marta, Magdalena, Colombia. [Baay-Guzman, Guillermina J.; Huerta-Yepez, Sara] Pediat Hosp Mexico Federico Gomez, Oncol Res Unit, Mexico City, DF, Mexico. RP Hernandez-Pando, R (reprint author), Natl Inst Med Sci & Nutr, Dept Pathol, Expt Pathol Sect, Mexico City, DF, Mexico. EM rhdezpando@hotmail.com OI Marino-Ramirez, Leonardo/0000-0002-5716-8512 FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; National Center for Biotechnology Information; CONACyT [84456]; National University of Colombia [15129] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, National Center for Biotechnology Information, and CONACyT (grant 84456). M.G.-P. was supported by the National University of Colombia (Convocatoria Apoyo de la DIB a Tesis de Investigacion en Posgrados-Quinto Corte; Proyecto 15129). NR 67 TC 4 Z9 5 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2013 VL 81 IS 11 BP 4001 EP 4012 DI 10.1128/IAI.00150-13 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 235LI UT WOS:000325719900006 PM 23959717 ER PT J AU Robertson, GT Child, R Ingle, C Celli, J Norgard, MV AF Robertson, Gregory T. Child, Robert Ingle, Christine Celli, Jean Norgard, Michael V. TI IglE Is an Outer Membrane-Associated Lipoprotein Essential for Intracellular Survival and Murine Virulence of Type A Francisella tularensis SO INFECTION AND IMMUNITY LA English DT Article ID VI SECRETION SYSTEM; HUMAN MACROPHAGES; SCHU S4; PSEUDOMONAS-AERUGINOSA; SUBSP TULARENSIS; LIVE VACCINE; IFN-GAMMA; PROTEIN; ACTIVATION; PHAGOSOME AB IglE is a small, hypothetical protein encoded by the duplicated Francisella pathogenicity island (FPI). Inactivation of both copies of iglE rendered Francisella tularensis subsp. tularensis Schu S4 avirulent and incapable of intracellular replication, owing to an inability to escape the phagosome. This defect was fully reversed following single-copy expression of iglE in trans from attTn7 under the control of the Francisella rpsL promoter, thereby establishing that the loss of iglE, and not polar effects on downstream vgrG gene expression, was responsible for the defect. IglE is exported to the Francisella outer membrane as an similar to 13.9-kDa lipoprotein, determined on the basis of a combination of selective Triton X-114 solubilization, radiolabeling with [H-3]palmitic acid, and sucrose density gradient membrane partitioning studies. Lastly, a genetic screen using the iglE-null live vaccine strain resulted in the identification of key regions in the carboxyl terminus of IglE that are required for intracellular replication of Francisella tularensis in J774A.1 macrophages. Thus, IglE is essential for Francisella tularensis virulence. Our data support a model that likely includes protein-protein interactions at or near the bacterial cell surface that are unknown at present. C1 [Robertson, Gregory T.; Ingle, Christine; Norgard, Michael V.] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Child, Robert; Celli, Jean] NIAID, Tularemia Pathogenesis Sect, Intracellular Parasites Lab, NIH,Rocky Mt Labs, Hamilton, MT USA. RP Norgard, MV (reprint author), Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. EM Michael.Norgard@UTSouthwestern.edu RI Robertson, Gregory/E-1601-2017 OI Robertson, Gregory/0000-0001-7157-4034 FU National Institute of Allergy and Infectious Diseases (NIAID), NIH [U54 AI057156] FX This work was supported by grant number U54 AI057156 from the National Institute of Allergy and Infectious Diseases (NIAID), NIH. NR 66 TC 10 Z9 10 U1 0 U2 4 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 NOV PY 2013 VL 81 IS 11 BP 4026 EP 4040 DI 10.1128/IAI.00595-13 PG 15 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 235LI UT WOS:000325719900008 PM 23959721 ER PT J AU Spinner, JL Carmody, AB Jarrett, CO Hinnebusch, BJ AF Spinner, Justin L. Carmody, Aaron B. Jarrett, Clayton O. Hinnebusch, B. Joseph TI Role of Yersinia pestis Toxin Complex Family Proteins in Resistance to Phagocytosis by Polymorphonuclear Leukocytes SO INFECTION AND IMMUNITY LA English DT Article ID BACTERIUM PHOTORHABDUS-LUMINESCENS; OUTER-MEMBRANE PROTEINS; LOW-CALCIUM RESPONSE; INSECTICIDAL TOXIN; GENE-EXPRESSION; III SECRETION; PLASMINOGEN-ACTIVATOR; ESCHERICHIA-COLI; GLOBAL CHANGES; ORAL TOXICITY AB Yersinia pestis carries homologues of the toxin complex (Tc) family proteins, which were first identified in other Gram-negative bacteria as having potent insecticidal activity. The Y. pestis Tc proteins are neither toxic to fleas nor essential for survival of the bacterium in the flea, even though tc gene expression is highly upregulated and much more of the Tc proteins YitA and YipA are produced in the flea than when Y. pestis is grown in vitro. We show that Tc+ and Tc- Y. pestis strains are transmitted equivalently from coinfected fleas, further demonstrating that the Tc proteins have no discernible role, either positive or negative, in transmission by the flea vector. Tc proteins did, however, confer Y. pestis with increased resistance to killing by polymorphonuclear leukocytes (PMNs). Resistance to killing was not the result of decreased PMN viability or increased intracellular survival but instead correlated with a Tc protein-dependent resistance to phagocytosis that was independent of the type III secretion system (T3SS). Correspondingly, we did not detect T3SS-dependent secretion of the native Tc proteins YitA and YipA or the translocation of YitA- or YipA-beta-lactamase fusion proteins into CHO-K1 (CHO) cells or human PMNs. Thus, although highly produced by Y. pestis within the flea and related to insecticidal toxins, the Tc proteins do not affect interaction with the flea or transmission. Rather, the Y. pestis Tc proteins inhibit phagocytosis by mouse PMNs, independent of the T3SS, and may be important for subverting the mammalian innate immune response immediately following transmission from the flea. C1 [Spinner, Justin L.; Jarrett, Clayton O.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Carmody, Aaron B.] NIAID, Flow Cytometry Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Spinner, JL (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM Justin.Spinner@nih.gov FU Intramural Research Program of the NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 53 TC 5 Z9 5 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 NOV PY 2013 VL 81 IS 11 BP 4041 EP 4052 DI 10.1128/IAI.00648-13 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 235LI UT WOS:000325719900009 PM 23959716 ER PT J AU Ito, D Hasegawa, T Miura, K Yamasaki, T Arumugam, TU Thongkukiatkul, A Takeo, S Takashima, E Sattabongkot, J Han, ET Long, CA Torii, M Tsuboi, T AF Ito, Daisuke Hasegawa, Tomoyuki Miura, Kazutoyo Yamasaki, Tsutomu Arumugam, Thangavelu U. Thongkukiatkul, Amporn Takeo, Satoru Takashima, Eizo Sattabongkot, Jetsumon Han, Eun-Taek Long, Carole A. Torii, Motomi Tsuboi, Takafumi TI RALP1 Is a Rhoptry Neck Erythrocyte-Binding Protein of Plasmodium falciparum Merozoites and a Potential Blood-Stage Vaccine Candidate Antigen SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA PARASITES; INVASION; AMA1; DISCOVERY; EVENTS; CELLS; RON2 AB Erythrocyte invasion by merozoites is an obligatory stage of Plasmodium infection and is essential to disease progression. Proteins in the apical organelles of merozoites mediate the invasion of erythrocytes and are potential malaria vaccine candidates. Rhoptry-associated, leucine zipper-like protein 1 (RALP1) of Plasmodium falciparum was previously found to be specifically expressed in schizont stages and localized to the rhoptries of merozoites by immunofluorescence assay (IFA). Also, RALP1 has been refractory to gene knockout attempts, suggesting that it is essential for blood-stage parasite survival. These characteristics suggest that RALP1 can be a potential blood-stage vaccine candidate antigen, and here we assessed its potential in this regard. Antibodies were raised against recombinant RALP1 proteins synthesized by using the wheat germ cell-free system. Immunoelectron microscopy demonstrated for the first time that RALP1 is a rhoptry neck protein of merozoites. Moreover, our IFA data showed that RALP1 translocates from the rhoptry neck to the moving junction during merozoite invasion. Growth and invasion inhibition assays revealed that anti-RALP1 antibodies inhibit the invasion of erythrocytes by merozoites. The findings that RALP1 possesses an erythrocyte-binding epitope in the C-terminal region and that anti-RALP1 antibodies disrupt tight-junction formation, are evidence that RALP1 plays an important role during merozoite invasion of erythrocytes. In addition, human sera collected from areas in Thailand and Mali where malaria is endemic recognized this protein. Overall, our findings indicate that RALP1 is a rhoptry neck erythrocyte-binding protein and that it qualifies as a potential blood-stage vaccine candidate. C1 [Ito, Daisuke; Hasegawa, Tomoyuki; Yamasaki, Tsutomu; Arumugam, Thangavelu U.; Takeo, Satoru; Takashima, Eizo; Tsuboi, Takafumi] Ehime Univ, Div Malaria Res, Proteosci Ctr, Matsuyama, Ehime, Japan. [Tsuboi, Takafumi] Ehime Univ, Venture Business Lab, Matsuyama, Ehime, Japan. [Miura, Kazutoyo; Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Thongkukiatkul, Amporn] Burapha Univ, Fac Sci, Dept Biol, Chon Buri, Thailand. [Sattabongkot, Jetsumon] Mahidol Univ, Fac Trop Med, Mahidol Vivax Res Unit, Bangkok, Thailand. [Han, Eun-Taek] Kangwon Natl Univ, Sch Med, Dept Med Environm Biol & Trop Med, Chunchon, Gangwon Do, South Korea. [Torii, Motomi] Ehime Univ, Proteosci Ctr, Div Mol Parasitol, Toon, Ehime, Japan. RP Tsuboi, T (reprint author), Ehime Univ, Div Malaria Res, Proteosci Ctr, Matsuyama, Ehime, Japan. EM tsuboi@ccr.ehime-u.ac.jp FU MEXT KAKENHI [23117008]; JSPS KAKENHI in Japan [23406007]; Ministry of Health, Labor, and Welfare, Japan [H21-Chikyukibo-ippan-005]; NIAID; NIH; PATH Malaria Vaccine Initiative FX This work was supported in part by MEXT KAKENHI (23117008) and JSPS KAKENHI (23406007) in Japan and a grant from the Ministry of Health, Labor, and Welfare (H21-Chikyukibo-ippan-005), Japan. The study with Malian samples was supported by the intramural program of the NIAID, NIH, and by the PATH Malaria Vaccine Initiative. NR 29 TC 9 Z9 9 U1 1 U2 5 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 NOV PY 2013 VL 81 IS 11 BP 4290 EP 4298 DI 10.1128/IAI.00690-13 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 235LI UT WOS:000325719900034 PM 24002067 ER PT J AU Mackey-Lawrence, NM Guo, XT Sturdevant, DE Virtaneva, K Hernandez, MM Houpt, E Sher, A Porcella, SF Petri, WA AF Mackey-Lawrence, Nicole M. Guo, Xiaoti Sturdevant, Daniel E. Virtaneva, Kimmo Hernandez, Matthew M. Houpt, Eric Sher, Alan Porcella, Stephen F. Petri, William A., Jr. TI Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica (vol 81, pg 1460, 2013) SO INFECTION AND IMMUNITY LA English DT Correction C1 [Mackey-Lawrence, Nicole M.] Univ Virginia, Sch Med, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. North Shore Long Isl Hlth Syst, Manhasset, NY USA. NIAID, Rocky Mt Lab, Res Technol Sect, Genom Unit,NIH, Hamilton, MT 59840 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Mackey-Lawrence, NM (reprint author), Univ Virginia, Sch Med, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 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 NOV PY 2013 VL 81 IS 11 BP 4322 EP 4322 DI 10.1128/IAI.00689-13 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 235LI UT WOS:000325719900038 ER PT J AU Federovitch, CM Jones, YZ Tong, AH Boone, C Prinz, WA Hampton, RY AF Federovitch, Christine M. Jones, Ying Z. Tong, Amy H. Boone, Charles Prinz, William A. Hampton, Randolph Y. TI Genetic and Structural Analysis of Hmg2p-induced Endoplasmic Reticulum Remodeling in Saccharomyces cerevisiae SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HMG-COA REDUCTASE; 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE; PHOSPHATIDYLSERINE DECARBOXYLASE; STEROL BIOSYNTHESIS; DELETION MUTANTS; YEAST; PROTEIN; CELLS; ER; DEGRADATION AB The endoplasmic reticulum (ER) is highly plastic, and increased expression of distinct single ER-resident membrane proteins, such as HMG-CoA reductase (HMGR), can induce a dramatic restructuring of ER membranes into highly organized arrays. Studies on the ER-remodeling behavior of the two yeast HMGR isozymes, Hmg1p and Hmg2p, suggest that they could be mechanistically distinct. We examined the features of Hmg2p required to generate its characteristic structures, and we found that the molecular requirements are similar to those of Hmg1p. However, the structures generated by Hmg1p and Hmg2p have distinct cell biological features determined by the transmembrane regions of the proteins. In parallel, we conducted a genetic screen to identify HER genes (required for Hmg2p-induced ER Remodeling), further confirming that the mechanisms of membrane reorganization by these two proteins are distinct because most of the HER genes were required for Hmg2p but not Hmg1p-induced ER remodeling. One of the HER genes identified was PSD1, which encodes the phospholipid biosynthetic enzyme phosphatidylserine decarboxylase. This direct connection to phospholipid biosynthesis prompted a more detailed examination of the effects of Hmg2p on phospholipid mutants and composition. Our analysis revealed that overexpression of Hmg2p caused significant and specific growth defects in nulls of the methylation pathway for phosphatidylcholine biosynthesis that includes the Psd1p enzyme. Furthermore, increased expression of Hmg2p altered the composition of cellular phospholipids in a manner that implied a role for PSD1. These phospholipid effects, unlike Hmg2p-induced ER remodeling, required the enzymatic activity of Hmg2p. Together, our results indicate that, although related, Hmg2p- and Hmg1p-induced ER remodeling are mechanistically distinct. C1 [Federovitch, Christine M.; Hampton, Randolph Y.] Univ Calif San Diego, UCSD Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. [Jones, Ying Z.] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, Dept Neurosci, La Jolla, CA 92093 USA. [Jones, Ying Z.] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada. [Prinz, William A.] NIDDK, Lab Cell Biochem & Biol, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hampton, RY (reprint author), Univ Calif San Diego, UCSD Div Biol Sci, Sect Cell & Dev Biol, La Jolla, CA 92093 USA. EM rhampton@ucsd.edu FU National Institutes of Health [5 R01 DK051996-15]; National Institutes of Health genetic training [5T32GM008666] FX We thank Scott Emr for use of the DeltaVision microscope, Gentry Patrick for use of the Leica DM6000 microscope, and National Center for Microscopy and Imaging Research at UCSD for use of the JEOL 1200 microscope. Plasmid pIU2589 was a kind gift from Martin Bard (Indiana University-Purdue University Indianapolis, Indianapolis, IN). Mark Rose (Princeton University, Princeton, NJ) provided anti-Kar2p antibody. We thank Dennis Voelker (University of Colorado Health Sciences Center, Denver, CO) for insightful discussions and the rescue plasmid YCp50-PSD1. CMF wishes to thank Matthew Kinseth, Alicia Bicknell, Danielle Huffman, and Renee Garza for many scientific discussions regarding this work. RYH wishes to thank the Hampton laboratory for patience, flexibility, and independent spirit during the past (sabbatical) year. These studies were supported by National Institutes of Health grant 5 R01 DK051996-15 (to R.Y.H.). C.M.F. was a trainee under the National Institutes of Health genetic training grant 5T32GM008666. NR 50 TC 0 Z9 0 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD NOV PY 2013 VL 195 IS 21 BP 4506 EP 4520 DI 10.1091/mbc.E07-11-1188 PG 15 WC Microbiology SC Microbiology GA 235XI UT WOS:000325755400007 ER PT J AU Han, H Noureddin, M Witthaus, M Park, YJ Hoofnagle, JH Liang, TJ Rotman, Y AF Han, Hwalih Noureddin, Mazen Witthaus, Michael Park, Yoon J. Hoofnagle, Jay H. Liang, T. Jake Rotman, Yaron TI Temperature rise after peginterferon alfa-2a injection in patients with chronic hepatitis C is associated with virological response and is modulated by IL28B genotype SO JOURNAL OF HEPATOLOGY LA English DT Article DE Fever; Temperature; Interferon alfa; IL28B; Hepatitis C; Treatment ID RIBAVIRIN COMBINATION THERAPY; PLUS RIBAVIRIN; GENETIC-VARIATION; IMMUNE-RESPONSE; VIRUS-INFECTION; INTERFERON; CLEARANCE; FEVER; UPDATE AB Background & Aims: Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity. Methods: 60 treatment-naive patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24 h and the maximal increase from baseline during that time (Delta T-max) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs - CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped. Results: Temperatures rose by 1.2 +/- 0.8 degrees C, peaking after 12.5 h. Delta T-max was strongly associated with 1st phase virological decline (r = 0.59, p < 0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12989760CC genotype (r = 0.65, p < 0.0001) but not in CC/CT (r = 0.13, p = 0.53) and patients with CC genotype had a higher Delta T-max (1.4 +/- 0.8 degrees C vs. 0.8 +/- 0.6 degrees C, p = 0.001). Delta T-max was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12989760CC. Delta T-max weakly predicted early virological response (AUC = 0.68, CI 0.49-0.88). Conclusions: Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Han, Hwalih; Noureddin, Mazen; Witthaus, Michael; Park, Yoon J.; Hoofnagle, Jay H.; Liang, T. Jake; Rotman, Yaron] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Rotman, Y (reprint author), NIDDK, Liver Dis Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9C434,MSC 1800, Bethesda, MD 20892 USA. EM rotmany@mail.nih.gov OI Rotman, Yaron/0000-0002-7549-8216 FU intramural research program of NIDDK FX This work was supported by the intramural research program of NIDDK. NR 30 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2013 VL 59 IS 5 BP 957 EP 963 DI 10.1016/j.jhep.2013.07.004 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 235WZ UT WOS:000325754200009 PM 23850879 ER PT J AU Kapanadze, T Gamrekelashvili, J Ma, C Chan, C Zhao, F Hewitt, S Zender, L Kapoor, V Felsher, DW Manns, MP Korangy, F Greten, TF AF Kapanadze, Tamar Gamrekelashvili, Jaba Ma, Chi Chan, Carmen Zhao, Fei Hewitt, Stephen Zender, Lars Kapoor, Veena Felsher, Dean W. Manns, Michael P. Korangy, Firouzeh Greten, Tim F. TI Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma SO JOURNAL OF HEPATOLOGY LA English DT Article DE Tumor immunology; Immunotherapy; Cancer vaccine ID COLONY-STIMULATING FACTOR; TUMOR-BEARING MICE; DENDRITIC CELLS; LIVER-CANCER; T-CELLS; SUBPOPULATIONS; INFLAMMATION; POPULATIONS; PROGRESSION; IMMUNITY AB Background & Aims: Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease. Methods: The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages. Results: An accumulation of MDSC was found in mice with HCC irrespective of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL6, IL1 beta) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF overexpression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib. Conclusions: Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Kapanadze, Tamar; Gamrekelashvili, Jaba; Ma, Chi; Chan, Carmen; Zhao, Fei; Korangy, Firouzeh; Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Kapanadze, Tamar; Gamrekelashvili, Jaba; Manns, Michael P.] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Hewitt, Stephen] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zender, Lars] Univ Tubingen, Dept Gastroenterol, Tubingen, Germany. [Kapoor, Veena] NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Felsher, Dean W.] Stanford Univ, Div Med Oncol, Dept Med, Stanford, CA 94305 USA. RP Korangy, F (reprint author), NCI, NIH, CCR Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tim.greten@nih.gov RI Greten, Tim/B-3127-2015; OI Greten, Tim/0000-0002-0806-2535; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research; Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer FX The research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by the Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer to MPM. NR 41 TC 37 Z9 38 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2013 VL 59 IS 5 BP 1007 EP 1013 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 235WZ UT WOS:000325754200016 PM 23796475 ER PT J AU Miyagawa, F Okiyama, N Villarroel, V Katz, SI AF Miyagawa, Fumi Okiyama, Naoko Villarroel, Vadim Katz, Stephen I. TI Identification of CD3(+)CD4(-)CD8(-) T Cells as Potential Regulatory Cells in an Experimental Murine Model of Graft-Versus-Host Skin Disease (GVHD) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID CARDIAC XENOGRAFT SURVIVAL; RECEPTOR TRANSGENIC MICE; NONOBESE DIABETIC MICE; CLONAL ELIMINATION; IMMUNE-RESPONSES; MOUSE MODEL; ANTIGEN; TOLERANCE; DIFFERENTIATION; PEPTIDE AB We have developed K14-mOVA transgenic (Tg) mice that express membrane-associated ovalbumin (mOVA) under the control of a K14 promoter, as well as double Tg mice, by crossing them with OT-I mice that have a TCR recognizing the OVA peptide. When injected with CD8(+) OT-I cells, K14-mOVA Tg mice develop graft-versus-host disease (GVHD), whereas double Tg mice are protected. This suggests that, in double Tg mice, regulatory mechanisms may prevent infused OT-I cells from inducing GVHD. We demonstrated that, after adoptive transfer, TCR alpha beta(+)CD3(+)CD4(-)CD8(-)NK1.1(-) double-negative (DN) T cells are increased in the peripheral lymphoid organs and skin of double Tg mice and exhibit a V alpha 2(+)V beta 5(+)TCR that has the same TCR specificity as OT-I cells. These DN T cells isolated from tolerant double Tg mice proliferated in response to OVA peptide and produced IFN-gamma in the presence of IL-2. These cells could also suppress the proliferation of OT-I cells and were able to specifically kill activated OT-I cells through Fas/Fas ligand interaction. These findings suggest that DN T cells that accumulate in double Tg mice have regulatory functions and may have a role in the maintenance of peripheral tolerance in vivo. C1 [Miyagawa, Fumi; Okiyama, Naoko; Villarroel, Vadim; Katz, Stephen I.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NCI, Dermatol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM katzs@od.niams.nih.gov FU Intramural NIH HHS [ZIA SC003657-38] NR 36 TC 6 Z9 7 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2013 VL 133 IS 11 BP 2538 EP 2545 DI 10.1038/jid.2013.212 PG 8 WC Dermatology SC Dermatology GA 236OM UT WOS:000325807800010 PM 23648548 ER PT J AU Odia, Y Orr, BA Bell, WR Eberhart, CG Rodriguez, FJ AF Odia, Yazmin Orr, Brent A. Bell, W. Robert Eberhart, Charles G. Rodriguez, Fausto J. TI cMYC expression in infiltrating gliomas: associations with IDH1 mutations, clinicopathologic features and outcome SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE cMYC; IDH1; IDH1 (R132H); Gliomas; Glioblastoma; Astrocytoma; Prognosis; Survival ID CENTRAL-NERVOUS-SYSTEM; C-MYC AMPLIFICATION; ASTROCYTIC TUMORS; STEM-CELLS; GLIOBLASTOMA; MEDULLOBLASTOMA; CLASSIFICATION; METABOLISM; TELOMERES; GROWTH AB Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. cMYC is an oncogene also implicated in aberrant metabolism, but its prognostic impact remains unclear. Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1. We evaluated nuclear cMYC protein levels and IDH1 (R132H) by immunohistochemistry in patients with oligodendroglioma/oligoastrocytomas (n = 20), astrocytomas (grade II) (n = 19), anaplastic astrocytomas (n = 21) or glioblastomas (n = 111). Of 158 tumors with sufficient tissue, 110 (70 %) showed nuclear cMYC immunopositivity-most frequent (95 %, chi(2) p = 0.0248) and intense (mean 1.33, ANOVA p = 0.0179) in anaplastic astrocytomas versus glioblastomas (63 %) or low grade gliomas (74 %). cMYC expression associated with younger age as well as p53 immunopositivity (OR = 3.6, p = 0.0332) and mutant IDH1 (R132H) (OR = 7.4, p = 0.06) among malignant gliomas in our cohort. Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression. Both IDH1 (R132H) and cMYC protein expression were associated with improved overall survival by univariate analysis. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas. C1 [Odia, Yazmin] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Odia, Yazmin] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Orr, Brent A.; Bell, W. Robert; Eberhart, Charles G.; Rodriguez, Fausto J.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol,Johns Hopkins Hosp, Baltimore, MD 21205 USA. [Orr, Brent A.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Eberhart, Charles G.; Rodriguez, Fausto J.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. RP Rodriguez, FJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol,Johns Hopkins Hosp, Sheikh Zayed Tower,Room M2101,1800 Orleans St, Baltimore, MD 21205 USA. EM frodrig4@jhmi.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [NINDS 5R25NS065729-02]; Children's Cancer Foundation, Inc. [5R01NS055089]; James S. McDonnell Foundation FX Grant funding provided in part by the National Institute of Neurological Disorders and Stroke (NINDS) Research Education Program for Residents and Fellows in Neurology and Neurosurgery (2009-10)-Primary Investigator Argye Hillis, MD MS, Johns Hopkins Hospital, Baltimore, MD [NINDS 5R25NS065729-02] (YO); Children's Cancer Foundation, Inc. (CGE, FJR), 5R01NS055089 (CGE), and James S. McDonnell Foundation (CGE). Jessica Hicks performed all cMYC immunohistochemistry on glioma specimens. The authors also thank the Mayo Clinic cytogenetic shared resource for technical assistance. NR 44 TC 4 Z9 5 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2013 VL 115 IS 2 BP 249 EP 259 DI 10.1007/s11060-013-1221-4 PG 11 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 236TJ UT WOS:000325821900014 PM 23934175 ER PT J AU Derdeyn, CP Fiorella, D Lynn, MJ Barnwell, SL Zaidat, OO Meyers, PM Gobin, YP Dion, J Lane, BF Turan, TN Janis, LS Chimowitz, MI AF Derdeyn, Colin P. Fiorella, David Lynn, Michael J. Barnwell, Stanley L. Zaidat, Osama O. Meyers, Philip M. Gobin, Y. Pierre Dion, Jacques Lane, Bethany F. Turan, Tanya N. Janis, L. Scott Chimowitz, Marc I. CA SAMMPRIS Trial Investigators TI Impact of operator and site experience on outcomes after angioplasty and stenting in the SAMMPRIS trial SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article DE Stroke; Stent; Angioplasty ID INTRACRANIAL ARTERIAL-STENOSIS; AGGRESSIVE MEDICAL-MANAGEMENT; PREVENTING RECURRENT STROKE; ATHEROSCLEROTIC-DISEASE; WINGSPAN STENT; THERAPY; DESIGN AB Background and purpose To investigate the relationship between physician and site experience and the risk of 30 day hemorrhagic and ischemic strokes in the stenting arm of the Stenting and Aggressive Medical Management for the Prevention of Recurrent Ischemic Stroke (SAMMPRIS) trial. Methods Study records and an investigator survey were examined for physician and site related factors, including: number of Wingspan and aneurysm stents submitted for credentialing, number of study procedures performed in SAMMPRIS, years in practice after training, primary specialty, and site enrollment. Bivariate and multivariate analyses were performed to determine if these factors were associated with the 30 day rate of cerebrovascular events after angioplasty and stenting. Results 213 patients underwent angioplasty alone (n=5) or angioplasty and stenting (n=208) with study devices by 63 interventionists at 48 sites. For credentialing, the median number of Wingspan and similar aneurysm stent cases submitted by study interventionists were 10 and 6, respectively. Interventionists with higher numbers (>10) of Wingspan cases submitted for credentialing tended to have higher rates of 30 day events (19.0% vs 9.9%) than those with <10 cases. High enrolling sites in the trial tended to have lower rates of hemorrhagic stroke (9.8% at sites enrolling <12 patients vs 2.7% at sites enrolling >12 patients). Conclusions Interventionists credentialed with less Wingspan experience were not responsible for the high rate of periprocedural stroke in SAMMPRIS. Hemorrhagic stroke may be related to low enrollment in the trial but not previous Wingspan experience. C1 [Derdeyn, Colin P.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63130 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Derdeyn, Colin P.] Washington Univ, Sch Med, Dept Neurosurg, St Louis, MO USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR USA. [Barnwell, Stanley L.] Oregon Hlth & Sci Univ, Dotter Intervent Inst, Portland, OR USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. [Zaidat, Osama O.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Meyers, Philip M.] Columbia Univ, Dept Radiol, New York, NY USA. [Gobin, Y. Pierre] Cornell Univ, Dept Radiol, New York, NY 10021 USA. [Dion, Jacques] Emory Univ, Dept Radiol & Neurosurg, Atlanta, GA 30322 USA. [Turan, Tanya N.; Chimowitz, Marc I.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Janis, L. Scott] NINDS, NIH, Bethesda, MD 20892 USA. RP Derdeyn, CP (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO 63130 USA. EM derdeync@mir.wustl.edu OI Turan, Tanya/0000-0001-5399-8845; Derdeyn, Colin/0000-0002-5932-2683 FU US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS058728]; National Institutes of Health; Medical University of South Carolina [UL1RR029882]; University of Florida [UL1RR029889]; University of Cincinnati [UL1RR029890]; University of California, San Francisco [UL1RR024131]; Stryker Neurovascular FX The SAMMPRIS trial was funded by a research grant (U01 NS058728) from the US Public Health Service National Institute of Neurological Disorders and Stroke (NINDS). In addition, the following Clinical and Translational Science Awards, funded by the National Institutes of Health, provided local support for the evaluation of patients in the trial: Medical University of South Carolina (UL1RR029882), University of Florida (UL1RR029889), University of Cincinnati (UL1RR029890), and University of California, San Francisco (UL1RR024131). Stryker Neurovascular (formerly Boston Scientific Neurovascular) provided study devices and supplemental funding for third party device distribution, site monitoring, and study auditing. NR 13 TC 19 Z9 20 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD NOV PY 2013 VL 5 IS 6 BP 528 EP 533 DI 10.1136/neurintsurg-2012-010504 PG 6 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 232JT UT WOS:000325490700020 PM 22977278 ER PT J AU Rais-Bahrami, S Siddiqui, MM Turkbey, B Stamatakis, L Logan, J Hoang, AN Walton-Diaz, A Vourganti, S Truong, H Kruecker, J Merino, MJ Wood, BJ Choyke, PL Pinto, PA AF Rais-Bahrami, Soroush Siddiqui, M. Minhaj Turkbey, Baris Stamatakis, Lambros Logan, Jennifer Hoang, Anthony N. Walton-Diaz, Annerleim Vourganti, Srinivas Truong, Hong Kruecker, Jochen Merino, Maria J. Wood, Bradford J. Choyke, Peter L. Pinto, Peter A. TI Utility of Multiparametric Magnetic Resonance Imaging Suspicion Levels for Detecting Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE neoplasm grading; magnetic resonance imaging; digital rectal examination; prostate; biopsy ID ACTIVE SURVEILLANCE; ULTRASOUND FUSION; TUMOR VOLUME; BIOPSY; SPECIMENS; MRI AB Purpose: We determine the usefulness of multiparametric magnetic resonance imaging in detecting prostate cancer, with a specific focus on detecting higher grade prostate cancer. Materials and Methods: Prospectively 583 patients who underwent multiparametric magnetic resonance imaging and subsequent prostate biopsy at a single institution were evaluated. On multiparametric magnetic resonance imaging, lesions were identified and scored as low, moderate or high suspicion for prostate cancer based on a validated scoring system. Magnetic resonance/ultra-sound fusion guided biopsies of magnetic resonance imaging lesions in addition to systematic 12-core biopsies were performed. Correlations between the highest assigned multiparametric magnetic resonance imaging suspicion score and presence of cancer and biopsy Gleason score on the first fusion biopsy session were assessed using univariate and multivariate logistic regression models. Sensitivity, specificity, negative predictive value and positive predictive value were calculated and ROC curves were developed to assess the discriminative ability of multiparametric magnetic resonance imaging as a diagnostic tool for various biopsy Gleason score cohorts. Results: Significant correlations were found between age, prostate specific antigen, prostate volume, and multiparametric magnetic resonance imaging suspicion score and the presence of prostate cancer (p < 0.0001). On multivariate analyses controlling for age, prostate specific antigen and prostate volume, increasing multiparametric magnetic resonance imaging suspicion was an independent prognosticator of prostate cancer detection (OR 2.2, p < 0.0001). Also, incremental increases in multiparametric magnetic resonance imaging suspicion score demonstrated stronger associations with cancer detection in patients with Gleason 7 or greater (OR 3.3, p < 0.001) and Gleason 8 or greater (OR 4.2, p < 0.0001) prostate cancer. Assessing multiparametric magnetic resonance imaging as a diagnostic tool for all prostate cancer, biopsy Gleason score 7 or greater, and biopsy Gleason score 8 or greater separately via ROC analyses demonstrated increasing accuracy of multiparametric magnetic resonance imaging for higher grade disease (AUC 0.64, 0.69, and 0.72, respectively). Conclusions: Multiparametric magnetic resonance imaging is a clinically useful modality to detect and characterize prostate cancer, particularly in men with higher grade disease. C1 [Rais-Bahrami, Soroush; Siddiqui, M. Minhaj; Stamatakis, Lambros; Logan, Jennifer; Hoang, Anthony N.; Walton-Diaz, Annerleim; Vourganti, Srinivas; Truong, Hong; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Kruecker, Jochen; Wood, Bradford J.; Pinto, Peter A.] Natl Canc Inst & Clin Ctr, Ctr Intervent Oncol, NIH, Bethesda, MD USA. [Kruecker, Jochen] Philips Res North America, Briarcliff Manor, NY USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. OI Siddiqui, Mohummad/0000-0002-4484-6820; Rais-Bahrami, Soroush/0000-0001-9466-9925 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NIH and Philips Healthcare have a cooperative research and development agreement. NIH and Philips share intellectual property in the field. NR 26 TC 78 Z9 79 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD NOV PY 2013 VL 190 IS 5 BP 1721 EP 1727 DI 10.1016/j.juro.2013.05.052 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 232DV UT WOS:000325471400030 PM 23727310 ER PT J AU Hourigan, CS Forde, PM Ambinder, RF Gladstone, DE AF Hourigan, Christopher S. Forde, Patrick M. Ambinder, Richard F. Gladstone, Douglas E. TI Bortezomib salvage therapy in refractory acute adult T-cell leukemia/lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Letter ID PROTEASOME INHIBITOR; TRANSPLANTATION; LYMPHOMA; EXPERIENCE; EFFICACY; SUBTYPES; ATL C1 [Hourigan, Christopher S.] NHLBI, Myeloid Malignancies Sect, Bethesda, MD 20892 USA. [Hourigan, Christopher S.; Forde, Patrick M.; Ambinder, Richard F.; Gladstone, Douglas E.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. RP Hourigan, CS (reprint author), NHLBI, Myeloid Malignancies Sect, Room 6C-103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM hourigan@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU Intramural NIH HHS [ZIA HL006163-01]; NCI NIH HHS [P30 CA006973] NR 14 TC 2 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2013 VL 54 IS 11 BP 2563 EP 2564 DI 10.3109/10428194.2013.780289 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 232MV UT WOS:000325498900043 PM 23445368 ER PT J AU Coussens, NP Hayashi, R Brown, PH Balagopalan, L Balbo, A Akpan, I Houtman, JCD Barr, VA Schuck, P Appella, E Samelson, LE AF Coussens, Nathan P. Hayashi, Ryo Brown, Patrick H. Balagopalan, Lakshmi Balbo, Andrea Akpan, Itoro Houtman, Jon C. D. Barr, Valarie A. Schuck, Peter Appella, Ettore Samelson, Lawrence E. TI Multipoint Binding of the SLP-76 SH2 Domain to ADAP Is Critical for Oligomerization of SLP-76 Signaling Complexes in Stimulated T Cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ANTIGEN RECEPTOR; GRB2-SH2 DOMAIN; COOPERATIVE INTERACTIONS; PHOSPHOLIPASE C-GAMMA-1; PROTEIN INTERACTIONS; TYROSINE KINASES; HIGH-AFFINITY; ACTIVATION; MICROCLUSTERS; ACTIN AB The adapter molecules SLP-76 and LAT play central roles in T cell activation by recruiting enzymes and other adapters into multiprotein complexes that coordinate highly regulated signal transduction pathways. While many of the associated proteins have been characterized, less is known concerning the mechanisms of assembly for these dynamic and potentially heterogeneous signaling complexes. Following T cell receptor (TCR) stimulation, SLP-76 is found in structures called microclusters, which contain many signaling complexes. Previous studies showed that a mutation to the SLP-76 C-terminal SH2 domain nearly abolished SLP-76 microclusters, suggesting that the SH2 domain facilitates incorporation of signaling complexes into microclusters. S. C. Bunnell, A. L. Singer, D. I. Hong, B. H. Jacque, M. S. Jordan, M. C. Seminario, V. A. Barr, G. A. Koretzky, and L. E. Samelson, Mol. Cell. Biol., 26: 7155-7166, 2006). Using biophysical methods, we demonstrate that the adapter, ADAP, contains three binding sites for SLP-76, and that multipoint binding to ADAP fragments oligomerizes the SLP-76 SH2 domain in vitro. These results were complemented with confocal imaging and functional studies of cells expressing ADAP with various mutations. Our results demonstrate that all three binding sites are critical for SLP-76 microcluster assembly, but any combination of two sites will partially induce microclusters. These data support a model whereby multipoint binding of SLP-76 to ADAP facilitates the assembly of SLP-76 microclusters. This model has implications for the regulation of SLP-76 and LAT microclusters and, as a result, T cell signaling. C1 [Coussens, Nathan P.; Balagopalan, Lakshmi; Akpan, Itoro; Houtman, Jon C. D.; Barr, Valarie A.; Samelson, Lawrence E.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Hayashi, Ryo; Appella, Ettore] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Brown, Patrick H.; Balbo, Andrea] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, NIH, Bethesda, MD USA. RP Samelson, LE (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM samelsonl@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966; Houtman, Jon/0000-0002-5307-9854 FU Intramural Research Programs of the Center for Cancer Research; NCI; NIBIB, National Institutes of Health FX This research was supported by the Intramural Research Programs of the Center for Cancer Research, NCI, and NIBIB, National Institutes of Health. NR 52 TC 19 Z9 19 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2013 VL 33 IS 21 BP 4140 EP 4151 DI 10.1128/MCB.00410-13 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 235XS UT WOS:000325756800001 PM 23979596 ER PT J AU Gatch, MB Kozlenkov, A Huang, RQ Yang, WJ Nguyen, JD Gonzalez-Maeso, J Rice, KC France, CP Dillon, GH Forster, MJ Schetz, JA AF Gatch, Michael B. Kozlenkov, Alexey Huang, Ren-Qi Yang, Wenjuan Nguyen, Jacques D. Gonzalez-Maeso, Javier Rice, Kenner C. France, Charles P. Dillon, Glenn H. Forster, Michael J. Schetz, John A. TI The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE hallucinogen; adverse neuropsychiatric events; side effects; AIDS ID MONOAMINE TRANSPORTER; DOPAMINE-RECEPTORS; 5-HT2C RECEPTORS; IN-VIVO; HALLUCINOGENS; MICE; RATS; MECHANISM; INFECTION; PSYCHOSIS AB Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)- 4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABA(A) and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABA(A)-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication. C1 [Gatch, Michael B.; Huang, Ren-Qi; Nguyen, Jacques D.; Dillon, Glenn H.; Forster, Michael J.; Schetz, John A.] Univ N Texas, Dept Pharmacol & Neurosci, Hlth Sci Ctr, Ft Worth, TX 76107 USA. [Kozlenkov, Alexey; Gonzalez-Maeso, Javier] Mt Sinai Sch Med, Dept Psychiat & Neurol, New York, NY USA. [Yang, Wenjuan; France, Charles P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. [Dillon, Glenn H.; Forster, Michael J.; Schetz, John A.] Univ N Texas, Inst Aging & Alzheimers Dis Res, Hlth Sci Ctr, Ft Worth, TX USA. [Schetz, John A.] Univ N Texas, Texas Coll Osteopath Med, Dept Psychiat, Hlth Sci Ctr, Ft Worth, TX 76107 USA. [Schetz, John A.] Univ N Texas, Dept Hlth Management & Policy, Sch Publ Hlth, Hlth Sci Ctr, Ft Worth, TX USA. RP Schetz, JA (reprint author), Univ N Texas, Dept Pharmacol & Neurosci, Hlth Sci Ctr, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA. EM John.Schetz@unthsc.edu FU National Institutes of Health [R01-MH063162, K05DA17918, R01 MH084894, R01-DA022370, N01DA-7-8872 (HHSN271200700014C)]; UNTHSC Intramural Grant [RI-6015]; Intramural Research Programs of the National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX We thank Dr Michael Oglesby for critical reading of early versions of the manuscript, Dr Kathyrn Cunningham for insightful discussions related to this work, and Brian Weiss, Shahnawaz Amdani, Marshayla McPhaul, Terrell Holloway and Fatima Sahyouni for technical assistance. We also thank Dr David Lynch (University of Pennsylvania) for providing the cDNAs encoding rat NR1a, NR2A, and NR2B, Dr Eldo Kuzhikandathil (UMDNJ-New Jersey Medical School) for providing an Att20 cell line stably expressing the human D3 receptor, and Dr David B Bylund (University of Nebraska Medical Center) for providing the HEK293 cell line stably expressing the human alpha2C adrenergic receptor. This work was supported, in part, by the National Institutes of Health (Grant R01-MH063162 (JAS); K05DA17918 (CPF); R01 MH084894 (JGM); R01-DA022370 (GHD, MJF); N01DA-7-8872 (HHSN271200700014C) (MJF)), UNTHSC Intramural Grant RI-6015 (JAS, MG, and MJF), and institutional funds (JAS, MJF, and GHD). A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism (KCR). NR 43 TC 18 Z9 20 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2013 VL 38 IS 12 BP 2373 EP 2384 DI 10.1038/npp.2013.135 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 235IF UT WOS:000325710200005 PM 23702798 ER PT J AU Iemolo, A Blasio, A St Cyr, SA Jiang, F Rice, KC Sabino, V Cottone, P AF Iemolo, Attilio Blasio, Angelo St Cyr, Stephen A. Jiang, Fanny Rice, Kenner C. Sabino, Valentina Cottone, Pietro TI CRF-CRF1 Receptor System in the Central and Basolateral Nuclei of the Amygdala Differentially Mediates Excessive Eating of Palatable Food SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE corticotropin-releasing factor; BNST; addiction; anxiety; hypophagia ID CORTICOTROPIN-RELEASING-FACTOR; DARK SIDE; DRUG-ADDICTION; INTERMITTENT ACCESS; PREFERRED FOOD; DEPENDENT RATS; ANIMAL-MODELS; WITHDRAWAL; STRESS; CRF AB Highly palatable foods and dieting are major contributing factors for the development of compulsive eating in obesity and eating disorders. We previously demonstrated that intermittent access to palatable food results in corticotropin-releasing factor-1 (CRF1) receptor antagonist-reversible behaviors, which include excessive palatable food intake, hypophagia of regular chow, and anxiety-like behavior. However, the brain areas mediating these effects are still unknown. Male Wistar rats were either fed chow continuously for 7 days/week (Chow/Chow group), or fed chow intermittently 5 days/week, followed by a sucrose, palatable diet 2 days/week (Chow/Palatable group). Following chronic diet alternation, the effects of microinfusing the CRF1 receptor antagonist R121919 (0, 0.5, 1.5 mg/side) in the central nucleus of the amygdala (CeA), the basolateral nucleus of the amygdala (BlA), or the bed nucleus of the stria terminalis (BNST) were evaluated on excessive intake of the palatable diet, chow hypophagia, and anxiety-like behavior. Furthermore, CRF immunostaining was evaluated in the brain of diet cycled rats. Intra-CeA R121919 blocked both excessive palatable food intake and anxiety-like behavior in Chow/Palatable rats, without affecting chow hypophagia. Conversely, intra-BlA R121919 reduced the chow hypophagia in Chow/Palatable rats, without affecting excessive palatable food intake or anxiety-like behavior. Intra-BNST treatment had no effect. The treatments did not modify the behavior of Chow/Chow rats. Immunohistochemistry revealed an increased number of CRF-positive cells in CeA-but not in BlA or BNST-of Chow/Palatable rats, during both withdrawal and renewed access to the palatable diet, compared with controls. These results provide functional evidence that the CRF-CRF1 receptor system in CeA and BlA has a differential role in mediating maladaptive behaviors resulting from palatable diet cycling. Neuropsychopharmacology (2013) C1 [Iemolo, Attilio; Blasio, Angelo; St Cyr, Stephen A.; Jiang, Fanny; Sabino, Valentina; Cottone, Pietro] Boston Univ, Sch Med, Dept Pharmacol, Lab Addict Disorders, Boston, MA 02118 USA. [Iemolo, Attilio; Blasio, Angelo; St Cyr, Stephen A.; Jiang, Fanny; Sabino, Valentina; Cottone, Pietro] Boston Univ, Sch Med, Dept Psychiat, Lab Addict Disorders, Boston, MA 02118 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. RP Cottone, P (reprint author), Boston Univ, Sch Med, Dept Pharmacol, Lab Addict Disorders, 72 East Concord St,R-618, Boston, MA 02118 USA. EM cottone@bu.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012 OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279 FU National Institute on Drug Abuse(NIDA) [DA023680, DA030425, MH091945, MH093650, AA016731]; National Institute of Mental Health (NIMH); National Institute on Alcohol Abuse and Alcoholism (NIAAA); Peter Paul Career Development Professorship; Boston University's Undergraduate Research Opportunities Program (UROP); NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS FX We thank Duncan Momaney, Aditi R Narayan, Jina Kwak for technical assistance, and Tamara Zeric for technical and editorial assistance. We also thank Elena F Crawford for helpful suggestions related to CRF immunohistochemistry. This publication was made possible by grant numbers DA023680, DA030425, MH091945, MH093650, and AA016731, from the National Institute on Drug Abuse(NIDA), the National Institute of Mental Health (NIMH), and the National Institute on Alcohol Abuse and Alcoholism (NIAAA), by the Peter Paul Career Development Professorship (PC) and by Boston University's Undergraduate Research Opportunities Program (UROP). This research was also 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. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 49 TC 18 Z9 18 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2013 VL 38 IS 12 BP 2456 EP 2466 DI 10.1038/npp.2013.147 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 235IF UT WOS:000325710200014 PM 23748225 ER PT J AU Blasio, A Iemolo, A Sabino, V Petrosino, S Steardo, L Rice, KC Orlando, P Iannotti, FA Di Marzo, V Zorrilla, EP Cottone, P AF Blasio, Angelo Iemolo, Attilio Sabino, Valentina Petrosino, Stefania Steardo, Luca Rice, Kenner C. Orlando, Pierangelo Iannotti, Fabio Arturo Di Marzo, Vincenzo Zorrilla, Eric P. Cottone, Pietro TI Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE obesity; eating disorders; compulsive eating; withdrawal; SR141716A; endocannabinoids ID CORTICOTROPIN-RELEASING-FACTOR; ELEVATED PLUS-MAZE; DARK SIDE; ENDOCANNABINOID SYSTEM; CANNABINOID WITHDRAWAL; RECEPTOR ANTAGONISTS; INTERMITTENT ACCESS; ABSTINENCE SYNDROME; COCAINE SEEKING; PREFERRED FOOD AB The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB1) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB1 receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB1 receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB1 receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB1 receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity. C1 [Blasio, Angelo; Iemolo, Attilio; Sabino, Valentina; Cottone, Pietro] Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol & Psychiat, Boston, MA 02118 USA. [Petrosino, Stefania; Iannotti, Fabio Arturo; Di Marzo, Vincenzo] CNR, Inst Biomol Chem, Endocannabinoid Res Grp, Pozzuoli, Italy. [Steardo, Luca] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. [Orlando, Pierangelo] CNR, Endocannabinoid Res Grp, Inst Prot Biochem, Naples, Italy. [Zorrilla, Eric P.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. RP Cottone, P (reprint author), Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol & Psychiat, 72 E Concord St,R-618, Boston, MA 02118 USA. EM ezorrill@scripps.edu; cottone@bu.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012; OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279; Steardo, Luca/0000-0003-3570-2195; Di Marzo, Vincenzo/0000-0002-1490-3070 FU National Institute on Drug Abuse (NIDA) [DA023680, DA030425, MH091945, MH093650, AA016731, AA06420, DK070118]; National Institute of Mental Health (NIMH); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute on Diabetes, Digestive and Kidney Disorders; Peter Paul Career Development Professorship; Boston University's Undergraduate Research Opportunities Program (UROP); NIH Intramural Research Programs of the National Institute on Drug Abuse; National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS FX This publication was made possible by grant numbers DA023680, DA030425, MH091945, MH093650, AA016731, AA06420, and DK070118 from the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and the National Institute on Diabetes, Digestive and Kidney Disorders, by the Peter Paul Career Development Professorship (P.C.) and by Boston University's Undergraduate Research Opportunities Program (UROP). This research was also 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 declare no conflict of interest. NR 57 TC 11 Z9 11 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD NOV PY 2013 VL 38 IS 12 BP 2498 EP 2507 DI 10.1038/npp.2013.153 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 235IF UT WOS:000325710200018 PM 23793355 ER PT J AU Wiener, L Vasserman-Stokes, E Battles, H Loucas, C Muriel, A AF Wiener, Lori Vasserman-Stokes, Elaina Battles, Haven Loucas, Caitlyn Muriel, Anna TI How Helpful is Dyadic Coping to Parents' Relationship During the Pediatric Cancer Experience? SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Wiener, Lori; Vasserman-Stokes, Elaina; Battles, Haven] NCI, Bethesda, MD 20892 USA. [Loucas, Caitlyn; Muriel, Anna] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2013 VL 22 SU 3 SI SI BP 3 EP 3 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 235AS UT WOS:000325687200005 ER PT J AU Galway, K Black, A Cantwell, M Cardwell, C Mills, M Donnelly, M AF Galway, Karen Black, Amanda Cantwell, Marie Cardwell, Chris Mills, Moyra Donnelly, Michael TI Psychosocial Interventions to Improve Quality of Life and Emotional Wellbeing for Recently Diagnosed Cancer Patients SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Galway, Karen; Cantwell, Marie; Cardwell, Chris; Donnelly, Michael] Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland. [Black, Amanda] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2013 VL 22 SU 3 SI SI BP 253 EP 254 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 235AS UT WOS:000325687200394 ER PT J AU Joyce, DW Averbeck, BB Frith, CD Shergill, SS AF Joyce, D. W. Averbeck, B. B. Frith, C. D. Shergill, S. S. TI Examining belief and confidence in schizophrenia SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Belief; computational model; delusions; metacognition; schizophrenia ID DECISION-MAKING; PREFRONTAL CORTEX; PERSECUTORY DELUSIONS; ACTION SELECTION; LINKING BIOLOGY; DOPAMINE; METACOGNITION; CONCLUSIONS; PERFORMANCE; PREDICTION AB Background. People with psychoses often report fixed, delusional beliefs that are sustained even in the presence of unequivocal contrary evidence. Such delusional beliefs are the result of integrating new and old evidence inappropriately in forming a cognitive model. We propose and test a cognitive model of belief formation using experimental data from an interactive 'Rock Paper Scissors' (RPS) game. Method. Participants (33 controls and 27 people with schizophrenia) played a competitive, time-pressured interactive two-player game (RPS). Participants' behavior was modeled by a generative computational model using leaky integrator and temporal difference methods. This model describes how new and old evidence is integrated to form a playing strategy to beat the opponent and to provide a mechanism for reporting confidence in one's playing strategy to win against the opponent. Results. People with schizophrenia fail to appropriately model their opponent's play despite consistent (rather than random) patterns that can be exploited in the simulated opponent's play. This is manifest as a failure to weigh existing evidence appropriately against new evidence. Furthermore, participants with schizophrenia show a 'jumping to conclusions' (JTC) bias, reporting successful discovery of a winning strategy with insufficient evidence. Conclusions. The model presented suggests two tentative mechanisms in delusional belief formation: (i) one for modeling patterns in other's behavior, where people with schizophrenia fail to use old evidence appropriately, and (ii) a metacognitive mechanism for 'confidence' in such beliefs, where people with schizophrenia overweight recent reward history in deciding on the value of beliefs about the opponent. C1 [Joyce, D. W.; Shergill, S. S.] Kings Coll London, Inst Psychiat, Cognit Schizophrenia & Imaging Lab, Dept Psychosis Studies, London SE5 8AF, England. [Averbeck, B. B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Frith, C. D.] UCL, Wellcome Ctr Imaging Neurosci, London WC1E 6BT, England. RP Shergill, SS (reprint author), Kings Coll London, Inst Psychiat, Cognit Schizophrenia & Imaging Lab, POB 96,Crespigny Pk, London SE5 8AF, England. EM Sukhi.Shergill@kcl.ac.uk RI Nagra, Sasha/I-8863-2014 FU Medical Research Centre (MRC) FX S.S.S. was funded by a Medical Research Centre (MRC) New Investigator Award. NR 68 TC 8 Z9 8 U1 2 U2 17 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD NOV PY 2013 VL 43 IS 11 BP 2327 EP 2338 DI 10.1017/S0033291713000263 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 234KB UT WOS:000325641200009 PM 23521846 ER PT J AU Szot, CS Buchanan, CF Freeman, JW Rylander, MN AF Szot, Christopher S. Buchanan, Cara F. Freeman, Joseph W. Rylander, Marissa Nichole TI In Vitro Angiogenesis Induced by Tumor-Endothelial Cell Co-Culture in Bilayered, Collagen I Hydrogel Bioengineered Tumors SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; CANCER CELLS; INDUCTION; EXPRESSION; INVASION; HYPOXIA; INVITRO; SWITCH; MODEL AB Although successful remission has been achieved when cancer is diagnosed and treated during its earliest stages of development, a tumor that has established neovascularization poses a significantly greater risk of mortality. The inability to recapitulate the complexities of a maturing in vivo tumor microenvironment in an in vitro setting has frustrated attempts to identify and test anti-angiogenesis therapies that are effective at permanently halting cancer progression. We have established an in vitro tumor angiogenesis model driven solely by paracrine signaling between MDA-MB-231 breast cancer cells and telomerase-immortalized human microvascular endothelial (TIME) cells co-cultured in a spatially relevant manner. The bilayered bioengineered tumor model consists of TIME cells cultured as an endothelium on the surface of an acellular collagen I hydrogel under which MDA-MB-231 cells are cultured in a separate collagen I hydrogel. Results showed that TIME cells co-cultured with the MDA-MB-231 cells demonstrated a significant increase in cell number, rapidly developed an elongated morphology, and invasively sprouted into the underlying acellular collagen I layer. Comparatively, bioengineered tumors cultured with less aggressive MCF7 breast cancer cells did not elicit an angiogenic response. Angiogenic sprouting was demonstrated by the formation of a complex capillary-like tubule network beneath the surface of a confluent endothelial monolayer with lumen formation and anastomosing branches. In vitro angiogenesis was dependent on vascular endothelial growth factor secretion, matrix concentration, and duration of co-culture. Basic fibroblast growth factor supplemented to the co-cultures augmented angiogenic sprouting. The development of improved preclinical tumor angiogenesis models, such as the one presented here, is critical for accurate evaluation and refinement of anti-angiogenesis therapies. C1 [Szot, Christopher S.; Buchanan, Cara F.; Rylander, Marissa Nichole] Wake Forest Univ, Virginia Polytech Inst, Sch Biomed Engn & Sci, Blacksburg, VA USA. [Freeman, Joseph W.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. [Rylander, Marissa Nichole] Virginia Polytech Inst & State Univ, Dept Mech Engn, Blacksburg, VA 24061 USA. RP Szot, CS (reprint author), NCI, Mouse Canc Genet Program, Tumor Angiogenesis Sect, Frederick Natl Lab Canc Res, POB B,Bldg 560 1050 Boyles St, Frederick, MD 21702 USA. EM szotc@vt.edu RI Rylander, Marissa Nichole/F-2455-2014 FU National Science Foundation [CBET 0955072]; National Institute of Health [1R21CA158454-01A1] FX The authors would like to thank Andrea Martin for generously donating the Sprague Dawley rat tails for collagen isolation. Funding for this study was provided by the National Science Foundation Early CAREER Award CBET 0955072 and the National Institute of Health grant 1R21CA158454-01A1. NR 37 TC 20 Z9 20 U1 0 U2 35 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 EI 1937-3392 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD NOV 1 PY 2013 VL 19 IS 11 BP 864 EP 874 DI 10.1089/ten.tec.2012.0684 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 234JJ UT WOS:000325639100005 PM 23516987 ER PT J AU Zazerskaya, IE Ishkaraeva, VV Frolova, EV Solodovnikova, NG Grigorova, YN Adair, CD Fedorova, OV Bagrov, AY AF Zazerskaya, Irina E. Ishkaraeva, Valentina V. Frolova, Elena V. Solodovnikova, Nelly G. Grigorova, Yulia N. Adair, C. David Fedorova, Olga V. Bagrov, Alexei Y. TI Magnesium Sulfate Potentiates Effect of Digifab on Marinobufagenin-Induced Na/K-ATPase Inhibition SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; cardiotonic steroids; digifab; digitalis-like factors; hypertension; immunotherapy; magnesium; marinobufagenin; NA; K-ATPase; preeclampsia ID PREECLAMPSIA; ECLAMPSIA; SODIUM AB Immunoneutralization of elevated circulating levels of endogenous digitalis-like Na/K-ATPase inhibitors (i.e. cardiotonic steroids (CTS)) represents a novel approach in the treatment of preeclampsia (PE). Recently we demonstrated that DigiFab (Fab fragments of affinity-purified ovine digoxin antibody) restores PE-induced inhibition of Na/K-ATPase in erythrocytes ex vivo. Previously magnesium ions were shown to antagonize digitalis-induced toxicity, which is mediated by Na/K-ATPase inhibition. We hypothesized that magnesium sulfate would potentiate the effect of DigiFab in the reversal of CTS-induced Na/K-ATPase inhibition. To test this hypothesis, we studied the ex vivo effect of DigiFab on Na/K-ATPase activity in erythrocytes from patients with PE in the absence and in the presence of 3 mmol/L magnesium sulfate. Compared with 11 normotensive pregnant subjects (291 years; gestational age 39.00.2 weeks; blood pressure 1112/732mm Hg), the 12 patients with PE (301 years; gestational age 37.90.3 weeks; blood pressure 1595/993mm Hg) had plasma levels of marino bufagenin increased 3-fold (1.380.40 vs. 0.380.10 nmol/L; P < 0.01) and activity of Na/K-ATPase in erythrocytes was inhibited (1.160.11 vs. 2.800.20 mol Pi/ml/h; P < 0.01). Ex vivo, DigiFab (1 g/ml) restored erythrocyte Na/K-ATPase activity (1.720.13 mol Pi/ml/h; P < 0.01), and 3 mmol magnesium sulfate potentiated the effect of DigiFab (2.300.20 mol Pi/ml/h; P < 0.01). Magnesium is capable of increasing the efficacy of immunoneutralization of marinobufagenin-induced Na/K-ATPase inhibition. C1 [Zazerskaya, Irina E.; Ishkaraeva, Valentina V.; Solodovnikova, Nelly G.; Grigorova, Yulia N.] Almazov Fed Heart Blood & Endocrinol Ctr, Inst Neonatol, St Petersburg, Russia. [Zazerskaya, Irina E.; Ishkaraeva, Valentina V.; Solodovnikova, Nelly G.; Grigorova, Yulia N.] Almazov Fed Heart Blood & Endocrinol Ctr, Inst Heart & Vessels, St Petersburg, Russia. [Frolova, Elena V.] Sechenov Inst Evolutionary Physiol & Biochem, St Petersburg, Russia. [Grigorova, Yulia N.; Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, NIH, Baltimore, MD 21224 USA. [Adair, C. David] Univ Tennessee, Dept Obstet & Gynecol, Chattanooga, TN USA. RP Bagrov, AY (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM bagrova@mail.nih.gov FU National Institute on Aging, National Institutes of Health; Ministry of Science and Education of Russian Federation [14.740.11.0928]; Glenveigh Pharmaceuticals, Chattanooga, Tennessee FX This work was supported by Intramural Research Program, National Institute on Aging, National Institutes of Health (O.V.F. and A.Y.B.); by a grant from Ministry of Science and Education of Russian Federation Nr. 14.740.11.0928 (I.E.Z., V. V. I., E. V. F., N.G.S.); and by Glenveigh Pharmaceuticals, Chattanooga, Tennessee (C. D. A.). We are grateful to Brigit Sullivan, NIH Library, for editing assistance. NR 14 TC 0 Z9 0 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD NOV PY 2013 VL 26 IS 11 BP 1269 EP 1272 DI 10.1093/ajh/hpt117 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 232HW UT WOS:000325484800003 PM 23878005 ER PT J AU Chen, JQ Heldman, MR Herrmann, MA Kedei, N Woo, W Blumberg, PM Goldsmith, PK AF Chen, Jin-Qiu Heldman, Madeleine R. Herrmann, Michelle A. Kedei, Noemi Woo, Wonhee Blumberg, Peter M. Goldsmith, Paul K. TI Absolute quantitation of endogenous proteins with precision and accuracy using a capillary Western system SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Protein kinase C (PKC); Capillary immunoassay; Simple Western; Quantitative protein analysis ID BIOMARKER DISCOVERY; MESSENGER-RNA; PHORBOL ESTER; BRYOSTATIN 1; KINASE-C; CELL; EXPRESSION; CANCER; PROSTATE; ANALOGS AB Precise and accurate quantification of protein expression levels in a complex biological setting is challenging. Here, we describe a method for absolute quantitation of endogenous proteins in cell lysates using an automated capillary immunoassay system, the size-based Simple Western system (recently developed by ProteinSimple). The method was able to accurately measure the absolute amounts of target proteins at picogram or sub-picogram levels per nanogram of cell lysates. The measurements were independent of the cell matrix or the cell lysis buffer and were not affected by different antibody affinities for their specific epitopes. We then applied this method to quantitate absolute levels of expression of protein kinase C (PKC) isoforms in LNCaP and U937 cells, two cell lines used extensively for probing the downstream biological responses to PKC targeted ligands. Our absolute quantitation confirmed the predominance of PKC delta in both cells, supporting the important functional role of this PKC isoform in these cell lines. The method described here provides an approach to accurately quantitate levels of protein expression and correlate protein level with function. In addition to enhanced accuracy relative to conventional Western analysis, it circumvents the distortions inherent in comparison with signal intensities from different antibodies with different affinities. Published by Elsevier Inc. C1 [Chen, Jin-Qiu; Heldman, Madeleine R.; Herrmann, Michelle A.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kedei, Noemi; Woo, Wonhee; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Goldsmith, Paul K.] NCI, Off Sci & Technol Partnership, Off Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Chen, JQ (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM chenj13@mail.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health [Z1A BC 005270, Z1C BC 011434] FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health (Z1A BC 005270, Z1C BC 011434). NR 19 TC 24 Z9 25 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD NOV 1 PY 2013 VL 442 IS 1 BP 97 EP 103 DI 10.1016/j.ab.2013.07.022 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 225OL UT WOS:000324972100012 PM 23896461 ER PT J AU Shah, R Stieltjes, B Andrulis, M Pfeiffer, R Sumkauskaite, M Delorme, S Schlemmer, HP Goldschmidt, H Landgren, O Hillengass, J AF Shah, Rajiv Stieltjes, Bram Andrulis, Mindaugas Pfeiffer, Ruth Sumkauskaite, Migle Delorme, Stefan Schlemmer, Heinz-Peter Goldschmidt, Hartmut Landgren, Ola Hillengass, Jens TI Intravoxel incoherent motion imaging for assessment of bone marrow infiltration of monoclonal plasma cell diseases SO ANNALS OF HEMATOLOGY LA English DT Article DE Diffusion-weighted imaging; Monoclonal gammopathy of undetermined significance; Multiple myeloma; Cellularity; Microcirculation ID APPARENT DIFFUSION-COEFFICIENT; POSITRON-EMISSION-TOMOGRAPHY; DIAGNOSED MULTIPLE-MYELOMA; SURVIVAL; TRANSPLANTATION; GAMMOPATHIES; PATTERN; MRI AB Modern imaging techniques have demonstrated that monoclonal plasma cell diseases infiltrate the bone marrow in a diffuse, focal, mixed pattern. While focal lesions can be easily counted and measured, the diffuse lesions of the infiltration are hard to assess. We therefore investigated 31 patients with monoclonal plasma cell diseases of all stages with intravoxel incoherent motion imaging of the same region of the pelvis from where afterwards a biopsy was obtained. We found a significant correlation between plasma cell percentage in bone marrow histology and the imaging parameters "apparent diffusion coefficient" and the diffusion coefficient D. Furthermore, those parameters correlated with other factors of disease activity, e.g., monoclonal protein, hemoglobin, and immunoparesis. In summary, we found that the non-invasively acquired imaging parameters correlated with the degree of plasma cell infiltration in the bone marrow. C1 [Shah, Rajiv; Stieltjes, Bram; Sumkauskaite, Migle; Delorme, Stefan; Schlemmer, Heinz-Peter] German Canc Res Ctr, Heidelberg, Germany. [Andrulis, Mindaugas] Heidelberg Univ, Inst Pathol, Heidelberg, Germany. [Pfeiffer, Ruth; Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. [Goldschmidt, Hartmut; Hillengass, Jens] Univ Heidelberg Hosp, Dept Hematol Oncol & Rheumatol, D-69126 Heidelberg, Germany. [Shah, Rajiv] Univ Heidelberg Hosp, Dept Thorac Oncol, Thoraxklin, D-69126 Heidelberg, Germany. RP Shah, R (reprint author), Univ Heidelberg Hosp, Dept Thorac Oncol, Thoraxklin, Amalienstr 5, D-69126 Heidelberg, Germany. EM rajiv.shah@thoraxklinik-heidelberg.de OI Delorme, Stefan/0000-0002-1000-2582 FU German Research Foundation (Transregio 79); International Myeloma Foundation FX Parts of this study have been supported by a grant from the German Research Foundation (Transregio 79) and a grant from the International Myeloma Foundation. NR 20 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 J9 ANN HEMATOL JI Ann. Hematol. PD NOV PY 2013 VL 92 IS 11 BP 1553 EP 1557 DI 10.1007/s00277-013-1786-1 PG 5 WC Hematology SC Hematology GA 230QQ UT WOS:000325357600014 PM 23680869 ER PT J AU Meissner, A Boshoff, HI Vasan, M Duckworth, BP Barry, CE Aldrich, CC AF Meissner, Anja Boshoff, Helena I. Vasan, Mahalakshmi Duckworth, Benjamin P. Barry, Clifton E., III Aldrich, Courtney C. TI Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Mycobacterium tuberculosis; Aminothiazole; High-throughput screening; Antibacterial agent ID PHARMACOKINETIC PROPERTIES; AGENTS; STREPTOMYCIN; HETEROCYCLES; ANTIBIOTICS; DERIVATIVES; INHIBITORS; GROWTH AB A series of 2-aminothiazoles was synthesized based on a HTS scaffold from a whole-cell screen against Mycobacterium tuberculosis (Mtb). The SAR shows the central thiazole moiety and the 2-pyridyl moiety at C-4 of the thiazole are intolerant to modification. However, the N-2 position of the aminothiazole exhibits high flexibility and we successfully improved the antitubercular activity of the initial hit by more than 128-fold through introduction of substituted benzoyl groups at this position. N-(3-Chlorobenzoyl)-4-(2-pyridinyl)-1,3-thiazol-2-amine (55) emerged as one of the most promising analogues with a MIC of 0.024 mu M or 0.008 mu g/mL in 7H9 media and therapeutic index of nearly similar to 300. However, 55 is rapidly metabolized by human liver microsomes (t(1/2) = 28 min) with metabolism occurring at the invariant aminothiazole moiety and Mtb develops spontaneous low-level resistance with a frequency of similar to 10 (5). (C) 2013 Elsevier Ltd. All rights reserved. C1 [Meissner, Anja; Vasan, Mahalakshmi; Duckworth, Benjamin P.; Aldrich, Courtney C.] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. RP Aldrich, CC (reprint author), Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. EM aldri015@umn.edu RI Barry, III, Clifton/H-3839-2012 FU National Institutes of Health [AI070219]; NIAID, NIH FX This research was supported by a National Institutes of Health Grant AI070219 (to C.C.A.) and the Intramural Research Program of the NIAID, NIH. NR 47 TC 16 Z9 16 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 1 PY 2013 VL 21 IS 21 BP 6385 EP 6397 DI 10.1016/j.bmc.2013.08.048 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 228DC UT WOS:000325164500013 PM 24075144 ER PT J AU Ha, TH Ryu, H Kim, SE Kim, HS Ann, J Tran, PT Hoang, VH Son, K Cui, MH Choi, S Blumberg, PM Frank, R Bahrenberg, G Schiene, K Christoph, T Frormann, S Lee, J AF Ha, Tae-Hwan Ryu, HyungChul Kim, Sung-Eun Kim, Ho Shin Ann, Jihyae Tran, Phuong-Thao Hoang, Van-Hai Son, Karam Cui, Minghua Choi, Sun Blumberg, Peter M. Frank, Robert Bahrenberg, Gregor Schiene, Klaus Christoph, Thomas Frormann, Sven Lee, Jeewoo TI TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE TRPV1 antagonists; Analgesic; Capsaicin; Resiniferatoxin ID CAPSAICIN RECEPTORS; RESINIFERATOXIN; TARGET AB A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ha, Tae-Hwan; Ryu, HyungChul; Kim, Sung-Eun; Kim, Ho Shin; Ann, Jihyae; Tran, Phuong-Thao; Hoang, Van-Hai; Lee, Jeewoo] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. [Son, Karam; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Div Life & Pharmaceut Sci, Natl Leading Res Lab NLRL Mol Modeling & Drug Des, Coll Pharm, Seoul 120750, South Korea. [Son, Karam; Cui, Minghua; Choi, Sun] Ewha Womans Univ, Global Res Program Top5, Seoul 120750, South Korea. [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Frank, Robert; Bahrenberg, Gregor; Schiene, Klaus; Christoph, Thomas; Frormann, Sven] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany. RP Lee, J (reprint author), Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr FU Grunenthal; National Research Foundation of Korea (NRF) [R11-2007-107-02001-0]; National Leading Research Lab (NLRL) program [2011-0028885]; Intramural Research Program of NIH, Center for Cancer Research, NCI [Z1A BC 005270] FX This research was supported by Research Grants from Grunenthal, Grants from the National Research Foundation of Korea (NRF) (R11-2007-107-02001-0), Grants from the National Leading Research Lab (NLRL) program (2011-0028885), and in part by the Intramural Research Program of NIH, Center for Cancer Research, NCI (Project Z1A BC 005270). NR 23 TC 9 Z9 9 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 1 PY 2013 VL 21 IS 21 BP 6657 EP 6664 DI 10.1016/j.bmc.2013.08.015 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 228DC UT WOS:000325164500042 PM 24035514 ER PT J AU MacDonough, MT Strecker, TE Hamel, E Hall, JJ Chaplin, DJ Trawick, ML Pinney, KG AF MacDonough, Matthew T. Strecker, Tracy E. Hamel, Ernest Hall, John J. Chaplin, David J. Trawick, Mary Lynn Pinney, Kevin G. TI Synthesis and biological evaluation of indole-based, anti-cancer agents inspired by the vascular disrupting agent 2-(3 '-hydroxy-4 '-methoxyphenyl)-3-(3 '',4 '',5 ''-trimethoxybenzoyl)-6-methoxyindole (OXi8006) SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Vascular disrupting agent (VDA); Inhibitor of tubulin assembly; Functionalized indole; Combretastatin ID ANTINEOPLASTIC AGENTS; TUBULIN POLYMERIZATION; COMBRETASTATIN A-4; COMBRETUM-CAFFRUM; BINDING-ACTIVITY; INHIBITORS; POTENT; ANALOGS; CYTOTOXICITY; MICROTUBULES AB The discovery of a 2-aryl-3-aroyl indole-based small-molecule inhibitor of tubulin assembly (referred to as OXi8006) inspired the design, synthesis, and biological evaluation of a series of diversely functionalized analogues. In the majority of examples, the pendant 2-aryl ring contained a 3-hydroxy-4-methoxy substitution pattern, and the fused aryl ring featured a 6-methoxy group. Most of the variability was in the 3-aroyl moiety, which was modified to incorporate methoxy (33-36), nitro (25-27), halogen (28-29), trifluoromethyl (30), or trifluoromethoxy (31-32) functionalities. In two analogues (34 and 36), the methoxy substitution pattern in the fused aryl ring varied, while in another derivative (35) the phenolic moiety was translocated from the pendant 2-aryl ring to position-7 of the fused aryl ring. Each of the compounds were evaluated for their cytotoxicity (in vitro) against the SK-OV-3 (ovarian), NCI-H460 (lung), and DU-145 (prostate) human cancer cell lines and for their ability to inhibit tubulin assembly. Four of the compounds (30, 31, 35, 36) proved to be potent inhibitors of tubulin assembly (IC50 < 5 mu M), and three of these compounds (31, 35, 36) were strongly cytotoxic against the three cancer cell lines. The most active compound (36) in this series, which incorporated a methoxy group at position-7, was comparable in terms of inhibition of tubulin assembly and cytotoxicity to the lead compound OXi8006. (C) 2013 Elsevier Ltd. All rights reserved. C1 [MacDonough, Matthew T.; Strecker, Tracy E.; Hall, John J.; Trawick, Mary Lynn; Pinney, Kevin G.] Baylor Univ, Dept Chem & Biochem, Waco, TX 76798 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Chaplin, David J.] Oxigene Inc, San Francisco, CA 94080 USA. RP Pinney, KG (reprint author), Baylor Univ, Dept Chem & Biochem, 1 Bear Pl 97348, Waco, TX 76798 USA. EM Kevin_Pinney@baylor.edu OI Pinney, Kevin/0000-0003-1262-8631 FU National Cancer Institute of the National Institutes of Health [5R01CA140674]; Oxigene Inc.; NSF [CHE-0420802] FX The authors are grateful to the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P. and M.L.T.) and Oxigene Inc. (grant to K.G.P. and M.L.T.) for their financial support of this project, and to the NSF for funding the Varian 500 MHz NMR spectrometer (Grant No. CHE-0420802). The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. The authors also thank Dr. James Karban and Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University, Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor University), and Dr. Kevin Klausmeyer (X-ray analysis). The authors are grateful to Mr. Robert Harris, Ms. Priscilla Hor, and Ms. Siri Ancha for their valuable contributions to the synthesis of certain analogues. NR 54 TC 20 Z9 20 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 EI 1464-3391 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD NOV 1 PY 2013 VL 21 IS 21 BP 6831 EP 6843 DI 10.1016/j.bmc.2013.07.028 PG 13 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 228DC UT WOS:000325164500061 PM 23993969 ER PT J AU Alonso, WJ Schuck-Paim, C AF Alonso, W. J. Schuck-Paim, C. TI What can the 2009 influenza outbreak teach us about the risk of a severe pandemic? The Madagascar experience SO EPIDEMIOLOGY AND INFECTION LA English DT Letter ID AFRICA C1 [Alonso, W. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Alonso, W. J.; Schuck-Paim, C.] Origem Sci, Sao Paulo, Brazil. RP Alonso, WJ (reprint author), NIH, Fogarty Int Ctr, 16 Ctr Dr,Bldg 16, Bethesda, MD 20892 USA. EM alonsow@mail.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD NOV PY 2013 VL 141 IS 11 BP 2454 EP 2455 DI 10.1017/S0950268812003068 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 228WH UT WOS:000325222100023 PM 23328345 ER PT J AU Ashmore, JH Lesko, SM Miller, PE Cross, AJ Muscat, JE Zhu, JJ Liao, J Harper, G Lazarus, P Hartman, TJ AF Ashmore, Joseph H. Lesko, Samuel M. Miller, Paige E. Cross, Amanda J. Muscat, Joshua E. Zhu, Junjia Liao, Jason Harper, Gregory Lazarus, Philip Hartman, Terryl J. TI Association of dietary and supplemental iron and colorectal cancer in a population-based study SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE colorectal cancer; heme; iron; supplements ID HEME IRON; COLON-CANCER; RED MEAT; ALCOHOL-CONSUMPTION; RISK; WOMEN; ZINC; VALIDATION; OVERLOAD; DISEASES AB We evaluated the role of dietary iron, heme iron, and supplemental iron on colorectal cancer (CRC) risk in a population-based case-control study in Pennsylvania, including 1005 incident cases and 1062 controls. Diet was assessed through a modified food frequency questionnaire that included supplement use and a meat-specific module. Cases reported intakes for the year before diagnosis, whereas controls reported intakes for the year before interview. Heme iron intake was calculated using a new heme database developed by the US National Cancer Institute. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. After multivariate adjustment, there were no significant associations between heme iron or total iron intake and CRC incidence. Dietary iron intake was inversely associated with CRC among women (OR Q(5) vs. Q(1)=0.45; 95% CI=0.22-0.92), but not among men. Supplemental iron intake of more than 18 mg/day versus none was positively associated with CRC incidence (OR=2.31; 95% CI=1.48-3.59; P-trend<0.001), an effect that was observed in both men (OR=2.56; 95% CI=1.30-5.05) and women (OR=2.46; 95% CI=1.34-4.52). These findings suggest that consumption of more than 18 mg/day of supplemental iron may increase risk for CRC. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Ashmore, Joseph H.; Hartman, Terryl J.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Lesko, Samuel M.] Northeast Reg Canc Inst, Scranton, PA USA. [Muscat, Joshua E.; Zhu, Junjia; Liao, Jason; Lazarus, Philip] Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Lazarus, Philip] Penn State Coll Med, Dept Pharmacol, Hershey, PA USA. [Harper, Gregory] Lehigh Valley Hosp, Dept Med & Pharmacol, Allentown, PA USA. [Miller, Paige E.] Exponent Inc, Dept Hlth Sci, Chicago, IL USA. [Cross, Amanda J.] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ashmore, JH (reprint author), Penn State Univ, Dept Nutr Sci, 110 Chandlee Lab, University Pk, PA 16802 USA. EM jha133@psu.edu FU Pennsylvania Department of Health [4100038714] FX This study was partially support by the Pennsylvania Department of Health (Grant number 4100038714). NR 35 TC 8 Z9 8 U1 1 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD NOV PY 2013 VL 22 IS 6 BP 506 EP 511 DI 10.1097/CEJ.0b013e32836056f8 PG 6 WC Oncology SC Oncology GA 227FH UT WOS:000325095300003 PM 23492957 ER PT J AU Hirabayashi, K Shiohara, M Yamada, K Sueki, A Ide, Y Takeuchi, K Hagimoto, R Kinoshita, T Yabuhara, A Mudd, SH Koike, K AF Hirabayashi, Koichi Shiohara, Masaaki Yamada, Kazuhiro Sueki, Akane Ide, Yuichiro Takeuchi, Koichi Hagimoto, Rokuro Kinoshita, Tatsuya Yabuhara, Akihiko Mudd, S. Harvey Koike, Kenichi TI Neurologically normal development of a patient with severe methionine adenosyltransferase I/III deficiency after continuing dietary methionine restriction SO GENE LA English DT Article DE Methionine adenosyltransferase I/III deficiency; Hypermethioninemia; Homocystinuria; Dietary methionine restriction; Psychomotor development ID BETA-SYNTHASE DEFICIENCY; S-ADENOSYLMETHIONINE; PERSISTENT HYPERMETHIONINEMIA; HOMOCYSTINURIA; DEMYELINATION; HOMOCYSTEINE; PATHWAY; STATES; BRAIN AB Background: There is not much information on established standard therapy for patients with severe methionine adenosyltransferase (MAT) I/III deficiency. Case presentation: We report a boy with MAT I/III deficiency, in whom plasma methionine and total homocysteine, and urinary homocystine were elevated. Molecular genetic studies showed him to have novel compound heterozygous mutations of the MAT1A gene: c.191T>A (p.M64K) and c.589delC (p.P197Lf5X26). A low methionine milk diet was started at 31 days of age, and during continuing dietary methionine restriction plasma methionine levels have been maintained at less than 750 mu mol/L. He is now 5 years old, and has had entirely normal physical growth and psychomotor development Conclusions: Although some severely MAT I/III deficient patients have developed neurologic abnormalities, we report here the case of a boy who has remained neurologically and otherwise normal for 5 years during methionine restriction, suggesting that perhaps such management, started in early infancy, may help prevent neurological complications. (C) 2013 Elsevier B.V. All rights reserved. C1 [Hirabayashi, Koichi; Hagimoto, Rokuro; Kinoshita, Tatsuya; Yabuhara, Akihiko] Ina Cent Hosp, Dept Pediat, Ina, Saitama, Japan. [Hirabayashi, Koichi; Shiohara, Masaaki; Koike, Kenichi] Shinshu Univ, Sch Med, Dept Pediat, Matsumoto, Nagano 3908621, Japan. [Yamada, Kazuhiro] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Koganei, Tokyo, Japan. [Sueki, Akane; Ide, Yuichiro] Shinshu Univ, Sch Med, Dept Lab Med, Matsumoto, Nagano 3908621, Japan. [Takeuchi, Koichi] Nagano Childrens Hosp, Dept Pediat Interdisciplinary Med, Azumino, Japan. [Mudd, S. Harvey] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Hirabayashi, K (reprint author), Shinshu Univ, Sch Med, Dept Pediat, Asahi 3-1-1, Matsumoto, Nagano 3908621, Japan. EM kohira@shinshu-u.ac.jp NR 31 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD NOV 1 PY 2013 VL 530 IS 1 BP 104 EP 108 DI 10.1016/j.gene.2013.08.025 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 229ZV UT WOS:000325307300015 PM 23973726 ER PT J AU Butterfield, RJ Foley, AR Dastgir, J Asman, S Dunn, DM Zou, YQ Hu, Y Donkervoort, S Flanigan, KM Swoboda, KJ Winder, TL Weiss, RB Bonnemann, CG AF Butterfield, Russell J. Foley, A. Reghan Dastgir, Jahannaz Asman, Stephanie Dunn, Diane M. Zou, Yaqun Hu, Ying Donkervoort, Sandra Flanigan, Kevin M. Swoboda, Kathryn J. Winder, Thomas L. Weiss, Robert B. Boennemann, Carsten G. TI Position of Glycine Substitutions in the Triple Helix of COL6A1, COL6A2, and COL6A3 is Correlated with Severity and Mode of Inheritance in Collagen VI Myopathies SO HUMAN MUTATION LA English DT Article DE collagen VI; Ullrich congenital muscular dystrophy; Bethlem myopathy; genotype-phenotype correlation ID CONGENITAL MUSCULAR-DYSTROPHY; BETHLEM MYOPATHY; VONWILLEBRAND-FACTOR; SEQUENCE-ANALYSIS; GLOBULAR DOMAINS; IV COLLAGEN; MUTATIONS; DOMINANT; COMMON; MUSCLE AB Glycine substitutions in the conserved Gly-X-Y motif in the triple helical (TH) domain of collagen VI are the most commonly identified mutations in the collagen VI myopathies including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate (INT) phenotypes. We describe clinical and genetic characteristics of 97 individuals with glycine substitutions in the TH domain of COL6A1, COL6A2, or COL6A3 and add a review of 97 published cases, for a total of 194 cases. Clinical findings include severe, INT, and mild phenotypes even from patients with identical mutations. INT phenotypes were most common, accounting for almost half of patients, emphasizing the importance of INT phenotypes to the overall phenotypic spectrum. Glycine substitutions in the TH domain are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they are acting as dominants. The most severe cases are clustered in an even smaller region including Gly-X-Y triplets 10-15, accounting for only 5% of the TH domain. Our findings suggest that clustering of glycine substitutions in the N-terminal region of collagen VI is not based on features of the primary sequence. We hypothesize that this region may represent a functional domain within the triple helix. C1 [Butterfield, Russell J.; Asman, Stephanie; Swoboda, Kathryn J.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Foley, A. Reghan] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Foley, A. Reghan] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London, England. [Foley, A. Reghan] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Dastgir, Jahannaz; Zou, Yaqun; Hu, Ying; Donkervoort, Sandra; Boennemann, Carsten G.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Dunn, Diane M.; Weiss, Robert B.] Univ Utah, Dept Human Genet, Salt Lake City, UT USA. [Flanigan, Kevin M.] Nationwide Childrens Hosp, Ctr Gene Therapy, Columbus, OH USA. [Winder, Thomas L.] Prevent Genet, Marshfield, WI USA. RP Bonnemann, CG (reprint author), Bldg 35 Porter NRC,Room 2A-116,35 Convent Dr MSC, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov OI Flanigan, Kevin/0000-0001-6440-3376 FU MDA Clinical Research Training Grant; Primary Children's Medical Center Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health [5K12HD001410-10]; Muscular Dystrophy Campaign; NIH/NINDS Intramural Research Funds FX Contract grant sponsors: MDA Clinical Research Training Grant (RJB); Primary Children's Medical Center Foundation (RJB); Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (5K12HD001410-10) (RJB); Muscular Dystrophy Campaign (ARF); NIH/NINDS Intramural Research Funds (CGB). NR 36 TC 20 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD NOV PY 2013 VL 34 IS 11 BP 1558 EP 1567 DI 10.1002/humu.22429 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 231OP UT WOS:000325426900015 PM 24038877 ER PT J AU Sprung, CL Danis, M Iapichino, G Artigas, A Kesecioglu, J Moreno, R Lippert, A Curtis, JR Meale, P Cohen, SL Levy, MM Truog, RD AF Sprung, Charles L. Danis, Marion Iapichino, Gaetano Artigas, Antonio Kesecioglu, Jozef Moreno, Rui Lippert, Anne Curtis, J. Randall Meale, Paula Cohen, Simon L. Levy, Mitchell M. Truog, Robert D. TI Triage of intensive care patients: identifying agreement and controversy SO INTENSIVE CARE MEDICINE LA English DT Article DE Consensus statement; Triage; Intensive care unit; Elderly ID CRITICALLY-ILL PATIENTS; PATIENTS REFUSED ADMISSION; DECISION-MAKING; UNITS; MORTALITY; ICU; DETERMINANTS; ALLOCATION; RESOURCES; SURVIVAL AB Intensive care unit (ICU) resources are limited in many hospitals. Patients with little likelihood of surviving are often admitted to ICUs. Others who might benefit from ICU are not admitted. To provide an updated consensus statement on the principles and recommendations for the triage of patients for ICU beds. The previous Society of Critical Care Medicine (SCCM) consensus statement was used to develop drafts of general and specific principles and recommendations. Investigators and consultants were sent the statements and responded with their agreement or disagreement. The Eldicus project (triage decision making for the elderly in European intensive care units). Eldicus investigators, consultants, and experts consisting of intensivists, users of ICU services, ethicists, administrators, and public policy officials. Consensus development was used to grade the statements and recommendations. Consensus was defined as 80 % agreement or more. Consensus was obtained for 54 (87 %) of 62 statements including all (19) general principles, 31 (86 %) of the specific principles, and 10 (71 %) of the recommendations. Inconsistencies in responses were noted for ICU admission and discharge. Despite agreement for guidelines applying to individual patients and an objective triage score, there was no agreement for a survival cutoff for triage, not even for a chance of survival of 0.1 %. Consensus was reached for most general and specific ICU triage principles and recommendations. Further debate and discussion should help resolve the remaining discrepancies. C1 [Sprung, Charles L.] Hadassah Hebrew Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, Gen Intens Care Unit, IL-91120 Jerusalem, Israel. [Danis, Marion] NIH, Sect Eth & Hlth Policy, Bethesda, MD 20892 USA. [Iapichino, Gaetano] Univ Milan, San Paolo Hosp, Milan, Italy. [Artigas, Antonio] Autonomous Univ Barcelona, Parc Tauli Univ Inst, CIBER Enfermedades Resp, Crit Care Ctr,Sabadell Hosp, Sabadell, Spain. [Kesecioglu, Jozef] Univ Med Ctr Utrecht, Dept Intens Care Med, Utrecht, Netherlands. [Moreno, Rui] Ctr Hosp Lisboa Cent, Hosp Sao Jose, EPE, Unidade Cuidados Intens Neurocrit, Lisbon, Portugal. [Lippert, Anne] Herlev Univ Hosp, Copenhagen, Denmark. [Curtis, J. Randall] Univ Washington, Harborview Med Ctr, Div Pulm & Crit Care Med, Seattle, WA 98104 USA. [Meale, Paula] UCL, Div Surg & Intervent Sci, London, England. [Cohen, Simon L.] UCL, Dept Intens Care Med, London, England. [Levy, Mitchell M.] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Div Pulm & Crit Care Med, Providence, RI 02903 USA. [Truog, Robert D.] Harvard Univ, Childrens Hosp, Sch Med, Div Med Eth, Boston, MA 02115 USA. [Truog, Robert D.] Harvard Univ, Childrens Hosp, Sch Med, Div Anaesthesiol, Boston, MA 02115 USA. [Truog, Robert D.] Harvard Univ, Childrens Hosp, Sch Med, Div Pediat, Boston, MA 02115 USA. RP Sprung, CL (reprint author), Hadassah Hebrew Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, Gen Intens Care Unit, POB 12000, IL-91120 Jerusalem, Israel. EM sprung@cc.huji.ac.il FU European Commission [QLK6-CT-2002-00251]; European Society of Intensive Care Medicine; European Critical Care Research Network; Israel National Institute for Health Policy and Health Services Research [1998/11/G]; Red GIRA [G03/063] FX Supported by the European Commission contract QLK6-CT-2002-00251, the European Society of Intensive Care Medicine and the European Critical Care Research Network, The Israel National Institute for Health Policy and Health Services Research grant number 1998/11/G and by Red GIRA G03/063. The EU Commission and other sponsors had no role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. All authors participated in the design of the study, helped in the analysis of the data, and collaborated in drafting and revising the manuscript. As this is a study of triage and ethical issues, the authors' have no financial or personal relationships or affiliations that could influence (or bias) their decisions, work, or manuscript. NR 33 TC 28 Z9 28 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2013 VL 39 IS 11 BP 1916 EP 1924 DI 10.1007/s00134-013-3033-6 PG 9 WC Critical Care Medicine SC General & Internal Medicine GA 227KE UT WOS:000325110800004 PM 23925544 ER PT J AU Koepke, KM Miller, B AF Koepke, Kathleen Mann Miller, Brett TI At the Intersection of Math and Reading Disabilities: Introduction to the Special Issue SO JOURNAL OF LEARNING DISABILITIES LA English DT Editorial Material DE math; reading; learning disabilities; comorbidity ID REMEDIATING NUMBER COMBINATION; LEARNING-DIFFICULTIES; MATHEMATICS; CHILDREN; COMORBIDITY; STUDENTS; DEFICITS; PREVALENCE; DISORDERS; COGNITION AB Individuals with comorbid disabilities in mathematics and reading face significant challenges in acquiring the componential skills related to each domain. Persons with these comorbid conditions are significantly understudied and this paucity of work limits how effective practitioners can be at addressing the needs of this population. In the United States, roughly 7% of all children suffer from math disability; of these, an estimated 17% to 66% also has a comorbid reading disability. Underspecification of current conceptualizations of math and reading disabilities, including how to best identify and classify individuals with one or more of these disabilities, hampers our efforts to intervene effectively. To conceptualize how to move forward in these areas, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop focused on examining the etiology, classification, and remediation of comorbid math and reading disabilities. This special issue, titled At the Intersection of Math and Reading Disabilities, continues that discussion. Contributing authors articulate a path forward to address the needs of these learners and inform the foundational understanding of both conditions in isolation and as they interact. C1 [Koepke, Kathleen Mann; Miller, Brett] US NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20852 USA. RP Koepke, KM (reprint author), US NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,Suite 4B05,MSC 7510, Bethesda, MD 20852 USA. EM kmk@nih.gov NR 36 TC 6 Z9 6 U1 3 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-2194 J9 J LEARN DISABIL-US JI J. Learn. Disabil. PD NOV PY 2013 VL 46 IS 6 SI SI BP 483 EP 489 DI 10.1177/0022219413498200 PG 7 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 232GB UT WOS:000325479000001 ER PT J AU Nicoll, RA Roche, KW AF Nicoll, Roger A. Roche, Katherine W. TI Long-term potentiation: Peeling the onion SO NEUROPHARMACOLOGY LA English DT Review DE NMDA receptor; AMPA receptor; CaMKII; Long-term potentiation; Synapse ID AMPA RECEPTOR TRAFFICKING; SINGLE DENDRITIC SPINES; DEPENDENT KINASE-II; SYNAPTIC PLASTICITY; HIPPOCAMPAL SLICE; PRESYNAPTIC ENHANCEMENT; PROTEIN-SYNTHESIS; SILENT SYNAPSES; GLUR1 SUBUNIT; LTP AB Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often difficult, especially for someone not directly involved in the field, not to be overwhelmed. The goal of this review is to peel away as many layers as possible, and probe the core properties of LTP. We would argue that the many dozens of proteins that have been implicated in the phenomenon are not essential, but rather modulate, often in indirect ways, the threshold and/or magnitude of LTP. What is required is NMDA receptor activation followed by CaMKII activation. The consequence of CaMKII activation is the rapid recruitment of AMPA receptors to the synapse. This recruitment is independent of AMPA receptor subunit type, but absolutely requires an adequate pool of surface receptors. An important unresolved issue is how exactly CaMKII activation leads to modifications in the PSD to allow rapid enrichment. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Nicoll, Roger A.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [Nicoll, Roger A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA. [Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Nicoll, RA (reprint author), Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, Genentech Hall,600 16th St,Box 2140, San Francisco, CA 94143 USA. EM roger.nicoll@ucsf.edu OI Roche, Katherine/0000-0001-7282-6539 FU NIMH NIH HHS [R01 MH070957]; NINDS NIH HHS [P01 NS016033] NR 65 TC 43 Z9 43 U1 4 U2 72 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD NOV PY 2013 VL 74 SI SI BP 18 EP 22 DI 10.1016/j.neuropharm.2013.02.010 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 229DD UT WOS:000325241100004 PM 23439383 ER PT J AU Lodge, D Tidball, P Mercier, MS Lucas, SJ Hanna, L Ceolin, L Kritikos, M Fitzjohn, SM Sherwood, JL Bannister, N Volianskis, A Jane, DE Bortolotto, ZA Collingridge, GL AF Lodge, David Tidball, Patrick Mercier, Marion S. Lucas, Sarah J. Hanna, Lydia Ceolin, Laura Kritikos, Minos Fitzjohn, Stephen M. Sherwood, John L. Bannister, Neil Volianskis, Arturas Jane, David E. Bortolotto, Zuner A. Collingridge, Graham L. TI Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors SO NEUROPHARMACOLOGY LA English DT Article DE Metabotropic glutamate receptors; mGlul; mGlu2; mGlu5; mGlu8; DHPG; DCG-IV; Long-term depression ID LONG-TERM DEPRESSION; PROTEIN-COUPLED RECEPTORS; EXCITATORY SYNAPTIC-TRANSMISSION; AGONIST-INDUCED INTERNALIZATION; HIPPOCAMPAL CA1 REGION; RAT PREFRONTAL CORTEX; MGLUR-DEPENDENT LTD; DHPG-INDUCED LTD; MOSSY FIBER LTD; DENTATE GYRUS AB Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Lodge, David; Tidball, Patrick; Mercier, Marion S.; Lucas, Sarah J.; Hanna, Lydia; Ceolin, Laura; Kritikos, Minos; Fitzjohn, Stephen M.; Sherwood, John L.; Bannister, Neil; Volianskis, Arturas; Jane, David E.; Bortolotto, Zuner A.; Collingridge, Graham L.] Univ Bristol, Sch Physiol & Pharmacol, Ctr Synapt Plast, Bristol BS1 3NY, Avon, England. [Lucas, Sarah J.] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Ceolin, Laura] Univ Montpellier 2, Univ Montpellier 1, INSERM U661, Inst Funct Genom,CNRS UMR5203, F-34000 Montpellier, France. [Fitzjohn, Stephen M.; Sherwood, John L.] Eli Lilly & Co, Lilly Res Ctr, Neurosci Res Div, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England. [Collingridge, Graham L.] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul 151746, South Korea. RP Lodge, D (reprint author), Univ Bristol, Sch Physiol & Pharmacol, Ctr Synapt Plast, Dorothy Hodgkin Bldg, Bristol BS1 3NY, Avon, England. EM David.Lodge@Bristol.ac.uk RI Collingridge, Graham/C-4605-2015; OI Collingridge, Graham/0000-0002-9572-5359; Sherwood, John/0000-0002-8484-1100; Fitzjohn, Stephen/0000-0002-3859-7530; Lucas, Sarah/0000-0002-5577-763X FU Eli Lilly; BBSRC; MRC; Wellcome Trust; WCU Program (Republic of Korea) FX This work was supported by Eli Lilly, BBSRC, MRC and Wellcome Trust (all UK) and the WCU Program (Republic of Korea). NR 108 TC 12 Z9 12 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD NOV PY 2013 VL 74 SI SI BP 135 EP 146 DI 10.1016/j.neuropharm.2013.03.011 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 229DD UT WOS:000325241100017 PM 23542080 ER PT J AU Darnell, MC Sun, JY Mehta, M Johnson, C Arany, PR Suo, ZG Mooney, DJ AF Darnell, Max C. Sun, Jeong-Yun Mehta, Manav Johnson, Christopher Arany, Praveen R. Suo, Zhigang Mooney, David J. TI Performance and biocompatibility of extremely tough alginate/polyacrylamide hydrogels SO BIOMATERIALS LA English DT Article DE Biocompatibility; Hydrogel; Mechanical properties; Tendon prosthesis ID IN-VITRO BIOCOMPATIBILITY; POLYACRYLAMIDE HYDROGELS; DEGRADATION; ACRYLAMIDE; BIOMATERIALS; OXIDATION; CARTILAGE; STRENGTH; RELEASE; CELLS AB Although hydrogels now see widespread use in a host of applications, low fracture toughness and brittleness have limited their more broad use. As a recently described interpenetrating network (IPN) of alginate and polyacrylamide demonstrated a fracture toughness of similar to 9000 J/m(2), we sought to explore the biocompatibility and maintenance of mechanical properties of these hydrogels in cell culture and in vivo conditions. These hydrogels can sustain a compressive strain of over 90% with minimal loss of Young's Modulus as well as minimal swelling for up to 50 days of soaking in culture conditions. Mouse mesenchymal stem cells exposed to the IPN gel-conditioned media maintain high viability, and although cells exposed to conditioned media demonstrate slight reductions in proliferation and metabolic activity (WST assay), these effects are abrogated in a dose-dependent manner. Implantation of these IPN hydrogels into subcutaneous tissue of rats for 8 weeks led to mild fibrotic encapsulation and minimal inflammatory response. These results suggest the further exploration of extremely tough alginate/PAAM IPN hydrogels as biomaterials. (c) 2013 Elsevier Ltd. All rights reserved. C1 [Darnell, Max C.; Sun, Jeong-Yun; Mehta, Manav; Arany, Praveen R.; Suo, Zhigang; Mooney, David J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Darnell, Max C.; Mehta, Manav; Johnson, Christopher; Arany, Praveen R.; Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Sun, Jeong-Yun; Suo, Zhigang] Kavli Inst Bionano Sci & Technol, Cambridge, MA 02138 USA. [Arany, Praveen R.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20982 USA. RP Mooney, DJ (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM mooneyd@deas.harvard.edu RI Suo, Zhigang/B-1067-2008 OI Suo, Zhigang/0000-0002-4068-4844 FU National Institutes of Health [R01 DE013349, R37 DEO013033]; intramural research program of the NIDCR/NIH(PA) FX The authors would like to thank Dr. Evi Lippens for helpful discussions regarding the histology, and funding support from the National Institutes of Health (R01 DE013349, R37 DEO013033). This research was partially supported by the intramural research program of the NIDCR/NIH (PA). NR 24 TC 52 Z9 53 U1 20 U2 208 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2013 VL 34 IS 33 BP 8042 EP 8048 DI 10.1016/j.biomaterials.2013.06.061 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 222HB UT WOS:000324720700004 PM 23896005 ER PT J AU Jaeger, AA Das, CK Morgan, NY Pursley, RH McQueen, PG Hall, MD Pohida, TJ Gottesman, MM AF Jaeger, Ashley A. Das, Chandan K. Morgan, Nicole Y. Pursley, Randall H. McQueen, Philip G. Hall, Matthew D. Pohida, Thomas J. Gottesman, Michael M. TI Microfabricated polymeric vessel mimetics for 3-D cancer cell culture SO BIOMATERIALS LA English DT Article DE Bioreactor; Silicone; Hydrogel; Microstructure; Oxygenation; Carcinogenesis ID BASEMENT-MEMBRANE MATRIX; EXTRACELLULAR-MATRIX; DRUG-RESISTANCE; BREAST-CANCER; IN-VITRO; TUMOR MICROENVIRONMENT; BIOARTIFICIAL LIVER; SPHEROID CULTURE; RAT HEPATOCYTES; GENE-EXPRESSION AB Modeling tumor growth in vitro is essential for cost-effective testing of hypotheses in preclinical cancer research. 3-D cell culture offers an improvement over monolayer culture for studying cellular processes in cancer biology because of the preservation of cell cell and cell-ECM interactions. Oxygen transport poses a major barrier to mimicking in vivo environments and is not replicated in conventional cell culture systems. We hypothesized that we can better mimic the tumor microenvironment using a bioreactor system for controlling gas exchange in cancer cell cultures with silicone hydrogel synthetic vessels. Soft-lithography techniques were used to fabricate oxygen-permeable silicone hydrogel membranes containing arrays of micropillars. These membranes were inserted into a bioreactor and surrounded by basement membrane extract (BME) within which fluorescent ovarian cancer (OVCAR8) cells were cultured. Cell clusters oxygenated by synthetic vessels showed a similar to 100 mu m drop-off to anoxia, consistent with in vivo studies of tumor nodules fed by the microvasculature. Oxygen transport in the bioreactor system was characterized by experimental testing with a dissolved oxygen probe and finite element modeling of convective flow. Our study demonstrates differing growth patterns associated with controlling gas distributions to better mimic in vivo conditions. Published by Elsevier Ltd. C1 [Jaeger, Ashley A.; Das, Chandan K.; Hall, Matthew D.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Jaeger, Ashley A.; Pursley, Randall H.; McQueen, Philip G.; Pohida, Thomas J.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Morgan, Nicole Y.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Information Technology; National Institute of Biomedical Imaging and Bioengineering FX This work was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Information Technology, and the National Institute of Biomedical Imaging and Bioengineering. NR 68 TC 7 Z9 7 U1 1 U2 55 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD NOV PY 2013 VL 34 IS 33 BP 8301 EP 8313 DI 10.1016/j.biomaterials.2013.07.013 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 222HB UT WOS:000324720700029 PM 23911071 ER PT J AU Valente, AJ Sakamuri, SSVP Siddesha, JM Yoshida, T Gardner, JD Prabhu, R Siebenlist, U Chandrasekar, B AF Valente, Anthony J. Sakamuri, Siva S. V. P. Siddesha, Jalahalli M. Yoshida, Tadashi Gardner, Jason D. Prabhu, Ramesh Siebenlist, Ulrich Chandrasekar, Bysani TI TRAF3IP2 mediates interleukin-18-induced cardiac fibroblast migration and differentiation SO CELLULAR SIGNALLING LA English DT Article DE RNA interference; Cardiac fibroblasts; Migration; TRAF3IP2; Cardiac fibrosis; Remodeling ID NF-KAPPA-B; GROWTH-FACTOR; TRANSCRIPTION FACTORS; CIKS ACT1; IN-VIVO; EXPRESSION; CELL; PROTEIN; INFLAMMATION; ACTIVATION AB TRAF3IP2 is a cytoplasmic adapter protein and an upstream regulator of IKK/NF-kappa B and JNK/AP-1. Here we demonstrate for the first time that the proinflammatory cytokine interleukin (IL)-18 induces TRAF3IP2 expression in primary cardiac fibroblasts (CF) in a Nox4/hydrogen peroxide-dependent manner. Silencing TRAF3IP2 using a phosphorothioated, 2'-O-methyl modified, cholesterol-tagged TRAF3IP2 siRNA duplex markedly attenuated IL-18-induced NF-kappa B and AP-1 activation and CF migration. Using co-IP/IB and co-localization experiments, we show that Nox4 physically associates with IL-18 receptor proteins, and IL-18 enhances their binding. Further, IL-18 promotes fibroblast to myofibroblast transition, as evidenced by enhanced a-smooth muscle actin expression, types 1 and 3 collagen induction, and soluble collagen secretion, via TRAF3IP2. These results indicate that TRAF3IP2 is a critical intermediate in IL-18-induced CF migration and differentiation in vitro. TRAF3IP2 could serve as a potential therapeutic target in cardiac fibrosis and adverse remodeling in vivo. (C) 2013 Elsevier Inc. All rights reserved. C1 [Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Valente, Anthony J.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Sakamuri, Siva S. V. P.; Siddesha, Jalahalli M.; Yoshida, Tadashi; Chandrasekar, Bysani] Tulane Univ, Sch Med, Inst Heart & Vasc, New Orleans, LA 70112 USA. [Gardner, Jason D.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Prabhu, Ramesh] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Chandrasekar, Bysani] Southeast Louisiana Vet Hlth Care Syst, Res Serv, New Orleans, LA 70161 USA. RP Chandrasekar, B (reprint author), Tulane Univ, Sch Med, Inst Heart & Vasc, 1430 Tulane Ave, New Orleans, LA 70112 USA. EM bchandra@tulane.edu OI Yoshida, Tadashi/0000-0002-4544-1497 FU Department of Veterans Affairs Research Career Scientist award; VA Office of Research and Development Biomedical Laboratory Research and Development Service Award [1IO1BX000246]; NIH/NHLBI [HL-86787] FX BC is a recipient of the Department of Veterans Affairs Research Career Scientist award, and is supported by VA Office of Research and Development Biomedical Laboratory Research and Development Service Award 1IO1BX000246 and the NIH/NHLBI grant HL-86787. The contents of this report do not represent the views of the Department of Veterans Affairs or the United States Government NR 30 TC 18 Z9 19 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD NOV PY 2013 VL 25 IS 11 BP 2176 EP 2184 DI 10.1016/j.cellsig.2013.07.013 PG 9 WC Cell Biology SC Cell Biology GA 225OI UT WOS:000324971800011 PM 23872479 ER PT J AU Lin, YC Tsai, JY Yang, JS Lee, YH Hamel, E Lee, KH Kuo, SC Huang, LJ AF Lin, Yi-Chien Tsai, Jui-Ying Yang, Jai-Sing Lee, Yueh-Hsuan Hamel, Ernest Lee, Kuo-Hsiung Kuo, Sheng-Chu Huang, Li-Jiau TI The novel synthetic compound 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b]indole induces mitotic arrest and apoptosis in human COLO 205 cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b]indole; alpha-caboline derivative; human colon carcinoma COLO 205; mitotic arrest; apoptosis; aurora kinase ID AURORA-KINASE INHIBITORS; CANCER-THERAPY; COLORECTAL-CANCER; ANTICANCER AGENTS; BCL-2 FAMILY; PATHWAYS; GROWTH; BAX; MECHANISMS; PROTEINS AB A novel synthetic compound 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido[2,3-b]indole (HAC-Y6) demonstrated selective anticancer activity. In the present study, COLO 205 cells were treated with HAC-Y6 to investigate the molecular mechanisms underlying its effects. HAC-Y6 induced growth inhibition, G(2)/M arrest and apoptosis in COLO 205 cells with an IC50 of 0.52 +/- 0.035 mu M. Annexin V/PI double staining demonstrated the presence of apoptotic cells. JC-1 staining analysis showed that HAC-Y6 decreased mitochondrial membrane potential in support of apoptosis. An immunostaining assay revealed that HAC-Y6 depolymerized microtubules. Treatment of COLO 205 cells with HAC-Y6 resulted in increased expression of BubR1 and cyclin B1 and decreased expression of aurora A, phospho-aurora A, aurora B, phospho-aurora B and phospho-H3. HAC-Y6 treatment increased protein levels of active caspase-3, caspase-9, Endo G, AIF, Apaf-1, cytochrome c and Bax, but treatment with the compound caused reduced levels of procaspase-3, procaspase-9, Bcl-xL and Bcl-2. Overall, our results suggest that HAC-Y6 exerts anticancer effects by disrupting microtubule assembly and inducing G(2)/M arrest, polyploidy and apoptosis via mitochondrial pathways in COLO 205 cells. C1 [Lin, Yi-Chien; Tsai, Jui-Ying; Lee, Yueh-Hsuan; Kuo, Sheng-Chu; Huang, Li-Jiau] China Med Univ, Grad Inst Pharmaceut Chem, Taichung 40402, Taiwan. [Yang, Jai-Sing] China Med Univ, Dept Pharmacol, Taichung 40402, Taiwan. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Lee, Kuo-Hsiung] Univ N Carolina, Nat Prod Res Labs, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Lee, Kuo-Hsiung] China Med Univ Hosp, Chinese Med Res & Dev Ctr, Taichung 40402, Taiwan. RP Huang, LJ (reprint author), China Med Univ, Grad Inst Pharmaceut Chem, 91 Hsueh Shih Rd, Taichung 40402, Taiwan. EM ljhuang@mail.cmu.edu.tw RI Yang, Jai Sing/M-1162-2015 FU National Science Council of the Republic of China [NSC 98-2628-B-039-018-MY3] FX This study was supported by a research grant from the National Science Council of the Republic of China, awarded to L.-J.H. (NSC 98-2628-B-039-018-MY3). Experiments and data analysis were performed, in part, through the use of the Medical Research Core Facilities Center, Office of Research and Development, China Medical University, Taichung, Taiwan, R.O.C. NR 44 TC 3 Z9 3 U1 0 U2 10 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 NOV PY 2013 VL 43 IS 5 BP 1596 EP 1606 DI 10.3892/ijo.2013.2069 PG 11 WC Oncology SC Oncology GA 225SN UT WOS:000324982700031 PM 23970288 ER PT J AU Wood, AC Maris, JM Gorlick, R Kolb, EA Keir, ST Reynolds, CP Kang, MH Wu, JR Kurmasheva, RT Whiteman, K Houghton, PJ Smith, MA AF Wood, Andrew C. Maris, John M. Gorlick, Richard Kolb, E. Anders Keir, Stephen T. Reynolds, C. Patrick Kang, Min H. Wu, Jianrong Kurmasheva, Raushan T. Whiteman, Kathleen Houghton, Peter J. Smith, Malcolm A. TI Initial Testing (Stage 1) of the Antibody-Maytansinoid Conjugate, IMGN901 (Lorvotuzumab Mertansine), by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE antibody-maytansinoid conjugate; developmental therapeutics; microtubules; preclinical testing ID CELL-ADHESION MOLECULE; TUMOR XENOGRAFTS; DRUG CONJUGATE; USEFUL MARKER; PHASE-I; CANCER; CD56; EXPRESSION; COMBINATION; RHABDOMYOSARCOMA AB BackgroundIMGN901 (lorvotuzumab mertansine) is an antibody-drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is conjugated to the maytansinoid, DM1 (a microtubule targeting agent). ProceduresIMGN901 and DM1-SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01nM to 0.1 mu M and 0.3pM to 3nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated. ResultsNeuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1-SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non-neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high-level staining by IHC for CD56, but not all xenografts with homogenous high-level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models. ConclusionsIMGN901 has anti-tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. Pediatr Blood Cancer 2013;60:1860-1867. (c) 2013 Wiley Periodicals, Inc. C1 [Wood, Andrew C.; Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Hematol Oncol Div Oncol, Philadelphia, PA 19104 USA. [Wood, Andrew C.; Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Whiteman, Kathleen] ImmunoGen Inc, Waltham, MD USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Maris, JM (reprint author), Childrens Hosp Philadelphia, Hematol Oncol Div Oncol, 3615 Civ Ctr Blvd,CTRB 3060, Philadelphia, PA 19104 USA. EM maris@chop.edu OI Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CM91001-03, CA21765, CA108786]; ImmunoGen, Inc. FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CM91001-03, CA21765, CA108786; Grant sponsor: Robert Lutz of ImmunoGen, Inc. NR 43 TC 7 Z9 7 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2013 VL 60 IS 11 BP 1860 EP 1867 DI 10.1002/pbc.24647 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 216QU UT WOS:000324299800029 PM 23798344 ER PT J AU Cheng, J Zhen, YY Miksys, S Beyoglu, D Krausz, KW Tyndale, RF Yu, AM Idle, JR Gonzalez, FJ AF Cheng, Jie Zhen, Yueying Miksys, Sharon Beyoglu, Diren Krausz, Kristopher W. Tyndale, Rachel F. Yu, Aiming Idle, Jeffrey R. Gonzalez, Frank J. TI Potential role of CYP2D6 in the central nervous system SO XENOBIOTICA LA English DT Article DE Anxiety; brain; CYP2D6; serotonin ID HARMALINE-INDUCED TREMOR; MONOXIDE-BINDING PIGMENT; HUMANIZED MOUSE MODEL; FORCED SWIMMING TEST; CYTOCHROME-P450 2D6; DEBRISOQUINE SULFATE; CEREBROSPINAL-FLUID; LIVER MICROSOMES; DRUG-METABOLISM; HUMAN BRAIN AB 1. Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest that CYP2D6 may have a function in the central nervous system. 2. To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type (WT) C57BL/6 mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including the CYP2D6 gene and 5'- and 3'-flanking sequences. 3. Human CYP2D6 was expressed not only in the liver but also in the brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice, either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of L-carnitine, acetyl-L-carnitine, pantothenic acid, 2'-deoxycytidine diphosphate (dCDP), anandamide, N-acetylglucosaminylamine and a down-regulation of stearoyl-L-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety. 4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function. C1 [Cheng, Jie; Zhen, Yueying; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miksys, Sharon; Tyndale, Rachel F.] Univ Toronto, Dept Pharmacol & Toxicol, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Miksys, Sharon; Tyndale, Rachel F.] Univ Toronto, Dept Psychiat, Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Beyoglu, Diren; Idle, Jeffrey R.] Univ Bern, Dept Clin Res, Hepatol Res Grp, Bern, Switzerland. [Yu, Aiming] SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov OI Idle, Jeff/0000-0002-6143-1520 FU National Cancer Institute Intramural Research Program; CIHR [MOP97751]; CAMH; Canada Foundation for Innovation [20289, 16014]; CAMH Foundation; Ontario Ministry of Research and Innovation FX This study was supported by the National Cancer Institute Intramural Research Program, a CIHR grant MOP97751, CAMH and the Canada Foundation for Innovation (#20289 and #16014), the CAMH Foundation and the Ontario Ministry of Research and Innovation. NR 63 TC 17 Z9 19 U1 1 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD NOV PY 2013 VL 43 IS 11 BP 973 EP 984 DI 10.3109/00498254.2013.791410 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 227GN UT WOS:000325099600005 PM 23614566 ER PT J AU Hong, SP Fuciarelli, AF Johnson, JD Graves, SW Bates, DJ Smith, CS Waidyanatha, S AF Hong, S. Peter Fuciarelli, Alfred F. Johnson, Jerry D. Graves, Steven W. Bates, Derrick J. Smith, Cynthia S. Waidyanatha, Suramya TI Toxicokinetics of Isoeugenol in F344 rats and B6C3F(1) mice SO XENOBIOTICA LA English DT Article DE Bioavailability; Isoeugenol; toxicokinetics ID FISCHER-344 RAT; METABOLISM; SAFROLE; PHARMACOKINETICS; METHYLEUGENOL; CONSTITUENTS; DERIVATIVES; INDUCTION; TOXICITY; MOUSE AB 1. Isoeugenol (IEG) has been tested for toxicity and carcinogenicity due to high potential for human exposure and the structural resemblance to known carcinogenic allylbenzenes. In order to support the interpretation of toxicity and carcinogenecity study outcomes, a toxicokinetic study was performed in which both sexes of F344 rats and B6C3F(1) mice were given IEG as a single intravenous (IV) or gavage administration. 2. Following IV administration, IEG was rapidly eliminated from systemic circulation in both species and sexes. Gavage administration revealed a rapid absorption of IEG with t(max) values <= 20 min for both species and sexes. In rats, AUC increased in a greater than dose-proportional manner and Cl-app values decreased with increasing dose in both sexes suggesting saturation of IEG metabolism. On the other hand, Cl-app values in male mice increased with increasing dose suggesting induction of IEG metabolism although this was not evident in the females. 3. Absolute bioavailability was greater in female rats (19%) than male rats (10%) (p < 0.0001), but was not different between the sexes for mice (28% males; 31% females) (p = 0.2437). The collective toxicokinetic data supported that low bioavailability following administration of IEG was the result of extensive first-pass metabolism. C1 [Hong, S. Peter; Johnson, Jerry D.; Graves, Steven W.] Battelle Mem Inst, Columbus, OH 43201 USA. [Fuciarelli, Alfred F.] Valdosta State Univ, Valdosta, GA USA. [Bates, Derrick J.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Smith, Cynthia S.; Waidyanatha, Suramya] NIEHS, Res Triangle Pk, NC 27709 USA. RP Hong, SP (reprint author), Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. EM hongs@battelle.org NR 32 TC 2 Z9 2 U1 2 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0049-8254 J9 XENOBIOTICA JI Xenobiotica PD NOV PY 2013 VL 43 IS 11 BP 1010 EP 1017 DI 10.3109/00498254.2013.790576 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 227GN UT WOS:000325099600008 PM 23627552 ER PT J AU Zoico, E Corzato, F Bambace, C Rossi, AP Micciolo, R Cinti, S Harris, TB Zamboni, M AF Zoico, Elena Corzato, Francesca Bambace, Clara Rossi, Andrea P. Micciolo, Rocco Cinti, Saverio Harris, Tamara B. Zamboni, Mauro TI Myosteatosis and myofibrosis: Relationship with aging, inflammation and insulin resistance SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE Muscle quality; Fat infiltration; Fibrosis; Aging ID ADIPOSE-TISSUE INFILTRATION; SKELETAL-MUSCLE; BODY-COMPOSITION; SARCOPENIA; STRENGTH; FIBROSIS; ACTIVATION; MYOSTATIN; THERAPY; HEALTH AB The mechanisms impairing muscle quality and leading to myofibrosis (MF) and myosteatosis (MS) are incompletely known. In biopsies of paraspinous muscle (PM) of 16 elderly men undergoing elective vertebral surgery, we histologically determined the area of MF and MS expressed as muscle quality index (MQI), in order to investigate the relation between them, as well as the main predictors of muscle quality. Total PM area and intermuscular adipose tissue (IMAT) were evaluated by MRI and body composition by DXA. Circulating fasting glucose, insulin, hs-CRP, leptin, adiponectin and IL-6 were measured and HOMA index calculated. Quantification of gene expression in PM and in subcutaneous adipose tissue (SAT) overlying the muscle was performed by rt-PCR. The degree of MS and MF was significantly and positively related to each other and positively associated with BMI, waist, FM and FM% as well as with IMAT. The area of PM was negatively related with MF even after adjustment for weight. Leptin was positively associated with MF and MS, whereas hs-CRP to MF. In backward regression analyses, larger waist and smaller PM area explained 90% of MF variance, whereas leptin about 80% of MS variance. IL-6 expression in SAT was significantly higher in participants with higher MQI values. In PM biopsies we found significantly higher expression of SOCS-3 and a trend toward higher expression of myostatin with greater degrees of MQI. MS and MF are related phenomena that concur to alter muscle quality and both should be considered in further studies on the evolution of sarcopenia. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Zoico, Elena; Corzato, Francesca; Bambace, Clara; Rossi, Andrea P.; Zamboni, Mauro] Univ Verona, Div Geriatr Med, I-37126 Verona, Italy. [Micciolo, Rocco] Univ Trento, Fac Sociol, Trento, Italy. [Cinti, Saverio] Univ Ancona, Inst Normal Human Morphol, Ancona, Italy. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Interdisciplinary Studies Aging Sect, Bethesda, MD 20892 USA. RP Zoico, E (reprint author), Univ Verona, Div Geriatr Med, Osped Maggiore, Ple A Stefani 1, I-37126 Verona, Italy. EM elena.zoico@univr.it OI ZAMBONI, Mauro/0000-0001-6961-9483; ZOICO, Elena/0000-0002-5235-1545 FU Intramural NIH HHS [ZIA AG004050-05] NR 27 TC 11 Z9 11 U1 1 U2 24 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD NOV-DEC PY 2013 VL 57 IS 3 BP 411 EP 416 DI 10.1016/j.archger.2013.06.001 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 213AE UT WOS:000324024300026 PM 23809667 ER EF