FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Crooks, D Natarajan, T Chen, CM Huang, HZ Ghosh, M Tong, WH Haller, R Wu, C Rouault, T AF Crooks, Daniel Natarajan, Thanemozhi Chen, Chuming Huang, Hongzhan Ghosh, Manik Tong, Wing-Hang Haller, Ronald Wu, Cathy Rouault, Tracey TI RESPIRATORY CHAIN DEFICIENCY DUE TO FE-S CLUSTER DEFICIENCY IN SKELETAL MUSCLE LEADS TO A SYSTEMIC STARVATION RESPONSE CHARACTERIZED BY INCREASED FGF-21 SECRETION AND UP-REGULATION OF KETOGENIC ENZYME HMGCS2 IN SKELETAL MUSCLE FIBERS OF ISCU MYOPATHY PATI SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Crooks, Daniel] NICHD, Bethesda, MD USA. [Natarajan, Thanemozhi] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Chen, Chuming; Huang, Hongzhan; Wu, Cathy] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE USA. [Ghosh, Manik; Tong, Wing-Hang; Rouault, Tracey] NICHHD, NIH, Bethesda, MD 20892 USA. [Haller, Ronald] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E45 EP E45 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500069 ER PT J AU Gozzelino, R Andrade, BB Larsen, R Luz, NF Vanoaica, L Coutinho, A Cardoso, S Rebelo, S Poli, M Barral-Netto, M Darshan, D Kuhn, L Soares, MP AF Gozzelino, Raffaella Andrade, Bruno Bezerril Larsen, Rasmus Luz, Nivea F. Vanoaica, Liviu Coutinho, Antonio Cardoso, Silvia Rebelo, Sofia Poli, Maura Barral-Netto, Manoel Darshan, Deepak Kuehn, Lukas Soares, Miguel P. TI METABOLIC ADAPTATION TO TISSUE IRON OVERLOAD CONFERS TOLERANCE TO MALARIA SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Andrade, Bruno Bezerril] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Larsen, Rasmus; Coutinho, Antonio; Cardoso, Silvia; Rebelo, Sofia; Soares, Miguel P.] Inst Gulbenkian Ciencias, Inflammat Lab, Oeiras, Portugal. [Luz, Nivea F.] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Vanoaica, Liviu; Darshan, Deepak; Kuehn, Lukas] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland. [Poli, Maura] Univ Brescia, Dipartimento Materno Infantile & Tecnol Biomed, I-25121 Brescia, Italy. [Barral-Netto, Manoel] Univ Fed Bahia, Fac Med, Salvador, BA, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E7 EP E7 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500003 ER PT J AU Leidgens, S Bullough, K Shi, HF Yabe, T Shakoury-Elizeh, M Subramanian, P Hsu, E Natarayan, N Nandal, A Stemmler, T Philpott, C AF Leidgens, Sebastien Bullough, Kimberley Shi, Haifeng Yabe, Toshiki Shakoury-Elizeh, Minoo Subramanian, Poorna Hsu, Emory Natarayan, Navin Nandal, Anjali Stemmler, Timothy Philpott, Caroline TI EACH MEMBER OF THE PCBP FILY EXHIBITS IRON CHAPERONE ACTIVITY TOWARD FERRITIN SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Leidgens, Sebastien; Bullough, Kimberley; Shi, Haifeng; Yabe, Toshiki; Shakoury-Elizeh, Minoo; Hsu, Emory; Natarayan, Navin; Nandal, Anjali; Philpott, Caroline] NIDDK, NIH, Bethesda, MD 20892 USA. [Subramanian, Poorna; Stemmler, Timothy] Wayne State Univ, Detroit, MI 48202 USA. RI Yabe-Wada, Toshiki/L-9942-2016 OI Yabe-Wada, Toshiki/0000-0002-6208-0590 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E20 EP E20 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500024 ER PT J AU Nandal, A Frey, A Park, JH Yabe, T Park, MH Philpott, C AF Nandal, Anjali Frey, Avery Park, Jong-Hwan Yabe, Toshiki Park, Myung-Hee Philpott, Caroline TI ACTIVATION OF THE ESSENTIAL DIIRON ENZYME DEOXYHYPUSINE HYDROXYLASE BY THE IRON CHAPERONES PCBP1 AND PCBP2 SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Nandal, Anjali; Frey, Avery; Yabe, Toshiki; Philpott, Caroline] NIDDK, NIH, Bethesda, MD 20892 USA. [Park, Jong-Hwan; Park, Myung-Hee] NIDCR, NIH, Bethesda, MD USA. RI Nandal, Anjali/A-5376-2013 NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E197 EP E197 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500332 ER PT J AU Porter, J Walter, P Neumayr, L Evans, P Weyhmiller, M Harmatz, P Wood, J Miller, J Weiss, G Yuan, Q Wang, ZY Grosse, R Schoennagel, B Meerpohl, J Fischer, R Nielsen, P Seifert, M Vichinsky, E AF Porter, John Walter, Patrick Neumayr, Lynne Evans, Patricia Weyhmiller, Marcela Harmatz, Paul Wood, John Miller, Jeff Weiss, Guenter Yuan, Quing Wang, Zhiyue Grosse, Regine Schoennagel, Bjoern Meerpohl, Joerg Fischer, Roland Nielsen, Peter Seifert, Markus Vichinsky, Elliott TI BIO-MARKERS OF IRON TRAFFICKING AND DISTRIBUTION IN TRANSFUSIONAL OVERLOAD: INSIGHTS FROM COMPARING DIOND BLACKFAN ANEMIA WITH SICKLE CELL DISEASE AND THALASSEMIA (MCSIO PILOT STUDY) SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Porter, John; Evans, Patricia] UCL, London WC1E 6BT, England. [Wood, John] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Miller, Jeff] NIDDK, Bethesda, MD 20892 USA. [Weiss, Guenter; Seifert, Markus] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Yuan, Quing; Wang, Zhiyue] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Grosse, Regine; Schoennagel, Bjoern; Fischer, Roland; Nielsen, Peter] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Meerpohl, Joerg] Univ Med Ctr Freiburg, Freiburg, Germany. RI Meerpohl, Joerg/J-4224-2013 OI Meerpohl, Joerg/0000-0002-1333-5403 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E46 EP E47 PG 2 WC Hematology SC Hematology GA 132BT UT WOS:000318043500071 ER PT J AU Spottiswoode, N Williams, A Armitage, A Eddowes, L Newbold, C Pinches, B Draper, S Townsend, A Duffy, P Drakesmith, H AF Spottiswoode, Natasha Williams, Andrew Armitage, Andrew Eddowes, Lucy Newbold, Chris Pinches, Bob Draper, Simon Townsend, Alain Duffy, Patrick Drakesmith, Hal TI HEPCIDIN REGULATION IN MALARIA INFECTION SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Spottiswoode, Natasha] Univ Oxford, Oxford OX1 2JD, England. [Spottiswoode, Natasha] NIH, Bethesda, MD 20892 USA. [Williams, Andrew; Draper, Simon] Jenner Inst, Oxford, England. [Armitage, Andrew; Eddowes, Lucy; Townsend, Alain; Drakesmith, Hal] Weatherall Inst Mol Med, Mol Immunol Grp, Oxford, England. [Newbold, Chris; Pinches, Bob] Weatherall Inst Mol Med, Mol Parasitol Grp, Oxford, England. [Duffy, Patrick] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E8 EP E8 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500004 ER PT J AU Wang, ZYJ Wood, JC Walter, PB Schoennagel, BP Evans, P Neumayr, LD Weyhmiller, MG Harmatz, P Moon, JC Yuan, Q Miller, JL Weiss, G Grosse, R Meerpohl, J Nielsen, P Vichinsky, E Porter, JB Fischer, R AF Wang, Zhiyue J. Wood, John C. Walter, Patrick B. Schoennagel, Bjoern P. Evans, Patricia Neumayr, Lynne D. Weyhmiller, Marcela G. Harmatz, Paul Moon, James C. Yuan, Quing Miller, Jeffery L. Weiss, Guenter Grosse, Regine Meerpohl, Joerg Nielsen, Peter Vichinsky, Elliott Porter, John B. Fischer, Roland TI IRON DISTRIBUTION ASSESSED BY MRI IN SICKLE CELL DISEASE, THALASSEMIA AND DIAMOND BLACKFAN ANEMIA (MCSIO PILOT STUDY) SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Wang, Zhiyue J.; Yuan, Quing] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Wood, John C.] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Walter, Patrick B.; Neumayr, Lynne D.; Weyhmiller, Marcela G.; Harmatz, Paul; Vichinsky, Elliott] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Schoennagel, Bjoern P.; Grosse, Regine; Nielsen, Peter; Fischer, Roland] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Evans, Patricia; Moon, James C.; Porter, John B.] UCL, London WC1E 6BT, England. [Miller, Jeffery L.] NIDDKD, Bethesda, MD USA. [Weiss, Guenter] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Meerpohl, Joerg] Univ Med Ctr Freiburg, Freiburg, Germany. RI Meerpohl, Joerg/J-4224-2013; Moon, James/F-1031-2014; Wang, Zhiyue/L-3851-2014 OI Meerpohl, Joerg/0000-0002-1333-5403; Moon, James/0000-0001-8071-1491; Wang, Zhiyue/0000-0002-5649-2900 NR 0 TC 2 Z9 2 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAY PY 2013 VL 88 IS 5 BP E96 EP E96 PG 1 WC Hematology SC Hematology GA 132BT UT WOS:000318043500156 ER PT J AU Rimmer, CA Sharpless, KE Wise, SA Betz, JM Coates, PM AF Rimmer, Catherine A. Sharpless, Katherine E. Wise, Stephen A. Betz, Joseph M. Coates, Paul M. TI Standard reference materials for dietary supplement analysis SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article ID BITTER-ORANGE ALKALOIDS; INSTITUTES-OF-HEALTH; LIQUID-CHROMATOGRAPHY; CERTIFICATION; ABSORBENCY C1 [Rimmer, Catherine A.; Sharpless, Katherine E.; Wise, Stephen A.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Betz, Joseph M.; Coates, Paul M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Rimmer, CA (reprint author), NIST, Div Analyt Chem, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM catherine.rimmer@nist.gov OI Sharpless, Katherine/0000-0001-6569-198X NR 29 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2013 VL 405 IS 13 BP 4337 EP 4344 DI 10.1007/s00216-013-6942-x PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 131DK UT WOS:000317972200004 PM 23575912 ER PT J AU Sander, LC Bedner, M Duewer, DL Lippa, KA Phillips, MM Phinney, KW Rimmer, CA Schantz, MM Sharpless, KE Tai, SSC Thomas, JB Wise, SA Wood, LJ Betz, JM Coates, PM AF Sander, L. C. Bedner, M. Duewer, D. L. Lippa, K. A. Phillips, M. M. Phinney, K. W. Rimmer, C. A. Schantz, M. M. Sharpless, K. E. Tai, S. S. -C. Thomas, J. B. Wise, S. A. Wood, L. J. Betz, J. M. Coates, P. M. TI The development and implementation of quality assurance programs to support nutritional measurements SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Quality assurance; Accuracy; Precision; Comparability; Concordance; Nutrients; Dietary supplements; Vitamin D metabolites; Fatty acids ID MEASUREMENT PERFORMANCE; TIME AB The National Institute of Standards and Technology administers quality assurance programs devoted to improving measurements of nutrients and related metabolites in foods, dietary supplements, and serum and plasma samples. These programs have been developed in collaboration with the National Institutes of Health to assist measurement communities in their efforts to achieve accurate results that are comparable among different laboratories and over time. Targeted analytes include micronutrients, botanical markers, nutritional elements, contaminants, fatty acids, and vitamin D metabolites. C1 [Sander, L. C.; Bedner, M.; Duewer, D. L.; Lippa, K. A.; Phillips, M. M.; Phinney, K. W.; Rimmer, C. A.; Schantz, M. M.; Sharpless, K. E.; Tai, S. S. -C.; Thomas, J. B.; Wise, S. A.; Wood, L. J.] NIST, Div Chem Sci, Gaithersburg, MD 20899 USA. [Betz, J. M.; Coates, P. M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Sander, LC (reprint author), NIST, Div Chem Sci, 100 Bur Dr,MS 8392, Gaithersburg, MD 20899 USA. EM lane.sander@nist.gov NR 7 TC 1 Z9 1 U1 2 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2013 VL 405 IS 13 BP 4437 EP 4441 DI 10.1007/s00216-013-6864-7 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 131DK UT WOS:000317972200014 PM 23552970 ER PT J AU Schantz, MM Sander, LC Sharpless, KE Wise, SA Yen, JH NguyenPho, A Betz, JM AF Schantz, Michele M. Sander, Lane C. Sharpless, Katherine E. Wise, Stephen A. Yen, James H. NguyenPho, Agnes Betz, Joseph M. TI Development of botanical and fish oil standard reference materials for fatty acids SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Fatty acid; Omega-3; Omega-6; Plant oil; Fish oil; Reference material ID EXTRACT AB As part of a collaboration with the National Institutes of Health's Office of Dietary Supplements and the Food and Drug Administration's Center for Drug Evaluation and Research, the National Institute of Standards and Technology has developed Standard Reference Material (SRM) 3274 Botanical Oils Containing Omega-3 and Omega-6 Fatty Acids and SRM 3275 Omega-3 and Omega-6 Fatty Acids in Fish Oil. SRM 3274 consists of one ampoule of each of four seed oils (3274-1 Borage (Borago officinalis), 3274-2 Evening Primrose (Oenothera biennis), 3274-3 Flax (Linium usitatissimum), and 3274-4 Perilla (Perilla frutescens)), and SRM 3275 consists of two ampoules of each of three fish oils (3275-1 a concentrate high in docosahexaenoic acid, 3275-2 an anchovy oil high in docosahexaenoic acid and eicosapentaenoic acid, and 3275-3 a concentrate containing 60 % long-chain omega-3 fatty acids). Each oil has certified and reference mass fraction values for up to 20 fatty acids. The fatty acid mass fraction values are based on results from analyses using gas chromatography with flame ionization detection (GC-FID) and mass spectrometry (GC/MS). These SRMs will complement other reference materials currently available with mass fractions for similar analytes and are part of a series of SRMs being developed for dietary supplements. C1 [Schantz, Michele M.; Sander, Lane C.; Sharpless, Katherine E.; Wise, Stephen A.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Yen, James H.] NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. [NguyenPho, Agnes] US FDA, CDER, Silver Spring, MD 20993 USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Schantz, MM (reprint author), NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. EM michele.schantz@nist.gov OI Sharpless, Katherine/0000-0001-6569-198X NR 21 TC 5 Z9 5 U1 1 U2 31 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2013 VL 405 IS 13 BP 4531 EP 4538 DI 10.1007/s00216-013-6747-y PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 131DK UT WOS:000317972200023 PM 23371533 ER PT J AU Bergamaschi, MM Barnes, A Queiroz, RHC Hurd, YL Huestis, MA AF Bergamaschi, Mateus M. Barnes, Allan Queiroz, Regina H. C. Hurd, Yasmin L. Huestis, Marilyn A. TI Impact of enzymatic and alkaline hydrolysis on CBD concentration in urine SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Cannabidiol; Cannabidiol-glucuronide; Enzymatic hydrolysis; Urine; GC-MS ID TANDEM MASS-SPECTROMETRY; GAS-CHROMATOGRAPHY; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; DELTA(9)-TETRAHYDROCANNABINOL THC; SIMULTANEOUS QUANTIFICATION; CANNABIDIOL; CANNABINOIDS; METABOLISM; DELTA-9-TETRAHYDROCANNABINOL; PLASMA AB A sensitive and specific analytical method for cannabidiol (CBD) in urine was needed to define urinary CBD pharmacokinetics after controlled CBD administration, and to confirm compliance with CBD medications including Sativex-a cannabis plant extract containing 1:1 a dagger(9)-tetrahydrocannabinol (THC) and CBD. Non-psychoactive CBD has a wide range of therapeutic applications and may also influence psychotropic smoked cannabis effects. Few methods exist for the quantification of CBD excretion in urine, and no data are available for phase II metabolism of CBD to CBD-glucuronide or CBD-sulfate. We optimized the hydrolysis of CBD-glucuronide and/or -sulfate, and developed and validated a GC-MS method for urinary CBD quantification. Solid-phase extraction isolated and concentrated analytes prior to GC-MS. Method validation included overnight hydrolysis (16 h) at 37 A degrees C with 2,500 units beta-glucuronidase from Red Abalone. Calibration curves were fit by linear least squares regression with 1/x (2) weighting with linear ranges (r (2) > 0.990) of 2.5-100 ng/mL for non-hydrolyzed CBD and 2.5-500 ng/mL for enzyme-hydrolyzed CBD. Bias was 88.7-105.3 %, imprecision 1.4-6.4 % CV and extraction efficiency 82.5-92.7 % (no hydrolysis) and 34.3-47.0 % (enzyme hydrolysis). Enzyme-hydrolyzed urine specimens exhibited more than a 250-fold CBD concentration increase compared to alkaline and non-hydrolyzed specimens. This method can be applied for urinary CBD quantification and further pharmacokinetics characterization following controlled CBD administration. C1 [Bergamaschi, Mateus M.; Barnes, Allan; Huestis, Marilyn A.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. [Bergamaschi, Mateus M.; Queiroz, Regina H. C.] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil. [Hurd, Yasmin L.] Mt Sinai Sch Med, New York, NY 10029 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural Research Program, National Institute on Drug Abuse, NIH; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil); [DA027781]; [UL1RR029887] FX The authors acknowledge Jeff Hackett from United Chemical Technologies for his technical support and Georgia Yiannoulos for her assistance with the research subjects. Intramural Research Program, National Institute on Drug Abuse, NIH, funded this research as well as a grant DA027781 to YLH and UL1RR029887. MMB received grant from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil). NR 44 TC 8 Z9 8 U1 2 U2 18 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2013 VL 405 IS 14 BP 4679 EP 4689 DI 10.1007/s00216-013-6837-x PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 135TW UT WOS:000318312400002 PM 23494274 ER PT J AU Friesen, MC Pronk, A Wheeler, DC Chen, YC Locke, SJ Zaebst, DD Schwenn, M Johnson, A Waddell, R Baris, D Colt, JS Silverman, DT Stewart, PA Katki, HA AF Friesen, Melisa C. Pronk, Anjoeka Wheeler, David C. Chen, Yu-Cheng Locke, Sarah J. Zaebst, Dennis D. Schwenn, Molly Johnson, Alison Waddell, Richard Baris, Dalsu Colt, Joanne S. Silverman, Debra T. Stewart, Patricia A. Katki, Hormuzd A. TI Comparison of Algorithm-based Estimates of Occupational Diesel Exhaust Exposure to Those of Multiple Independent Raters in a Population-based CaseControl Study SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE casecontrol; diesel exhaust; expert judgement; exposure assessment ID INTERRATER AGREEMENT; RETROSPECTIVE ASSESSMENT; INDUSTRIAL-HYGIENE; TRUCKING INDUSTRY; EXPERT ASSESSMENT; LUNG-CANCER; MATRIX; ASSESSMENTS; QUESTIONNAIRE; RELIABILITY AB Algorithm-based exposure assessments based on patterns in questionnaire responses and professional judgment can readily apply transparent exposure decision rules to thousands of jobs quickly. However, we need to better understand how algorithms compare to a one-by-one job review by an exposure assessor. We compared algorithm-based estimates of diesel exhaust exposure to those of three independent raters within the New England Bladder Cancer Study, a population-based casecontrol study, and identified conditions under which disparities occurred in the assessments of the algorithm and the raters. Occupational diesel exhaust exposure was assessed previously using an algorithm and a single rater for all 14 983 jobs reported by 2631 study participants during personal interviews conducted from 2001 to 2004. Two additional raters independently assessed a random subset of 324 jobs that were selected based on strata defined by the cross-tabulations of the algorithm and the first raters probability assessments for each job, oversampling their disagreements. The algorithm and each rater assessed the probability, intensity and frequency of occupational diesel exhaust exposure, as well as a confidence rating for each metric. Agreement among the raters, their aggregate rating (average of the three raters ratings) and the algorithm were evaluated using proportion of agreement, kappa and weighted kappa ((w)). Agreement analyses on the subset used inverse probability weighting to extrapolate the subset to estimate agreement for all jobs. Classification and Regression Tree (CART) models were used to identify patterns in questionnaire responses that predicted disparities in exposure status (i.e., unexposed versus exposed) between the first rater and the algorithm-based estimates. For the probability, intensity and frequency exposure metrics, moderate to moderately high agreement was observed among raters ((w) 0.500.76) and between the algorithm and the individual raters ((w) 0.580.81). For these metrics, the algorithm estimates had consistently higher agreement with the aggregate rating ((w) 0.82) than with the individual raters. For all metrics, the agreement between the algorithm and the aggregate ratings was highest for the unexposed category (9093%) and was poor to moderate for the exposed categories (964%). Lower agreement was observed for jobs with a start year < 1965 versus 1965. For the confidence metrics, the agreement was poor to moderate among raters ((w) 0.170.45) and between the algorithm and the individual raters ((w) 0.240.61). CART models identified patterns in the questionnaire responses that predicted a fair-to-moderate (3389%) proportion of the disagreements between the raters and the algorithm estimates. The agreement between any two raters was similar to the agreement between an algorithm-based approach and individual raters, providing additional support for using the more efficient and transparent algorithm-based approach. CART models identified some patterns in disagreements between the first rater and the algorithm. Given the absence of a gold standard for estimating exposure, these patterns can be reviewed by a team of exposure assessors to determine whether the algorithm should be revised for future studies. C1 [Friesen, Melisa C.; Pronk, Anjoeka; Wheeler, David C.; Chen, Yu-Cheng; Locke, Sarah J.; Baris, Dalsu; Colt, Joanne S.; Silverman, Debra T.; Stewart, Patricia A.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MA USA. [Pronk, Anjoeka] TNO Qual & Safety, Zeist, Netherlands. [Wheeler, David C.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Zaebst, Dennis D.] WESTAT Corp, Rockville, MA USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Waddell, Richard] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. [Katki, Hormuzd A.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MA USA. RP Friesen, MC (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MA USA. EM friesenmc@mail.nih.gov RI Chen, Yu-Cheng/F-7689-2013; Katki, Hormuzd/B-4003-2015; Friesen, Melissa/A-5362-2009 FU National Cancer Institute of the National Institutes of Health FX This study was funded by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 42 TC 10 Z9 10 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD MAY PY 2013 VL 57 IS 4 BP 470 EP 481 DI 10.1093/annhyg/mes082 PG 12 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 132KH UT WOS:000318066000005 PM 23184256 ER PT J AU Deshpande, N Metter, EJ Guralnik, J Bandinelli, S Ferrucci, L AF Deshpande, Nandini Metter, E. Jeffrey Guralnik, Jack Bandinelli, Stefania Ferrucci, Luigi TI Predicting 3-Year Incident Mobility Disability in Middle-Aged and Older Adults Using Physical Performance Tests SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Aging; Disability evaluation; Mobility limitation; Rehabilitation ID LOWER-EXTREMITY FUNCTION; ASSOCIATION; INCHIANTI; MORTALITY; DISEASE; WALK AB Objective: To identify a standard physical performance test, which can predict 3-year incident mobility disability independent of demographics. Design: Longitudinal cohort study. Setting: Population-based middle-aged and older adult cohort assessment performed at a local geriatric clinical center. Participants: Community-living middle-aged and older persons (age, 50-85y) without baseline mobility disability (N=622). Interventions: Not applicable. Main Outcome Measures: Mobility disability was ascertained at baseline and at 3-year follow-up using an established self-report method: self-reported inability to walk a quarter mile without resting or inability to walk up a flight of stairs unsupported. Physical performance tests included self-selected usual gait speed, time required to complete 5 times sit-to-stand (5TSTS), and 400-m brisk walking. Demographic variables age, sex, height, and weight were recorded. Results: Overall, 13.5% participants reported 3-year incident mobility disability. Usual gait speed <1.2m/s, requiring >13.6 seconds to complete 5TSTS, and completing 400m at <1.19m/s walking speed were highly predictive of future mobility disability independent of demographics. Conclusions: Inability to complete 5TSTS in <13.7 seconds can be a clinically convenient guideline for monitoring and for further assessment of middle-aged and older persons, in order to prevent or delay future mobility disability. Archives of Physical Medicine and Rehabilitation 2013;94:994-7 (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Deshpande, Nandini] Queens Univ, Sch Rehabil Therapy, Kingston, ON K7L 3N6, Canada. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Guralnik, Jack] Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. RP Deshpande, N (reprint author), Queens Univ, Sch Rehabil Therapy, 31 George St, Kingston, ON K7L 3N6, Canada. EM nandinijd@yahoo.com FU Italian Ministry of Health [ICS 110.1\RS97.71]; National Institute on Aging [N01-AG-916413, N01-AG-821336, N01-AG-5-0002, R01 AG027012]; Intramural Research Program, National Institute on Aging, National Institutes of Health FX The InCHIANTI study was supported as a targeted project (ICS 110.1\RS97.71) by the Italian Ministry of Health; in part by the National Institute on Aging (contract nos. N01-AG-916413, N01-AG-821336, N01-AG-5-0002, and grant no. R01 AG027012); and the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 10 TC 3 Z9 3 U1 0 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAY PY 2013 VL 94 IS 5 BP 994 EP 997 DI 10.1016/j.apmr.2012.10.032 PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 134HX UT WOS:000318202100027 PM 23164980 ER PT J AU Carlsen, AL Schetter, AJ Nielsen, CT Lood, C Knudsen, S Voss, A Harris, CC Hellmark, T Segelmark, M Jacobsen, S Bengtsson, AA Heegaard, NHH AF Carlsen, Anting Liu Schetter, Aaron J. Nielsen, Christoffer T. Lood, Christian Knudsen, Steen Voss, Anne Harris, Curtis C. Hellmark, Thomas Segelmark, Marten Jacobsen, Soren Bengtsson, Anders A. Heegaard, Niels H. H. TI Circulating MicroRNA Expression Profiles Associated With Systemic Lupus Erythematosus SO ARTHRITIS AND RHEUMATISM LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; INTERFERON-ALPHA PRODUCTION; I INTERFERON; IMMUNE-COMPLEXES; SIGNALING PROTEINS; UP-REGULATION; INDUCTION; DIFFERENTIATION; MICROPARTICLES; PATHOGENESIS AB Objective To evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE). Methods Total RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcriptionpolymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients. Results Seven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 x 109). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis. Conclusion Circulating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor signaling pathways. Other targets include regulation of apoptosis, cytokinecytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes. C1 [Carlsen, Anting Liu; Nielsen, Christoffer T.; Heegaard, Niels H. H.] Statens Serum Inst, DK-2300 Copenhagen S, Denmark. [Schetter, Aaron J.; Harris, Curtis C.] NCI, NIH, Bethesda, MD 20892 USA. [Lood, Christian; Hellmark, Thomas; Bengtsson, Anders A.] Lund Univ, Lund, Sweden. [Knudsen, Steen] Med Prognosis Inst, Horsholm, Denmark. [Voss, Anne] Odense Univ Hosp, DK-5000 Odense, Denmark. [Segelmark, Marten] Cty Council Ostergotland, Linkoping, Sweden. [Segelmark, Marten] Linkoping Univ, Linkoping, Sweden. [Jacobsen, Soren] Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark. RP Heegaard, NHH (reprint author), Statens Serum Inst, Artillerivej 5,Bldg 85,Room 240, DK-2300 Copenhagen S, Denmark. EM nhe@ssi.dk OI Hellmark, Thomas/0000-0002-2952-1155 FU Danish Rheumatism Association [R99-A1937, R33-A1836]; National Cancer Institute, NIH; Medical Faculty at Lund University; Alfred Osterlund Foundation; Crafoord Foundation; Swedish Rheumatism Association; Greta and Johan Kock Foundation; King Gustaf V's 80-Year Foundation; Swedish Society of Medicine; Foundation of the Swedish National Board of Health and Welfare; Skane University Hospital, Lund, Sweden; A. P. Moller Foundation; Region of Southern Denmark; Swedish Renal Foundation; Swedish Research Council; Novo Nordisk Research Foundation; Foundation for the Advancement of Medical Science FX Supported by the Danish Rheumatism Association (grant R99-A1937). Drs. Schetter and Harris' work was supported by the Intramural Research Program of the National Cancer Institute, NIH. Drs. Lood and Bengtsson's work was supported by the Medical Faculty at Lund University, the Alfred Osterlund Foundation, the Crafoord Foundation, the Swedish Rheumatism Association, the Greta and Johan Kock Foundation, King Gustaf V's 80-Year Foundation, the Swedish Society of Medicine, the Foundation of the Swedish National Board of Health and Welfare, and Skane University Hospital, Lund, Sweden. Dr. Voss' work was supported by the Danish Rheumatism Association (grant R33-A1836), the A. P. Moller Foundation, and the Region of Southern Denmark. Drs. Hellmark and Segelmark's work was supported by the Swedish Renal Foundation and the Swedish Research Council. Dr. Jacobsen's work was supported by the Novo Nordisk Research Foundation. Dr. Heegaard's work was supported by the Foundation for the Advancement of Medical Science. NR 49 TC 79 Z9 90 U1 1 U2 27 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 MAY PY 2013 VL 65 IS 5 BP 1324 EP 1334 DI 10.1002/art.37890 PG 11 WC Rheumatology SC Rheumatology GA 133WC UT WOS:000318170600023 PM 23401079 ER PT J AU Faber, MT Kjaer, SK Dehlendorff, C Chang-Claude, J Andersen, KK Hogdall, E Webb, PM Jordan, SJ Rossing, MA Doherty, JA Lurie, G Thompson, PJ Carney, ME Goodman, MT Ness, RB Modugno, F Edwards, RP Bunker, CH Goode, EL Fridley, BL Vierkant, RA Larson, MC Schildkraut, J Cramer, DW Terry, KL Vitonis, AF Bandera, EV Olson, SH King, M Chandran, U Kiemeney, LA Massuger, LFAG van Altena, AM Vermeulen, SH Brinton, L Wentzensen, N Lissowska, J Yang, HP Moysich, KB Odunsi, K Kasza, K Odunsi-Akanji, O Song, HL Pharaoh, P Shah, M Whittemore, AS McGuire, V Sieh, W Sutphen, R Menon, U Gayther, SA Ramus, SJ Gentry-Maharaj, A Pearce, CL Wu, AH Pike, MC Risch, HA Jensen, A AF Faber, Mette T. Kjaer, Susanne K. Dehlendorff, Christian Chang-Claude, Jenny Andersen, Klaus K. Hogdall, Estrid Webb, Penelope M. Jordan, Susan J. Rossing, Mary Anne Doherty, Jennifer A. Lurie, Galina Thompson, Pamela J. Carney, Michael E. Goodman, Marc T. Ness, Roberta B. Modugno, Francesmary Edwards, Robert P. Bunker, Clareann H. Goode, Ellen L. Fridley, Brooke L. Vierkant, Robert A. Larson, Melissa C. Schildkraut, Joellen Cramer, Daniel W. Terry, Kathryn L. Vitonis, Allison F. Bandera, Elisa V. Olson, Sara H. King, Melony Chandran, Urmila Kiemeney, Lambertus A. Massuger, Leon F. A. G. van Altena, Anne M. Vermeulen, Sita H. Brinton, Louise Wentzensen, Nicolas Lissowska, Jolanta Yang, Hannah P. Moysich, Kirsten B. Odunsi, Kunle Kasza, Karin Odunsi-Akanji, Oluwatosin Song, Honglin Pharaoh, Paul Shah, Mitul Whittemore, Alice S. McGuire, Valerie Sieh, Weiva Sutphen, Rebecca Menon, Usha Gayther, Simon A. Ramus, Susan J. Gentry-Maharaj, Aleksandra Pearce, Celeste Leigh Wu, Anna H. Pike, Malcolm C. Risch, Harvey A. Jensen, Allan CA Australian Canc Study Ovarian Canc Australian Ovarian Canc Study Grp Ovarian Canc Assoc Consortium TI Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies SO CANCER CAUSES & CONTROL LA English DT Article DE Case-control studies; Histological type; Ovarian neoplasms; Smoking ID LIFE-STYLE FACTORS; ORAL-CONTRACEPTIVES; HORMONE-THERAPY; HISTOLOGIC TYPE; TOBACCO USE; BORDERLINE; ASSOCIATION; TUMORS; WOMEN; INFLAMMATION AB The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease. C1 [Faber, Mette T.; Kjaer, Susanne K.; Hogdall, Estrid; Jensen, Allan] Danish Canc Soc, Unit Virus Lifestyle & Genes, Res Ctr, DK-2100 Copenhagen, Denmark. [Kjaer, Susanne K.] Copenhagen Univ Hosp, Gynecol Clin, Copenhagen, Denmark. [Dehlendorff, Christian; Andersen, Klaus K.] Danish Canc Soc, Unit Stat Bioinformat & Registry, Res Ctr, DK-2100 Copenhagen, Denmark. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Hogdall, Estrid] Univ Copenhagen, Herlev Univ Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Webb, Penelope M.; Jordan, Susan J.; Australian Canc Study Ovarian Canc] Queensland Inst Med Res, Populat Hlth Dept, Brisbane, Qld 4006, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Rossing, Mary Anne; Doherty, Jennifer A.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Epidemiol & Biostat Sect, Dept Community & Family Med, Lebanon, NH USA. [Lurie, Galina; Thompson, Pamela J.; Carney, Michael E.; Goodman, Marc T.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Ness, Roberta B.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Modugno, Francesmary] Univ Pittsburgh, Sch Med, Div Gyn Onc, Dept Ob Gyn RS, Pittsburgh, PA USA. [Modugno, Francesmary] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol,Magee Womens Res Inst,Canc Inst, Ovarian Canc Ctr Excellence,Womens Canc Program, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Div Gyn Onc, Dept Ob Gyn RS, Pittsburgh, PA USA. [Edwards, Robert P.] Univ Pittsburgh, Ovarian Canc Ctr Excellence, Pittsburgh, PA USA. [Bunker, Clareann H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Goode, Ellen L.] Mayo Clin, Coll Med, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN USA. [Fridley, Brooke L.; Vierkant, Robert A.; Larson, Melissa C.] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN USA. [Schildkraut, Joellen] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Schildkraut, Joellen] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Cramer, Daniel W.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Terry, Kathryn L.; Bandera, Elisa V.; Chandran, Urmila] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Olson, Sara H.; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [King, Melony] UMDNJ Sch Publ Hlth, Piscataway, NJ USA. [Kiemeney, Lambertus A.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Ctr Comprehens Canc, NL-6525 ED Nijmegen, Netherlands. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynecol, NL-6525 ED Nijmegen, Netherlands. [Brinton, Louise; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Moysich, Kirsten B.; Kasza, Karin; Odunsi-Akanji, Oluwatosin] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Odunsi, Kunle] Roswell Pk Canc Inst, Dept Gynecol Oncol, Buffalo, NY 14263 USA. [Song, Honglin; Pharaoh, Paul; Shah, Mitul] Univ Cambridge, Strangeways Res Lab, Dept Oncol, Cambridge, England. [Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Sutphen, Rebecca] Univ S Florida, Coll Med, Epidemiol Ctr, Tampa, FL USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, EGA Inst Womens Hlth, London, England. [Gayther, Simon A.; Pearce, Celeste Leigh; Wu, Anna H.; Pike, Malcolm C.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Ramus, Susan J.; Risch, Harvey A.] Yale Univ, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, New Haven, CT 06520 USA. [Ramus, Susan J.; Risch, Harvey A.] Yale Univ, Sch Med, New Haven, CT USA. RP Jensen, A (reprint author), Danish Canc Soc, Unit Virus Lifestyle & Genes, Res Ctr, Strandblvd 49, DK-2100 Copenhagen, Denmark. EM allan@cancer.dk RI Kiemeney, Lambertus/D-3357-2009; Whittemore, Alice/F-9925-2014; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Fridley, Brooke/D-8315-2015; Brinton, Louise/G-7486-2015; van Altena, Anne/B-9824-2016; Vermeulen, H.H.M./L-4716-2015; Bowtell, David/H-1007-2016; OI Lissowska, Jolanta/0000-0003-2695-5799; Dehlendorff, Christian/0000-0001-6161-4565; Ramus, Susan/0000-0003-0005-7798; Kiemeney, Lambertus/0000-0002-2368-1326; Bandera, Elisa/0000-0002-8789-2755; Webb, Penelope/0000-0003-0733-5930; Fridley, Brooke/0000-0001-7739-7956; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Kjaer, Susanne/0000-0002-8347-1398 FU European Commission's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; National Institutes of Health [R01 CA074850, R01 CA080742, R01 CA112523, R01 CA87538, R01 CA58598, N01 CN55424, N01 PC67001, R01 CA95023, R01 CA61107, R01P50 CA136393, CA122443, R01 CA76016, R01 CA54419, P50 CA105009]; Danish Cancer Society [94 222 52 [MAL]]; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research [01 GB9401 (GER)]; German Cancer Research Center (GER); U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729 [AUS]]; National Health & Medical Research Council of Australia (AUS); Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania (AUS); Cancer Foundation of Western Australia (AUS); National Health and Medical Research Council of Australia [199600 [AUS]]; Department of Defense [DAMD17-02-1-0669 [HOP], DAMD17-02-1-0666 [NCO], W81XWH-10-1-02802 [NEC], DAMD17-98-1-8659 [TBO])]; The Cancer Institute of New Jersey (NJO); Radboud University Nijmegen Medical Centre (NTH); Intramural Research Program of the National Cancer Institute (POL); Roswell Park Alliance Foundation (RPI); Cancer Research UK [C490/A10119, C490/A10124 [SEA])]; National Health Research and Development Program of Health and Welfare Canada [(6613-1415-53 [SON])]; American Cancer Society [(CRTG-00-196-01-CCE [TBO])]; Celma Mastery Ovarian Cancer Foundation (TBO); Lon V Smith Foundation [(LVS-39420 [UCI])]; Cancer Research UK (UKO, SEA); Eve Appeal (UKO); OAK Foundation (UKO); California Cancer Research Program [00-01389V-20170, R03 CA113148, R03 CA115195, N01 CN25403 [USC]), 2II0200 [USC]]; National Cancer Institute [P01 CA17054 [USC]]; NIH [R01 CA106414, R01 CA063682, R01 CA063678, R01 CA080978, CA 8860, CA92044, PSA 042205, CA17054, CA14089, CA61132, N01-PC-67010, K07 CA095666, R01 CA83918, K22 CA138563, U01 CA71966, R01 CA16056, K07 CA143047, U01 CA69417] FX The work was supported by the European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175). It was also supported by the National Institutes of Health (R01 CA074850, and R01 CA080742 [CON], R01 CA112523, and R01 CA87538 [DOV], R01 CA58598, N01 CN55424, and N01 PC67001 [HAW], R01 CA95023 [HOP], R01 CA61107 [MAL], R01 CA122443, and P50 CA136393 [MAY], R01 CA76016 [NCO], R01 CA54419, and P50 CA105009 [NEC], K07 CA095666, R01 CA83918, and K22 CA138563 [NJO], U01 CA71966, R01 CA16056, K07 CA143047, and U01 CA69417 [STA], R01 CA106414 [TBO], R01 CA063682, R01 CA063678, and R01 CA080978 [TOR], CA 8860, CA92044, and PSA 042205 [UCI], CA17054, CA14089, CA61132, and N01-PC-67010 [USC]); Danish Cancer Society (94 222 52 [MAL]); Mermaid 1 (MAL); German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB9401 (GER); German Cancer Research Center (GER); U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729 [AUS]); National Health & Medical Research Council of Australia (AUS); Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania (AUS); Cancer Foundation of Western Australia (AUS); National Health and Medical Research Council of Australia (199600 [AUS]); Department of Defense (DAMD17-02-1-0669 [HOP], DAMD17-02-1-0666 [NCO], W81XWH-10-1-02802 [NEC], and DAMD17-98-1-8659 [TBO]); The Cancer Institute of New Jersey (NJO); Radboud University Nijmegen Medical Centre (NTH); Intramural Research Program of the National Cancer Institute (POL); Roswell Park Alliance Foundation (RPI); Cancer Research UK (C490/A10119, and C490/A10124 [SEA]); National Health Research and Development Program of Health and Welfare Canada (6613-1415-53 [SON]); American Cancer Society (CRTG-00-196-01-CCE [TBO]); Celma Mastery Ovarian Cancer Foundation (TBO); Lon V Smith Foundation (LVS-39420 [UCI]); Cancer Research UK (UKO, SEA); Eve Appeal (UKO); OAK Foundation (UKO); California Cancer Research Program (00-01389V-20170, R03 CA113148, R03 CA115195, and N01 CN25403 [USC]); California Cancer Research Program (2II0200 [USC]); and National Cancer Institute (P01 CA17054 [USC]). A portion of this work was done at UCLH/UCL within the 'Women's Health Theme' of the NIHR UCLH/UCL Comprehensive Biomedical Research Centre supported by the Department of Health (UKO). The German group thanks Ursula Eilber and Tanja Koehler for competent technical assistance (GER). The Australian group thanks all the clinical and scientific collaborators and the women for their contribution (AUS). The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged (CON). Some data used in the CON study were obtained from the Connecticut Tumor Registry, Connecticut Department of Public Health. The CON study assumes full responsibility for analyses and interpretation of these data. The MALOVA group is grateful to Nick Martinussen for data management assistance (MAL). The NJO group thanks Lorna Rodriguez, Lisa Paddock, and the staff at the New Jersey State Cancer Registry and Thanusha Puvananayagam for their contribution to the study (NJO). The SEARCH group thanks the SEARCH team, Craig Luccarini, Caroline Baynes, and Don Conroy (SEA). The UKOPS group thanks Ian Jacobs, Eva Wozniak, Andy Ryan, Jeremy Ford, and Nyaladzi Balogun for their contribution to the study (UKO). NR 65 TC 23 Z9 23 U1 0 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2013 VL 24 IS 5 BP 989 EP 1004 DI 10.1007/s10552-013-0174-4 PG 16 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 131ER UT WOS:000317975800015 PM 23456270 ER PT J AU Soliman, H Rawal, B Fulp, J Lee, JH Lopez, A Bui, MM Khalil, F Antonia, S Yfantis, HG Lee, DH Dorsey, TH Ambs, S AF Soliman, Hatem Rawal, Bhupendra Fulp, Jimmy Lee, Ji-Hyun Lopez, Alexis Bui, Marylin M. Khalil, Farah Antonia, Scott Yfantis, Harris G. Lee, Dong H. Dorsey, Tiffany H. Ambs, Stefan TI Analysis of indoleamine 2-3 dioxygenase (IDO1) expression in breast cancer tissue by immunohistochemistry SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Indoleamine 2; 3 dioxygenase; Breast cancer; Immunotherapy; Immunohistochemistry ID TRYPTOPHAN CATABOLISM; T-CELLS; 2,3-DIOXYGENASE; BIN1; INHIBITION; CARCINOMA; TOLERANCE AB The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated. Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests. IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors. IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design. C1 [Soliman, Hatem; Rawal, Bhupendra; Fulp, Jimmy; Lee, Ji-Hyun; Lopez, Alexis; Bui, Marylin M.; Khalil, Farah; Antonia, Scott] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Yfantis, Harris G.; Lee, Dong H.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Dorsey, Tiffany H.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Soliman, H (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM hatem.soliman@moffitt.org FU NCI NIH HHS [P30 CA076292] NR 21 TC 9 Z9 10 U1 2 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2013 VL 62 IS 5 BP 829 EP 837 DI 10.1007/s00262-013-1393-y PG 9 WC Oncology; Immunology SC Oncology; Immunology GA 135PC UT WOS:000318299700001 PM 23344392 ER PT J AU Arbes, SJ Calatroni, A Mitchell, HE Gergen, PJ AF Arbes, S. J., Jr. Calatroni, A. Mitchell, H. E. Gergen, P. J. TI Age-dependent interaction between atopy and eosinophils in asthma cases: results from NHANES 2005-2006 SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE asthma; atopy; eosinophils; epidemiology; immunoglobulin E; survey ID MEPOLIZUMAB AB Background Atopy is an established risk factor for asthma, and an elevated eosinophil level is a hallmark of atopic and non-atopic asthma. Whether atopy and eosinophils act independently or interact to influence asthma has clinical and public health implications. Objective To investigate the relationship between atopy and eosinophils in asthma. Methods Data on current asthma, atopy (IgE positive to 1 allergen), and blood eosinophil percent (dichotomized at the median) were obtained for persons aged 6years from the National Health and Nutrition Examination Survey 20052006. Interaction on an additive scale was evaluated by estimating the prevalences of asthma for combinations of atopy (yes or no) and eosinophil percent (high or low) and calculating the excess prevalence due to interaction. Results For all ages combined, the adjusted prevalences of asthma were 4.6%, 7.6%, 6.9% and 17.2% for persons with neither factor, atopy alone, a high eosinophil percent alone and both factors respectively. The excess prevalence of asthma due to interaction was 7.2%, indicating synergism. The excess prevalence was greatest in children aged 617years (15.3%), and it decreased with each older age category until it was absent in adults aged 55years (0.2%). In children, 94% of asthma cases attributable to the 2 factors were attributable to the interaction, whereas in the oldest adults, no cases were attributable to the interaction. Conclusions and Clinical Relevance Interaction between atopy and an elevated eosinophil level in asthma cases was very strong in children but absent in the oldest adults, which suggests different mechanistic pathways for these factors by age and supports the notion that asthma is a heterogeneous disease. In addition, the age-dependent interaction between the factors has potential implications for the selection of asthma patients for treatments that would target either IgE or a high eosinophil level. C1 [Arbes, S. J., Jr.; Calatroni, A.; Mitchell, H. E.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gergen, P. J.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Arbes, SJ (reprint author), Rho Inc, 6330 Quadrangle Dr,Rho Bldg, Chapel Hill, NC 27517 USA. EM sam_arbes@rhoworld.com FU National Institute of Allergy and Infectious Diseases [HHSN2722010000521] FX The authors are appreciative of Theresa Scocca, PhD (Rho, Inc., Chapel Hill, NC), who reviewed a draft of the article and provided useful edits and comments. This research was supported in part by the National Institute of Allergy and Infectious Diseases under contract number HHSN2722010000521. None of the authors has a financial relationship with a biotechnology or pharmaceutical manufacturer that has an interest in the subject matter or materials discussed in the submitted manuscript. NR 10 TC 10 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD MAY PY 2013 VL 43 IS 5 BP 544 EP 551 DI 10.1111/cea.12069 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 133AS UT WOS:000318110400009 PM 23600545 ER PT J AU Kumar, NP Anuradha, R Andrade, BB Suresh, N Ganesh, R Shankar, J Kumaraswami, V Nutman, TB Babu, S AF Kumar, Nathella Pavan Anuradha, R. Andrade, Bruno B. Suresh, N. Ganesh, R. Shankar, Janani Kumaraswami, V. Nutman, Thomas B. Babu, Subash TI Circulating Biomarkers of Pulmonary and Extrapulmonary Tuberculosis in Children SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID GAMMA RELEASE ASSAYS; MYCOBACTERIUM-TUBERCULOSIS; MATRIX METALLOPROTEINASES; MICROBIAL TRANSLOCATION; PEDIATRIC TUBERCULOSIS; INTRATHORACIC TUBERCULOSIS; CHILDHOOD TUBERCULOSIS; GLOBAL EPIDEMIOLOGY; ACTIVE TUBERCULOSIS; CARBON-MONOXIDE AB Tuberculosis (TB) in children is not only more likely to cause more severe disease than that seen in adults, it is also more likely to be extrapulmonary. Moreover, pediatric TB is very difficult to diagnose and suffers from a lack of understanding of host biomarkers for monitoring the progression of disease. Hence, we sought to identify the expression patterns of a variety of biomarkers in the plasma of children with pulmonary TB (PTB) and extrapulmonary TB (ETB), as well as in healthy control (HC) children. Thus, we examined a variety of circulating markers reflecting tissue inflammation, oxidative stress, innate immune activation, fibrosis, and the cytokine response. Children with active TB, compared to HC children, showed markedly elevated plasma levels of matrix metalloproteinases and their endogenous inhibitors. In addition, children with active TB had significantly elevated levels of C-reactive protein, alpha-2 macroglobulin, and haptoglobin, as well as hemoxygenase 1. Markers of innate immune activation (lipopolysaccharide [LPS] and lipopolysaccharide-binding protein [LBP]) were significantly lower in ETB than in PTB children. Although there were no significant differences between the two groups in their levels of cytokines (type 1 [gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), and IL-12], type 2 [IL-4, IL-5, IL-13, and IL-33], and most type 17 [IL-17A, IL-22, IL-1 beta, and IL-6] and type 1 interferons [IFN-alpha and IFN-beta]) or most of the cytokines associated with immune modulation (IL-10 and IL-20), pediatric TB was associated with elevated plasma transforming growth factor beta (TGF-beta), IL-21, and IL-23 levels. Thus, pediatric TB is characterized by elevated levels of a variety of biomarkers at homeostasis, suggesting that these responses may play a crucial role in disease pathogenesis. C1 [Kumar, Nathella Pavan; Anuradha, R.; Babu, Subash] NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Suresh, N.; Ganesh, R.; Shankar, Janani] Kanchi Kamakoti CHILDS Trust Hosp, Madras, Tamil Nadu, India. [Kumaraswami, V.] Natl Inst Res TB, Madras, Tamil Nadu, India. [Andrade, Bruno B.; Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov RI Andrade, Bruno/J-9111-2012 OI Andrade, Bruno/0000-0001-6833-3811 FU Division of Intramural Research, NIAID FX This work was supported by the Division of Intramural Research, NIAID. NR 51 TC 10 Z9 10 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2013 VL 20 IS 5 BP 704 EP 711 DI 10.1128/CVI.00038-13 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 133OY UT WOS:000318149500010 ER PT J AU Mahnke, YD Beddall, MH Roederer, M AF Mahnke, Yolanda D. Beddall, Margaret H. Roederer, Mario TI OMIP-017: Human CD4+helper T-cell subsets including follicular helper cells SO CYTOMETRY PART A LA English DT Article ID EXPRESSION C1 [Mahnke, Yolanda D.; Beddall, Margaret H.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mahnke, YD (reprint author), NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM mahnkey@mail.nih.gov FU Intramural NIH HHS [ZIA AI005020-13, ZIA AI005021-13] NR 7 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2013 VL 83A IS 5 BP 439 EP 440 DI 10.1002/cyto.a.22269 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 133CW UT WOS:000318116000005 PM 23450796 ER PT J AU Jager, J Schulenberg, JE O'Malley, PM Bachman, JG AF Jager, Justin Schulenberg, John E. O'Malley, Patrick M. Bachman, Jerald G. TI Historical variation in drug use trajectories across the transition to adulthood: The trend toward lower intercepts and steeper, ascending slopes SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID ALCOHOL-RELATED MORTALITY; STUDENTS AGES 18-24; COLLEGE-STUDENTS; CHILD MALTREATMENT; EMERGING ADULTHOOD; DRINKING PATTERNS; NATIONAL SAMPLE; YOUNG ADULTHOOD; NATURAL-HISTORY; PERCEIVED RISKS AB This study examines historical variation in individual trajectories of heavy drinking and marijuana use from age 18 to 22. Unlike most studies that have examined cohort differences in drug use, it focuses on differences in both level of use and rates of change (growth). Nearly 39,000 youths from the high school classes of 1976-2004 were surveyed at biennial intervals between the ages of 18 and 22 as part of the national Monitoring the Future study. Between 1976 and 2004, adolescent heavy drinking decreased substantially. However, because the age 18-22 heavy drinking growth rate increased threefold for males and sixfold for females during this period, heavy drinking among 21- to 22-year-olds remained largely stable. The growth rate for marijuana use was more stable across cohorts, and historical declines in use were sizable across the entire 18-22 age band. Generally, historical variation in use was unrelated to college status and living arrangements as well as to historical changes in the distribution of young adult social roles. Findings suggest that historical fluctuations in use were less the result of proximal young adult factors and more the result of historical variation in distal adolescent factors, the effect of which diminished with age, especially for heavy drinking. C1 [Jager, Justin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Schulenberg, John E.; O'Malley, Patrick M.; Bachman, Jerald G.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Jager, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM jagerjo@mail.nih.gov RI Schulenberg, John/A-2212-2008; Bachman, Jerald/J-6324-2014; OI Schulenberg, John/0000-0003-2129-8486; Bachman, Jerald/0000-0001-8280-5096; O'Malley, Patrick/0000-0001-9000-2824 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA001411, R01 DA001411-37, R01 DA01411, R01 DA016575, R01 DA016575-09] NR 77 TC 10 Z9 10 U1 7 U2 14 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD MAY PY 2013 VL 25 IS 2 BP 527 EP 543 DI 10.1017/S0954579412001228 PG 17 WC Psychology, Developmental SC Psychology GA 136LY UT WOS:000318364600018 PM 23627961 ER PT J AU Graff, M Gordon-Larsen, P Lim, U Fowke, JH Love, SA Fesinmeyer, M Wilkens, LR Vertilus, S Ritchie, MD Prentice, RL Pankow, J Monroe, K Manson, JE Le Marchand, L Kuller, LH Kolonel, LN Hong, CP Henderson, BE Haessler, J Gross, MD Goodloe, R Franceschini, N Carlson, CS Buyske, S Buzkova, P Hindorff, LA Matise, TC Crawford, DC Haiman, CA Peters, U North, KE AF Graff, Mariaelisa Gordon-Larsen, Penny Lim, Unhee Fowke, Jay H. Love, Shelly-Alm Fesinmeyer, Megan Wilkens, Lynne R. Vertilus, Shawyntee Ritchie, Marilyn D. Prentice, Ross L. Pankow, Jim Monroe, Kristine Manson, JoAnn E. Le Marchand, Loic Kuller, Lewis H. Kolonel, Laurence N. Hong, Ching P. Henderson, Brian E. Haessler, Jeff Gross, Myron D. Goodloe, Robert Franceschini, Nora Carlson, Christopher S. Buyske, Steven Buzkova, Petra Hindorff, Lucia A. Matise, Tara C. Crawford, Dana C. Haiman, Christopher A. Peters, Ulrike North, Kari E. TI The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course The PAGE Study SO DIABETES LA English DT Article ID BODY-MASS INDEX; GENOME-WIDE ASSOCIATION; FTO GENE; ADOLESCENT HEALTH; FAT MASS; VARIANTS; LOCI; EPIDEMIOLOGY; METAANALYSIS; CHILDHOOD AB Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26 49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages >= 70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (beta [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m(2), respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data. Diabetes 62:1763-1767, 2013 C1 [Graff, Mariaelisa; Love, Shelly-Alm; Vertilus, Shawyntee; Franceschini, Nora; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. [Graff, Mariaelisa; Gordon-Larsen, Penny] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Gordon-Larsen, Penny] Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. [Lim, Unhee; Wilkens, Lynne R.; Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Fowke, Jay H.] Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Fesinmeyer, Megan; Prentice, Ross L.; Haessler, Jeff; Carlson, Christopher S.; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Ritchie, Marilyn D.; Goodloe, Robert; Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Pankow, Jim; Hong, Ching P.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Monroe, Kristine; Henderson, Brian E.; Carlson, Christopher S.] Univ So Calif, Dept Prevent Med, Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Gross, Myron D.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Buyske, Steven] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Buzkova, Petra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [North, Kari E.] Univ N Carolina, Sch Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. RP North, KE (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27515 USA. EM migraff@email.unc.edu; kari_north@unc.edu OI Buyske, Steven/0000-0001-8539-5416 FU NICHD NIH HHS [R01 HD057194, R24 HD050924] NR 26 TC 10 Z9 10 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2013 VL 62 IS 5 BP 1763 EP 1767 DI 10.2337/db12-0863 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 133HE UT WOS:000318128700056 PM 23300277 ER PT J AU Mandal, S Sen, PK Peddada, SD AF Mandal, Siddhartha Sen, Pranab K. Peddada, Shyamal D. TI A hierarchical functional data analytic approach for analyzing physiologically based pharmacokinetic models SO ENVIRONMETRICS LA English DT Article DE benzene kinetics; functional basis; differential equations; cubic splines ID DIFFERENTIAL-EQUATION MODELS; PARAMETER-ESTIMATION; REGRESSION-MODELS; BENZENE AB Ordinary differential equation based models find application in a wide variety of biological and physiological phenomena. For instance, they arise in the description of gene regulatory networks, study of viral dynamics and other infectious diseases and so on. In the field of toxicology, they are used in physiologically based pharmacokinetic models for describing absorption, distribution, metabolism and excretion of a chemical in vivo. Knowledge about the model parameters is important in understanding the mechanism of action of a chemical and are often estimated using nonlinear least squares methodology. However, there are several challenges associated with the usual methodology. Using functional data analytic methodology, in this article, we develop a general framework for drawing inferences on parameters in models described by a system of differential equations. The proposed methodology takes into account variability between and within experimental units. The performance of the proposed methodology is evaluated using a simulation study and data obtained from a benzene inhalation study. We also describe an R-based software developed toward this purpose. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Mandal, Siddhartha] Norwegian Inst Publ Hlth, N-0473 Oslo, Norway. [Sen, Pranab K.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Peddada, Shyamal D.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Peddada, SD (reprint author), NIEHS, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES101744-04] FX The authors would like to thank Dr. Grace Kissling and Dr. Amy Herring for reading the manuscript and providing valuable inputs and suggestions. This work was supported in part by Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES101744-04]. NR 21 TC 0 Z9 0 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1180-4009 J9 ENVIRONMETRICS JI Environmetrics PD MAY PY 2013 VL 24 IS 3 BP 172 EP 179 DI 10.1002/env.2198 PG 8 WC Environmental Sciences; Mathematics, Interdisciplinary Applications; Statistics & Probability SC Environmental Sciences & Ecology; Mathematics GA 131HO UT WOS:000317983800004 PM 23682216 ER PT J AU Reidy, M Sharma, R Masison, DC AF Reidy, Michael Sharma, Ruchika Masison, Daniel C. TI Schizosaccharomyces pombe Disaggregation Machinery Chaperones Support Saccharomyces cerevisiae Growth and Prion Propagation SO EUKARYOTIC CELL LA English DT Article ID YEAST PSI+ PRION; GUANIDINE-HYDROCHLORIDE; PROTEIN DISAGGREGATION; IN-VIVO; HSP104; HSP70; THERMOTOLERANCE; TOXICITY; PSI(+); SYSTEM AB Hsp100 chaperones protect microorganisms and plants from environmental stress by cooperating with Hsp70 and its nucleotide exchange factor (NEF) and Hsp40 cochaperones to resolubilize proteins from aggregates. The Saccharomyces cerevisiae Hsp104 (Sc-Hsp104)-based disaggregation machinery also is essential for replication of amyloid-based prions. Escherichia coli ClpB can substitute for Hsp104 to propagate [PSI+] prions in yeast, but only if E. coli DnaK and GrpE (Hsp70 and NEF) are coexpressed. Here, we tested if the reported inability of Schizosaccharomyces pombe Hsp104 (Sp-Hsp104) to support [PSI+] propagation was due to similar species-specific chaperone requirements and find that Sp-Hsp104 alone supported propagation of three different yeast prions. Sp-Hsp70 and Sp-Fes1p (NEF) likewise functioned in place of their Sa. cerevisiae counterparts. Thus, chaperones of these long-diverged species possess conserved activities that function in processes essential for both cell growth and prion propagation, suggesting Sc. pombe can propagate its own prions. We show that curing by Hsp104 overexpression and inactivation can be distinguished and confirm the observation that, unlike Sc-Hsp104, Sp-Hsp104 cannot cure yeast of [PSI+] when it is over-expressed. These results are consistent with a view that mechanisms underlying prion replication and elimination are distinct. C1 [Reidy, Michael; Sharma, Ruchika; Masison, Daniel C.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM danielmas@helix.nih.gov OI Reidy, Michael/0000-0002-9290-7595 FU Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 38 TC 6 Z9 6 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD MAY PY 2013 VL 12 IS 5 BP 739 EP 745 DI 10.1128/EC.00301-12 PG 7 WC Microbiology; Mycology SC Microbiology; Mycology GA 133OP UT WOS:000318148300011 PM 23504563 ER PT J AU Abraham, SB Abel, BS Rubino, D Nansel, T Ramsey, S Nieman, LK AF Abraham, Smita Baid Abel, Brent S. Rubino, Domenica Nansel, Tonja Ramsey, Sheila Nieman, Lynnette K. TI A direct comparison of quality of life in obese and Cushing's syndrome patients SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID HEALTH; DISEASE; OVERWEIGHT; CORTISOL; SURGERY; WEIGHT; UPDATE AB Objective: Obese (OB) individuals and patients with Cushing's syndrome (CS) often have similar clinical presentations. While each group has reduced health-related quality of life (HRQL), it is not known whether the degree of impairment is different and might distinguish between them. The objective of this study was to compare HRQL in these two populations. Design: Cross-sectional study. Methods: Three hundred and twenty-seven OB patients (48.1 +/- 11.7 years; 72.5% women) with weight gain and at least two features of CS were recruited from an outpatient weight management clinic. Sixty-six untreated patients with CS (41.6 +/- 13.2 years; 78.8% women) presented to the NIH Clinical Center for evaluation. Subjects completed the SF-36 survey and a locally created symptom questionnaire. Results: After adjusting for symptom count, OB patients had a significantly higher (better HRQL) mean physical component summary (PCS) score than CS patients (44.9 +/- 0.6 vs 35.4 +/- 1.5, P<0.0001). However, the mean mental component summary (MCS) score was lower (worse HRQL) in the OB group (41.6 +/- 0.6 vs 50.7 +/- 1.6, P<0.0001). Symptom count showed significant correlations with PCS and MCS scores. BMI correlated with PCS (r=-0.29) in OB but not in CS patients. BMI was not associated with MCS in either group. Conclusion: HRQL is significantly different between OB and CS patients. Surprisingly, after adjusting for symptom count, OB patients showed worse mental health scores than the CS population. Significant differences in HRQL and symptom count may suggest which OB patients should be screened for CS. European Journal of Endocrinology 168 787-793 C1 [Abraham, Smita Baid; Abel, Brent S.; Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, Bethesda, MD 20892 USA. [Rubino, Domenica; Ramsey, Sheila] George Washington Univ, Weight Management Program, Washington, DC USA. [Rubino, Domenica; Ramsey, Sheila] Washington Ctr Weight Management & Res, Arlington, VA USA. [Nansel, Tonja] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. RP Abraham, SB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, CRC, 1-3140,MSC 1109,10 Ctr Dr, Bethesda, MD 20892 USA. EM baids@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported in part by the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 30 TC 3 Z9 3 U1 1 U2 6 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD MAY PY 2013 VL 168 IS 5 BP 787 EP 793 DI 10.1530/EJE-12-1078 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 131OP UT WOS:000318003300017 PM 23444412 ER PT J AU Wall, EH Hewitt, SC Liu, LW del Rio, R Case, LK Lin, CY Korach, KS Teuscher, C AF Wall, Emma H. Hewitt, Sylvia C. Liu, Liwen del Rio, Roxana Case, Laure K. Lin, Chin-Yo Korach, Kenneth S. Teuscher, Cory TI Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus SO FASEB JOURNAL LA English DT Article DE microarray; uterotropic response; phenotypic variation; inheritance; microarray ID QUANTITATIVE TRAIT LOCI; RECEPTOR-ALPHA; BONE LOSS; MICE; MECHANISMS; EXPRESSION; MODEL; OSTEOPOROSIS; OVARIECTOMY; DISCOVERY AB The uterotropic response of the uterus to 17 beta-estradiol (E-2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high [C57BL/6J (B6)] or low [C3H/HeJ (C3H)] responders to E-2 led to the identification of quantitative trait (QT) loci associated with phenotypic variation in uterine growth and leukocyte infiltration. The mechanisms underlying differential responsiveness to E-2, and the genes involved, are unknown. Therefore, we used a microarray approach to show association of distinct E-2-regulated transcriptional signatures with genetically controlled high and low responses to E-2 and their segregation in (C57BL/6J x C3H/HeJ) F-1 hybrids. Among the 6664 E-2-regulated transcripts, analysis of cellular functions of those that were strain specific indicated C3H-selective enrichment of apoptosis, consistent with a 7-fold increase in the apoptosis indicator CASP3, and a 2.4-fold decrease in the apoptosis inhibitor Naip1 (Birc1a) in C3H vs. B6 following treatment with E-2. In addition, several differentially expressed transcripts reside within our previously identified QT loci, including the ER alpha-tethering factor Runx1, demonstrated to enhance E-2-mediated transcript regulation. The level of RUNX1 in uterine epithelial cells was shown to be 3.5-fold greater in B6 compared to C3H. Our novel insights into the mechanisms underlying the genetic control of tissue sensitivity to estrogen have great potential to advance understanding of individualized effects in physiological and disease states.-Wall, E. H., Hewitt, S. C., Liu, L., del Rio, R., Case, L. K., Lin, C.-Y., Korach, K. S., Teuscher, C. Genetic control of estrogen-regulated transcriptional and cellular responses in mouse uterus. FASEB J. 27, 1874-1886 (2013). www.fasebj.org C1 [Wall, Emma H.; del Rio, Roxana; Case, Laure K.; Teuscher, Cory] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Receptor Biol Grp, NIH, Res Triangle Pk, NC 27709 USA. [Liu, Liwen] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Lin, Chin-Yo; Teuscher, Cory] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA. RP Teuscher, C (reprint author), Univ Vermont, Immunobiol Program, C331 Given Med Bldg, Burlington, VT 05405 USA. EM c.teuscher@uvm.edu OI Lin, Chin-Yo/0000-0002-4461-6216; Korach, Kenneth/0000-0002-7765-418X FU National Center for Research Resources [1S10RR019246]; U.S. National Institutes of Health (NIH) Intramural Research Project [Z01ES70065]; NIH [R01NS36526, R01NS061014, R01NS060901, R01NS069628, R01AI41747] FX The authors thank Stephen Grubb (Jackson Laboratory, Bar Harbor, ME, USA) for assistance with the SNP analysis, the U.S. National Institute of Environmental Health Sciences (NIEHS) Microarray Core for microarray analysis of uterine RNA samples, the NIEHS Histology Laboratory for embedding uterine samples, and the NIEHS Comparative Medicine Branch for surgeries. The staff at the Microscopy Imaging Center at the University of Vermont, funded, in part, by the National Center for Research Resources (1S10RR019246), performed staining and imaging of Runx1 and CC3. S.C.H. and K.S.K. were supported by U.S. National Institutes of Health (NIH) Intramural Research Project Z01ES70065. C.T. was supported by NIH Research Projects R01NS36526, R01NS061014, R01NS060901, R01NS069628, and R01AI41747. The authors declare no conflicts of interest. NR 47 TC 8 Z9 8 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2013 VL 27 IS 5 BP 1874 EP 1886 DI 10.1096/fj.12-213462 PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 134PU UT WOS:000318226100008 PM 23371066 ER PT J AU Ma, L Huang, DW Cuomo, CA Sykes, S Fantoni, G Das, B Sherman, BT Yang, J Huber, C Xia, Y Davey, E Kutty, G Bishop, L Sassi, M Lempicki, RA Kovacs, JA AF Ma, Liang Huang, Da-Wei Cuomo, Christina A. Sykes, Sean Fantoni, Giovanna Das, Biswajit Sherman, Brad T. Yang, Jun Huber, Charles Xia, Yun Davey, Emma Kutty, Geetha Bishop, Lisa Sassi, Monica Lempicki, Richard A. Kovacs, Joseph A. TI Sequencing and characterization of the complete mitochondrial genomes of three Pneumocystis species provide new insights into divergence between human and rodent Pneumocystis SO FASEB JOURNAL LA English DT Article DE inverted repeats; DNA replication; pneumonia ID F SP. HOMINIS; DNA-SEQUENCES; GENETIC-DIVERGENCE; TANDEM REPEATS; SP CARINII; EVOLUTION; MICE; FUNGI; CHAIN; IDENTIFICATION AB Pneumocystis jirovecii is an important opportunistic pathogen associated with AIDS and other immunodeficient conditions. Currently, very little is known about its nuclear and mitochondrial genomes. In this study, we sequenced the complete mitochondrial genome (mtDNA) of this organism and its closely related species Pneumocystis carinii and Pneumocystis murina by a combination of sequencing technologies. Our study shows that P. carinii and P. murina mtDNA share a nearly identical number and order of genes in a linear configuration, whereas P. jirovecii has a circular mtDNA containing nearly the same set of genes but in a different order. Detailed studies of the mtDNA terminal structures of P. murina and P. carinii suggest a unique replication mechanism for linear mtDNA. Phylogenetic analysis supports a close association of Pneumocystis species with Taphrina, Saitoella, and Schizosaccharomyces, and divergence within Pneumocystis species, with P. murina and P. carinii being more closely related to each other than either is to P. jirovecii. Comparative analysis of four complete P. jirovecii mtDNA sequences in this study and previously reported mtDNA sequences for diagnosing and genotyping suggests that the current diagnostic and typing methods can be improved using the complete mtDNA data. The availability of the complete P. jirovecii mtDNA also opens the possibility of identifying new therapeutic targets.-Ma, L., Huang, D. W., Cuomo, C. A., Sykes, S., Fantoni, G., Das, B., Sherman, B. T., Yang, J., Huber, C., Xia, Y., Davey, E., Kutty, G., Bishop, L., Sassi, M., Lempicki, R. A., Kovacs, J. A. Sequencing and characterization of the complete mitochondrial genomes of three Pneumocystis species provide new insights into divergence between human and rodent Pneumocystis. FASEB J. 27, 1962-1972 (2013). www.fasebj.org C1 [Ma, Liang; Fantoni, Giovanna; Xia, Yun; Davey, Emma; Kutty, Geetha; Bishop, Lisa; Sassi, Monica; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Huber, Charles] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Huang, Da-Wei; Das, Biswajit; Sherman, Brad T.; Yang, Jun; Lempicki, Richard A.] Sci Applicat Int Corp Frederick, Lab Immunopathogenesis & Bioinformat, Clin Serv Program, Frederick, MD USA. [Cuomo, Christina A.; Sykes, Sean] MIT, Broad Inst, Cambridge, MA 02139 USA. [Cuomo, Christina A.; Sykes, Sean] Harvard Univ, Cambridge, MA 02138 USA. RP Ma, L (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM mal3@mail.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Cuomo, Christina/0000-0002-5778-960X FU Intramural Research Program of the U.S. National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases [NOI-CO-56000]; National Human Genome Research Institute [U54HG003067]; Chongqing Medical University (Chongqing, China) FX This work was supported by the Intramural Research Program of the U.S. National Institutes of Health Clinical Center; the National Institute of Allergy and Infectious Diseases (contract NOI-CO-56000); and the National Human Genome Research Institute (grant U54HG003067). Y.X. was supported by a scholarship from Chongqing Medical University (Chongqing, China). The authors declare no conflicts of interests. The authors thank Rene Costello and Howard Mostowski for their support of the animal studies. NR 44 TC 18 Z9 20 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2013 VL 27 IS 5 BP 1962 EP 1972 DI 10.1096/fj.12-224444 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 134PU UT WOS:000318226100016 PM 23392351 ER PT J AU Brinton, LA Felix, AS McMeekin, DS Creasman, WT Sherman, ME Mutch, D Cohn, DE Walker, JL Moore, RG Downs, LS Soslow, RA Zaino, R AF Brinton, Louise A. Felix, Ashley S. McMeekin, D. Scott Creasman, William T. Sherman, Mark E. Mutch, David Cohn, David E. Walker, Joan L. Moore, Richard G. Downs, Levi S. Soslow, Robert A. Zaino, Richard TI Etiologic heterogeneity in endometrial cancer: Evidence from a Gynecologic Oncology Group trial SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Endometrial cancer; Type II endometrial cancer; Serous endometrial cancer; Carcinosarcoma; Etiology; Epidemiology ID UTERINE SEROUS CARCINOMA; MIXED MULLERIAN TUMORS; BREAST-CANCER; CORPUS CANCER; RISK-FACTORS; INTRAEPITHELIAL CARCINOMA; POSTMENOPAUSAL WOMEN; HISTOLOGIC SUBTYPES; TAMOXIFEN TREATMENT; UNITED-STATES AB Objective. Although the epidemiology of typical endometrial carcinomas (grades 1-2 endometrioid or Type I) is well established, less is known regarding higher grade endometrioid or non-endometrioid carcinomas (Type II). Within a large Gynecologic Oncology Group trial (GOG-210), which included central pathology review, we investigated the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologic categories. Methods. Based on epidemiologic questionnaire data, risk factor associations, expressed as odds ratios (OR) with 95% confidence intervals (CI), were estimated comparing grade 3 endometrioid and Type II cancers (including histologic subtypes) to grades 1-2 endometrioid cancers. Results. Compared with 2244 grades 1-2 endometrioid cancers, women with Type II cancers (321 serous, 141 carcinosarcomas, 77 clear cell, 42 mixed epithelial with serous or clear cell components) were older; more often non-white, multiparous, current smokers; and less often obese. Risk factors for grade 3 endometrioid carcinomas (n = 354) were generally similar to those identified for Type II cancers, although patients with grade 3 endometrioid tumors more often had histories of breast cancer without tamoxifen exposure while those with Type II tumors were more frequently treated with tamoxifen. Patients with serous cancers and carcinosarcomas more frequently had breast cancer histories with tamoxifen treatment compared to patients with other tumors. Conclusions. Risk factors for aggressive endometrial cancers, including grade 3 endometrioid and non-endometrioid tumors, appear to differ from lower grade endometrioid carcinomas. Our findings support etiologic differences between Type I and II endometrial cancers as well as additional heterogeneity within Type II cancers. Published by Elsevier Inc. C1 [Brinton, Louise A.; Felix, Ashley S.; Sherman, Mark E.] NCI, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. [McMeekin, D. Scott; Walker, Joan L.] Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK USA. [Creasman, William T.] Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. [Mutch, David] Washington Univ, Sch Med, St Louis, MO USA. [Cohn, David E.] Ohio State Univ, Coll Med, Div Gynecol Oncol, Columbus, OH 43210 USA. [Moore, Richard G.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Downs, Levi S.] Univ Minnesota, Minneapolis, MN USA. [Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zaino, Richard] Penn State Milton S Hersey Med Ctr, Hershey, PA USA. RP Brinton, LA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Execut Plaza South,Room 5018,6120 Execut Blvd,MSC, Rockville, MD 20852 USA. EM Brintonl@exchange.nih.gov RI Brinton, Louise/G-7486-2015; Felix, Ashley/A-3240-2016; OI Brinton, Louise/0000-0003-3853-8562; Soslow, Robert/0000-0002-7269-5898 FU National Cancer Institute [CA 27469]; Gynecologic Oncology Group Statistical and Data Center [CA 37517]; intramural research program of the National Cancer Institute, National Institutes of Health FX This study was supported in part by the National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). In addition, this research was supported in part by funds provided by the intramural research program of the National Cancer Institute, National Institutes of Health. NR 48 TC 47 Z9 51 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2013 VL 129 IS 2 BP 277 EP 284 DI 10.1016/j.ygyno.2013.02.023 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 132HN UT WOS:000318058600003 PM 23485770 ER PT J AU Levinson, KL Abuelo, C Salmeron, J Chyung, E Zou, J Belinson, SE Wang, GX Santos, C Vallejos, CS Belinson, JL AF Levinson, Kimberly L. Abuelo, Carolina Salmeron, Jorge Chyung, Eunice Zou, Jing Belinson, Suzanne E. Wang, Guixiang Santos (Ortiz), Carlos Vallejos, Carlos Santiago Belinson, Jerome L. TI The Peru Cervical Cancer Prevention Study (PERCAPS): The technology to make screening accessible SO GYNECOLOGIC ONCOLOGY LA English DT Article ID MASS-SPECTROMETRY SYSTEM; HIGH-RISK HPV; HUMAN-PAPILLOMAVIRUS; ACCEPTABILITY; SAMPLES; PART; DNA; CYTOLOGY; COHORT; TRIAL AB Objective. This study utilized a combination of HPV self-sampling, iFTA elute specimen cards, and long distance transport for centralized processing of specimens to determine the feasibility of large-scale screening in remote and transient populations. Methods. This study was performed in two locations in Peru (Manchay and Iquitos). The "Just For Me" cervico-vaginal brush and iFTA elute cards were used for the collection and transport of specimens. Samples were shipped via FedEx to China and tested for 14 types of high-risk HPV using PCR based MALDI-TOF. HPV positive women were treated with cryotherapy after VIA triage, and followed-up with colposcopy, biopsy, ECC, and repeat HPV testing at 6 months. Results. Six hundred and forty three women registered, and 632 returned a sample over a 10 day period. Within 2 weeks, specimens were shipped, samples tested, and results received by study staff. Sixty-eight women (10.8%) tested positive, and these results were delivered over 4 days. Fifty-nine HPV positive women (87%) returned for evaluation and treatment, and 2 had large lesions not suitable for cryotherapy. At 6 months, 42 women (74%) returned for follow-up, and 3 had CIN 2 (all positive samples from the endocervical canal). Ninety eight percent of participants reported that they would participate in this type of program again. Conclusions. Utilizing HPV self-sampling, solid media specimen cards for long distance transport, and centralized high throughput processing, we achieved rapid delivery of results, high satisfaction levels, and low loss to follow-up for cervical cancer screening in remote and transient populations. (c) 2013 Elsevier Inc. All rights reserved. C1 [Levinson, Kimberly L.] Cleveland Clin, Cleveland, OH 44195 USA. [Abuelo, Carolina] NIH, Bethesda, MD 20892 USA. [Salmeron, Jorge] Inst Mexicano Seguro Social, Cuernavaca, Morelos, Mexico. [Chyung, Eunice] Case Western Reserve Sch Med, Cleveland, OH 44106 USA. [Zou, Jing] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Belinson, Suzanne E.; Wang, Guixiang; Belinson, Jerome L.] Prevent Oncol Int, Cleveland, OH 44118 USA. [Santos (Ortiz), Carlos; Vallejos, Carlos Santiago] Div Invest Oncosalud, Lima 2525, Peru. [Belinson, Jerome L.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. RP Levinson, KL (reprint author), Cleveland Clin, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM kimlynnlev@gmail.com; princesa_carolina@yahoo.com; jsalme@prodigy.net.mx; eunice.chyung@gmail.com; zoujing@genomics.cn; seb@poiinc.org; wgx828@yahoo.com; c_santos_o@yahoo.com; cvallejos@oncosalud.pe; jlb@poiinc.org FU Preventive Oncology International; Investigator-Initiated Studies Program of Merck Sharp Dohme Corp.; National Institutes of Health Office of the Director; Fogarty International Center; Office of AIDS Research; National Cancer Center; National Eye Institute; National Heart, Blood, and Lung Institute; National Institute of Dental and Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases; National Institutes of Health Office of Women's Health and Research through the Fogarty International Clinical Research Scholars; Fellows Program at Vanderbilt University [R24 TW007988]; American Relief and Recovery Act; Hologic Inc.; Qiagen; Gen-Probe; Merck Inc.; BGI Shenzhen; GE Healthcare FX 1) Preventive Oncology International.2) Supported in part by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc 3) This work was supported by the National Institutes of Health Office of the Director, Fogarty International Center, Office of AIDS Research, National Cancer Center, National Eye Institute, National Heart, Blood, and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, and National Institutes of Health Office of Women's Health and Research through the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988) and the American Relief and Recovery Act.; Preventive Oncology International has received support in kind (reagents and testing) and/or funds for direct support and research from Hologic Inc., Qiagen, Gen-Probe, Merck Inc., BGI Shenzhen, and GE Healthcare. NR 23 TC 10 Z9 10 U1 6 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2013 VL 129 IS 2 BP 318 EP 323 DI 10.1016/j.ygyno.2013.01.026 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 132HN UT WOS:000318058600009 PM 23385153 ER PT J AU Aung, PP Killian, K Poropatich, CO Linehan, WM Merino, MJ AF Aung, Phyu P. Killian, Keith Poropatich, Carrie O. Linehan, W. Marston Merino, Maria J. TI Primary neuroendocrine tumors of the kidney: morphological and molecular alterations of an uncommon malignancy SO HUMAN PATHOLOGY LA English DT Article DE Comparative genomic hybridization analysis; Immunohistochemical stain; Loss of heterozygosity analysis; Primary neuroendocrine tumors of the kidney ID PRIMARY CARCINOID-TUMOR; HORSESHOE KIDNEY; CELL; ASSOCIATION; TERATOMA AB Primary neuroendocrine (NE) tumors of the kidney (PNRTs) are rare and frequently mistaken for other renal and urothelial cancers. We evaluated morphological and molecular findings of 11 PNRTs classified according to the World Health Organization classification of lung NE tumors. Patients included 5 men and 6 women with a median age of 50 years. These tumors occurred in the left (5/11), right (3/11), and horseshoe (1/11) kidney. The histologic patterns were predominantly solid, trabecular, and pseudoglandular. Lymphovascular invasion and calcification were found in 3 and 1 cases, respectively. There were 2 atypical and 9 typical carcinoids. At the time of surgery, 2 patients with atypical carcinoids had hepatic metastasis, and 1 of the typical carcinoid patients had lymph node metastasis. All cases showed <1% proliferative rate, except 2 cases with hepatic metastasis, which showed 3% to 5% with MIB1/Ki-67 immunostaining. Immunostainings were frequently positive for synaptophysin, chromogranin, CD56, CD99, and neuron-specific enolase. Follow-up data (average 4 years) were available for 6 patients. Two patients with distant metastasis were alive with disease, and four patients with no metastasis were alive without disease. We evaluated the association of PNRT and loss of heterozygosity (LOH) on chromosome 3p21 and found LOH in 2 of 3 cases. However, the comparative genomic hybridization study (2/2) did not demonstrate significant chromosomal imbalances. We conclude that PNRTs are positive for NE markers and may have LOH on chromosome 3p21. PNRTs should be classified as NE tumors in other sites, and proliferative rate can be an indicator of aggressive behavior/metastasis. Published by Elsevier Inc. C1 [Aung, Phyu P.; Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Killian, Keith] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Poropatich, Carrie O.] Virginia Hosp Ctr, Dept Pathol, Arlington, VA 22205 USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov NR 27 TC 9 Z9 10 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD MAY PY 2013 VL 44 IS 5 BP 873 EP 880 DI 10.1016/j.humpath.2012.08.013 PG 8 WC Pathology SC Pathology GA 134HQ UT WOS:000318201400024 PM 23199527 ER PT J AU Arnold, MA Arnold, CA Li, G Chae, U El-Etriby, R Lee, CCR Tsokos, M AF Arnold, Michael A. Arnold, Christina A. Li, Guang Chae, Uisoo El-Etriby, Rana Lee, Chyi-Chia Richard Tsokos, Maria TI A unique pattern of INI1 immunohistochemistry distinguishes synovial sarcoma from its histologic mimics SO HUMAN PATHOLOGY LA English DT Article DE Ewing sarcoma; INI1 immunohistochemistry (IHC); Malignant peripheral nerve sheath tumor (MPNST); Malignant rhabdoid tumor; Synovial sarcoma ID SOFT-TISSUE TUMORS; RHABDOID TUMORS; TRANSCRIPTION FACTOR; EWING SARCOMA; IDENTIFICATION; EXPRESSION; MUTATIONS; FUSION; INI1/SMARCB1; CHROMOSOME AB The absence of INI1 (SMARCB1, hSNF5, BAF47) immunohistochemical reactivity is a central feature of malignant rhabdoid tumor, renal medullary carcinoma, and epithelioid sarcoma. We characterized INI1 immunoreactivity in synovial sarcoma (49 cases) in comparison with its closest histologic mimics (68 cases). We observed a unique pattern of decreased INI1 immunoreactivity with a high specificity (100%) and sensitivity (86%) for synovial sarcoma and particular sensitivity for poorly differentiated subtypes of synovial sarcoma (94%; 16/17 cases). Decreased INI1 immunoreactivity was not seen in any of the other lesions we examined, including 14 cases of Ewing sarcoma and 22 cases of malignant peripheral nerve sheath tumor. Furthermore, decreased INI1 immunoreactivity is distinct from the complete absence of Nil immunoreactivity seen in malignant rhabdoid tumor or other INI1-negative neoplasms. We propose that this distinct INI1 immunohistochemical pattern serves as a useful diagnostic tool to provide preliminary results before molecular test results are available, especially in cases of poorly differentiated synovial sarcoma and in cases where limited material precludes confirmatory molecular studies. Awareness of this unique pattern is critical to avoid misinterpreting decreased INI1 immunoreactivity as a complete absence of INI1 and, consequently, misdiagnosing synovial sarcoma as an INI1-negative neoplasm. (C) 2013 Elsevier Inc. All rights reserved. C1 [Arnold, Michael A.] Nationwide Childrens Hosp, Dept Pathol, Columbus, OH 43205 USA. [Arnold, Christina A.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Li, Guang; Chae, Uisoo; El-Etriby, Rana; Lee, Chyi-Chia Richard; Tsokos, Maria] NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. RP Arnold, MA (reprint author), Nationwide Childrens Hosp, Dept Pathol, Columbus, OH 43205 USA. EM Michael.Arnold@Nationwidechildrens.org RI Lee, Chyi-Chia/I-1938-2013; OI Lee, Chyi-Chia/0000-0002-5306-7781; Arnold, Christina/0000-0002-2255-4042; Arnold, Michael/0000-0002-6921-3720 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Department of Pathology, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Department of Pathology, Bethesda, MD 20892. NR 34 TC 17 Z9 19 U1 0 U2 4 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 J9 HUM PATHOL JI Hum. Pathol. PD MAY PY 2013 VL 44 IS 5 BP 881 EP 887 DI 10.1016/j.humpath.2012.08.014 PG 7 WC Pathology SC Pathology GA 134HQ UT WOS:000318201400025 PM 23245672 ER PT J AU Boyd, A Bennuru, S Wang, YY Sanprasert, V Law, M Chaussabel, D Nutman, TB Semnani, RT AF Boyd, Alexis Bennuru, Sasisekhar Wang, Yuanyuan Sanprasert, Vivornpun Law, Melissa Chaussabel, Damien Nutman, Thomas B. Semnani, Roshanak Tolouei TI Quiescent Innate Response to Infective Filariae by Human Langerhans Cells Suggests a Strategy of Immune Evasion SO INFECTION AND IMMUNITY LA English DT Article ID ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; BRUGIA-MALAYI; CUTANEOUS LEISHMANIASIS; TOXOPLASMA-GONDII; T-CELLS; SKIN; EXPRESSION; STAGE; DIFFERENTIATION AB Filarial infection is initiated by mosquito-derived third-stage larvae (L3) deposited on the skin that transit through the epidermis, which contains Langerhans cells (LC) and keratinocytes (KC), among other cells. This earliest interaction between L3 and the LC likely conditions the priming of the immune system to the parasite. To determine the nature of this interaction, human LC (langerin(+) E-cadherin(+) CD1a(+)) were generated in vitro and exposed to live L3. LC exposed to live L3 for 48 h showed no alterations in the cell surface markers CD14, CD86, CD83, CD207, E-cadherin, CD80, CD40, and HLA-DR or in mRNA expression of inflammation-associated genes, such as those for interleukin 18 (IL-18), IL-18BP, and caspase 1. In contrast to L3, live tachyzoites of Toxoplasma gondii, an intracellular parasite, induced production of CXCL9, IP-10, and IL-6 in LC. Furthermore, preexposure of LC to L3 did not alter Toll-like receptor 3 (TLR3)- or TLR4-mediated expression of the proinflammatory cytokines IL-1 beta, gamma interferon (IFN-gamma), IL-6, or IL-10. Interestingly, cocultures of KC and LC produced significantly more IL-18, IL-1 alpha, and IL-8 than did cultures of LC alone, although exposure of the cocultures to live L3 did not result in altered cytokine production. Microarray examination of ex vivo LC from skin blisters that were exposed to live L3 also showed few significant changes in gene expression compared with unexposed blisters, further underscoring the relatively muted response of LC to L3. Our data suggest that failure by LC to initiate an inflammatory response to the invasive stage of filarial parasites may be a strategy for immune evasion by the filarial parasite. C1 [Boyd, Alexis; Bennuru, Sasisekhar; Sanprasert, Vivornpun; Law, Melissa; Nutman, Thomas B.; Semnani, Roshanak Tolouei] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Wang, Yuanyuan; Chaussabel, Damien] Baylor Inst Immunol Res, Dallas, TX USA. RP Semnani, RT (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. EM rsemnani@niaid.nih.gov OI Chaussabel, Damien/0000-0002-6131-7242 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 35 TC 7 Z9 7 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2013 VL 81 IS 5 BP 1420 EP 1429 DI 10.1128/IAI.01301-12 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 126AE UT WOS:000317582700005 PM 23429540 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 SO INFECTION AND IMMUNITY LA English DT Article ID SURVIVAL STRATEGIES; PHOSPHOLIPASE A(2); EPITHELIAL-CELLS; GENE-EXPRESSION; S100 PROTEINS; MOUSE MODEL; TNF-ALPHA; T-CELLS; DEFICIENCY; DISEASE AB Resistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected with Entamoeba histolytica than those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected against E. histolytica via STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanized LEPRQ or R allele at codon 223 were intracecally infected with E. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had cleared E. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2, S100A8/9, PLA2G7, ITBG2, and MMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection by E. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity. C1 [Mackey-Lawrence, Nicole M.; Guo, Xiaoti; Houpt, Eric; Petri, William A., Jr.] Univ Virginia, Sch Med, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. [Guo, Xiaoti] N Shore Long Isl Hlth Syst, Manhasset, NY USA. [Sturdevant, Daniel E.; Virtaneva, Kimmo; Hernandez, Matthew M.; Porcella, Stephen F.] NIAID, Rocky Mt Lab, Res Technol Sect, Genom Unit,NIH, Hamilton, MT 59840 USA. [Sher, Alan] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Petri, WA (reprint author), Univ Virginia, Sch Med, Dept Med, Div Infect Dis & Int Hlth, Charlottesville, VA 22908 USA. EM wap3g@virginia.edu FU NIH [5RO1 AI026649]; BioDefense Research Training and Career Development NIH [T32AI07046-32] FX This work was supported by NIH grant 5RO1 AI026649 to W.A.P. N.M.M.-L was supported by BioDefense Research Training and Career Development NIH grant T32AI07046-32. NR 73 TC 15 Z9 15 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2013 VL 81 IS 5 BP 1460 EP 1470 DI 10.1128/IAI.01383-12 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 126AE UT WOS:000317582700009 PM 23429533 ER PT J AU Miura, K Herrera, R Diouf, A Zhou, H Mu, JB Hu, ZH MacDonald, NJ Reiter, K Nguyen, V Shimp, RL Singh, K Narum, DL Long, CA Miller, LH AF Miura, Kazutoyo Herrera, Raul Diouf, Ababacar Zhou, Hong Mu, Jianbing Hu, Zonghui MacDonald, Nicholas J. Reiter, Karine Vu Nguyen Shimp, Richard L., Jr. Singh, Kavita Narum, David L. Long, Carole A. Miller, Louis H. TI Overcoming Allelic Specificity by Immunization with Five Allelic Forms of Plasmodium falciparum Apical Membrane Antigen 1 SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA VACCINE CANDIDATE; IN-VITRO; TRIAL; AMA1; ANTIBODIES; DIVERSITY; RESPONSES; IMMUNOGENICITY; SELECTION; CHILDREN AB Apical membrane antigen 1 (AMA1) is a leading vaccine candidate, but the allelic polymorphism is a stumbling block for vaccine development. We previously showed that a global set of AMA1 haplotypes could be grouped into six genetic populations. Using this information, six recombinant AMA1 proteins representing each population were produced. Rabbits were immunized with either a single recombinant AMA1 protein or mixtures of recombinant AMA1 proteins (mixtures of 4, 5, or 6 AMA1 proteins). Antibody levels were measured by enzyme-linked immunosorbent assay (ELISA), and purified IgG from each rabbit was used for growth inhibition assay (GIA) with 12 different clones of parasites (a total of 108 immunogen-parasite combinations). Levels of antibodies to all six AMA1 proteins were similar when the antibodies were tested against homologous antigens. When the percent inhibitions in GIA were plotted against the number of ELISA units measured with homologous AMA1, all data points followed a sigmoid curve, regardless of the immunogen. In homologous combinations, there were no differences in the percent inhibition between the single-allele and allele mixture groups. However, all allele mixture groups showed significantly higher percent inhibition than the single-allele groups in heterologous combinations. The 5-allele-mixture group showed significantly higher inhibition to heterologous parasites than the 4-allele-mixture group. On the other hand, there was no difference between the 5- and 6-allele-mixture groups. These data indicate that mixtures with a limited number of alleles may cover a majority of the parasite population. In addition, using the data from 72 immunogen-parasite combinations, we mathematically identified 13 amino acid polymorphic sites which significantly impact GIA activities. These results could be a foundation for the rational design of a future AMA1 vaccine. C1 [Miura, Kazutoyo; Diouf, Ababacar; Zhou, Hong; Mu, Jianbing; Long, Carole A.; Miller, Louis H.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Herrera, Raul; MacDonald, Nicholas J.; Reiter, Karine; Vu Nguyen; Shimp, Richard L., Jr.; Narum, David L.] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Hu, Zonghui] NIAID, Biostat Res Branch, NIH, Bethesda, MD USA. [Singh, Kavita] NIAID, Struct Biol Sect, Res Technol Branch, NIH, Rockville, MD USA. RP Miura, K (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM kmiura@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, NIH; PATH Malaria Vaccine Initiative FX The study was supported by the intramural program of the National Institute of Allergy and Infectious Diseases, NIH, and GIA work was supported partially by the PATH Malaria Vaccine Initiative. NR 39 TC 20 Z9 20 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2013 VL 81 IS 5 BP 1491 EP 1501 DI 10.1128/IAI.01414-12 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 126AE UT WOS:000317582700012 PM 23429537 ER PT J AU Jena, AB Prasad, V AF Jena, Anupam B. Prasad, Vinay TI Falsification End Points for Observational Studies Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID SURGERY C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Prasad, Vinay] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 1 PY 2013 VL 309 IS 17 BP 1770 EP 1771 DI 10.1001/jama.2013.3112 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 134SU UT WOS:000318235600017 PM 23632713 ER PT J AU Liu, ZF Ren, C Jones, W Chen, P Seminara, SB Chan, YM Smith, NF Covey, JM Wang, J Chan, KK AF Liu, Zhongfa Ren, Chen Jones, William Chen, Ping Seminara, Stephanie B. Chan, Yee-Ming Smith, Nicola F. Covey, Joseph M. Wang, Jeffrey Chan, Kenneth K. TI LC-MS/MS quantification of a neuropeptide fragment kisspeptin-10 (NSC 741805) and characterization of its decomposition product and pharmacokinetics in rats SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE Kisspeptin-10; LC-MS/MS; Pharmacokinetics; Metabolites ID METASTASIS-SUPPRESSOR GENE; PROTEIN-COUPLED RECEPTOR; PITUITARY-GONADAL AXIS; HORMONE-RELEASE; KISS-1 PEPTIDE; GPR54; ACTIVATION; HUMANS; LIGAND AB The kisspeptins are critical regulators of mammalian reproduction. Kisspeptin-10 ((45)YNWNSFGLRF-NH254, kisspeptin-112-121 or metastin 45-54, NSC 741805), an active fragment of kisspeptin, has been shown to be a potent stimulator of gonadotropin-releasing hormone and secretion of luteinizing hormone in both rodents and primates. This shorter peptide fragment may have clinical utility potential and it is important to characterize its pharmacokinetic property. Recently, the pharmacokinetics of both kisspeptin-54 and kisspeptin-10 were characterized in humans using a radioimmunoassay (RIA), which measures only the immunoreactive kisspeptin (kisspeptin-IR). In this study, a highly sensitive and specific LC-MS/MS assay was developed to quantify kisspeptin-10 levels in rat plasma. The lower limit of quantitation (LLOQ) was 0.5 ng/mL, the within-day and between-day coefficient of variations (CVs) ranged from 5.2 to 15.4% and 1.3 to 14.2%, and the accuracy values ranged from 98 to 114% and 99 to 105%, respectively. With this method, stability studies demonstrated that kisspeptin-10 degraded rapidly with decomposition half-lives of 6.8 min, 2.9 min and 1.7 min at 4 degrees C, 25 degrees C, and 37 degrees C, respectively. The principal decomposition product was characterized as the N-terminal tyrosine deleted kisspeptin-10 (46)NWDSFGLRF-NH254. Pharmacokinetic study in rats showed that low ng/mL kisspeptin-10 was detected in the first few minutes, and eliminated rapidly and became undetectable 30 min after intravenous (i.v.) bolus administration of 1.0 mg/kg kisspeptin-10. (C) 2013 Elsevier B.V. All rights reserved. C1 [Liu, Zhongfa; Ren, Chen; Jones, William; Chen, Ping; Chan, Kenneth K.] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Seminara, Stephanie B.; Chan, Yee-Ming; Chan, Kenneth K.] Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Seminara, Stephanie B.; Chan, Yee-Ming; Chan, Kenneth K.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Smith, Nicola F.; Covey, Joseph M.] NCI, Rockville, MD 20852 USA. [Liu, Zhongfa; Ren, Chen; Jones, William; Chen, Ping; Seminara, Stephanie B.; Chan, Yee-Ming; Smith, Nicola F.; Covey, Joseph M.; Wang, Jeffrey; Chan, Kenneth K.] Ohio State Univ, Coll Med & Publ Hlth, Columbus, OH 43210 USA. [Wang, Jeffrey] Western Univ Hlth Sci, Coll Pharm, Pomona, CA 91766 USA. RP Chan, KK (reprint author), Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA. EM chan.56@osu.edu RI Liu, Zhongfa/G-8549-2013 FU NIH-RAID program; NICHD; NIDDK under the National Cancer Institute (NCI) [N01-CM-52205] FX This research was supported by the NIH-RAID program, NICHD and NIDDK under the National Cancer Institute (NCI) contract N01-CM-52205. NR 18 TC 6 Z9 7 U1 0 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 1 PY 2013 VL 926 BP 1 EP 8 DI 10.1016/j.jchromb.2013.02.027 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 131NQ UT WOS:000318000800001 PM 23524040 ER PT J AU Ayas, M Saber, W Davies, SM Harris, RE Hale, GA Socie, G LeRademacher, J Thakar, M Deeg, HJJ Al-Seraihy, A Battiwalla, M Camitta, BM Olsson, R Bajwa, RS Bonfim, CM Pasquini, R MacMillan, ML George, B Copelan, EA Wirk, B Al Jefri, A Fasth, AL Guinan, EC Horn, BN Lewis, VA Slavin, S Stepensky, P Bierings, M Gale, RP AF Ayas, Mouhab Saber, Wael Davies, Stella M. Harris, Richard E. Hale, Gregory A. Socie, Gerard LeRademacher, Jennifer Thakar, Monica Deeg, H. Joachim J. Al-Seraihy, Amal Battiwalla, Minoo Camitta, Bruce M. Olsson, Richard Bajwa, Rajinder S. Bonfim, Carmem M. Pasquini, Ricardo MacMillan, Margaret L. George, Biju Copelan, Edward A. Wirk, Baldeep Al Jefri, Abdullah Fasth, Anders L. Guinan, Eva C. Horn, Biljana N. Lewis, Victor A. Slavin, Shimon Stepensky, Polina Bierings, Marc Gale, Robert Peter TI Allogeneic Hematopoietic Cell Transplantation for Fanconi Anemia in Patients With Pretransplantation Cytogenetic Abnormalities, Myelodysplastic Syndrome, or Acute Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; LOW-DOSE CYCLOPHOSPHAMIDE; UNRELATED DONORS; SIBLING DONOR; RISK-FACTOR; FLUDARABINE; REGISTRY; CANCER; EXPERIENCE; GRAFT AB Purpose Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed. Patients and Methods We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007. Results Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (<= v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (<= v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival. Conclusion Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival. J Clin Oncol 31: 1669-1676. (C) 2013 by American Society of Clinical Oncology C1 [Ayas, Mouhab; Al-Seraihy, Amal; Al Jefri, Abdullah] King Faisal Specialist Hosp & Res Ctr, Riyadh 11211, Saudi Arabia. [Saber, Wael; LeRademacher, Jennifer] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Thakar, Monica] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Med Coll Wisconsin, Midwest Ctr Canc & Blood Disorders, Milwaukee, WI 53226 USA. [Camitta, Bruce M.] Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA. [Davies, Stella M.; Harris, Richard E.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Bajwa, Rajinder S.] Nationwide Childrens Hosp, Columbus, OH USA. [Copelan, Edward A.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, St Petersburg, FL 33701 USA. [Wirk, Baldeep] Shands Healthcare, Gainesville, FL USA. [Wirk, Baldeep] Univ Florida, Gainesville, FL USA. [Deeg, H. Joachim J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Battiwalla, Minoo] NHLBI, Bethesda, MD 20892 USA. [MacMillan, Margaret L.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Guinan, Eva C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Horn, Biljana N.] Univ Calif San Francisco, Med Ctr, San Francisco, CA USA. [Socie, Gerard] Hop St Louis, Paris, France. [Olsson, Richard] Karolinska Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Fasth, Anders L.] Univ Gothenburg, Gothenburg, Sweden. [Bonfim, Carmem M.; Pasquini, Ricardo] Univ Fed Parana, Hosp Clin, BR-80060000 Curitiba, Parana, Brazil. [George, Biju] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Lewis, Victor A.] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. [Slavin, Shimon] Int Ctr Cell Therapy & Canc Immunotherapy, Tel Aviv, Israel. [Stepensky, Polina] Hadassah Med Ctr, IL-91120 Jerusalem, Israel. [Bierings, Marc] Wihelmina Childrens Hosp, Utrecht, Netherlands. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, London, England. RP Ayas, M (reprint author), King Faisal Specialist Hosp & Res Ctr, POB 3354,MBC 53, Riyadh 11211, Saudi Arabia. EM mouhab@kfshrc.edu.sa RI Bajwa, Rajinder/E-2685-2011; OI Olsson, Richard/0000-0001-5970-2128; Fasth, Anders/0000-0002-0033-740X FU NCI NIH HHS [U24-CA76518]; NHLBI NIH HHS [5U01HL069294]; PHS HHS [HHSH234200637015C, N00014-06-1-0704, N00014-08-1-0058] NR 55 TC 21 Z9 21 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2013 VL 31 IS 13 BP 1669 EP + DI 10.1200/JCO.2012.45.9719 PG 10 WC Oncology SC Oncology GA 133PU UT WOS:000318152200015 PM 23547077 ER PT J AU Pacak, K Jochmanova, I Prodanov, T Yang, CZ Merino, MJ Fojo, T Prchal, JT Tischler, AS Lechan, RM Zhuang, ZP AF Pacak, Karel Jochmanova, Ivana Prodanov, Tamara Yang, Chunzhang Merino, Maria J. Fojo, Tito Prchal, Josef T. Tischler, Arthur S. Lechan, Ronald M. Zhuang, Zhengping TI New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIPPEL-LINDAU-DISEASE; NEUROENDOCRINE TUMORS; APUD SERIES; HIF2A GENE; ERYTHROCYTOSIS; CELLS; HYPOXIA; CANCER; PHEOCHROMOCYTOMA; DIFFERENTIATION AB Purpose The occurrence of >= two distinct types of tumors, one of them paraganglioma (PGL), is unusual in an individual patient, except in hereditary cancer syndromes. Patients and Methods Four unrelated patients were investigated, with thorough clinical evaluation. Plasma and tissue catecholamines and metanephrines were measured by high-performance liquid chromatography. Anatomic and functional imaging were performed for tumor visualization. Germline and tumor tissue DNA were analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. The prolyl hydroxylation and stability of the mutant HIF2 alpha protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes were also investigated. Immunohistochemical staining for HIF1/2 alpha was performed on formalin-fixed, paraffin-embedded tumor tissue. Results Patients were found to have polycythemia, multiple PGLs, and duodenal somatostatinomas by imaging or biochemistry with somatic gain-of-function HIF2A mutations. Each patient carried an identical unique mutation in both types of tumors but not in germline DNA. The HIF2A mutations in these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2 alpha interaction with the prolyl hydroxylase domain 2-containing protein, decreasing the hydroxylation of HIF2 alpha, and reducing HIF2 alpha affinity for the von Hippel-Lindau protein and its degradation. An increase in the half-life of HIF2 alpha was associated with upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors. Conclusion Our findings indicate the existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia. This new syndrome results from somatic gain-of-function HIF2A mutations, which cause an upregulation of hypoxia-related genes, including EPO and genes important in cancer biology. J Clin Oncol 31: 1690-1698. (C) 2013 by American Society of Clinical Oncology C1 [Pacak, Karel; Jochmanova, Ivana; Prodanov, Tamara] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Merino, Maria J.; Fojo, Tito] NCI, Bethesda, MD 20892 USA. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, NIH, Bethesda, MD 20892 USA. [Prchal, Josef T.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Prchal, Josef T.] VA Hosp, Salt Lake City, UT USA. [Tischler, Arthur S.; Lechan, Ronald M.] Tufts Med Ctr, Boston, MA USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, Program Reprod & Adult Endocrinol, NIH,CRC, Bldg 10,Room 1E-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Jochmanova, Ivana/I-9011-2016 OI Jochmanova, Ivana/0000-0003-2346-461X FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Neurological Disorders and Stroke FX Supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Institute of Neurological Disorders and Stroke. NR 43 TC 46 Z9 47 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2013 VL 31 IS 13 BP 1690 EP + DI 10.1200/JCO.2012.47.1912 PG 10 WC Oncology SC Oncology GA 133PU UT WOS:000318152200018 PM 23509317 ER PT J AU Langan, RC Sherry, RM Avital, I Heller, T Henderson, C Holland, SM Freeman, AF Rudloff, U AF Langan, Russell C. Sherry, Richard M. Avital, Itzhak Heller, Theo Henderson, Carolyn Holland, Steven M. Freeman, Alexandra F. Rudloff, Udo TI Safety of Major Abdominal Surgical Procedures in Patients with Hyperimmunoglobulinemia E (Job's Syndrome): a Changing Paradigm? SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Job's syndrome; Hyperimmunoglobulinemia E; Immunodeficiency; Liver resection; Gastrectomy; Colon resection ID HYPER-IGE SYNDROME; STAT3 AB Autosomal dominant hyperimmunoglobulinemia E syndrome (HIES), also called Job's syndrome, is a primary immunodeficiency characterized by the triad of elevated immunoglobulin E levels, eczema, and infections. Its clinical course manifests as recurrent skin and pulmonary infections, and variable skeletal, connective tissue, and vascular abnormalities. There is evidence of abnormal tissue remodeling with pneumatocoeles frequently complicating pyogenic pneumonias and leading to secondary infections that cause the majority of morbidity and mortality. Complications are known to occur after lung surgery with a high frequency of bronchopleural fistulae, but little has been reported concerning abdominal surgeries. Here, we report on the outcome and safety of two separate complex cases (hepatectomy and subtotal gastrectomy) and document our entire experience with abdominal surgical procedures performed on patients with HIES. Despite initial complications, all patients eventually made a full recovery. As HIES patients now frequently live beyond the third and fourth decade, surgical issues similar to those in the general population may increase. Complex surgical procedures can be performed safely and benefit select patients with HIES, but benefit strongly from multidisciplinary teams and awareness of complications related to abnormal healing. We discuss current treatment and potential complications post-operatively in patients with HIES. C1 [Langan, Russell C.; Sherry, Richard M.; Rudloff, Udo] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Langan, Russell C.] Georgetown Univ Hosp, Dept Surg, Washington, DC 20007 USA. [Avital, Itzhak] Bon Secours Canc Inst, Richmond, VA USA. [Heller, Theo] NIDDKD, Bethesda, MD 20892 USA. [Henderson, Carolyn; Holland, Steven M.; Freeman, Alexandra F.] NIAID, NIH, CCR, Bethesda, MD 20892 USA. RP Langan, RC (reprint author), Georgetown Univ Hosp, Dept Surg, 3800 Reservoir Rd,NW 2 GOR, Washington, DC 20007 USA. EM Russell.Langan@gmail.com FU NIH FX This study was supported by the NIH intramural grant. NR 15 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD MAY PY 2013 VL 17 IS 5 BP 1009 EP 1014 DI 10.1007/s11605-012-2077-1 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 129SJ UT WOS:000317862200022 PM 23188219 ER PT J AU Morgan, TK Tolosa, JE Mele, L Wapner, RJ Spong, CY Sorokin, Y Dudley, DJ Peaceman, AM Mercer, BM Thorp, JM O'Sullivan, MJ Ramin, SM Rouse, DJ Sibai, B AF Morgan, Terry K. Tolosa, Jorge E. Mele, Lisa Wapner, Ronald J. Spong, Catherine Y. Sorokin, Yoram Dudley, Donald J. Peaceman, Alan M. Mercer, Brian M. Thorp, John M. O'Sullivan, Mary Jo Ramin, Susan M. Rouse, Dwight J. Sibai, Baha CA Eunice Kennedy Shriver Natl Inst C Maternal-Fetal Med Units Network TI Placental villous hypermaturation is associated with idiopathic preterm birth SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Chorioamnionitis; histology; idiopathic preterm labor; placenta; Tenney-Parker change ID SPIRAL ARTERIES; AMNIOTIC-FLUID; ANTENATAL CORTICOSTEROIDS; PREECLAMPSIA; INFECTION; HISTOLOGY; GROWTH; LABOR; BED; RELIABILITY AB Objective: Pregnancy complications such as intra-amniotic infection, preeclampsia, and fetal intrauterine growth restriction (IUGR) account for most cases of preterm birth (PTB), but many spontaneous PTB cases do not have a clear etiology. We hypothesize that placental insufficiency may be a potential cause of idiopathic PTB. Methods: Secondary analysis of 82 placental samples from women with PTB obtained from a multicenter trial of repeat versus single antenatal corticosteroids. Samples were centrally reviewed by a single placental pathologist masked to clinical outcomes. The histopathologic criterion for infection was the presence of acute chorioamnionitis defined as neutrophils marginating into the chorionic plate. Placental villous hypermaturation (PVH) was defined as a predominance of terminal villi (similar to term placenta) with extensive syncytial knotting. Idiopathic PTB comprised a group without another known etiology such as preeclampsia, IUGR or infection. Results: Acute chorioamnionitis was observed in 33/82 (40%) cases. Other known causes of PTB were reported in 18/82 (22%). The remaining 31/82 (38%) were idiopathic. The frequency of PVH in idiopathic PTB (26/31 = 84%) was similar to cases with IUGR or preeclampsia (16/18 = 89%), but significantly more common than PVH in the group with acute chorioamnionitis (10/33 = 30%) (p<0.001). Conclusions: PVH, which is a histologic marker of relative placental insufficiency, is a common finding in idiopathic PTB. C1 [Morgan, Terry K.; Tolosa, Jorge E.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97239 USA. [Morgan, Terry K.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. [Mele, Lisa] George Washington Univ, Ctr Biostat, Washington, DC USA. [Wapner, Ronald J.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Spong, Catherine Y.] NICHD, Bethesda, MD USA. [Sorokin, Yoram] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Dudley, Donald J.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Mercer, Brian M.] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [O'Sullivan, Mary Jo] Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Sibai, Baha] Univ Tennessee, Ctr Hlth Sci, Dept Obstet & Gynecol, Memphis, TN 38163 USA. RP Morgan, TK (reprint author), Oregon Hlth & Sci Univ, Dept Pathol, 3181 SW Sam Jackson Pk Rd,Mail Code L471, Portland, OR 97239 USA. EM morgante@ohsu.edu OI Peaceman, Alan/0000-0002-4515-4850 FU Office of Research on Women's Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Oregon BIRCWH [HD043488-08]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801]; National Center for Research Resources (NCRR) [M01-RR-000080] FX The authors report no declarations of interest other than the following finanacial support. Dr Morgan was funded by the Office of Research on Women's Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Oregon BIRCWH: HD043488-08. This research was also supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD36801] and M01-RR-000080 from the National Center for Research Resources (NCRR) and its content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHD, the National Institutes of Health and the NCRR. NR 39 TC 13 Z9 13 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD MAY PY 2013 VL 26 IS 7 BP 647 EP 653 DI 10.3109/14767058.2012.746297 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 130OY UT WOS:000317929200004 PM 23130816 ER PT J AU Zhuang, ZP Lonser, RR AF Zhuang, Zhengping Lonser, Russell R. TI Glioma grade RESPONSE SO JOURNAL OF NEUROSURGERY LA English DT Letter C1 [Zhuang, Zhengping; Lonser, Russell R.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Lonser, Russell R.] Ohio State Univ, Columbus, OH 43210 USA. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD MAY PY 2013 VL 118 IS 5 BP 1151 EP 1152 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 131LT UT WOS:000317995900049 PM 23776936 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI Family Income and Education Were Related with 30-Year Time Trends in Dietary and Meal Behaviors of American Children and Adolescents SO JOURNAL OF NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEYS; SUGAR-SWEETENED BEVERAGES; 2 DECADES 1973-1994; UNITED-STATES; SOCIOECONOMIC-STATUS; NATIONAL-HEALTH; NUTRIENT INTAKE; ENERGY DENSITY; SECULAR TRENDS; US CHILDREN AB Recent survey data reveal the persistence of long-acknowledged socioeconomic status (SES) differentials in the prevalence of obesity in U.S. children and adolescents. We examined 30-y changes in the association of dietary and meal behaviors with family income and education to understand the possible contribution of these trends to SES trends in obesity rates in 2- to 19-y-old Americans. We used dietary and SES data for 2- to 19-y olds from the NHANES 1971-1974 to 2003-2008 (n = 39,822). The secular changes in the independent association of family income and education with 24-h dietary behaviors [energy intake (kcal), amount of foods and beverages (g), percent energy from all beverages and from nutritive beverages, and energy density of foods] and 24-h meal behaviors [number of eating occasions, energy from snack episodes (%), and mention of breakfast] were examined using multivariable regression methods. The secular increase in energy intake and food and beverage amount was significant in the lowest family SES categories. The positive association of family income and education with intakes of energy, food amounts, and beverage energy, noted in 1971-1974 or 1976-1980, was not observed in later surveys. There was an age gradient in changes in most diet and SES associations over time, with largest adverse changes in 12- to 19-y olds. Higher education was associated with lower energy from snack episodes, breakfast skipping, and energy density of foods and these associations did not change overtime. Overall, these results suggest both income and education differentials in secular increases in food amounts and energy intakes. J. Nutr. 143: 690-700, 2013. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU NIH [HD060217]; Department of Health and Human Services, National Cancer Institute, NIH FX Supported in part by an NIH grant award (HD060217 to A.K.K.) and the intramural research program of the Department of Health and Human Services, National Cancer Institute, NIH (to B.I.G.). NR 66 TC 25 Z9 25 U1 0 U2 35 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD MAY PY 2013 VL 143 IS 5 BP 690 EP 700 DI 10.3945/jn.112.165258 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 132GU UT WOS:000318056700019 PM 23514763 ER PT J AU Towbin, K Axelson, D Leibenluft, E Birmaher, B AF Towbin, Kenneth Axelson, David Leibenluft, Ellen Birmaher, Boris TI Differentiating Bipolar Disorder-Not Otherwise Specified and Severe Mood Dysregulation SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE bipolar disorder; bipolar disorder not otherwise specified; severe mood dysregulation; irritability ID PLACEBO-CONTROLLED TRIAL; HOSPITALIZED AGGRESSIVE-CHILDREN; OPPOSITIONAL DEFIANT DISORDER; DOUBLE-BLIND; CONDUCT DISORDER; SPECTRUM DISORDERS; MANIC SYMPTOMS; PSYCHIATRIC-DISORDERS; CYCLOTHYMIC DISORDER; LONGITUDINAL COURSE AB Objective: Bipolar disorder not otherwise specified (BP-NOS) and severe mood dysregulation (SMD) are severe mood disorders that were defined to address questions about the diagnosis of bipolar disorder (BD) in youth. SMD and BP-NOS are distinct phenotypes that differ in clinical presentation and longitudinal course. The purpose of this review is to inform clinicians about the clinical features of the two phenotypes and about the research literature distinguishing them. Method: A literature review was performed on SMD as studied in the National Institute of Mental Health Intramural Research Program and on BP-NOS in youth. For BP-NOS, the phenotype defined in the Course of Bipolar Youth study is the focus, because this has received the most study. Results: SMD is characterized by impairing, chronic irritability without distinct manic episodes. Most commonly, BP-NOS is characterized by manic, mixed, or hypomanic episodes that are too short to meet the DSM-IV-TR duration criterion. Research provides strong, albeit suggestive, evidence that SMD is not a form of BD; the most convincing evidence are longitudinal data indicating that youth with SMD are not at high risk to develop BD as they age. The BP-NOS phenotype appears to be on a diagnostic continuum with BD types I and II. Subjects with BP-NOS and those with BD type I have similar symptom and family history profiles, and youth with BP-NOS are at high risk to develop BD as they age. Currently, little research guides treatment for either phenotype. Conclusions: Pressing research needs include identifying effective treatments for these phenotypes, ascertaining biomarkers that predict conversion from BP-NOS to BD, elucidating associations between SMD and other disorders, and defining the neural circuitry mediating each condition. J. Am. Acad. Child Adolesc. Psychiatry, 2013;52(5):466-481. C1 [Towbin, Kenneth; Leibenluft, Ellen] NIMH, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Axelson, David; Birmaher, Boris] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Axelson, David; Birmaher, Boris] Univ Pittsburgh, Med Ctr, Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. RP Towbin, K (reprint author), NIMH, Emot & Dev Branch, Intramural Res Program, 9000 Rockville Pike,Bldg 10,Room 1-3616, Bethesda, MD 20892 USA. EM Kenneth.Towbin@nih.gov FU NIMH/National Institutes of Health; NIMH; Random House, Inc. (New Hope for Children and Teens with Bipolar Disorder); Lippincott Williams and Wilkins (Treating Child and Adolescent Depression) FX This research was supported in port by the Intramural Program of the NIMH/National Institutes of Health.; Dr. Birmaher has received research funding from the NIMH. He has received or will receive royalties for publications from Random House, Inc. (New Hope for Children and Teens with Bipolar Disorder) and Lippincott Williams and Wilkins (Treating Child and Adolescent Depression). Drs. Towbin, Axelson, and Leibenluft report no biomedical financial interests or potential conflicts of interest. NR 88 TC 18 Z9 18 U1 1 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAY PY 2013 VL 52 IS 5 BP 466 EP 481 DI 10.1016/j.jaac.2013.02.006 PG 16 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 136WW UT WOS:000318395100005 PM 23622848 ER PT J AU Johnson, SLM Wang, L Alpert, KI Greenstein, D Clasen, L Lalonde, F Miller, R Rapoport, J Gogtay, N AF Johnson, Sarah L. M. Wang, Lei Alpert, Kathryn I. Greenstein, Deanna Clasen, Liv Lalonde, Francois Miller, Rachel Rapoport, Judith Gogtay, Nitin TI Hippocampal Shape Abnormalities of Patients With Childhood-Onset Schizophrenia and Their Unaffected Siblings SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE hippocampus; longitudinal; magnetic resonance imaging; neurodevelopment; schizophrenia ID VOLUME REDUCTIONS; BRAIN-DEVELOPMENT; METAANALYSIS; DEFORMITIES; RELATIVES; DISORDER; DEFICITS; AMYGDALA; MODEL; MRI AB Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers. Method: Two hundred twenty-five anatomic brain magnetic resonance images were obtained from 103 patients with COS, 169 from their 79 healthy siblings, and 255 from 101 age- and sex-matched healthy volunteers (age range = 9-29 years). The hippocampus was segmented using Free-Surfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at more than 6,000 vertices on the left and right hippocampal surfaces. Longitudinal data were examined using mixed model regression analysis. Results: Patients with COS showed significant bilateral inward deformation in the anterior hippocampus. Healthy siblings also showed a trend for anterior inward deformation. However, the trajectory of shape change did not differ significantly between the groups. Inward deformations in the anterior hippocampus were positively related to positive symptom severity, whereas outward surface displacement was positively related to overall functioning. Conclusion: This is the first and largest longitudinal three-way analysis of subregional hippocampal shape abnormalities in patients with COS and their healthy siblings compared with healthy controls. The anterior hippocampal abnormalities in COS suggest the pathophysiologic importance of this subregion in schizophrenia. The trend level and overlapping shape abnormalities in the healthy siblings suggest a more subtle, subregionally specific neuroanatomic endophenotype. J. Am. Acad. Child Adolesc. Psychiatry, 2013;52(5):527-536. C1 [Johnson, Sarah L. M.; Greenstein, Deanna; Clasen, Liv; Lalonde, Francois; Miller, Rachel; Rapoport, Judith; Gogtay, Nitin] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Wang, Lei; Alpert, Kathryn I.] Northwestern Univ, Feinburg Sch Med, Evanston, IL 60208 USA. RP Johnson, SLM (reprint author), NIMH, Child Psychiat Branch, 10-3N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM sarahmetthe@gmail.com RI Gogtay, Nitin/A-3035-2008 FU Intramural Division of the National Institute of Health; National Institute of Health; Pfizer, Inc. FX This research was funded by the Intramural Division of the National Institute of Health. Ms. Johnson's participation was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the National Institute of Health and Pfizer, Inc. (by a grant to the Foundation for the National Institute of Health from Pfizer, Inc.). NR 56 TC 11 Z9 11 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAY PY 2013 VL 52 IS 5 BP 527 EP 536 DI 10.1016/j.jaac.2013.02.003 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 136WW UT WOS:000318395100011 PM 23622854 ER PT J AU Leen, EN Kwok, KYR Birtley, JR Simpson, PJ Subba-Reddy, CV Chaudhry, Y Sosnovtsev, SV Green, KY Prater, SN Tong, M Young, JC Chung, LMW Marchant, J Roberts, LO Kao, CC Matthews, S Goodfellow, IG Curry, S AF Leen, Eoin N. Kwok, K. Y. Rex Birtley, James R. Simpson, Peter J. Subba-Reddy, Chennareddy V. Chaudhry, Yasmin Sosnovtsev, Stanislav V. Green, Kim Y. Prater, Sean N. Tong, Michael Young, Joanna C. Chung, Liliane M. W. Marchant, Jan Roberts, Lisa O. Kao, C. Cheng Matthews, Stephen Goodfellow, Ian G. Curry, Stephen TI Structures of the Compact Helical Core Domains of Feline Calicivirus and Murine Norovirus VPg Proteins SO JOURNAL OF VIROLOGY LA English DT Article ID DEPENDENT RNA-POLYMERASE; GENOME-LINKED PROTEIN; NORWALK VIRUS POLYMERASE; NONSTRUCTURAL POLYPROTEIN; IN-VITRO; ARABIDOPSIS-THALIANA; CRYSTAL-STRUCTURES; CHEMICAL-SHIFTS; CLEAVAGE SITES; INFECTED-CELLS AB We report the solution structures of the VPg proteins from feline calicivirus (FCV) and murine norovirus (MNV), which have been determined by nuclear magnetic resonance spectroscopy. In both cases, the core of the protein adopts a compact helical structure flanked by flexible N and C termini. Remarkably, while the core of FCV VPg contains a well-defined three-helix bundle, the MNV VPg core has just the first two of these secondary structure elements. In both cases, the VPg cores are stabilized by networks of hydrophobic and salt bridge interactions. The Tyr residue in VPg that is nucleotidylated by the viral NS7 polymerase (Y24 in FCV, Y26 in MNV) occurs in a conserved position within the first helix of the core. Intriguingly, given its structure, VPg would appear to be unable to bind to the viral polymerase so as to place this Tyr in the active site without a major conformation change to VPg or the polymerase. However, mutations that destabilized the VPg core either had no effect on or reduced both the ability of the protein to be nucleotidylated and virus infectivity and did not reveal a clear structure-activity relationship. The precise role of the calicivirus VPg core in virus replication remains to be determined, but knowledge of its structure will facilitate future investigations. C1 [Leen, Eoin N.; Birtley, James R.; Prater, Sean N.; Tong, Michael; Young, Joanna C.; Curry, Stephen] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Div Cell & Mol Biol, London, England. [Kwok, K. Y. Rex; Simpson, Peter J.; Marchant, Jan; Matthews, Stephen] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Div Biomol Sci, London, England. [Chaudhry, Yasmin; Chung, Liliane M. W.; Goodfellow, Ian G.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Virol Sect, London, England. [Roberts, Lisa O.] Univ Surrey, Sch Biomed & Mol Sci, Guildford GU2 5XH, Surrey, England. [Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Subba-Reddy, Chennareddy V.; Kao, C. Cheng] Indiana Univ, Dept Mol & Cellular Biochem, Bloomington, IN USA. RP Curry, S (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Div Cell & Mol Biol, London, England. EM s.curry@imperial.ac.uk OI Leen, Eoin/0000-0002-1845-5949; Curry, Stephen/0000-0002-0552-8870; Matthews, Steve/0000-0003-0676-0927; Goodfellow, Ian/0000-0002-9483-510X FU Biotechnology and Biological Sciences Research Council (United Kingdom) [BB/J001708/1, BB/I012303/1, BB/I01232X/1]; Indiana Economic Development grant; Wellcome Trust [083248]; Intramural Research Program of the NIH, NIAID; Medical Research Council, United Kingdom; Wellcome Senior Fellow [WT097997MA] FX This work was funded by research grants from the Biotechnology and Biological Sciences Research Council (United Kingdom) to S.C. (reference number BB/J001708/1) and to I.G.G. and L.O.R. (reference numbers BB/I012303/1 and BB/I01232X/1), an Indiana Economic Development grant to C.K., and funding from the Wellcome Trust to I.G.G. I.G.G. is a Wellcome Senior Fellow (reference number WT097997MA). The work was also supported by the Intramural Research Program of the NIH, NIAID. E.N.L. was funded by a Wellcome Trust Ph.D. studentship (reference number 083248). J.R.B. and J.C.Y. were supported by Ph.D. studentships from the Medical Research Council, United Kingdom. NR 72 TC 17 Z9 17 U1 0 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5318 EP 5330 DI 10.1128/JVI.03151-12 PG 13 WC Virology SC Virology GA 133QT UT WOS:000318155000001 PM 23487472 ER PT J AU Olejnik, J Alonso, J Schmidt, KM Yan, Z Wang, W Marzi, A Ebihara, H Yang, JH Patterson, JL Ryabchikova, E Muhlberger, E AF Olejnik, Judith Alonso, Jesus Schmidt, Kristina M. Yan, Zhen Wang, Wei Marzi, Andrea Ebihara, Hideki Yang, Jinghua Patterson, Jean L. Ryabchikova, Elena Muehlberger, Elke TI Ebola Virus Does Not Block Apoptotic Signaling Pathways SO JOURNAL OF VIROLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; DEPENDENT PROTEIN-KINASE; NF-KAPPA-B; CELL-DEATH; HEMORRHAGIC-FEVER; DENDRITIC CELLS; IN-VITRO; LYMPHOCYTE APOPTOSIS; CYNOMOLGUS MACAQUES; INFECTED PATIENTS AB Since viruses rely on functional cellular machinery for efficient propagation, apoptosis is an important mechanism to fight viral infections. In this study, we sought to determine the mechanism of cell death caused by Ebola virus (EBOV) infection by assaying for multiple stages of apoptosis and hallmarks of necrosis. Our data indicate that EBOV does not induce apoptosis in infected cells but rather leads to a nonapoptotic form of cell death. Ultrastructural analysis confirmed necrotic cell death of EBOV-infected cells. To investigate if EBOV blocks the induction of apoptosis, infected cells were treated with different apoptosis-inducing agents. Surprisingly, EBOV-infected cells remained sensitive to apoptosis induced by external stimuli. Neither receptor- nor mitochondrion-mediated apoptosis signaling was inhibited in EBOV infection. Although double-stranded RNA (dsRNA)-induced activation of protein kinase R (PKR) was blocked in EBOV-infected cells, induction of apoptosis mediated by dsRNA was not suppressed. When EBOV-infected cells were treated with dsRNA-dependent caspase recruiter (dsCARE), an antiviral protein that selectively induces apoptosis in cells containing dsRNA, virus titers were strongly reduced. These data show that the inability of EBOV to block apoptotic pathways may open up new strategies toward the development of antiviral therapeutics. C1 [Olejnik, Judith; Schmidt, Kristina M.; Muehlberger, Elke] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Olejnik, Judith; Schmidt, Kristina M.; Muehlberger, Elke] Boston Univ, Natl Emerging Infect Dis Labs, Boston, MA 02118 USA. [Olejnik, Judith] Univ Marburg, Inst Virol, D-35032 Marburg, Germany. [Alonso, Jesus; Patterson, Jean L.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Yan, Zhen; Wang, Wei] Fourth Mil Med Univ, Sch Pharm, Dept Pharmacogen, State Key Lab Canc Biol, Xian 710032, Peoples R China. [Marzi, Andrea; Ebihara, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Yang, Jinghua] Boston Univ, VA Boston Healthcare Syst, Dept Surg, Boston, MA 02118 USA. [Ryabchikova, Elena] Russian Acad Sci, Siberian Branch, Inst Chem Biol & Fundamental Med, Novosibirsk, Russia. RP Muhlberger, E (reprint author), Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. EM muehlber@bu.edu RI Ryabchikova, Elena /G-3089-2013 OI Muhlberger, Elke/0000-0003-3547-9376; Ryabchikova, Elena /0000-0003-4714-1524 FU NIH [U01-AI082954, CO6 RR12087]; Boston University; German Research Foundation [SFB 535]; Manchot Foundation; National Natural Science Foundation of China [NSFC 3092803, NSFC 81071369]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by NIH grants U01-AI082954 (to E.M.) and CO6 RR12087 (to J.L.P. and J.A.), start-up funds from Boston University (to E.M.), and funding from the German Research Foundation (grant SFB 535 to E.M.) and the Manchot Foundation (to J.O. and E.M). The production of dsCARE was supported by grants from the National Natural Science Foundation of China (grants NSFC 3092803 and NSFC 81071369 to J.Y. and Z.Y.). Funding was also provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 77 TC 10 Z9 10 U1 1 U2 23 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5384 EP 5396 DI 10.1128/JVI.01461-12 PG 13 WC Virology SC Virology GA 133QT UT WOS:000318155000007 PM 23468487 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, Takeo Takaki, Kaori Yoshimura, Kazuhisa Enomoto, Ikumi Wu, Fan Ourmanov, Ilnour Hirsch, Vanessa M. Yokoyama, Masaru Sato, Hironori Matsushita, Shuzo TI Conformational Epitope Consisting of the V3 and V4 Loops as a Target for Potent and Broad Neutralization of Simian Immunodeficiency Viruses SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1/SIV CHIMERIC VIRUS; CORECEPTOR-BINDING-SITE; FUSION INHIBITOR T-20; MONOCLONAL-ANTIBODIES; RHESUS MACAQUE; VACCINE DEVELOPMENT; ENVELOPE GLYCOPROTEIN; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; IN-VIVO AB Inducing neutralizing antibodies (NAb) is the key to developing a protective vaccine against human immunodeficiency virus type 1 (HIV-1). To clarify the neutralization mechanism of simian immunodeficiency virus (SIV), we analyzed NAb B404, which showed potent and broad neutralizing activity against various SIV strains. In 4 SIVsmH635FC-infected macaques, B404-like antibodies using the specific VH3 gene with a long complementarity-determining region 3 loop and lambda light chain were the major NAbs in terms of the number and neutralizing potency. This biased NAb induction was observed in all 4 SIVsmH635FC-infected macaques but not in 2 macaques infected with a SIV mix, suggesting that induction of B404-like NAbs depended on the inoculated virus. Analysis using Env mutants revealed that the V3 and V4 loops were critical for B404 binding. The reactivity to the B404 epitope on trimeric, but not monomeric, Env was enhanced by CD4 ligation. The B404-resistant variant, which was induced by passages with increasing concentrations of B404, accumulated amino acid substitutions in the C2 region of gp120. Molecular dynamics simulations of the gp120 outer domains indicated that the C2 mutations could effectively alter the structural dynamics of the V3/V4 loops and their neighboring regions. These results suggest that a conformational epitope consisting of the V3 and V4 loops is the target for potent and broad neutralization of SIV. Identifying the new neutralizing epitope, as well as specifying the VH3 gene used for epitope recognition, will help to develop HIV-1 vaccines. C1 [Kuwata, Takeo; Takaki, Kaori; Enomoto, Ikumi; Matsushita, Shuzo] Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan. [Yoshimura, Kazuhisa] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo, Japan. [Wu, Fan; Ourmanov, Ilnour; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Yokoyama, Masaru; Sato, Hironori] Natl Inst Infect Dis, Pathogen Genom Ctr, Tokyo, Japan. RP Matsushita, S (reprint author), Kumamoto Univ, Ctr AIDS Res, Kumamoto, Japan. EM shuzo@kumamoto-u.ac.jp RI Matsushita, Shuzo/F-5782-2013; Kumamoto University, CAIDS/G-8446-2013; Publications, Remarkable/I-1756-2013 FU Special Coordination Funds for Promoting Science and Technology; Program of Founding Research Centres for Emerging and Re-emerging Infectious Diseases; Global COE program Global Education and Research Centre Aiming at the Control of AIDS; Ministry of Education, Culture, Sport, Science and Technology, Japan [C-24591484]; Ministry of Health, Welfare and Labor of Japan [H24-AIDS-007] FX This work was supported in part by the Special Coordination Funds for Promoting Science and Technology, the Program of Founding Research Centres for Emerging and Re-emerging Infectious Diseases, the Global COE program Global Education and Research Centre Aiming at the Control of AIDS, a grant-in-aid for scientific research (C-24591484) from the Ministry of Education, Culture, Sport, Science and Technology, Japan, and a grant from the Ministry of Health, Welfare and Labor of Japan (H24-AIDS-007). NR 84 TC 12 Z9 12 U1 1 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5424 EP 5436 DI 10.1128/JVI.00201-13 PG 13 WC Virology SC Virology GA 133QT UT WOS:000318155000010 PM 23468483 ER PT J AU Lopker, M Easlick, J Sterrett, S Decker, JM Barbian, H Learn, G Keele, BF Robinson, JE Li, H Hahn, BH Shaw, GM Bar, KJ AF Lopker, Michael Easlick, Juliet Sterrett, Sarah Decker, Julie M. Barbian, Hannah Learn, Gerald Keele, Brandon F. Robinson, James E. Li, Hui Hahn, Beatrice H. Shaw, George M. Bar, Katharine J. TI Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS MONOCLONAL-ANTIBODIES; INFECTIOUS MOLECULAR CLONES; B-CELL RESPONSES; SOOTY MANGABEY; ENVELOPE GLYCOPROTEIN; SIV INFECTION; PRIMATE LENTIVIRUS; PROTEIN EVOLUTION; TYPE-1 INFECTION; HIV-1 INFECTION AB The sooty mangabey-derived simian immunodeficiency virus (SIV) strain E660 (SIVsmE660) is a genetically heterogeneous, pathogenic isolate that is commonly used as a vaccine challenge strain in the nonhuman primate (NHP) model of human immunodeficiency virus type 1 (HIV-1) infection. Though it is often employed to assess antibody-based vaccine strategies, its sensitivity to antibody-mediated neutralization has not been well characterized. Here, we utilize single-genome sequencing and infectivity assays to analyze the neutralization sensitivity of the uncloned SIVsmE660 isolate, individual viruses comprising the isolate, and transmitted/founder (T/F) viruses arising from low-dose mucosal inoculation of macaques with the isolate. We found that the SIVsmE660 isolate overall was highly sensitive to neutralization by SIV-infected macaque plasma samples (50% inhibitory concentration [IC50] < 10(-5)) and monoclonal antibodies targeting V3 (IC50 < 0.01 mu g/ml), CD4-induced (IC50 < 0.1 mu g/ml), CD4 binding site (IC50 similar to 1 mu g/ml), and V4 (IC50, similar to 5 mu g/ml) epitopes. In comparison, SIVmac251 and SIVmac239 were highly resistant to neutralization by these same antibodies. Differences in neutralization sensitivity between SIVsmE660 and SIVmac251/239 were not dependent on the cell type in which virus was produced or tested. These findings indicate that in comparison to SIVmac251/239 and primary HIV-1 viruses, SIVsmE660 generally exhibits substantially less masking of antigenically conserved Env epitopes. Interestingly, we identified a minor population of viruses (similar to 10%) in both the SIVsmE660 isolate and T/F viruses arising from it that were substantially more resistant (>1,000-fold) to antibody neutralization and another fraction (similar to 20%) that was intermediate in neutralization resistance. These findings may explain the variable natural history and variable protection afforded by heterologous Env-based vaccines in rhesus macaques challenged by high-dose versus low-dose SIVsmE660 inoculation regimens. C1 [Lopker, Michael; Easlick, Juliet; Sterrett, Sarah; Decker, Julie M.] Univ Alabama Birmingham, Birmingham, AL USA. [Barbian, Hannah; Learn, Gerald; Li, Hui; Hahn, Beatrice H.; Shaw, George M.; Bar, Katharine J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Keele, Brandon F.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Robinson, James E.] Tulane Univ, Med Ctr, New Orleans, LA USA. RP Bar, KJ (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM bark@upenn.edu FU Center for HIV/AIDS Vaccine Immunology; National Institutes of Health [AI087383, AI088564, AI095985]; HIV Vaccines Trials Network [U19AI067854] FX This work was supported by an early-stage investigator grant through the Center for HIV/AIDS Vaccine Immunology and the HIV Vaccines Trials Network (U19AI067854) and by grants from the National Institutes of Health (AI087383, AI088564, and AI095985). NR 104 TC 20 Z9 20 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5477 EP 5492 DI 10.1128/JVI.03419-12 PG 16 WC Virology SC Virology GA 133QT UT WOS:000318155000015 PM 23468494 ER PT J AU Fontana, J Steven, AC AF Fontana, Juan Steven, Alasdair C. TI At Low pH, Influenza Virus Matrix Protein M1 Undergoes a Conformational Change Prior to Dissociating from the Membrane SO JOURNAL OF VIROLOGY LA English DT Article ID CONTRAST ELECTRON-MICROSCOPY; M2 PROTEIN; CRYOELECTRON TOMOGRAPHY; A VIRUS; FUSOGENIC ACTIVITY; FUSION; HEMAGGLUTININ; AMANTADINE; CHANNEL; TRANSPORT AB The M1 matrix protein of influenza A virus, which plays multiple roles in virion assembly and infection, underlies the viral envelope. However, previous studies have given differing accounts of the number of layers in the M1-envelope complex and their thicknesses and compositions. To resolve this issue, we performed cryo-electron microscopy and cryo-electron tomography on the self-same specimens. At neutral pH, there were two kinds of complexes, corresponding to a lipid bilayer with embedded glycoproteins, with and without a closely associated, 4-nm-thick sheet of M1 protein. The reported discrepancies arose from differences in imaging conditions, i.e., in defocus and in whole-particle projections versus thin tomographic slices. Exposure of virions to low pH (as in the endosome) promotes membrane fusion, and previous work has shown that the M2 ion channel causes the virion interior to acidify also. We found that after 5 min at pH 4.9, the proportion of virions lacking an M1 layer increased from 10% to 50%. In virions retaining an M1 layer under these conditions, the M1-envelope complex exhibited two states, viz, the original, neutral-pH state and one in which the M1 layer appeared thinner and/or closer to the membrane. These observations extend previous indications that acidic pH causes the M1 layer to dissociate, leaving the envelope more pliable and, consequently, fusion compatible, and they show that dissociation is preceded by a conformational change in M1. C1 [Fontana, Juan; Steven, Alasdair C.] NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Fontana, Juan/A-9138-2009 OI Fontana, Juan/0000-0002-9084-2927 FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 43 TC 26 Z9 26 U1 2 U2 19 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5621 EP 5628 DI 10.1128/JVI.00276-13 PG 8 WC Virology SC Virology GA 133QT UT WOS:000318155000027 PM 23468509 ER PT J AU Buckner, CM Moir, S Ho, J Wang, W Posada, JG Kardava, L Funk, EK Nelson, AK Li, YX Chun, TW Fauci, AS AF Buckner, Clarisa M. Moir, Susan Ho, Jason Wang, Wei Posada, Jacqueline G. Kardava, Lela Funk, Emily K. Nelson, Amy K. Li, Yuxing Chun, Tae-Wook Fauci, Anthony S. TI Characterization of Plasmablasts in the Blood of HIV-Infected Viremic Individuals: Evidence for Nonspecific Immune Activation SO JOURNAL OF VIROLOGY LA English DT Article ID MEMORY B-CELLS; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; ANTIBODY-SECRETING CELLS; TYPE-1 INFECTION; INFLUENZA VACCINATION; HUMORAL IMMUNITY; RESPONSES; DISEASE; HYPERGAMMAGLOBULINEMIA AB Terminal differentiation of B cells and hypergammaglobulinemia are hallmarks of B-cell hyperactivity in HIV disease. Plasmablasts are terminally differentiating B cells that circulate transiently in the blood following infection or vaccination; however, in HIV infection, they arise early and are maintained at abnormally high levels in viremic individuals. Here we show that only a small fraction of plasmablasts in the blood of viremic individuals is HIV specific. Assessment of plasmablast immunoglobulin isotype distribution revealed increased IgG(+) plasmablasts in early and most prominently during chronic HIV viremia, contrasting with a predominantly IgA(+) plasmablast profile in HIV-negative individuals or in aviremic HIV-infected individuals on treatment. Of note, IgG is the predominant immunoglobulin isotype of plasmablasts that arise transiently in the blood following parenteral immunization. Serum immunoglobulin levels were also elevated in HIV-infected viremic individuals, especially IgG, and correlated with levels of IgG(+) plasmablasts. Several soluble factors associated with immune activation were also increased in the sera of HIV-infected individuals, especially in viremic individuals, and correlated with serum immunoglobulin levels, particularly IgG. Thus, our data suggest that while plasmablasts in the blood may contribute to the HIV-specific immune response, the majority of these cells are not HIV specific and arise early, likely from indirect immune-activating effects of HIV replication, and reflect over time the effects of chronic antigenic stimulation. Such B-cell dysregulation may help explain why the antibody response is inadequate in HIV-infected individuals, even during early infection. C1 [Buckner, Clarisa M.; Moir, Susan; Ho, Jason; Wang, Wei; Posada, Jacqueline G.; Kardava, Lela; Funk, Emily K.; Nelson, Amy K.; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Li, Yuxing] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Li, Yuxing] Scripps Res Inst, IAVI Ctr Neutralizing Antibodies, La Jolla, CA 92037 USA. [Li, Yuxing] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural Research Program of NIAID, NIH FX This work was supported by the Intramural Research Program of NIAID, NIH. NR 68 TC 26 Z9 26 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2013 VL 87 IS 10 BP 5800 EP 5811 DI 10.1128/JVI.00094-13 PG 12 WC Virology SC Virology GA 133QT UT WOS:000318155000041 PM 23487459 ER PT J AU Lee, CR Park, YH Kim, M Kim, YR Park, S Peterkofsky, A Seok, YJ AF Lee, Chang-Ro Park, Young-Ha Kim, Miri Kim, Yeon-Ran Park, Soyoung Peterkofsky, Alan Seok, Yeong-Jae TI Reciprocal regulation of the autophosphorylation of enzyme INtr by glutamine and -ketoglutarate in Escherichia coli SO MOLECULAR MICROBIOLOGY LA English DT Article ID SIGNAL-TRANSDUCTION PROTEINS; GLOBAL REPRESSOR MLC; PHOSPHOTRANSFERASE SYSTEM; ALPHA-KETOGLUTARATE; AZOTOBACTER-VINELANDII; GLUCOSE-TRANSPORTER; NITROGEN-METABOLISM; PSEUDOMONAS-PUTIDA; K-12; PII AB In addition to the phosphoenolpyruvate:sugar phosphotransferase system (sugar PTS), most proteobacteria possess a paralogous system (nitrogen phosphotransferase system, PTSNtr). The first proteins in both pathways are enzymes (enzyme Isugar and enzyme INtr) that can be autophosphorylated by phosphoenolpyruvate. The most striking difference between enzyme Isugar and enzyme INtr is the presence of a GAF domain at the N-terminus of enzyme INtr. Since the PTSNtr was identified in 1995, it has been implicated in a variety of cellular processes in many proteobacteria and many of these regulations have been shown to be dependent on the phosphorylation state of PTSNtr components. However, there has been little evidence that any component of this so-called PTSNtr is directly involved in nitrogen metabolism. Moreover, a signal regulating the phosphorylation state of the PTSNtr had not been uncovered. Here, we demonstrate that glutamine and -ketoglutarate, the canonical signals of nitrogen availability, reciprocally regulate the phosphorylation state of the PTSNtr by direct effects on enzyme INtr autophosphorylation and the GAF signal transduction domain is necessary for the regulation of enzyme INtr activity by the two signal molecules. Taken together, our results suggest that the PTSNtr senses nitrogen availability. C1 [Lee, Chang-Ro; Park, Young-Ha; Kim, Miri; Kim, Yeon-Ran; Seok, Yeong-Jae] Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. [Lee, Chang-Ro; Park, Young-Ha; Kim, Miri; Kim, Yeon-Ran; Seok, Yeong-Jae] Seoul Natl Univ, Inst Microbiol, Seoul 151742, South Korea. [Park, Soyoung; Seok, Yeong-Jae] Seoul Natl Univ, Dept Biophys & Chem Biol, Seoul 151742, South Korea. [Lee, Chang-Ro] Myongji Univ, Dept Biol Sci, Yongin 449728, Gyeonggido, South Korea. [Peterkofsky, Alan] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Seok, YJ (reprint author), Seoul Natl Univ, Dept Biol Sci, Seoul 151742, South Korea. EM yjseok@snu.ac.kr FU Korea Research Foundation [NRF 2010-0017384]; WCU programme from Ministry of Education, Science, and Technology [R31-2009-000-10032-0]; Marine and Extreme Genome Research Center Program of the Ministry of Land, Transportation and Maritime Affairs, Republic of Korea; BK21 Research Fellowship; Intramural Research Program of NHLBI, National Institutes of Health FX This work was supported by the Korea Research Foundation Grant (NRF 2010-0017384) and the WCU programme (R31-2009-000-10032-0) from Ministry of Education, Science, and Technology, and by the Marine and Extreme Genome Research Center Program of the Ministry of Land, Transportation and Maritime Affairs, Republic of Korea. C.-R.L. was supported by BK21 Research Fellowship. A. P. was supported by the Intramural Research Program of NHLBI, National Institutes of Health. NR 50 TC 25 Z9 25 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2013 VL 88 IS 3 BP 473 EP 485 DI 10.1111/mmi.12196 PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 133CC UT WOS:000318114000002 PM 23517463 ER PT J AU Velez, JI Chandrasekharappa, SC Henao, E Martinez, AF Harper, U Jones, M Solomon, BD Lopez, L Garcia, G Aguirre-Acevedo, DC Acosta-Baena, N Correa, JC Lopera-Gomez, CM Jaramillo-Elorza, MC Rivera, D Kosik, KS Schork, NJ Swanson, JM Lopera, F Arcos-Burgos, M AF Velez, J. I. Chandrasekharappa, S. C. Henao, E. Martinez, A. F. Harper, U. Jones, M. Solomon, B. D. Lopez, L. Garcia, G. Aguirre-Acevedo, D. C. Acosta-Baena, N. Correa, J. C. Lopera-Gomez, C. M. Jaramillo-Elorza, M. C. Rivera, D. Kosik, K. S. Schork, N. J. Swanson, J. M. Lopera, F. Arcos-Burgos, M. TI Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease SO MOLECULAR PSYCHIATRY LA English DT Article DE Alzheimer's disease; bootstrap; DNA pooling; GWAS; modifiers; PSEN1 ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; POPULATION-STRUCTURE; GENETIC ASSOCIATION; BOOTSTRAP SAMPLES; NUMBER; NEPHROCYSTIN; PROBABILITY; ASTROCYTES; HYPOTHESIS AB The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p. Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P = 1.29 x 10(-12); NPHP1, rs10173717, P = 1.74 x 10(-12); CADPS2, rs3757536, P = 1.54 x 10(-10); GREM2, rs12129547, P = 1.69 x 10(-13), among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions. Molecular Psychiatry (2013) 18, 568-575; doi:10.1038/mp.2012.81; published online 19 June 2012 C1 [Velez, J. I.; Martinez, A. F.; Solomon, B. D.; Arcos-Burgos, M.] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. [Chandrasekharappa, S. C.; Harper, U.; Jones, M.] NHGRI, NIH, Genome Technol Branch, Bethesda, MD 20892 USA. [Henao, E.; Lopez, L.; Garcia, G.; Aguirre-Acevedo, D. C.; Acosta-Baena, N.; Rivera, D.; Lopera, F.; Arcos-Burgos, M.] Univ Antioquia, Fac Med, Grp Neurociencias Antioquia, Medellin, Colombia. [Correa, J. C.; Lopera-Gomez, C. M.; Jaramillo-Elorza, M. C.] Univ Nacl Colombia, Escuela Estadist, Medellin, Colombia. [Kosik, K. S.] Univ Calif Santa Barbara, Neurosci Res Inst, Santa Barbara, CA 93106 USA. [Schork, N. J.] Scripps Res Inst, Dept Biostatist & Bioinformat, La Jolla, CA 92037 USA. [Swanson, J. M.] Florida Int Univ, Dept Psychiat, Miami, FL 33199 USA. [Swanson, J. M.] Univ Calif Irvine, Child Dev Ctr, Irvine, CA USA. [Arcos-Burgos, M.] Australian Natl Univ, John Curtin Sch Med Res, ANU Coll Med Biol & Environm, Translat Genom Grp,Dept Translat Med, Canberra, ACT 2601, Australia. RP Arcos-Burgos, M (reprint author), Australian Natl Univ, John Curtin Sch Med Res, ANU Coll Med Biol & Environm, Translat Genom Grp, Bldg 131 Garran Rd, Canberra, ACT 0200, Australia. EM Mauricio.arcos-burgos@anu.edu.au OI Aguirre-Acevedo, Daniel Camilo/0000-0002-8195-8821 FU Whole Genome Search of Alzheimer's Disease Age of Onset Modifiers [111540820543]; COLCIENCIAS; University of Antioquia, Colombia; Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, of the United States of America; John Curtin School of Medical Research of the Australian National University, Australia FX We extend our deepest gratitude to all the patients and families from Antioquia, Colombia who took part in our research on Alzheimer's disease. This research was supported in part by the project 'Whole Genome Search of Alzheimer's Disease Age of Onset Modifiers' code: 111540820543 supported by COLCIENCIAS and the University of Antioquia, Colombia; in part by the Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, of the United States of America; and in part by a Start Package Allocated to MA-B by The John Curtin School of Medical Research of the Australian National University, Australia. We want to provide special acknowledgement to Julia Fekecs who provided invaluable graphical assistance with figures. NR 45 TC 8 Z9 8 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAY PY 2013 VL 18 IS 5 BP 568 EP 575 DI 10.1038/mp.2012.81 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 130XF UT WOS:000317952700008 PM 22710270 ER PT J AU Taira, K Kaneto, S Nakano, K Watanabe, S Takahashi, E Arimoto, S Okamoto, K Schaaper, RM Negishi, K Negishi, T AF Taira, Kentaro Kaneto, Satomi Nakano, Kota Watanabe, Shinji Takahashi, Eizo Arimoto, Sakae Okamoto, Keinosuke Schaaper, Roel M. Negishi, Kazuo Negishi, Tomoe TI Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents SO MUTAGENESIS LA English DT Article ID DNA MISMATCH REPAIR; NEGATIVE MUTATOR MUTATIONS; ESCHERICHIA-COLI; O-6-METHYLGUANINE; PROTEIN; DAMAGE; GENE; METHYLTRANSFERASES; BINDING; SYSTEM AB DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O-6-alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation-induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the F'prolac from strain CC102 (F'CC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O-6-alkylguanine. The results showed the repair of O-6-methylguanine to be performed by AGT >> MMR > NER in order of importance, whereas the repair of O-6-ethylguanine followed the order NER > AGT > MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation-induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N-alkyl-N-nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells. C1 [Taira, Kentaro; Kaneto, Satomi; Nakano, Kota; Watanabe, Shinji; Takahashi, Eizo; Arimoto, Sakae; Okamoto, Keinosuke; Negishi, Tomoe] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Schaaper, Roel M.] NIEHS, Res Triangle Pk, NC 27709 USA. [Negishi, Kazuo] Nihon Pharmaceut Univ, Ina, Saitama 3620806, Japan. RP Negishi, T (reprint author), Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. EM isaka@pheasant.pharm.okayama-u.ac.jp FU National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) [ES065086] FX This research was supported by in part by project ES065086 of the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS). NR 28 TC 3 Z9 3 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD MAY PY 2013 VL 28 IS 3 BP 341 EP 350 DI 10.1093/mutage/get010 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 133UR UT WOS:000318166600014 PM 23446177 ER PT J AU Desjardins, CA Cerqueira, GC Goldberg, JM Hotopp, JCD Haas, BJ Zucker, J Ribeiro, JMC Saif, S Levin, JZ Fan, L Zeng, QD Russ, C Wortman, JR Fink, DL Birren, BW Nutman, TB AF Desjardins, Christopher A. Cerqueira, Gustavo C. Goldberg, Jonathan M. Hotopp, Julie C. Dunning Haas, Brian J. Zucker, Jeremy Ribeiro, Jose M. C. Saif, Sakina Levin, Joshua Z. Fan, Lin Zeng, Qiandong Russ, Carsten Wortman, Jennifer R. Fink, Doran L. Birren, Bruce W. Nutman, Thomas B. TI Genomics of Loa loa, a Wolbachia-free filarial parasite of humans SO NATURE GENETICS LA English DT Article ID CAENORHABDITIS-ELEGANS; PATHWAY/GENOME DATABASES; BIOCYC COLLECTION; PROTEIN-KINASES; BRUGIA-MALAYI; MATRIX; MODEL; TOOL; IDENTIFICATION; ANNOTATION AB Loa loa, the African eyeworm, is a major filarial pathogen of humans. Unlike most filariae, L. loa does not contain the obligate intracellular Wolbachia endosymbiont. We describe the 91.4-Mb genome of L. loa and that of the related filarial parasite Wuchereria bancrofti and predict 14,907 L. loa genes on the basis of microfilarial RNA sequencing. By comparing these genomes to that of another filarial parasite, Brugia malayi, and to those of several other nematodes, we demonstrate synteny among filariae but not with nonparasitic nematodes. The L. loa genome encodes many immunologically relevant genes, as well as protein kinases targeted by drugs currently approved for use in humans. Despite lacking Wolbachia, L. loa shows no new metabolic synthesis or transport capabilities compared to other filariae. These results suggest that the role of Wolbachia in filarial biology is more subtle than previously thought and reveal marked differences between parasitic and nonparasitic nematodes. C1 [Desjardins, Christopher A.; Cerqueira, Gustavo C.; Goldberg, Jonathan M.; Haas, Brian J.; Zucker, Jeremy; Saif, Sakina; Levin, Joshua Z.; Fan, Lin; Zeng, Qiandong; Russ, Carsten; Wortman, Jennifer R.; Birren, Bruce W.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Hotopp, Julie C. Dunning] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Genome Sci, Baltimore, MD 21201 USA. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Fink, Doran L.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Nutman, TB (reprint author), NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov RI Dunning Hotopp, Julie/E-7762-2010; Zucker, Jeremy/M-3643-2016; OI Dunning Hotopp, Julie/0000-0003-3862-986X; Zucker, Jeremy/0000-0002-7276-9009; Wortman, Jennifer/0000-0002-8713-1227; Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH), Department of Health and Human Services [HHSN272200900018C]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; NIH [1-DP2-OD007372] FX We thank members of the Broad Institute Genomics Platform for sequencing and D. Neafsey for comments on the manuscript. This project has been funded in part by the National Institute of Allergy and Infectious Diseases, US National Institutes of Health (NIH), Department of Health and Human Services under contract number HHSN272200900018C and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH. J.C.D.H. is funded by the NIH Director's New Innovator Award Program (1-DP2-OD007372). NR 56 TC 69 Z9 69 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2013 VL 45 IS 5 BP 495 EP U55 DI 10.1038/ng.2585 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 133RU UT WOS:000318158200010 PM 23525074 ER PT J AU Berndt, SI Gustafsson, S Magi, R Ganna, A Wheeler, E Feitosa, MF Justice, AE Monda, KL Croteau-Chonka, DC Day, FR Esko, T Fall, T Ferreira, T Gentilini, D Jackson, AU Luan, JA Randall, JC Vedantam, S Willer, CJ Winkler, TW Wood, AR Workalemahu, T Hu, YJ Lee, SH Liang, LM Lin, DY Min, JL Neale, BM Thorleifsson, G Yang, J Albrecht, E Amin, N Bragg-Gresham, JL Cadby, G den Heijer, M Eklund, N Fischer, K Goel, A Hottenga, JJ Huffman, JE Jarick, I Johansson, A Johnson, T Kanoni, S Kleber, ME Konig, IR Kristiansson, K Kutalik, Z Lamina, C Lecoeur, C Li, G Mangino, M McArdle, WL Medina-Gomez, C Muller-Nurasyid, M Ngwa, JS Nolte, IM Lavinia, P Pechlivanis, S Perola, M Peters, MJ Preuss, M Rose, LM Shi, JX Shungin, D Smith, AV Strawbridge, RJ Surakka, I Teumer, A Trip, MD Tyrer, J Van Vliet-Ostaptchouk, JV Vandenput, L Waite, LL Zhao, JH Absher, D Asselbergs, FW Atalay, M Attwood, AP Balmforth, AJ Basart, H Beilby, J Bonnycastle, LL Brambilla, P Bruinenberg, M Campbell, H Chasman, DI Chines, PS Collins, FS Connell, JM Cookson, WO de Faire, U de Vegt, F Dei, M Dimitriou, M Edkins, S Estrada, K Evans, DM Farrall, M Ferrario, MM Ferrieres, J Franke, L Frau, F Gejman, PV Grallert, H Gronberg, H Gudnason, V Hall, AS Hall, P Hartikainen, AL Hayward, C Heard-Costa, NL Heath, AC Hebebrand, J Homuth, G Hu, FB Hunt, SE Hypponen, E Iribarren, C Jacobs, KB Jansson, JO Jula, A Kahonen, M Kathiresan, S Kee, F Khaw, KT Kivimaki, M Koenig, W Kraja, AT Kumari, M Kuulasmaa, K Kuusisto, J Laitinen, JH Lakka, TA Langenberg, C Launer, LJ Lind, L Lindstrom, J Liu, JJ Liuzzi, A Lokki, ML Lorentzon, M Madden, PA Magnusson, PK Manunta, P Marek, D Marz, W Leach, IM McKnight, B Medland, SE Mihailov, E Milani, L Montgomery, GW Mooser, V Muhleisen, TW Munroe, PB Musk, AW Narisu, N Navis, G Nicholson, G Nohr, EA Ong, KK Oostra, BA Palmer, CNA Palotie, A Peden, JF Pedersen, N Peters, A Polasek, O Pouta, A Pramstaller, PP Prokopenko, I Putter, C Radhakrishnan, A Raitakari, O Rendon, A Rivadeneira, F Rudan, I Saaristo, TE Sambrook, JG Sanders, AR Sanna, S Saramies, J Schipf, S Schreiber, S Schunkert, H Shin, SY Signorini, S Sinisalo, J Skrobek, B Soranzo, N Stancakova, A Stark, K Stephens, JC Stirrups, K Stolk, RP Stumvoll, M Swift, AJ Theodoraki, EV Thorand, B Tregouet, DA Tremoli, E Van der Klauw, MM van Meurs, JBJ Vermeulen, SH Viikari, J Virtamo, J Vitart, V Waeber, G Wang, ZM Widen, E Wild, SH Willemsen, G Winkelmann, BR Witteman, JCM Wolffenbuttel, BHR Wong, A Wright, AF Zillikens, MC Amouyel, P Boehm, BO Boerwinkle, E Boomsma, DI Caulfield, MJ Chanock, SJ Cupples, LA Cusi, D Dedoussis, GV Erdmann, J Eriksson, JG Franks, PW Froguel, P Gieger, C Gyllensten, U Hamsten, A Harris, TB Hengstenberg, C Hicks, AA Hingorani, A Hinney, A Hofman, A Hovingh, KG Hveem, K Illig, T Jarvelin, MR Jockel, KH Keinanen-Kiukaanniemi, SM Kiemeney, LA Kuh, D Laakso, M Lehtimaki, T Levinson, DF Martin, NG Metspalu, A Morris, AD Nieminen, MS Njolstad, I Ohlsson, C Oldehinkel, AJ Ouwehand, WH Palmer, LJ Penninx, B Power, C Province, MA Psaty, BM Qi, L Rauramaa, R Ridker, PM Ripatti, S Salomaa, V Samani, NJ Snieder, H Sorensen, TIA Spector, TD Stefansson, K Tonjes, A Tuomilehto, J Uitterlinden, AG Uusitupa, M van der Harst, P Vollenweider, P Wallaschofski, H Wareham, NJ Watkins, H Wichmann, HE Wilson, JF Abecasis, GR Assimes, TL Barroso, I Boehnke, M Borecki, IB Deloukas, P Fox, CS Frayling, T Groop, LC Haritunian, T Heid, IM Hunter, D Kaplan, RC Karpe, F Moffatt, MF Mohlke, KL O'Connell, JR Pawitan, Y Schadt, EE Schlessinger, D Steinthorsdottir, V Strachan, DP Thorsteinsdottir, U van Duijn, CM Visscher, PM Di Blasio, AM Hirschhorn, JN Lindgren, CM Morris, AP Meyre, D Scherag, A McCarthy, MI Speliotes, EK North, KE Loos, RJF Ingelsson, E AF Berndt, Sonja I. Gustafsson, Stefan Maegi, Reedik Ganna, Andrea Wheeler, Eleanor Feitosa, Mary F. Justice, Anne E. Monda, Keri L. Croteau-Chonka, Damien C. Day, Felix R. Esko, Tonu Fall, Tove Ferreira, Teresa Gentilini, Davide Jackson, Anne U. Luan, Jian'an Randall, Joshua C. Vedantam, Sailaja Willer, Cristen J. Winkler, Thomas W. Wood, Andrew R. Workalemahu, Tsegaselassie Hu, Yi-Juan Lee, Sang Hong Liang, Liming Lin, Dan-Yu Min, Josine L. Neale, Benjamin M. Thorleifsson, Gudmar Yang, Jian Albrecht, Eva Amin, Najaf Bragg-Gresham, Jennifer L. Cadby, Gemma den Heijer, Martin Eklund, Niina Fischer, Krista Goel, Anuj Hottenga, Jouke-Jan Huffman, Jennifer E. Jarick, Ivonne Johansson, Asa Johnson, Toby Kanoni, Stavroula Kleber, Marcus E. Koenig, Inke R. Kristiansson, Kati Kutalik, Zoltn Lamina, Claudia Lecoeur, Cecile Li, Guo Mangino, Massimo McArdle, Wendy L. Medina-Gomez, Carolina Mueller-Nurasyid, Martina Ngwa, Julius S. Nolte, Ilja M. Paternoster, Lavinia Pechlivanis, Sonali Perola, Markus Peters, Marjolein J. Preuss, Michael Rose, Lynda M. Shi, Jianxin Shungin, Dmitry Smith, Albert Vernon Strawbridge, Rona J. Surakka, Ida Teumer, Alexander Trip, Mieke D. Tyrer, Jonathan Van Vliet-Ostaptchouk, Jana V. Vandenput, Liesbeth Waite, Lindsay L. Zhao, Jing Hua Absher, Devin Asselbergs, Folkert W. Atalay, Mustafa Attwood, Antony P. Balmforth, Anthony J. Basart, Hanneke Beilby, John Bonnycastle, Lori L. Brambilla, Paolo Bruinenberg, Marcel Campbell, Harry Chasman, Daniel I. Chines, Peter S. Collins, Francis S. Connell, John M. Cookson, William O. de Faire, Ulf de Vegt, Femmie Dei, Mariano Dimitriou, Maria Edkins, Sarah Estrada, Karol Evans, David M. Farrall, Martin Ferrario, Marco M. Ferrieres, Jean Franke, Lude Frau, Francesca Gejman, Pablo V. Grallert, Harald Groenberg, Henrik Gudnason, Vilmundur Hall, Alistair S. Hall, Per Hartikainen, Anna-Liisa Hayward, Caroline Heard-Costa, Nancy L. Heath, Andrew C. Hebebrand, Johannes Homuth, Georg Hu, Frank B. Hunt, Sarah E. Hyppoenen, Elina Iribarren, Carlos Jacobs, Kevin B. Jansson, John-Olov Jula, Antti Kahonen, Mika Kathiresan, Sekar Kee, Frank Khaw, Kay-Tee Kivimaki, Mika Koenig, Wolfgang Kraja, Aldi T. Kumari, Meena Kuulasmaa, Kari Kuusisto, Johanna Laitinen, Jaana H. Lakka, Timo A. Langenberg, Claudia Launer, Lenore J. Lind, Lars Lindstrom, Jaana Liu, Jianjun Liuzzi, Antonio Lokki, Marja-Liisa Lorentzon, Mattias Madden, Pamela A. Magnusson, Patrik K. Manunta, Paolo Marek, Diana Maerz, Winfried Leach, Irene Mateo McKnight, Barbara Medland, Sarah E. Mihailov, Evelin Milani, Lili Montgomery, Grant W. Mooser, Vincent Muehleisen, Thomas W. Munroe, Patricia B. Musk, Arthur W. Narisu, Narisu Navis, Gerjan Nicholson, George Nohr, Ellen A. Ong, Ken K. Oostra, Ben A. Palmer, Colin N. A. Palotie, Aarno Peden, John F. Pedersen, Nancy Peters, Annette Polasek, Ozren Pouta, Anneli Pramstaller, Peter P. Prokopenko, Inga Puetter, Carolin Radhakrishnan, Aparna Raitakari, Olli Rendon, Augusto Rivadeneira, Fernando Rudan, Igor Saaristo, Timo E. Sambrook, Jennifer G. Sanders, Alan R. Sanna, Serena Saramies, Jouko Schipf, Sabine Schreiber, Stefan Schunkert, Heribert Shin, So-Youn Signorini, Stefano Sinisalo, Juha Skrobek, Boris Soranzo, Nicole Stancakova, Alena Stark, Klaus Stephens, Jonathan C. Stirrups, Kathleen Stolk, Ronald P. Stumvoll, Michael Swift, Amy J. Theodoraki, Eirini V. Thorand, Barbara Tregouet, David-Alexandre Tremoli, Elena Van der Klauw, Melanie M. van Meurs, Joyce B. J. Vermeulen, Sita H. Viikari, Jorma Virtamo, Jarmo Vitart, Veronique Waeber, Gerard Wang, Zhaoming Widen, Elisabeth Wild, Sarah H. Willemsen, Gonneke Winkelmann, Bernhard R. Witteman, Jacqueline C. M. Wolffenbuttel, Bruce H. R. Wong, Andrew Wright, Alan F. Zillikens, M. Carola Amouyel, Philippe Boehm, Bernhard O. Boerwinkle, Eric Boomsma, Dorret I. Caulfield, Mark J. Chanock, Stephen J. Cupples, L. Adrienne Cusi, Daniele Dedoussis, George V. Erdmann, Jeanette Eriksson, Johan G. Franks, Paul W. Froguel, Philippe Gieger, Christian Gyllensten, Ulf Hamsten, Anders Harris, Tamara B. Hengstenberg, Christian Hicks, Andrew A. Hingorani, Aroon Hinney, Anke Hofman, Albert Hovingh, Kees G. Hveem, Kristian Illig, Thomas Jarvelin, Marjo-Riitta Joeckel, Karl-Heinz Keinanen-Kiukaanniemi, Sirkka M. Kiemeney, Lambertus A. Kuh, Diana Laakso, Markku Lehtimaki, Terho Levinson, Douglas F. Martin, Nicholas G. Metspalu, Andres Morris, Andrew D. Nieminen, Markku S. Njolstad, Inger Ohlsson, Claes Oldehinkel, Albertine J. Ouwehand, Willem H. Palmer, Lyle J. Penninx, Brenda Power, Chris Province, Michael A. Psaty, Bruce M. Qi, Lu Rauramaa, Rainer Ridker, Paul M. Ripatti, Samuli Salomaa, Veikko Samani, Nilesh J. Snieder, Harold Sorensen, Thorkild I. A. Spector, Timothy D. Stefansson, Kari Tonjes, Anke Tuomilehto, Jaakko Uitterlinden, Andre G. Uusitupa, Matti van der Harst, Pim Vollenweider, Peter Wallaschofski, Henri Wareham, Nicholas J. Watkins, Hugh Wichmann, H-Erich Wilson, James F. Abecasis, Goncalo R. Assimes, Themistocles L. Barroso, Ines Boehnke, Michael Borecki, Ingrid B. Deloukas, Panos Fox, Caroline S. Frayling, Timothy Groop, Leif C. Haritunian, Talin Heid, Iris M. Hunter, David Kaplan, Robert C. Karpe, Fredrik Moffatt, Miriam F. Mohlke, Karen L. O'Connell, Jeffrey R. Pawitan, Yudi Schadt, Eric E. Schlessinger, David Steinthorsdottir, Valgerdur Strachan, David P. Thorsteinsdottir, Unnur van Duijn, Cornelia M. Visscher, Peter M. Di Blasio, Anna Maria Hirschhorn, Joel N. Lindgren, Cecilia M. Morris, Andrew P. Meyre, David Scherag, Andr McCarthy, Mark I. Speliotes, Elizabeth K. North, Kari E. Loos, Ruth J. F. Ingelsson, Erik TI Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture SO NATURE GENETICS LA English DT Article ID BODY-MASS INDEX; EXTREME OBESITY; MISSING HERITABILITY; COMMON VARIANTS; CONFER RISK; EARLY-ONSET; ASSOCIATION; POPULATION; EXPRESSION; SORTILIN AB Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. C1 [Berndt, Sonja I.; Shi, Jianxin; Jacobs, Kevin B.; Wang, Zhaoming; Chanock, Stephen J.] NCI, US Dept HHS, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Gustafsson, Stefan; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. [Gustafsson, Stefan; Ganna, Andrea; Fall, Tove; Groenberg, Henrik; Hall, Per; Magnusson, Patrik K.; Pedersen, Nancy; Pawitan, Yudi; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Maegi, Reedik; Ferreira, Teresa; Randall, Joshua C.; Min, Josine L.; Prokopenko, Inga; Lindgren, Cecilia M.; Morris, Andrew P.; McCarthy, Mark I.; Ingelsson, Erik] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Maegi, Reedik; Esko, Tonu; Fischer, Krista; Perola, Markus; Mihailov, Evelin; Milani, Lili; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Wheeler, Eleanor; Randall, Joshua C.; Kanoni, Stavroula; Edkins, Sarah; Hunt, Sarah E.; Palotie, Aarno; Radhakrishnan, Aparna; Shin, So-Youn; Soranzo, Nicole; Stirrups, Kathleen; Ouwehand, Willem H.; Ripatti, Samuli; Barroso, Ines; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Feitosa, Mary F.; Kraja, Aldi T.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Justice, Anne E.; Monda, Keri L.; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Monda, Keri L.] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA USA. [Croteau-Chonka, Damien C.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Day, Felix R.; Luan, Jian'an; Zhao, Jing Hua; Langenberg, Claudia; Ong, Ken K.; Wareham, Nicholas J.; Loos, Ruth J. F.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Esko, Tonu; Mihailov, Evelin; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Gentilini, Davide; Di Blasio, Anna Maria] Ist Auxol Italiano, Dept Mol Biol, Milan, Italy. [Jackson, Anne U.; Bragg-Gresham, Jennifer L.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Vedantam, Sailaja; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Vedantam, Sailaja; Kathiresan, Sekar; Hirschhorn, Joel N.] Broad Inst, Metab Initiat, Cambridge, MA USA. [Vedantam, Sailaja; Kathiresan, Sekar; Hirschhorn, Joel N.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Vedantam, Sailaja; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Willer, Cristen J.] Univ Michigan, Dept Internal Med Cardiovasc, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen J.; Speliotes, Elizabeth K.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Med Ctr, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Wood, Andrew R.; Frayling, Timothy; Ingelsson, Erik] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Workalemahu, Tsegaselassie; Hu, Frank B.; Franks, Paul W.; Qi, Lu; Hunter, David] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Workalemahu, Tsegaselassie; Qi, Lu; Hunter, David] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Workalemahu, Tsegaselassie; Qi, Lu; Hunter, David] Harvard Univ, Sch Med, Boston, MA USA. [Lee, Sang Hong; Visscher, Peter M.] Emory Univ, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Liang, Liming] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Thorleifsson, Gudmar; Stefansson, Kari; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur] deCODE Genet, Reykjavik, Iceland. [Yang, Jian; Visscher, Peter M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Yang, Jian; Medland, Sarah E.; Montgomery, Grant W.; Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Albrecht, Eva; Amin, Najaf; Mueller-Nurasyid, Martina; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Rivadeneira, Fernando; van Meurs, Joyce B. J.; Witteman, Jacqueline C. M.; Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Cadby, Gemma; Palmer, Lyle J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Cadby, Gemma; Palmer, Lyle J.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Cadby, Gemma] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Crawley, WA, Australia. [den Heijer, Martin] Vrije Univ Amsterdam, Med Ctr, Dept Internal Med, Amsterdam, Netherlands. [Eklund, Niina; Kristiansson, Kati; Perola, Markus; Surakka, Ida] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Unit Publ Hlth Gen, Helsinki, Finland. [Goel, Anuj; Farrall, Martin; Ripatti, Samuli; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hottenga, Jouke-Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Huffman, Jennifer E.; Hayward, Caroline; Vitart, Veronique; Wright, Alan F.] Western Gen Hosp, MRC, Inst Genet & Mol Med, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Jarick, Ivonne] Univ Marburg, Inst Med Biometry & Epidemiol, Marburg, Germany. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Johansson, Asa] Univ Uppsala Hosp, Uppsala Clin Res Ctr, Uppsala, Sweden. [Johnson, Toby; Munroe, Patricia B.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med & Dent, Genome Ctr, London, England. [Johnson, Toby; Munroe, Patricia B.; Caulfield, Mark J.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Kleber, Marcus E.] Ludwigshafen Risk & Cardiovasc Hlth LURIC Study, Freiburg, Germany. [Koenig, Inke R.; Preuss, Michael] Heidelberg Univ, Med Fac Mannheim, Mannheim Inst Publ Hlth Social & Prevent Med, Mannheim, Germany. [Koenig, Inke R.; Preuss, Michael] Med Univ Lubeck, Inst Med Biometrie & Stat, Univ Klinikum Schleswig Holstein, D-23538 Lubeck, Germany. [Kutalik, Zoltn; Marek, Diana] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Kutalik, Zoltn; Marek, Diana] Swiss Inst Bioinformat, Lausanne, Switzerland. [Lamina, Claudia] Med Univ Innsbruck, Div Genet Epidemiol Mol & Clin Pharmacol, Dept Med Genet, A-6020 Innsbruck, Austria. [Lecoeur, Cecile; Skrobek, Boris; Froguel, Philippe; Meyre, David] Univ Lille Nord France, Lille, France. [Lecoeur, Cecile; Skrobek, Boris; Froguel, Philippe; Meyre, David] Inst Pasteur, CNRS, UMR 8199, Inst Biol Lille, F-59019 Lille, France. [Li, Guo; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Mangino, Massimo; Soranzo, Nicole; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Medina-Gomez, Carolina; Peters, Marjolein J.; Estrada, Karol; Rivadeneira, Fernando; van Meurs, Joyce B. J.; Zillikens, M. Carola; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Mueller-Nurasyid, Martina] Univ Munich, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina; Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Ngwa, Julius S.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Nolte, Ilja M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. 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F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY USA. RP Ingelsson, E (reprint author), Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden. EM erik.ingelsson@medsci.uu.se RI Medland, Sarah/C-7630-2013; Boehm, Bernhard/F-8750-2015; Grallert, Harald/B-3424-2013; Milani, Lili/C-8759-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Vegt, F./L-4704-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Montgomery, Grant/B-7148-2008; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Johansson, Asa/G-5270-2011; Colaus, PsyColaus/K-6607-2013; Deloukas, Panos/B-2922-2013; van der Klauw, Melanie/A-2138-2014; Hypponen, Elina/B-2596-2014; Kiemeney, Lambertus/D-3357-2009; Palmer, Colin/C-7053-2008; Pramstaller, Peter/C-2357-2008; Palmer, Lyle/K-3196-2014; Fall, Tove/O-7226-2014; Hinney, Anke/D-6953-2011; Evans, David/H-6325-2013; Lee, Sang Hong/A-2569-2011; Strawbridge, Rona/H-5422-2012; Erdmann, Jeanette/P-7513-2014; Magnusson, Patrik/C-4458-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Thorand, Barbara/B-5349-2014; Peters, Annette/A-6117-2011; Tregouet, David-Alexandre/E-3961-2016; Vermeulen, H.H.M./L-4716-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Yang, Jian/A-5852-2010; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Franke, Lude/P-7036-2016; Wong, Andrew/M-8899-2016; Konig, Inke/A-4544-2009 OI Medland, Sarah/0000-0003-1382-380X; Milani, Lili/0000-0002-5323-3102; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Montgomery, Grant/0000-0002-4140-8139; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Johansson, Asa/0000-0002-2915-4498; Deloukas, Panos/0000-0001-9251-070X; van der Klauw, Melanie/0000-0001-7178-009X; Hypponen, Elina/0000-0003-3670-9399; Kiemeney, Lambertus/0000-0002-2368-1326; Palmer, Colin/0000-0002-6415-6560; Palmer, Lyle/0000-0002-1628-3055; Hinney, Anke/0000-0001-5659-0706; Lee, Sang Hong/0000-0001-9701-2718; Strawbridge, Rona/0000-0001-8506-3585; Kristiansson, Kati/0000-0003-4688-107X; Willer, Cristen/0000-0001-5645-4966; Rendon, Augusto/0000-0001-8994-0039; TREMOLI, ELENA/0000-0002-0929-6106; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Johnson, Toby/0000-0002-5998-3270; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Hunt, Sarah/0000-0002-8350-1235; Abecasis, Goncalo/0000-0003-1509-1825; Paternoster, Lavinia/0000-0003-2514-0889; Manunta, Paolo/0000-0003-3976-9696; Erdmann, Jeanette/0000-0002-4486-6231; Lakka, Timo/0000-0002-9199-2871; Ferrario, Marco M/0000-0003-2741-7124; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Franks, Paul/0000-0002-0520-7604; Wheeler, Eleanor/0000-0002-8616-6444; Sinisalo, Juha/0000-0002-0169-5137; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Ganna, Andrea/0000-0002-8147-240X; Watkins, Hugh/0000-0002-5287-9016; Medina-Gomez, Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Evans, David/0000-0003-0663-4621; Ouwehand, Willem/0000-0002-7744-1790; Scherag, Andre/0000-0002-9406-4704; Kumari, Meena/0000-0001-9716-1035; Kuulasmaa, Kari/0000-0003-2165-1411; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Vandenput, Liesbeth/0000-0002-1712-6131; Karpe, Fredrik/0000-0002-2751-1770; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Radhakrishnan, Aparna/0000-0002-8153-9037; Heard-Costa, Nancy/0000-0001-9730-0306; Cupples, L. Adrienne/0000-0003-0273-7965; Shungin, Dmitry/0000-0001-7900-5856; Day, Felix/0000-0003-3789-7651; Magi, Reedik/0000-0002-2964-6011; Peters, Marjolein/0000-0003-3167-9063; Esko, Tonu/0000-0003-1982-6569; Thorand, Barbara/0000-0002-8416-6440; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Yang, Jian/0000-0003-2001-2474; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Franke, Lude/0000-0002-5159-8802; Wong, Andrew/0000-0003-2079-4779; FU Aarno Koskelo Foundation; Agency for Science, Technology and Research of Singapore; Australian National Health and Medical Research Council; Australian Research Council; BDA Research; BioSHaRE Consortium; British Heart Foundation; Cedars-Sinai Board of Governors' Chair in Medical Genetics; Centre for Clinical Research at the University of Leipzig; Centre of Excellence in Genomics; University of Tartu; Chief Scientist Office of the Scottish government; City of Kuopio; Social Insurance Institution of Finland; Department of Educational Assistance; University and Research of the Autonomous Province of Bolzano; Donald W. Reynolds Foundation; Dutch Ministry for Health, Welfare and Sports; Dutch Ministry of Education, Culture and Science; Dutch BBRMI-NL; Dutch Brain Foundation; Dutch Centre for Medical Systems Biology; Dutch Diabetes Research Foundation; Dutch Government Economic Structure-Enhancing Fund; Dutch Inter-University Cardiology Institute; Dutch Kidney Foundation; Dutch Ministry of Economic Affairs; Dutch Ministry of Justice; Dutch Research Institute for Diseases in the Elderly; Eleanor Nichols endowments; Emil Aaltonen Foundation; Erasmus Medical Center; Erasmus University; Estonian government; European Commission; European Regional Development Fund; European Research Council; European Science Foundation; Faculty of Biology and Medicine of Lausanne; Finland's Slot Machine Association; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Foundation for Cardiovascular Research; Finnish Funding Agency for Technology and Innovation; Finnish Heart Association; Finnish Medical Society; Finnish Ministry of Education and Culture; Finnish Ministry of Health and Social Affairs; Finnish National Institute for Health and Welfare; Finnish Social Insurance Institution; Finska Lakaresallskapet; Folkhalsan Research Foundation; Foundation for Life and Health in Finland; French Ministry of Research; French National Research Agency; Genetic Association Information Network; German Diabetes Association; German Federal Ministry of Education and Research; German Ministry of Cultural Affairs; German National Genome Research Network; German Research Foundation; GlaxoSmithKline; Goteborg Medical Society; Greek General Secretary of Research and Technology; Gyllenberg Foundation; Health Care Centers in Vasa, Narpes and Korsholm; Heinz Nixdorf Foundation; Helmholtz Zentrum Munchen-German Research Center for Environmental Health; Icelandic Heart Association; Icelandic Parliament; Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, NIH; Italian Ministry of Education, Universities and Research; Italian Ministry of Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds; Leducq Foundation; Lundberg Foundation; March of Dimes; Munich Center of Health Sciences as part of LMUinnovativ; Municipal Health Care Center and Hospital in Jakobstad; Municipality of Rotterdam; Narpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression Young Investigator Awards; Netherlands Genomics Initiative; Netherlands Organization for Health Research and Development; UK NHSBT; US National Institutes of Health; Nordic Center of Cardiovascular Research; Nordic Center of Excellence in Disease Genetics; Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies; Northern Netherlands Collaboration of Provinces; Novo Nordisk Foundation; Ollqvist Foundation; Orion-Farmos Research Foundation; Paavo Nurmi Foundation; Paivikki and Sakari Sohlberg Foundation; Perklen Foundation; Petrus and Augusta Hedlunds Foundation; Province of Groningen; Republic of Croatia Ministry of Science, Education and Sport; Reynold's Foundation; Royal Society; Samfundet Folkhalsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Sophia Foundation for Medical Research; South Tyrolean Sparkasse Foundation; Southern California Diabetes Endocrinology Research Center; Stockholm County Council; Strategic Cardiovascular Program of Karolinska Institutet; Strategic Support for Epidemiological Research at Karolinska Institutet; Susan G. Komen Breast Cancer Foundation; Swedish Ministry for Higher Education; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Diabetes Association; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council; Swedish Ministry of Education; Swedish Research Council; Swedish Royal Academy of Science; Swedish Society for Medical Research; Swedish Society of Medicine; Swiss National Science Foundation; Tampere Tuberculosis Foundation; Great Wine Estates of the Margaret River Region of Western Australia; Paul Michael Donovan Charitable Foundation; Torsten and Ragnar Soderberg Foundation; Cancer Research UK; UK Diabetes Association; UK Heart Foundation; UK MRCUK NIHR, Biomedical Research Centre; UK West Anglia Primary and Community Care; University Medical Center Groningen; University of Groningen; Vastra Gotaland Foundation; VU University: the Institute for Health and Care Research and the Neuroscience Campus Amsterdam; Wellcome Trust; Yrjo Jahnsson Foundation FX A full list of acknowledgments appears in the Supplementary Note. Funding was provided by the Aarno Koskelo Foundation; the Academy of Finland; the Agency for Science, Technology and Research of Singapore; the Australian National Health and Medical Research Council; the Australian Research Council; BDA Research; the BioSHaRE Consortium; the British Heart Foundation; the Cedars-Sinai Board of Governors' Chair in Medical Genetics; the Centre for Clinical Research at the University of Leipzig; the Centre of Excellence in Genomics and the University of Tartu; the Chief Scientist Office of the Scottish government; the City of Kuopio and the Social Insurance Institution of Finland; the Department of Educational Assistance, the University and Research of the Autonomous Province of Bolzano; the Donald W.; Reynolds Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Education, Culture and Science; Dutch BBRMI-NL; the Dutch Brain Foundation; the Dutch Centre for Medical Systems Biology; the Dutch Diabetes Research Foundation; the Dutch Government Economic Structure-Enhancing Fund; the Dutch Inter-University Cardiology Institute; the Dutch Kidney Foundation; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Justice; the Dutch Research Institute for Diseases in the Elderly; Eleanor Nichols endowments; the Emil Aaltonen Foundation; Erasmus Medical Center and Erasmus University; the Estonian government; the European Commission; the European Regional Development Fund; the European Research Council; the European Science Foundation; the Faculty of Biology and Medicine of Lausanne; Finland's Slot Machine Association; the Finnish Cultural Foundation; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Funding Agency for Technology and Innovation; the Finnish Heart Association; the Finnish Medical Society; the Finnish Ministry of Education and Culture; the Finnish Ministry of Health and Social Affairs; the Finnish National Institute for Health and Welfare; the Finnish Social Insurance Institution; Finska Lakaresallskapet; the Folkhalsan Research Foundation; the Foundation for Life and Health in Finland; the French Ministry of Research; the French National Research Agency; the Genetic Association Information Network; the German Diabetes Association; the German Federal Ministry of Education and Research; the German Ministry of Cultural Affairs; the German National Genome Research Network; the German Research Foundation; GlaxoSmithKline; the Goteborg Medical Society; the Greek General Secretary of Research and Technology; the Gyllenberg Foundation; Health Care Centers in Vasa, Narpes and Korsholm; the Heinz Nixdorf Foundation; Helmholtz Zentrum Munchen-German Research Center for Environmental Health; the Icelandic Heart Association; the Icelandic Parliament; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, NIH; Italian Ministry of Education, Universities and Research; Italian Ministry of Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; the Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds; the Leducq Foundation; the Lundberg Foundation; the March of Dimes; the Munich Center of Health Sciences as part of LMUinnovativ; the Municipal Health Care Center and Hospital in Jakobstad; the Municipality of Rotterdam; the Narpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression Young Investigator Awards; the Netherlands Genomics Initiative; the Netherlands Organization for Health Research and Development; UK NHSBT; US National Institutes of Health; the Nordic Center of Cardiovascular Research; the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies; the Northern Netherlands Collaboration of Provinces; the Novo Nordisk Foundation; the Ollqvist Foundation; the Orion-Farmos Research Foundation; the Paavo Nurmi Foundation; the Paivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Petrus and Augusta Hedlunds Foundation; the Province of Groningen; the Republic of Croatia Ministry of Science, Education and Sport; the Reynold's Foundation; the Royal Society; Samfundet Folk; halsan; the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Social Ministry of the Federal State of Mecklenburg-West Pomerania; the Sophia Foundation for Medical Research; the South Tyrolean Sparkasse Foundation; the Southern California Diabetes Endocrinology Research Center; the Stockholm County Council; the Strategic Cardiovascular Program of Karolinska Institutet; Strategic Support for Epidemiological Research at Karolinska Institutet; the Susan G. Komen Breast Cancer Foundation; the Swedish Ministry for Higher Education; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Foundation for Strategic Research; the Swedish Heart-Lung Foundation; the Swedish Medical Research Council; the Swedish Ministry of Education; the Swedish Research Council; the Swedish Royal Academy of Science; the Swedish Society for Medical Research; the Swedish Society of Medicine; the Swiss National Science Foundation; the Tampere Tuberculosis Foundation; The Great Wine Estates of the Margaret River Region of Western Australia; The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Soderberg Foundation; Cancer Research UK; the UK Diabetes Association; the UK Heart Foundation; the UK MRC; the UK NIHR, Biomedical Research Centre; UK West Anglia Primary and Community Care; the University Medical Center Groningen and the University of Groningen; the Vastra Gotaland Foundation; VU University: the Institute for Health and Care Research and the Neuroscience Campus Amsterdam; the Wellcome Trust; and the Yrjo Jahnsson Foundation. NR 54 TC 177 Z9 185 U1 5 U2 103 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2013 VL 45 IS 5 BP 501 EP U69 DI 10.1038/ng.2606 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 133RU UT WOS:000318158200011 PM 23563607 ER PT J AU Bock, R Shin, JH Kaplan, AR Dobi, A Markey, E Kramer, PF Gremel, CM Christensen, CH Adrover, MF Alvarez, VA AF Bock, Roland Shin, J. Hoon Kaplan, Alanna R. Dobi, Alice Markey, Eric Kramer, Paul F. Gremel, Christina M. Christensen, Christine H. Adrover, Martin F. Alvarez, Veronica A. TI Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use SO NATURE NEUROSCIENCE LA English DT Article ID D2-LIKE AGONISTS; OPTOGENETIC CONTROL; NUCLEUS-ACCUMBENS; VENTRAL PALLIDUM; DOPAMINE D1-LIKE; DISTINCT ROLES; D2 RECEPTORS; ADDICTION; REWARD; RATS AB A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals. C1 [Bock, Roland; Shin, J. Hoon; Kaplan, Alanna R.; Dobi, Alice; Markey, Eric; Kramer, Paul F.; Gremel, Christina M.; Christensen, Christine H.; Adrover, Martin F.; Alvarez, Veronica A.] NIAAA, Lab Integrat Neurosci, US NIH, Bethesda, MD USA. [Alvarez, Veronica A.] NINDS, US NIH, Bethesda, MD 20892 USA. RP Alvarez, VA (reprint author), NIAAA, Lab Integrat Neurosci, US NIH, Bethesda, MD USA. EM alvarezva@mail.nih.gov RI Alvarez, Veronica /E-9745-2015; Bock, Roland/G-2982-2016; OI Alvarez, Veronica /0000-0003-2611-8675; Bock, Roland/0000-0002-8654-1080; Kramer, Paul/0000-0002-0095-3712; Kaplan, Alanna/0000-0002-2612-4736 FU Intramural Program of the National Institute on Alcohol Abuse and Alcoholism; Intramural Program of the National Institute of Neurological Disorders and Stroke [ZIA-AA000421] FX We are grateful to the staff of Fishers Lane Animal Center and to L. Chedester for technical support. We thank the members of the Alvarez laboratory, J.T. Williams, D.M. Lovinger and B.L. Sabatini for helpful comments on the manuscript. We also thank B. Roth (University of North Carolina) and K. Deisseroth (Stanford University) for their generosity in providing the constructs for hM4Di and ChR2, respectively, and B. Harvey (Optogenetics and Transgenic Technology Core at the National Institute on Drug Abuse) for the viral vector preparation. This study was funded by the Intramural Programs of the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Neurological Disorders and Stroke (ZIA-AA000421). NR 36 TC 84 Z9 86 U1 2 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAY PY 2013 VL 16 IS 5 BP 632 EP + DI 10.1038/nn.3369 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 131WT UT WOS:000318029300020 PM 23542690 ER PT J AU Wakefield, LM Hill, CS AF Wakefield, Lalage M. Hill, Caroline S. TI Beyond TGF beta: roles of other TGF beta superfamily members in cancer SO NATURE REVIEWS CANCER LA English DT Review ID GROWTH-FACTOR-BETA; EPITHELIAL-MESENCHYMAL TRANSITION; MORPHOGENETIC PROTEIN PATHWAY; EARLY MOUSE EMBRYO; STEM-CELLS; SELF-RENEWAL; SIGNAL-TRANSDUCTION; BONE METASTASIS; SMAD1/5 PHOSPHORYLATION; MALIGNANT PROGRESSION AB Much of the focus on the transforming growth factor-beta (TGF beta) superfamily in cancer has revolved around the TGF beta ligands themselves. However, it is now becoming apparent that deregulated signalling by many of the other superfamily members also has crucial roles in both the development of tumours and metastasis. Furthermore, these signalling pathways are emerging as plausible therapeutic targets. Their roles in tumorigenesis frequently reflect their function in embryonic development or in adult tissue homeostasis, and their influence extends beyond the tumours themselves, to the tumour microenvironment and more widely to complications of cancer such as cachexia and bone loss. C1 [Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Hill, Caroline S.] Canc Res UK London Res Inst, Dev Signalling Lab, London WC2A 3LY, England. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 4032A,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM lw34g@nih.gov; caroline.hill@cancer.org.uk FU Cancer Research UK; European Commission Network of Excellence EpiGeneSys [HEALTH-F4-2010-257082]; US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX The authors thank members of the Hill and Wakefield laboratories, K. Hunter, E. Sahai, M. Sporn, S. Yuspa and Y. Zhang for useful comments on the manuscript. C.S.H. acknowledges Cancer Research UK and the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082) for funding. L.M.W. acknowledges the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research for funding. NR 113 TC 106 Z9 108 U1 5 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAY PY 2013 VL 13 IS 5 BP 328 EP 341 DI 10.1038/nrc3500 PG 14 WC Oncology SC Oncology GA 131RM UT WOS:000318013000012 PM 23612460 ER PT J AU Vargas, JD Lima, JAC AF Vargas, Jose D. Lima, Joao A. C. TI CORONARY ARTERY DISEASE A gene-expression score to predict obstructive CAD SO NATURE REVIEWS CARDIOLOGY LA English DT Editorial Material ID NONDIABETIC PATIENTS; ALGORITHM; RISK AB The diagnosis of obstructive coronary artery disease (CAD) can be challenging and relies on noninvasive imaging methods and coronary angiography. Advances in genetic technologies have enabled large-scale gene-expression studies. A gene-expression score has been shown to predict the presence of obstructive CAD. Vargas, J. D. & Lima, J. A. C. Nat. Rev. Cardiol. 10, 243-244 (2013); published online 2 April 2013; doi: 10.1038/nrcardio.2013.50 C1 [Vargas, Jose D.] NIH, Dept Radiol & Imaging Sci, Baltimore, MD 21287 USA. [Lima, Joao A. C.] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. RP Vargas, JD (reprint author), NIH, Dept Radiol & Imaging Sci, 10 Ctr Dr,Bldg 10,Room 1C351, Baltimore, MD 21287 USA. EM jvargas4@jhmi.edu NR 9 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD MAY PY 2013 VL 10 IS 5 BP 243 EP 244 DI 10.1038/nrcardio.2013.50 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 131AP UT WOS:000317963000002 PM 23546447 ER PT J AU Kochenderfer, JN Rosenberg, SA AF Kochenderfer, James N. Rosenberg, Steven A. TI Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; IN-VIVO PERSISTENCE; ANTITUMOR-ACTIVITY; ADOPTIVE IMMUNOTHERAPY; ALLOGENEIC TRANSPLANTATION; GENETIC-MODIFICATION; CD19 ANTIGEN; HEMATOLOGIC MALIGNANCIES AB Most B-cell malignancies express CD19, and a majority of patients with B-cell malignancies are not cured by current standard therapies. Chimeric antigen receptors (CARs) are fusion proteins consisting of antigen recognition moieties and T-cell activation domains. T cells can be genetically modified to express CARs, and adoptive transfer of anti-CD19 CAR T cells is now being tested in clinical trials. Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells. Additional patients have subsequently obtained long-term remissions of advanced-stage B-cell malignancies after infusions of anti-CD19 CAR T cells. Long-term eradication of normal CD19(+) B cells from patients receiving infusions of anti-CD19 CAR T cells demonstrates the potent antigen-specific activity of these T cells. Some patients treated with anti-CD19 CAR T cells have experienced acute adverse effects, which were associated with increased levels of serum inflammatory cytokines. Although anti-CD19 CAR T cells are at an early stage of development, the potent antigen-specific activity observed in patients suggests that infusions of anti-CD19 CAR T cells might become a standard therapy for some B-cell malignancies. C1 [Kochenderfer, James N.; Rosenberg, Steven A.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Kochenderfer, JN (reprint author), NCI, Expt Transplantat & Immunol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Intramural NIH HHS NR 89 TC 115 Z9 127 U1 8 U2 115 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 MAY PY 2013 VL 10 IS 5 BP 267 EP 276 DI 10.1038/nrclinonc.2013.46 PG 10 WC Oncology SC Oncology GA 133RM UT WOS:000318157200005 PM 23546520 ER PT J AU Watnick, TJ Germino, GG AF Watnick, Terry J. Germino, Gregory G. TI POLYCYSTIC KIDNEY DISEASE Polycystin-1 and polycystin-2-it's complicated SO NATURE REVIEWS NEPHROLOGY LA English DT News Item ID CYST FORMATION; CELLS; PROLIFERATION AB Mutations in the genes that encode polycystin-1 and polycystin-2 are the principal cause of autosomal dominant polycystic kidney disease. These proteins form a receptor-ion-channel complex and were thought to regulate tubule luminal diameter in a codependent manner. However, new data suggest a more antagonistic relationship between the proteins. Watnick, T. J. & Germino, G. G. Nat. Rev. Nephrol. 9, 249-250 (2013); published online 9 April 2013; doi:10.1038/nrneph.2013.73 C1 [Watnick, Terry J.] Univ Maryland, Sch Med, Baltimore Polycyst Kidney Dis Res & Clin Core Ctr, Div Nephrol, Baltimore, MD 21201 USA. [Germino, Gregory G.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Watnick, TJ (reprint author), Univ Maryland, Sch Med, Baltimore Polycyst Kidney Dis Res & Clin Core Ctr, Div Nephrol, 22 South Greene St,Room N3W-143, Baltimore, MD 21201 USA. EM twatnick@medicine.umaryland.edu; germinogg@mail.nih.gov OI Germino, Gregory/0000-0002-3609-5588 FU Intramural NIH HHS; NIDDK NIH HHS [ZIA DK075042, DK095036, R01 DK095036, P30DK090868, P30 DK090868] NR 10 TC 4 Z9 4 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD MAY PY 2013 VL 9 IS 5 BP 249 EP 250 DI 10.1038/nrneph.2013.73 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 131UW UT WOS:000318023300001 PM 23567275 ER PT J AU Utreras, E Henriquez, D Contreras-Vallejos, E Olmos, C Di Genova, A Maass, A Kulkarni, AB Gonzalez-Billault, C AF Utreras, Elias Henriquez, Daniel Contreras-Vallejos, Erick Olmos, Cristina Di Genova, Alex Maass, Alejandro Kulkarni, Ashok B. Gonzalez-Billault, Christian TI Cdk5 regulates Rap1 activity SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE Signal transduction; Cyclin-dependent kinase 5; Rap1; C3G; Neurones ID NUCLEOTIDE EXCHANGE FACTOR; NEURONAL POLARITY; UBIQUITIN LIGASE; FACTOR C3G; ACTIVATION; MIGRATION; PHOSPHORYLATION; EXPRESSION; GTPASES; CRK AB Rap1 signaling is important for migration, differentiation, axonal growth, and during neuronal polarity. Rap1 can be activated by external stimuli, which in turn regulates specific guanine nucleotide exchange factors such as C3G, among others. Cdk5 functions are also important to neuronal migration and differentiation. Since we found that pharmacological inhibition of Cdk5 by using roscovitine reduced Rap1 protein levels in COS-7 cells and also C3G contains three putative phosphorylation sites for Cdk5, we examined whether the Cdk5-dependent phosphorylation of C3G could affect Rap1 expression and activity. We co-transfected C3G and tet-OFF system for p35 over-expression, an activator of Cdk5 activity into COS-7 cells, and then we evaluated phosphorylation in serine residues in C3G by immunoprecipitation and Western blot. We found that p35 over-expression increased C3G-serine-phosphorylation while inhibition of p35 expression by tetracycline or inhibition of Cdk5 activity with roscovitine decreased it. Interestingly, we found that MG-132, a proteasome inhibitor, rescue Rap1 protein levels in the presence of roscovitine. Besides, C3G-serine-phosphorylation and Rap1 protein levels were reduced in brain from Cdk5(-/-) as compared with the Cdk5(+/+) brain. Finally, we found that p35 over-expression increased Rap1 activity while inhibition of p35 expression by tetracycline or roscovitine decreased Rap1 activity. These results suggest that Cdk5-mediated serine-phosphorylation of C3G may control Rap1 stability and activity, and this may potentially impact various neuronal functions such as migration, differentiation, and polarity. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Utreras, Elias; Henriquez, Daniel; Contreras-Vallejos, Erick; Olmos, Cristina; Gonzalez-Billault, Christian] Univ Chile, Lab Cellular & Neuronal Dynam, Dept Biol, Fac Sci, Santiago 7800024, Chile. [Di Genova, Alex; Maass, Alejandro] Univ Chile, Ctr Math Modeling, Santiago 7800024, Chile. [Di Genova, Alex; Maass, Alejandro] Univ Chile, Ctr Genome Regulat, Santiago 7800024, Chile. [Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, NIH, Bethesda, MD USA. RP Gonzalez-Billault, C (reprint author), Univ Chile, Lab Cellular & Neuronal Dynam, Dept Biol, Fac Sci, Las Palmeras 3425, Santiago 7800024, Chile. EM chrgonza@uchile.cl RI Maass, Alejandro/D-5848-2012; utreras, elias/I-1038-2013 OI Maass, Alejandro/0000-0002-7038-4527; utreras, elias/0000-0002-1004-0466 FU Fondecyt [1095089, ACT114, ICM P05-001-F, PAI 79100009, 11110136]; Division of Intramural Research, NIDCR, NIH, Bethesda, MD, USA FX The work was supported by Fondecyt 1095089, ACT114 and ICM P05-001-F (to CG-B), and PAI 79100009 and Fondecyt 11110136 (to EU), and the Division of Intramural Research, NIDCR, NIH, Bethesda, MD, USA. NR 36 TC 6 Z9 6 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD MAY PY 2013 VL 62 IS 6 BP 848 EP 853 DI 10.1016/j.neuint.2013.02.011 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 133KC UT WOS:000318136300005 PM 23416045 ER PT J AU Hasler, WL Wilson, LA Parkman, HP Koch, KL Abell, TL Nguyen, L Pasricha, PJ Snape, WJ McCallum, RW Sarosiek, I Farrugia, G Calles, J Lee, L Tonascia, J Unalp-Arida, A Hamilton, F AF Hasler, W. L. Wilson, L. A. Parkman, H. P. Koch, K. L. Abell, T. L. Nguyen, L. Pasricha, P. J. Snape, W. J. McCallum, R. W. Sarosiek, I. Farrugia, G. Calles, J. Lee, L. Tonascia, J. Unalp-Arida, A. Hamilton, F. TI Factors related to abdominal pain in gastroparesis: contrast to patients with predominant nausea and vomiting SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE diabetes mellitus; gastric emptying; gastroparesis; opiates; psychological dysfunction; quality of life ID UPPER GASTROINTESTINAL DISORDERS; CARDINAL SYMPTOM INDEX; QUALITY-OF-LIFE; REFRACTORY GASTROPARESIS; FUNCTIONAL DYSPEPSIA; DIABETIC GASTROPARESIS; DYSFUNCTION; PREDICTORS; SEVERITY; HYPERSENSITIVITY AB Background Factors associated with abdominal pain in gastroparesis are incompletely evaluated and comparisons of pain vs other symptoms are limited. This study related pain to clinical factors in gastroparesis and contrasted pain/discomfort- with nausea/vomiting-predominant disease. Methods Clinical and scintigraphy data were compared in 393 patients from seven centers of the NIDDK Gastroparesis Clinical Research Consortium with moderate-severe (Patient Assessment of Upper Gastrointestinal Disorders Symptoms [PAGI-SYM] score3) vs none-mild (PAGI-SYM<3) upper abdominal pain and predominant pain/discomfort vs nausea/vomiting. Key Results Upper abdominal pain was moderate-severe in 261 (66%). Pain/discomfort was predominant in 81 (21%); nausea/vomiting was predominant in 172 (44%). Moderate-severe pain was more prevalent with idiopathic gastroparesis and with lack of infectious prodrome (P0.05) and correlated with scores for nausea/vomiting, bloating, lower abdominal pain/discomfort, bowel disturbances, and opiate and antiemetic use (P<0.05), but not gastric emptying or diabetic neuropathy or control. Gastroparesis severity, quality of life, and depression and anxiety were worse with moderate-severe pain (P0.008). Factors associated with moderate-severe pain were similar in diabetic and idiopathic gastroparesis. Compared to predominant nausea/vomiting, predominant pain/discomfort was associated with impaired quality of life, greater opiate, and less antiemetic use (P<0.01), but similar severity and gastric retention. Conclusions & Inferences Moderate-severe abdominal pain is prevalent in gastroparesis, impairs quality of life, and is associated with idiopathic etiology, lack of infectious prodrome, and opiate use. Pain is predominant in one fifth of gastroparetics. Predominant pain has at least as great an impact on disease severity and quality of life as predominant nausea/vomiting. C1 [Hasler, W. L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Wilson, L. A.; Lee, L.; Tonascia, J.; Unalp-Arida, A.] Johns Hopkins Univ, Baltimore, MD USA. [Parkman, H. P.] Temple Univ, Philadelphia, PA 19122 USA. [Koch, K. L.; Calles, J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, T. L.] Univ Mississippi, Jackson, MS 39216 USA. [Nguyen, L.; Pasricha, P. J.] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, W. J.] Calif Pacific Med Ctr, San Francisco, CA USA. [McCallum, R. W.; Sarosiek, I.] Texas Tech Univ Hlth Sci Ctr, El Paso, TX USA. [Farrugia, G.] Mayo Clin, Rochester, MN USA. [Hamilton, F.] NIDDK, Bethesda, MD USA. RP Hasler, WL (reprint author), 3912 Taubman Ctr, Ann Arbor, MI 48109 USA. EM whasler@umich.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Gastroparesis Clinical Research Consortium [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX This project received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008) as part of its funding of the Gastroparesis Clinical Research Consortium. NR 46 TC 17 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD MAY PY 2013 VL 25 IS 5 DI 10.1111/nmo.12091 PG 14 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 132DP UT WOS:000318048400015 PM 23414452 ER PT J AU Gulbrandsen, P Jensen, BF Finset, A Blanch-Hartigan, D AF Gulbrandsen, Pal Jensen, Bard Fossli Finset, Arnstein Blanch-Hartigan, Danielle TI Long-term effect of communication training on the relationship between physicians' self-efficacy and performance SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Communication skills training; Self-efficacy; Performance; Longitudinal study ID RANDOMIZED CONTROLLED-TRIAL; HABITS CODING SCHEME; HEALTH-PROFESSIONS; ASSESSMENT-TOOL; SKILLS; DOCTORS; COMPETENCE; ACCURACY; BEHAVIOR; IMPACT AB Objective: To examine the long term impact of a communication skills intervention on physicians' communication self-efficacy and the relationship between reported self-efficacy and actual performance. Methods: 62 hospital physicians were exposed to a 20-h communication skills course according to the Four Habits patient-centered approach in a crossover randomized trial. Encounters with real patients before and after the intervention (mean 154 days) were videotaped, for evaluation of performance using the Four Habits Coding Scheme. Participants completed a questionnaire about communication skills self-efficacy before the course, immediately after the course, and at 3 years follow-up. Change in self-efficacy and the correlations between performance and self-efficacy at baseline and follow-up were assessed. Results: Communication skills self-efficacy was not correlated to performance at baseline (r = -0.16; p = 0.22). The association changed significantly (p = 0.01) and was positive at follow-up (r = 0336, p = 0.042). The self-efficacy increased significantly (effect size d = 0.27). High performance after the course and low self-efficacy before the course were associated with larger increase in communication skills self-efficacy. Conclusion: A communication skills course led to improved communication skills self-efficacy more than 3 years later, and introduced a positive association between communication skills self-efficacy and performance not present at baseline. Practice implications: Communication skills training enhances physicians' insight in own performance. (c) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Gulbrandsen, Pal] Univ Oslo, Inst Clin Med, Oslo, Norway. [Gulbrandsen, Pal; Jensen, Bard Fossli] Akershus Univ Hosp, Res Ctr, HOKH, N-1478 Lorenskog, Norway. [Finset, Arnstein] Univ Oslo, Dept Behav Sci Med, Inst Basal Med Sci, Oslo, Norway. [Blanch-Hartigan, Danielle] NCI, Bethesda, MD 20892 USA. RP Gulbrandsen, P (reprint author), Akershus Univ Hosp, Res Ctr, HOKH, Mail Drawer 95, N-1478 Lorenskog, Norway. EM pal.gulbrandsen@medisin.uio.no FU Regional Health Enterprise for South-East Norway FX This work was partially funded by the Regional Health Enterprise for South-East Norway. NR 37 TC 10 Z9 11 U1 4 U2 18 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 MAY PY 2013 VL 91 IS 2 BP 180 EP 185 DI 10.1016/j.pec.2012.11.015 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 136AA UT WOS:000318330600008 PM 23414658 ER PT J AU Buchbinder, D Hsieh, L Puthenveetil, G Soni, A Stites, J Huynh, V Kirov, I Neudorf, S Rubin, E Sender, L Torno, L Margolis, D Childs, R Moore, T Nugent, D AF Buchbinder, David Hsieh, Loah Puthenveetil, Geetha Soni, Amit Stites, Jill Huynh, Van Kirov, Ivan Neudorf, Steve Rubin, Elyssa Sender, Leonard Torno, Lilibeth Margolis, David Childs, Richard Moore, Theodore Nugent, Diane TI Successful autologous cord blood transplantation in a child with acquired severe aplastic anemia SO PEDIATRIC TRANSPLANTATION LA English DT Article DE acquired aplastic anemia; cord blood; autologous transplantation ID STEM-CELL TRANSPLANTATION; TERM-FOLLOW-UP; MARROW TRANSPLANTATION; IMMUNOSUPPRESSIVE THERAPY; ANTITHYMOCYTE GLOBULIN; UNRELATED DONORS; CYCLOPHOSPHAMIDE; FLUDARABINE; FAILURE; SAA AB Over 400 cases of pediatric SAA occur annually in the United States. A growing number of children with SAA may have had their stem cells harvested through cord blood collection. We describe a nine-yr-old male with SAA treated successfully with an autologous cord blood transplant following immunoablative chemotherapy. With the increasing number of people cryopreserving autologous cord blood, the use of autologous cord blood in the treatment of SAA might be considered as initial therapy. This case serves to discuss approaches to preparative therapy as well as the potential complications in this growing cohort of patients. C1 [Buchbinder, David; Hsieh, Loah; Puthenveetil, Geetha; Soni, Amit; Stites, Jill; Nugent, Diane] CHOC Childrens Hosp, Div Hematol, Orange, CA 92868 USA. [Huynh, Van; Kirov, Ivan; Neudorf, Steve; Rubin, Elyssa; Sender, Leonard; Torno, Lilibeth] CHOC Childrens Hosp, Div Oncol, Orange, CA 92868 USA. [Margolis, David] Childrens Hosp Wisconsin, Wauwatosa, WI USA. [Childs, Richard] NIH, Bethesda, MD 20892 USA. [Moore, Theodore] Univ Calif Los Angeles, Mattel Childrens Hosp, Div Oncol, Los Angeles, CA USA. RP Buchbinder, D (reprint author), CHOC Childrens Hosp, Div Hematol, 455 S Main St, Orange, CA 92868 USA. EM dbuchbinder@choc.org FU Intramural NIH HHS [Z01 HL002345-07, Z99 HL999999] NR 20 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD MAY PY 2013 VL 17 IS 3 BP E104 EP E107 DI 10.1111/petr.12068 PG 4 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 133CL UT WOS:000318114900006 PM 23464883 ER PT J AU Sun, HZ Fang, ZZ Cao, YF Sun, XY Hong, M AF Sun, Hong-Zhi Fang, Zhong-Ze Cao, Yun-Feng Sun, Xiao-Yu Hong, Mo TI Investigation of the in Vitro Metabolism of Evodiamine: Characterization of Metabolites and Involved Cytochrome P450 Isoforms SO PHYTOTHERAPY RESEARCH LA English DT Article DE evodiamine; cytochrome P450 (CYP); human liver microsomes (HLMs) ID PHARMACOLOGICAL-PROPERTIES; GALENICAL PREPARATION; LIVER MICROSOMES; IDENTIFICATION; RUTAECARPINE; RATS; PHARMACOKINETICS; ALKALOIDS; APOPTOSIS; CELLS AB Evodiamine is the main active alkaloid of Evodia rutaecarpa (E. rutaecarpa) and has been demonstrated to exhibit many pharmacological activities including vasorelaxation, uterotonic action, anoxia and control of body temperature. The present study focused on the metabolism of evodiamine. Human and phenobarbital-induced rat liver microsomal incubation of evodiamine in the presence of NADPH resulted in the formation of five major metabolites (M-1, M-2, M-3, M-4, M-5). Four metabolites (M-1, M-2, M-3 and M-5) were identified to mono-hydroxylated evodiamine and one metabolite (M-4) was identified to be N-demethylated evodiamine. CYP3A4, CYP2C9 and CYP1A2 were identified to be the main CYP isoforms involved in the metabolism of evodiamine in human liver microsomes. Finding new metabolites can help us decipher novel substance basis of efficiency and toxicity. Elucidation of drug metabolizing enzymes will facilitate explaining the individual difference for response to the same drugs or herbs and the potential drugdrug interaction or herbdrug interaction. Taken together, these results are of significance for better understanding the pharmacokinetic behaviour of evodiamine and helpful for clinical application of evodiamine and E. rutaecarpa. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng; Sun, Xiao-Yu; Hong, Mo] Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Peoples R China. [Fang, Zhong-Ze] Liaoning Med Univ, Jinzhou 121001, Peoples R China. [Fang, Zhong-Ze] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Sun, Hong-Zhi; Fang, Zhong-Ze; Cao, Yun-Feng; Sun, Xiao-Yu; Hong, Mo] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Sun, Hong-Zhi; Fang, Zhong-Ze; Cao, Yun-Feng; Sun, Xiao-Yu; Hong, Mo] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. RP Sun, HZ (reprint author), Liaoning Med Univ, Affiliated Hosp 1, Jinzhou 121001, Peoples R China. EM cmushz@163.com NR 20 TC 12 Z9 12 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0951-418X J9 PHYTOTHER RES JI Phytother. Res. PD MAY PY 2013 VL 27 IS 5 BP 705 EP 712 DI 10.1002/ptr.4766 PG 8 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 131XK UT WOS:000318031500011 PM 22767428 ER PT J AU Locatelli-Hoops, S Sheen, FC Zoubak, L Gawrisch, K Yeliseev, AA AF Locatelli-Hoops, Silvia Sheen, Fangmin C. Zoubak, Lioudmila Gawrisch, Klaus Yeliseev, Alexei A. TI Application of Halo Tag technology to expression and purification of cannabinoid receptor CB2 SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE CB2; G protein-coupled receptor; HaloTag technology; Escherichia coli expression; Purification; Surface immobilization ID PROTEIN ALPHA-SUBUNITS; ESCHERICHIA-COLI; BACTERIAL EXPRESSION AB Expression of milligram quantities of functional, stable G protein-coupled receptors (GPCR) for high-resolution structural studies remains a challenging task. The goal of this work was to evaluate the usefulness of the HaloTag system (Promega) for expression and purification of the human cannabinoid receptor CB2, an important target for development of drugs for treatment of immune disorders, inflammation, and pain. Here we investigated expression in Escherichia coli cells of the integral membrane receptor CB2 as a fusion with the 34 kDa HaloTag at N- or C-terminal location, either in the presence or in the absence of the N-terminal maltose-binding protein (MBP). The CB2 was flanked at both ends by the tobacco etch virus (TEV) protease cleavage sites to allow for subsequent removal of expression partners. Expression by induction with either IPTG (in E. coli BL21(DE3) cell cultures) or by auto-induction (in E. coli KRX cells) were compared. While the N-terminal location of the HaloTag resulted in high levels of expression of the fusion CB2, the recombinant receptor was not functional. However, when the HaloTag was placed in the C-terminal location, a fully active receptor was produced irrespective of induction method or bacterial strain used. For purification, the fusion protein was captured onto HaloLink resin in the presence of detergents. Treatment with specific TEV protease released the CB2 upon washing. To our knowledge, this study represents the first example of expression, surface immobilization and purification of a functional GPCR using HaloTag technology. Published by Elsevier Inc. C1 [Locatelli-Hoops, Silvia; Zoubak, Lioudmila; Gawrisch, Klaus; Yeliseev, Alexei A.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Sheen, Fangmin C.] Promega Corp, Madison, WI 53711 USA. RP Yeliseev, AA (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM yeliseeva@mail.nih.gov OI Sheen, Fangmiin/0000-0002-5112-253X FU Intramural Research Program of the NIAAA, NIH FX This work was supported by the Intramural Research Program of the NIAAA, NIH. Authors wish to thank Dr. R. Ghana (Promega Corporation) for gift of materials and helpful suggestions. NR 36 TC 8 Z9 9 U1 3 U2 42 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 EI 1096-0279 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAY PY 2013 VL 89 IS 1 BP 62 EP 72 DI 10.1016/j.pep.2013.02.011 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 132HR UT WOS:000318059000009 PM 23470778 ER PT J AU Pipe, ME Orbach, Y Lamb, ME Abbott, CB Stewart, H AF Pipe, Margaret-Ellen Orbach, Yael Lamb, Michael E. Abbott, Craig B. Stewart, Heather TI Do Case Outcomes Change When Investigative Interviewing Practices Change? SO PSYCHOLOGY PUBLIC POLICY AND LAW LA English DT Article DE structured interview protocols; child abuse; case outcomes; child witnesses ID CHILD SEXUAL-ABUSE; FORENSIC INTERVIEWS; ALLEGED VICTIMS; JUSTICE SYSTEM; CASE FLOW; PROTOCOL; MALTREATMENT; PROSECUTION; PREDICTORS; RESPONSES AB To determine whether the introduction of evidence-based practice for interviewing child witnesses was accompanied by changes in the disposition of cases in which sexual abuse was suspected, we compared cases in which the investigative interviews of 3- to 14-year-old alleged victims were conducted either before (n = 350) or after (n = 410) investigators had been taught to use the NICHD Protocol. Analyses showed that when charges were filed, both pre-Protocol and Protocol interviews were highly (and similarly) likely to yield guilty pleas to one or more counts. However, charges were more likely to be filed when interviewers had been trained to use the Protocol; Protocol interviews were therefore associated with more guilty pleas than non-Protocol interviews. When cases were tried, furthermore, Protocol cases were more likely to yield guilty verdicts. These results point to important implications for policies concerning the investigation of suspected crimes involving young witnesses. C1 [Pipe, Margaret-Ellen; Orbach, Yael] CUNY, Brooklyn Coll, Dept Psychol, New York, NY 10021 USA. [Lamb, Michael E.] Univ Cambridge, Dept Psychol, Cambridge CB2 3RQ, England. [Abbott, Craig B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Stewart, Heather] Childrens Justice Ctr, Salt Lake City, UT USA. RP Lamb, ME (reprint author), Univ Cambridge, Dept Psychol, Free Sch Lane, Cambridge CB2 3RQ, England. EM Mel37@cam.ac.uk NR 60 TC 11 Z9 11 U1 4 U2 26 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1076-8971 J9 PSYCHOL PUBLIC POL L JI Psychol. Public Policy Law PD MAY PY 2013 VL 19 IS 2 BP 179 EP 190 DI 10.1037/a0030312 PG 12 WC Health Policy & Services; Law; Psychology, Multidisciplinary SC Health Care Sciences & Services; Government & Law; Psychology GA 133NU UT WOS:000318146000005 ER PT J AU Gutman, DA Cooper, LAD Hwang, SN Holder, CA Gao, JJ Aurora, TD Dunn, WD Scarpace, L Mikkelsen, T Jain, R Wintermark, M Jilwan, M Raghavan, P Huang, E Clifford, RJ Mongkolwat, P Kleper, V Freymann, J Kirby, J Zinn, PO Moreno, CS Jaffe, C Colen, R Rubin, DL Saltz, J Flanders, A Brat, DJ AF Gutman, David A. Cooper, Lee A. D. Hwang, Scott N. Holder, Chad A. Gao, JingJing Aurora, Tarun D. Dunn, William D., Jr. Scarpace, Lisa Mikkelsen, Tom Jain, Rajan Wintermark, Max Jilwan, Manal Raghavan, Prashant Huang, Erich Clifford, Robert J. Mongkolwat, Pattanasak Kleper, Vladimir Freymann, John Kirby, Justin Zinn, Pascal O. Moreno, Carlos S. Jaffe, Carl Colen, Rivka Rubin, Daniel L. Saltz, Joel Flanders, Adam Brat, Daniel J. TI MR Imaging Predictors of Molecular Profile and Survival: Multi-institutional Study of the TCGA Glioblastoma Data Set SO RADIOLOGY LA English DT Article ID PROGNOSTIC-SIGNIFICANCE; GENE-EXPRESSION; MULTIFORME AB Purpose: To conduct a comprehensive analysis of radiologist-made assessments of glioblastoma (GBM) tumor size and composition by using a community-developed controlled terminology of magnetic resonance (MR) imaging visual features as they relate to genetic alterations, gene expression class, and patient survival. Materials and Methods: Because all study patients had been previously deidentified by the Cancer Genome Atlas (TCGA), a publicly available data set that contains no linkage to patient identifiers and that is HIPAA compliant, no institutional review board approval was required. Presurgical MR images of 75 patients with GBM with genetic data in the TCGA portal were rated by three neuroradiologists for size, location, and tumor morphology by using a standardized feature set. Interrater agreements were analyzed by using the Krippendorff alpha statistic and intraclass correlation coefficient. Associations between survival, tumor size, and morphology were determined by using multivariate Cox regression models; associations between imaging features and genomics were studied by using the Fisher exact test. Results: Interrater analysis showed significant agreement in terms of contrast material enhancement, nonenhancement, necrosis, edema, and size variables. Contrast-enhanced tumor volume and longest axis length of tumor were strongly associated with poor survival (respectively, hazard ratio: 8.84, P = .0253, and hazard ratio: 1.02, P = .00973), even after adjusting for Karnofsky performance score (P = .0208). Proneural class GBM had significantly lower levels of contrast enhancement (P = .02) than other subtypes, while mesenchymal GBM showed lower levels of nonenhanced tumor (P < .01). Conclusion: This analysis demonstrates a method for consistent image feature annotation capable of reproducibly characterizing brain tumors; this study shows that radiologists' estimations of macroscopic imaging features can be combined with genetic alterations and gene expression subtypes to provide deeper insight to the underlying biologic properties of GBM subsets. (C) RSNA, 2013 C1 [Gutman, David A.; Cooper, Lee A. D.; Hwang, Scott N.; Holder, Chad A.; Gao, JingJing; Aurora, Tarun D.; Dunn, William D., Jr.; Moreno, Carlos S.; Saltz, Joel; Brat, Daniel J.] Emory Univ Hosp, Dept Biomed Informat, Atlanta, GA 30322 USA. [Scarpace, Lisa; Mikkelsen, Tom; Jain, Rajan] Henry Ford Hosp, Hermelin Brain Tumor Ctr, Detroit, MI 48202 USA. [Wintermark, Max; Jilwan, Manal; Raghavan, Prashant] Univ Virginia, Dept Radiol, Charlottesville, VA USA. [Huang, Erich; Clifford, Robert J.] NCI, Bethesda, MD 20892 USA. [Mongkolwat, Pattanasak; Kleper, Vladimir] Northwestern Univ, Dept Radiol, Chicago, IL 60611 USA. [Freymann, John; Kirby, Justin] SAIC Frederick Inc, Frederick, MD USA. [Zinn, Pascal O.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Moreno, Carlos S.; Brat, Daniel J.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Jaffe, Carl] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Zinn, Pascal O.; Colen, Rivka] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Flanders, Adam] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Rubin, Daniel L.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. RP Gutman, DA (reprint author), Emory Univ Hosp, Dept Biomed Informat, 36 Eagle Row,Room 572 PAIS, Atlanta, GA 30322 USA. EM dgutman@emory.edu RI Huang, Erich/B-1894-2008; Moreno, Carlos/B-3863-2009; OI Huang, Erich/0000-0001-5547-9408; Moreno, Carlos/0000-0002-5582-0028; Hwang, Scott/0000-0002-6496-2087; Wintermark, Max/0000-0002-6726-3951 FU National Institutes of Health [HHSN261200800001E]; GE Healthcare; Philips Healthcare; GE Medical Systems FX D.A.G. No relevant conflicts of interest to disclose. L.A.D.C. No relevant conflicts of interest to disclose. S.N.H. No relevant conflicts of interest to disclose. C.A.H. No relevant conflicts of interest to disclose. J.J.G. No relevant conflicts of interest to disclose. T.D.A. No relevant conflicts of interest to disclose. W.D.D. No relevant conflicts of interest to disclose. L.S. No relevant conflicts of interest to disclose. T.M. No relevant conflicts of interest to disclose. R.J. No relevant conflicts of interest to disclose. M.W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: grants to institution from GE Healthcare and Philips Healthcare. Other relationships: none to disclose. M.J. No relevant conflicts of interest to disclose. P.R. No relevant conflicts of interest to disclose. E.H. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: former stockholder GE and Johnson and Johnson. Other relationships: none to disclose. R.J.C. No relevant conflicts of interest to disclose. P.M. No relevant conflicts of interest to disclose. V K. No relevant conflicts of interest to disclose. J.F. No relevant conflicts of interest to disclose. J.K. No relevant conflicts of interest to disclose. P.O.Z. No relevant conflicts of interest to disclose. C.S.M. No relevant conflicts of interest to disclose. C.J. No relevant conflicts of interest to disclose. R.C. No relevant conflicts of interest to disclose. D.R. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: instution grants from GE Medical Systems. Other relationships: none to disclose. J.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: Board membership, Appistry; consultancy, Ceadars-Sinai; stock/stock options, Appistry. Other relationships: none to disclose. A.F. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: textbook royalties from LWW. Other relationships: none to disclose. D.J.B. No relevant conflicts of interest to disclose.; This research was supported by the National Institutes of Health (grant HHSN261200800001E). NR 27 TC 92 Z9 94 U1 1 U2 19 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAY PY 2013 VL 267 IS 2 BP 560 EP 569 DI 10.1148/radiol.13120118 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 132LM UT WOS:000318069700028 PM 23392431 ER PT J AU Steiner, AZ Long, DL Herring, AH Kesner, JS Meadows, JW Baird, DD AF Steiner, Anne Z. Long, D. Leann Herring, Amy H. Kesner, James S. Meadows, Juliana W. Baird, Donna D. TI Urinary Follicle-Stimulating Hormone as a Measure of Natural Fertility in a Community Cohort SO REPRODUCTIVE SCIENCES LA English DT Article DE fecundability; fertility; follicle-stimulating hormone; ovarian reserve; urine ID IN-VITRO FERTILIZATION; MENSTRUAL-CYCLE; OVARIAN RESERVE; LUTEINIZING-HORMONE; OVULATORY WOMEN; BASAL; TIME; CONCEPTION; PREGNANCY; FSH AB High serum follicle-stimulating hormone (FSH) levels have been associated with diminished ovarian reserve; however, the association between high urinary FSH and reduced natural fertility has yet to be established. We sought to characterize the relationship between a single or multiple measurements of early follicular phase urinary FSH and fertility. Women (n = 209), 30 to 44 years old with no history of infertility, who had been trying to conceive for less than 3 months, provided early follicular phase urine. Participants subsequently kept a diary to record bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. A subset of women (N = 95) collected urine on cycle day 3 for up to 6 cycles. Urine was analyzed for FSH and creatinine (cr) corrected. Proportional hazard models were used to calculate fecundability ratios (FRs). Urinary FSH levels across cycles from the same woman were highly correlated (adjusted intraclass correlation - .77); within-woman variance was 3-fold lower than variance among women. Women with an initial urinary FSH level <7 mIU/mg cr exhibited a nonsignificant reduction in the probability of pregnancy (adjusted FR 0.71, 95% confidence interval [CI]: 0.45-1.13), as did women with elevated urinary FSH (>= 12 mIU/mg cr; adjusted FR 0.78, 95% CI: 0.46-1.32). Using the most recent or maximum urinary FSH value did not strengthen the association. In the general population, urinary FSH levels appear to be nonlinearly associated with fertility; however, broad CIs indicate a lack of statistical significance. Repetitive testing appears to be of little benefit. C1 [Steiner, Anne Z.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC 27599 USA. [Long, D. Leann; Herring, Amy H.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA. [Kesner, James S.; Meadows, Juliana W.] NIOSH, Div Appl Res & Technol, Cincinnati, OH 45226 USA. [Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Steiner, AZ (reprint author), Univ N Carolina, Dept Obstet & Gynecol, CB 7570,4001 Old Clin Bldg, Chapel Hill, NC 27599 USA. EM asteiner@med.unc.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU NIH, National Institute of Environmental Health Sciences; NICHD/NIH [R21HD060229, K12HD050113]; NIEHS/NIH [T32ES007018] FX Drs Allen Wilcox and Carmen Williams provided helpful comments on an earlier draft of this manuscript. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ie, support for coauthor D.B.).; The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the NICHD/NIH (grant number R21HD060229 and K12HD050113 [UNC WRHR]) and NIEHS/NIH (grant number T32ES007018). NR 37 TC 4 Z9 4 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAY PY 2013 VL 20 IS 5 BP 549 EP 556 DI 10.1177/1933719112459226 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 131KF UT WOS:000317991200007 PM 23171685 ER PT J AU Kington, RS AF Kington, Raynard S. TI On Being an "African American Scientist" SO SCIENTIST LA English DT Editorial Material C1 [Kington, Raynard S.] Grinnell Coll, Grinnell, IA 50112 USA. [Kington, Raynard S.] Natl Inst Hlth, Bethesda, MD 20892 USA. [Kington, Raynard S.] Ctr Dis Control & Prevent, Atlanta, GA USA. RP Kington, RS (reprint author), Grinnell Coll, Grinnell, IA 50112 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SCIENTIST INC PI PHILADELPHIA PA 400 MARKET ST, STE 1250, PHILADELPHIA, PA 19106 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD MAY PY 2013 VL 27 IS 5 BP 28 EP 28 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 135VO UT WOS:000318319000007 ER PT J AU DeCherney, AH AF DeCherney, Alan H. TI Health Policy in Reproduction Preface SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Editorial Material C1 [DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP DeCherney, AH (reprint author), NICHHD, Reprod Biol & Med Branch, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM decherna@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD MAY PY 2013 VL 31 IS 3 BP 187 EP 187 DI 10.1055/s-0033-1336598 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 130ZM UT WOS:000317959800002 PM 23609148 ER PT J AU Brezina, PR Shah, AA Myers, ER Huang, A DeCherney, AH AF Brezina, Paul R. Shah, Anish A. Myers, Evan R. Huang, Andy DeCherney, Alan H. TI How Obamacare Will Impact Reproductive Health SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE patient protection and affordable care; Obamacare; health care; reproductive; infertility ID ACCOUNTABLE CARE ORGANIZATIONS; REFORM; INSURANCE AB For many years, health care delivery in the United States was accomplished through a complicated and evolving series of publicly and privately available insurance programs. In recent years, the increasing cost of health care as well as the relatively large number of individuals without any health care insurance coverage has prompted repeated attempts to modify or overhaul the current health care delivery paradigm. The largest legislative change to this system occurred on March 23, 2010, when President Barack Obama signed into law the Patient Protection and Affordable Care Act (PPACA). The PPACA is a multifaceted and sweeping piece of legislation. The law introduces a myriad number of changes into both public and private health insurance. Understanding the law, its implications, and how to navigate through these changes is essential to provide high-quality health care to patients. Although the law or parts of it are still at risk of being modified either through judicial or political action, it is important to recognize the current aspects of the law to understand any future modifications. Providing health care coverage in the United States is sure to be as it has always been: a constantly changing and evolving set of private and public policies that carry with them significant complexities and challenges. Health care providers must constantly strive to maximize access to and quality of medical care in whatever paradigm evolves in the future. C1 [Brezina, Paul R.] Fertil Associates, Memphis, TN 38120 USA. [Shah, Anish A.] Duke Univ, Sch Med, Dept Gynecol & Obstet, Div Reprod Endocrinol & Infertil,Duke Fertil Ctr, Durham, NC USA. [Myers, Evan R.] Duke Univ, Sch Med, Dept Gynecol & Obstet, Div Clin & Epidemiol Res, Durham, NC USA. [Huang, Andy] Reprod Partners Med Grp Inc, Beverly Hills, CA USA. [DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Reprod Endocrinol & Infertil, Dept Gynecol & Obstet, NIH, Bethesda, MD USA. RP Brezina, PR (reprint author), Fertil Associates, 80 Humphreys Ctr,Suite 307, Memphis, TN 38120 USA. EM pbrezina@fertilitymemphis.com FU Agency for Healthcare Research and Quality [T32 HS 019490] FX Anish A. Shah is funded by a grant from the Agency for Healthcare Research and Quality (T32 HS 019490). The others authors have nothing to disclose. NR 55 TC 3 Z9 3 U1 2 U2 32 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD MAY PY 2013 VL 31 IS 3 BP 189 EP 197 DI 10.1055/s-0033-1336599 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 130ZM UT WOS:000317959800003 PM 23609149 ER PT J AU Hill, MJ DeCherney, AH AF Hill, Micah J. DeCherney, Alan H. TI Negotiation for Physicians SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE negotiation; conflict resolution AB Physicians are involved in negotiations on a daily basis. Interactions with patients, support staff, nurses, fellow physicians, administrators, lawyers, and third parties all can occur within the context of negotiation. This article reviews the basic principles of negotiation and negotiation styles, models, and practical tools. C1 [Hill, Micah J.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Hill, MJ (reprint author), CRC RM, NIH, 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM hillmicah@mail.nih.gov FU Intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH FX This research was supported, in part, by Intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH. NR 2 TC 0 Z9 0 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD MAY PY 2013 VL 31 IS 3 BP 215 EP 218 DI 10.1055/s-0033-1336603 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 130ZM UT WOS:000317959800007 PM 23609153 ER PT J AU Cleveland, SM Smith, S Tripathi, R Mathias, EM Goodings, C Elliott, N Peng, DF El-Rifai, W Yi, DJ Chen, X Li, LQ Mullighan, C Downing, JR Love, P Dave, UP AF Cleveland, Susan M. Smith, Stephen Tripathi, Rati Mathias, Elizabeth M. Goodings, Charnise Elliott, Natalina Peng, Dunfa El-Rifai, Wael Yi, Dajun Chen, Xi Li, Liqi Mullighan, Charles Downing, James R. Love, Paul Dave, Utpal P. TI Lmo2 Induces Hematopoietic Stem Cell-Like Features in T-Cell Progenitor Cells Prior to Leukemia SO STEM CELLS LA English DT Article DE T cells; Hematopoiesis; Stem cells; Leukemia ID ACUTE LYMPHOBLASTIC-LEUKEMIA; LIM-PROTEIN LMO2; TRANSGENIC MICE; GENE-THERAPY; ALPHA-BETA; FORMS PART; RNA-SEQ; EXPRESSION; PROLIFERATION; DOMAIN AB LIM domain only 2 (Lmo2) is frequently deregulated in sporadic and gene therapy-induced acute T-cell lymphoblastic leukemia (T-ALL) where its overexpression is an important initiating mutational event. In transgenic and retroviral mouse models, Lmo2 expression can be enforced in multiple hematopoietic lineages but leukemia only arises from T cells. These data suggest that Lmo2 confers clonal growth advantage in T-cell progenitors. We analyzed proliferation, differentiation, and cell death in CD2-Lmo2 transgenic thymic progenitor cells to understand the cellular effects of enforced Lmo2 expression. Most impres-sively, Lmo2 transgenic T-cell progenitor cells were blocked in differentiation, quiescent, and immortalized in vitro on OP9-DL1 stromal cells. These cellular effects were concordant with a transcriptional signature in Lmo2 transgenic T-cell progenitor cells that is also present in hematopoietic stem cells (HSCs) and early T-cell precursor ALL. These results are significant in light of the crucial role of Lmo2 in the maintenance of the HSC. The cellular effects and transcriptional effects have implications for LMO2-dependent leukemogenesis and the treatment of LMO2-induced T-ALL. STEM CELLS 2013;31:882-894 C1 [Cleveland, Susan M.; Smith, Stephen; Tripathi, Rati; Mathias, Elizabeth M.; Goodings, Charnise; Elliott, Natalina; Dave, Utpal P.] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN 37232 USA. [Peng, Dunfa; El-Rifai, Wael] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37232 USA. [Yi, Dajun] Vanderbilt Univ, Med Ctr, Div Med Genet, Nashville, TN 37232 USA. [Chen, Xi] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37232 USA. [Tripathi, Rati] BIT, Dept Biotechnol, Ranchi, Bihar, India. [Li, Liqi; Love, Paul] NIH, Bethesda, MD 20892 USA. [Mullighan, Charles; Downing, James R.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Dave, UP (reprint author), Vanderbilt Univ, Dept Med, Med Ctr, Div Hematol Oncol,Tennessee Valley Healthcare Sys, 777 Preston Res Bldg, Nashville, TN 37232 USA. EM utpal.dave@vanderbilt.edu OI Mullighan, Charles/0000-0002-1871-1850 FU Vanderbilt Ingram Cancer Center [P30 CA68485]; Vanderbilt Digestive Disease Research Center [DK058404]; NIH [K08HL089403]; Leukemia & Lymphoma Society; Monforton family grant; T.J. Martell Foundation; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX We thank Dr. Juan Carlos Zuniga-Pflucker for OP9-DL1 and OP9-GFP cells and Dr. Monica Justice for MIG-Hhex plasmid. We thank Drs. M. Koury, S. Hiebert, and S. Zinkel for critically reviewing the manuscript and for helpful discussions. We thank Dr. Kevin Weller and the Flow Cytometry Core of Vanderbilt University. The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). This work was supported by NIH K08HL089403, the Leukemia & Lymphoma Society, the Vanderbilt Ingram Cancer Center (P30 CA68485), Monforton family grant, and the T.J. Martell Foundation (U. P. D.). This work was also supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. NR 52 TC 19 Z9 19 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2013 VL 31 IS 5 BP 882 EP 894 DI 10.1002/stem.1345 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 131RV UT WOS:000318014100006 PM 23378057 ER PT J AU Shaltouki, A Peng, J Liu, QY Rao, MS Zeng, XM AF Shaltouki, Atossa Peng, Jun Liu, Qiuyue Rao, Mahendra S. Zeng, Xianmin TI Efficient Generation of Astrocytes from Human Pluripotent Stem Cells in Defined Conditions SO STEM CELLS LA English DT Article DE Embryonic stem cells; Induced pluripotent stem cells; Astrocytes; Xenotransplantation; Differentiation; Neural stem cell ID GLIAL-RESTRICTED PRECURSORS; IN-VITRO DIFFERENTIATION; CENTRAL-NERVOUS-SYSTEM; DEVELOPING SPINAL-CORD; ADULT-RAT-BRAIN; NEURAL STEM; DOPAMINERGIC-NEURONS; PROGENITOR CELLS; GENE-EXPRESSION; RADIAL GLIA AB Astrocytes can be generated from various tissue sources including human pluripotent stem cells (PSC). In this manuscript, we describe a chemically defined xeno-free medium culture system for rapidly generating astrocytes from neural stem cells derived from PSC. We show that astrocyte development in vitro, mimics normal development in vivo, and also passes through a CD44(+) astrocyte precursor stage. Astrocytes generated by our method display similar gene expression patterns, morphological characteristics and functional properties to primary astrocytes, and they survive and integrate after xenotransplantation. Whole genome expression profiling of astrocyte differentiation was performed at several time points of differentiation, and the results indicate the importance of known regulators and identify potential novel regulators and stage-specific lineage markers. STEM CELLS 2013;31:941-952 C1 [Shaltouki, Atossa; Peng, Jun; Liu, Qiuyue; Zeng, Xianmin] Buck Inst Age Res, Novato, CA 94945 USA. [Rao, Mahendra S.] NIH, Natl Ctr Regenerat Med, Bethesda, MD 20892 USA. RP Zeng, XM (reprint author), Buck Inst Age Res, Novato, CA 94945 USA. EM xzeng@buckinstitute.org FU California Institute for Regenerative Medicine Grants [TR-01856, CL1-00501] FX This work was supported in part by California Institute for Regenerative Medicine Grants TR-01856 and CL1-00501. We are thankful to Dr. Andrzej Swistowski (XCell Science Inc.) for providing dopaminergic neurons for coculture experiment. We thank Steven S. Spusta for technical assistance with the flow cytometry and Justine Montoya-Sack for her assistance with the cell counting. NR 98 TC 40 Z9 40 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2013 VL 31 IS 5 BP 941 EP 952 DI 10.1002/stem.1334 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 131RV UT WOS:000318014100011 PM 23341249 ER PT J AU Landis, S Fisher, M AF Landis, Story Fisher, Marc TI Why the United States Needs a Network for Stroke Clinical Trials SO STROKE LA English DT Editorial Material DE clinical trials; comparative effectiveness; coordination; network; policy C1 [Landis, Story] NINDS, NIH, Bethesda, MD 20892 USA. [Fisher, Marc] Circulat Editorial Off, Boston, MA USA. RP Landis, S (reprint author), NINDS, NIH, 31 Ctr Dr,Suite 8A52, Bethesda, MD 20892 USA. EM LandisS@ninds.nih.gov NR 1 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2013 VL 44 IS 5 BP 1217 EP 1218 DI 10.1161/STROKEAHA.113.001534 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 131WZ UT WOS:000318030000019 PM 23579592 ER PT J AU Markus, HS Makela, KM Bevan, S Raitoharju, E Oksala, N Bis, JC O'Donnell, C Hainsworth, A Lehtimaki, T AF Markus, Hugh S. Makela, Kari-Matti Bevan, Steve Raitoharju, Emma Oksala, Niku Bis, Joshua C. O'Donnell, Chris Hainsworth, Atticus Lehtimaki, Terho TI Evidence HDAC9 Genetic Variant Associated With Ischemic Stroke Increases Risk via Promoting Carotid Atherosclerosis SO STROKE LA English DT Article DE atherosclerosis; carotid stenosis; expression experiments; genetics; intima-media thickness ID GENOME-WIDE ASSOCIATION; INTIMA-MEDIA THICKNESS; HISTONE DEACETYLASES; METAANALYSIS; PREDICTION AB Background and Purpose-A novel association between a single nucleotide polymorphism on chromosome 7p21.1 and large-vessel ischemic stroke was recently identified. The most likely underlying gene is histone deacetylase 9 (HDAC9). The mechanism by which HDAC9 increases stroke risk is not clear; both vascular and neuronal mechanisms have been proposed. Methods-We determined whether the lead single nucleotide polymorphisms were associated with asymptomatic carotid plaque (N=25 179) and carotid intima-media thickness (N=31 210) detected by carotid ultrasound in a meta-analysis of population-based and community cohorts. Immunohistochemistry was used to determine whether HDAC9 was expressed in healthy human cerebral and systemic arteries. In the Tampere Vascular Study, we determined whether HDAC9 mRNA expression was altered in carotid (N=29), abdominal aortic (N=15), and femoral (N=24) atherosclerotic plaques compared with control (left internal thoracic, N=28) arteries. Results-Both single nucleotide polymorphisms (rs11984041 and rs2107595) were associated with common carotid intima-media thickness (rs2107595; P=0.0018) and with presence of carotid plaque (rs2107595; P=0.0022). In both cerebral and systemic arteries, HDAC9 labeling was seen in nuclei and cytoplasm of vascular smooth muscle cells, and in endothelial cells. HDAC9 expression was upregulated in carotid plaques compared with left internal thoracic controls (P=0.00000103). It was also upregulated in aortic and femoral plaques compared with controls, with mRNA expression increased in carotid compared with femoral plaques (P=0.0038). Conclusions-Our results are consistent with the 7p21.1 association acting via promoting atherosclerosis, and consistent with alterations in HDAC9 expression mediating this increased risk. Further studies in experimental models are required to confirm this link. (Stroke. 2013;44:1220-1225.) C1 [Markus, Hugh S.; Bevan, Steve; Hainsworth, Atticus] St Georges Univ London, Stroke & Dementia Res Ctr, London SW19 3QZ, England. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Tampere Univ Hosp, Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Makela, Kari-Matti; Raitoharju, Emma; Oksala, Niku; Lehtimaki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Oksala, Niku] Tampere Univ, Dept Surg, Div Vasc Surg, FIN-33101 Tampere, Finland. [Oksala, Niku] Tampere Univ Hosp, Tampere, Finland. [Bis, Joshua C.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [O'Donnell, Chris] NHLBI, Framingham, MA USA. [O'Donnell, Chris] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Markus, HS (reprint author), St Georges Univ London, Stroke & Dementia Res Ctr, London SW19 3QZ, England. EM hmarkus@sgul.ac.uk OI Bevan, Steve/0000-0003-0490-6830 FU European Union [201668]; Academy of Finland, Tampere, University Hospital Medical Fund [9M048, 9N035]; Finnish Foundation of Cardiovascular Research; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Action Medical Research and Neuroscience Research Foundation FX This study was supported in part by European Union 7th Framework Program funding for the AtheroRemo project [201668]. Tampere Vascular study has been supported by the Academy of Finland, Tampere, University Hospital Medical Fund (grant 9M048 and 9N035 for TeLeht), the Finnish Foundation of Cardiovascular Research, the Tampere Tuberculosis Foundation, and the Emil Aaltonen Foundation. Dr Hainsworth is supported by Action Medical Research and Neuroscience Research Foundation. NR 21 TC 27 Z9 29 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2013 VL 44 IS 5 BP 1220 EP + DI 10.1161/STROKEAHA.111.000217 PG 11 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 131WZ UT WOS:000318030000020 PM 23449258 ER PT J AU Howard, G Cushman, M Howard, VJ Kissela, BM Kleindorfer, DO Moy, CS Switzer, J Woo, D AF Howard, George Cushman, Mary Howard, Virginia J. Kissela, Brett M. Kleindorfer, Dawn O. Moy, Claudia S. Switzer, Jeffery Woo, Daniel TI Risk Factors for Intracerebral Hemorrhage The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study SO STROKE LA English DT Article DE black race; hypertension; intracerebral hemorrhage; risk factors ID METAANALYSIS; CHOLESTEROL; POPULATION; ASPIRIN; TRIALS AB Background and Purpose-Risk factors for intracerebral hemorrhage (ICH) have been largely identified in case-control studies, with few longitudinal studies available. Methods-Predictors of incident ICH among 27 760 black and white participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study were assessed. Results-There were 62 incident ICH events during an average follow-up of 5.7 years. The increase in risk with age differed substantially between blacks and whites (P = 0.006), with a 2.25-fold (95% confidence interval, 1.63-3.12) increase per decade in whites, but no age association with ICH risk in blacks (hazard ratio = 1.09; 95% confidence interval, 0.70-1.68). We observed increased risk among men, those with higher systolic blood pressure, and warfarin users. Conclusions-The racial differences in the impact of age contributed to a risk of ICH that was > 5 times higher for blacks than whites at age 45, but only about one third as great by age 85. Confirming findings from other studies, men participants with elevated systolic blood pressure and warfarin users were also at greater risk. The contributors to the racial differences in ICH risk require additional investigation. (Stroke. 2013;44:1282-1287.) C1 [Howard, George] UAB Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Howard, Virginia J.] UAB Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Kissela, Brett M.; Kleindorfer, Dawn O.; Woo, Daniel] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. [Moy, Claudia S.] NINDS, Bethesda, MD 20892 USA. [Switzer, Jeffery] Georgia Hlth Sci Univ, Dept Neurol, Augusta, GA USA. RP Howard, G (reprint author), UAB Sch Publ Hlth, Dept Biostat, 1665 Univ Blvd, Birmingham, AL 35294 USA. EM ghoward@uab.edu OI Kissela, Brett/0000-0002-9773-4013 FU National Institutes of Health (National Institute of Neurological Disorders and Stroke cooperative agreement) [U01 NS041588] FX This research was supported by a grant from the National Institutes of Health (National Institute of Neurological Disorders and Stroke cooperative agreement U01 NS041588) to Dr Howard. NR 20 TC 17 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2013 VL 44 IS 5 BP 1282 EP 1287 DI 10.1161/STROKEAHA.111.000529 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 131WZ UT WOS:000318030000030 PM 23532012 ER PT J AU Kesarwala, AH Grover, S Rengan, R AF Kesarwala, Aparna H. Grover, Surbhi Rengan, Ramesh TI Role of particle beam therapy in a trimodality approach to locally advanced non-small cell lung cancer SO THORACIC CANCER LA English DT Review DE NSCLC; particle beam radiotherapy; trimodality therapy ID ACCELERATED RADIOTHERAPY CHART; RANDOMIZED MULTICENTER TRIAL; PREOPERATIVE CHEMOTHERAPY; SURGICAL RESECTION; PHASE-II; CONVENTIONAL RADIOTHERAPY; INDUCTION CHEMORADIATION; NEOADJUVANT THERAPY; RADIATION-THERAPY; SURGERY AB Lung cancer accounts for nearly one-fifth of all cancer deaths worldwide and is the most common cause of cancer-related death in the United States. Outcomes for locally advanced non-small cell lung cancer remain extremely poor with regards to both local control and overall survival. Modest gains in local control were obtained with the incorporation of multimodality treatment, including preoperative chemotherapy followed by surgical resection; combination chemoradiotherapy also improved survival, secondary to improved local control. While the natural progression to trimodality therapy resulted in superior local control, it did not translate to improved overall survival, secondary to increased toxicity. The additional morbidity is likely from radiation toxicity, the minimization of which will be crucial to the future success of trimodality therapy. One strategy to decrease toxicity is to utilize charged particles, such as protons, which deposit a high dose at the Bragg peak with a minimal dose beyond the peak, thereby reducing the dose to distal normal tissues. Trimodality therapy incorporating preoperative proton radiation therapy and chemotherapy, followed by surgery, is currently being evaluated as a potential strategy to achieve improved local control and overall survival in locally advanced non-small cell lung cancer. C1 [Kesarwala, Aparna H.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Grover, Surbhi; Rengan, Ramesh] Univ Penn, Perelman Sch Med, Perelman Ctr Adv Med, Philadelphia, PA 19104 USA. RP Rengan, R (reprint author), Perelman Sch Med, Dept Radiat Oncol, TRC 2 West,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM rengan@uphs.upenn.edu NR 38 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-7706 EI 1759-7714 J9 THORAC CANCER JI Thorac. Cancer PD MAY PY 2013 VL 4 IS 2 BP 95 EP 101 DI 10.1111/j.1759-7714.2012.00174.x PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 132XO UT WOS:000318102200002 ER PT J AU Savvides, P Nagaiah, G Lavertu, P Fu, PF Wright, JJ Chapman, R Wasman, J Dowlati, A Remick, SC AF Savvides, Panayiotis Nagaiah, Govardhanan Lavertu, Pierre Fu, Pingfu Wright, John J. Chapman, Robert Wasman, Jay Dowlati, Afshin Remick, Scot C. TI Phase II Trial of Sorafenib in Patients with Advanced Anaplastic Carcinoma of the Thyroid SO THYROID LA English DT Article ID CLINICAL-TRIALS; CANCER; PATHOGENESIS; THERAPY; BIOLOGY; GROWTH; BRAF AB Background: Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. Methods: The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. Results: Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. Conclusion: Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable. C1 [Savvides, Panayiotis; Lavertu, Pierre; Fu, Pingfu; Wasman, Jay; Dowlati, Afshin] Univ Hosp, Seidman Canc Ctr, Div Hematol Oncol, Cleveland, OH USA. [Savvides, Panayiotis; Lavertu, Pierre; Fu, Pingfu; Wasman, Jay; Dowlati, Afshin] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Nagaiah, Govardhanan; Remick, Scot C.] W Virginia Univ, Mary Babb Randolph Canc Ctr, Div Hematol Oncol, Morgantown, WV 26506 USA. [Wright, John J.] NCI, Canc Therapy & Evaluat Program, Bethesda, MD 20892 USA. [Chapman, Robert] Henry Ford Hosp Hlth Syst, Div Hematol Oncol, Detroit, MI USA. RP Dowlati, A (reprint author), Univ Hosp Seidman Canc Ctr, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM afshin.dowlati@case.edu FU National Institutes of Health [U01CA62502] FX This study was supported by National Institutes of Health Grant No. U01CA62502 and ClinicalTrials.gov Identifier No. NCT00126568. NR 19 TC 58 Z9 61 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD MAY PY 2013 VL 23 IS 5 BP 600 EP 604 DI 10.1089/thy.2012.0103 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 134OG UT WOS:000318220700010 PM 23113752 ER PT J AU Patel, AJ Wesley, R Leitman, SF Bryant, BJ AF Patel, A. J. Wesley, R. Leitman, S. F. Bryant, B. J. TI Capillary versus venous haemoglobin determination in the assessment of healthy blood donors SO VOX SANGUINIS LA English DT Article DE blood donor deferrals; capillary haemoglobin determination; haemoglobin screening of blood donors; handedness; venous haemoglobin determination ID DIFFERENT QUANTITATIVE METHODS; SCREENING METHODS; WHOLE-BLOOD; HEMOCUE; PARAMETERS; SAMPLES; ANEMIA; ADULTS AB Background and Objectives To determine the accuracy of fingerstick haemoglobin assessment in blood donors, the performance of a portable haemoglobinometer (HemoCue Hb 201+) was prospectively compared with that of an automated haematology analyzer (Cell-Dyn 4000). Haemoglobin values obtained by the latter were used as the true' result. Material and Methods Capillary fingerstick samples were assayed by HemoCue in 150 donors. Fingerstick samples from two sites, one on each hand, were obtained from a subset of 50 subjects. Concurrent venous samples were tested using both HemoCue and Cell-Dyn devices. Results Capillary haemoglobin values (HemoCue) were significantly greater than venous haemoglobin values (HemoCue), which in turn were significantly greater than venous haemoglobin values by Cell-Dyn (mean +/- SD: 14 center dot 05 +/- 1 center dot 51, 13 center dot 89 +/- 1 center dot 31, 13 center dot 62 +/- 1 center dot 23, respectively; P<0 center dot 01 for all comparisons among groups). Nine donors (6%) passed haemoglobin screening criteria (12 center dot 5g/dl) by capillary HemoCue, but were deferred by Cell-Dyn values (false-pass). Five donors (3%) were deferred by capillary sampling, but passed by Cell-Dyn (false-fail). Substantial variability in repeated fingerstick HemoCue results was seen (mean haemoglobin 13 center dot 72 vs. 13 center dot 70g/dl, absolute mean difference between paired samples 0 center dot 76g/dl). Hand dominance was not a factor. Conclusions Capillary samples assessed via a portable device yielded higher haemoglobin values than venous samples assessed on an automated analyzer. False-pass and false-fail rates were low and acceptable in the donor screening setting, with true' values not differing by a clinically significant degree from threshold values used to assess acceptability for blood donation. C1 [Patel, A. J.; Leitman, S. F.; Bryant, B. J.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Patel, A. J.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA. [Wesley, R.] NIH, Ctr Clin, Dept Biostat Serv, Bethesda, MD 20892 USA. [Bryant, B. J.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA. RP Bryant, BJ (reprint author), Univ Texas Med Branch, Dept Pathol, Blood Bank Div, 301 Univ Blvd,Route 0717, Galveston, TX 77555 USA. EM bbryant@utmb.edu FU Intramural NIH HHS [Z99 CL999999] NR 31 TC 16 Z9 17 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PD MAY PY 2013 VL 104 IS 4 BP 317 EP 323 DI 10.1111/vox.12006 PG 7 WC Hematology SC Hematology GA 133DV UT WOS:000318118500005 PM 23294266 ER PT J AU Folio, LR Choi, MM Solomon, JM Schaub, NP AF Folio, Les R. Choi, Michael M. Solomon, Jeffrey M. Schaub, Nicholas P. TI Automated Registration, Segmentation, and Measurement of Metastatic Melanoma Tumors in Serial CT Scans SO ACADEMIC RADIOLOGY LA English DT Article DE Registration; segmentation; measurement; quantitative CT; RECIST ID SOLID TUMORS; RESPONSE ASSESSMENT; IMAGE REGISTRATION; THORACIC CT; CRITERIA; CHEMOTHERAPY; VOLUMETRY; LYMPHOMA; EVALUATE; LESIONS AB Objectives: Our goal was to evaluate a new software capability that integrates registration, segmentation and tumor measurement across serial exams within a picture archiving communication system (PACS) to expedite tumor measurement. Materials and Methods: Patients treated under institutional review board-approved protocols for metastatic melanoma were retrospectively reviewed. Of the 19 included patients, five were male, the median age was 43.2, and all received treatment using an adoptive cell therapy. Seventy-one lung, liver, and subcutaneous tumors were manually measured using RECIST (Response Evaluation Criteria In Solid Tumors) criteria before therapy (baseline computed tomography [CT]) and within 3 months after therapy (follow-up CT). We performed semiautomated registration, segmentation, and RECIST measurements at both time points within PACS (Carestream Health, Rochester, NY). We compared manual and software-generated RECIST measurements using Bland-Altman plots. Results: The median manually measured RECIST diameter for all baseline tumors was 2.1 (1.0-6.2) cm. The refined registration function identified 70/71 (98.6%) tumors on the follow-up CT. On the baseline CT, all 21 liver, 27/32 (84%) lung, and 10/18 (55%) subcutaneous tumors completed segmentation. On the follow-up CT, 19/21 (90%) liver, 21/27 (78%) lung, and 8/10 (80%) subcutaneous tumors completed segmentation. The Bland-Altman plot demonstrated a 95% confidence interval of +/- 0.7 cm when comparing the software-generated and manual RECIST measurements. Conclusions: The PACS software performed semiautomated baseline tumor measurements and fully automated follow-up tumor measurements in a majority of lung, liver, and subcutaneous tumors. In our patients, semiautomated metastatic tumor measurement did not obviate the need for physician oversight due to disease and treatment-related factors. C1 [Folio, Les R.; Solomon, Jeffrey M.] NIH, Bethesda, MD 20892 USA. [Choi, Michael M.] Thomas Jefferson High Sch Sci & Technol, Alexandria, VA USA. [Solomon, Jeffrey M.] Expert Image Anal LLC, Potomac, MD USA. [Schaub, Nicholas P.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Folio, LR (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 1C340, Bethesda, MD 20892 USA. EM les.folio@nih.gov NR 32 TC 6 Z9 6 U1 0 U2 11 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 MAY PY 2013 VL 20 IS 5 BP 604 EP 613 DI 10.1016/j.acra.2012.12.013 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 128WS UT WOS:000317801000012 PM 23477826 ER PT J AU Micale, RT La Maestra, S Di Pietro, A Visalli, G Baluce, B Balansky, R Steele, VE De Flora, S AF Micale, Rosanna T. La Maestra, Sebastiano Di Pietro, Angela Visalli, Giuseppa Baluce, Barbara Balansky, Roumen Steele, Vernon E. De Flora, Silvio TI Oxidative stress in the lung of mice exposed to cigarette smoke either early in life or in adulthood SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Cigarette smoke; Mouse lung; Age; Oxidative stress; Mitochondrial alterations ID N-ACETYLCYSTEINE; NEONATAL MICE; MOUSE LUNG; NEWBORN; CARCINOGENICITY; BIRTH; LIGHT; LIVER AB Birth and early life stages are critical periods characterized by severe alterations of the redox balance and by "physiological" genomic changes in lung cells, which may be responsible for cancer and other diseases in adulthood. Oxidative stress is a major mechanism accounting for the carcinogenicity of cigarette smoke (CS), which becomes more potently carcinogenic in mice when exposure starts at birth and continues early in life. We compared herewith a variety of end-points related to oxidative stress, mitochondrial alterations, and cell turnover in the lung of Swiss H mice, either sham-exposed or CS-exposed for 4 weeks, starting either at birth or at 4 months of age. The results showed that the physiological levels of certain end-points are affected by age. In fact, the baseline proportion of hypodiploid cells and the mitochondrial potential and mass were higher in adults, whereas 8-hydroxy-2'-deoxyguanosine (8-oxo-dGuo) levels, the proportion of necrotic cells, and the extent of autophagy were higher early in life. Adult mice were more responsive to CS by increasing the proportion of necrotic cells and of cells in S/G(2) phase, whereas young mice maintained a high extent of autophagy, exhibited a greater increase of lipid peroxidation products and 8-oxo-dGuo levels, and had a higher frequency of micronucleated cells. In addition, exposure to CS affected the mitochondrial potential/mass, especially in young mice. In conclusion, these data provide evidence that oxidative stress and the resulting DNA damage provide a major contribution to the high susceptibility of mice to CS early in life. C1 [Micale, Rosanna T.; La Maestra, Sebastiano; Balansky, Roumen; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Di Pietro, Angela; Visalli, Giuseppa; Baluce, Barbara] Univ Messina, Dept Hyg Publ Hlth & Prevent Med, I-98125 Messina, Italy. [Baluce, Barbara] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Dept Regenerat Med, I-20122 Milan, Italy. [Balansky, Roumen] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD 20852 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM rosannamicale@yahoo.it; lamaestra78@yahoo.it; adipietr@unime.it; giusyvisally@yahoo.it; barbarabaluce@yahoo.it; rubalansky@sbaloncology.bg; steelev@mail.nih.gov; sdf@unige.it FU US National Cancer Institute [N01-CN53301]; Bulgarian Ministry of Youth and Science (National Science Fund); Hasumi International Foundation FX The authors acknowledge the financial support by the US National Cancer Institute (contract N01-CN53301), the Bulgarian Ministry of Youth and Science (National Science Fund), and the Hasumi International Foundation. The authors thank Dr. Ilaria Righi for her contribution in preparing the manuscript. NR 17 TC 14 Z9 14 U1 0 U2 15 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD MAY PY 2013 VL 87 IS 5 BP 915 EP 918 DI 10.1007/s00204-012-0993-1 PG 4 WC Toxicology SC Toxicology GA 127FM UT WOS:000317682700014 PM 23423711 ER PT J AU Oelsner, EC Pottinger, TD Burkart, KM Allison, M Buxbaum, SG Hansel, NN Kumar, R Larkin, EK Lange, LA Loehr, LR London, SJ O'Connor, GT Papanicolaou, G Petrini, MF Rabinowitz, D Raghavan, S Redline, S Thyagarajan, B Tracy, RP Wilk, JB White, WB Rich, SS Barr, RG AF Oelsner, E. C. Pottinger, T. D. Burkart, K. M. Allison, M. Buxbaum, S. G. Hansel, N. N. Kumar, R. Larkin, E. K. Lange, L. A. Loehr, L. R. London, S. J. O'Connor, G. T. Papanicolaou, G. Petrini, M. F. Rabinowitz, D. Raghavan, S. Redline, S. Thyagarajan, B. Tracy, R. P. Wilk, J. B. White, W. B. Rich, S. S. Barr, R. G. TI Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts SO BIOMARKERS LA English DT Article DE Genetic polymorphisms; growth factors/cytokines/inflammatory mediators; respiratory disease ID OBSTRUCTIVE PULMONARY-DISEASE; BRONCHOALVEOLAR LAVAGE FLUID; BRONCHIAL EPITHELIAL-CELLS; MENDELIAN RANDOMIZATION; ATHEROSCLEROSIS MESA; PLASMA ENDOTHELIN-1; REFERENCE VALUES; UP-REGULATION; P-SELECTIN; ASSOCIATION AB Context: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. Objective: Test associations of endothelial biomarkers with FEV1 using instrumental variables. Methods: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. Results: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p<0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. Conclusion: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal. C1 [Oelsner, E. C.; Pottinger, T. D.; Burkart, K. M.; Raghavan, S.; Barr, R. G.] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10032 USA. [Allison, M.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Buxbaum, S. G.] Jackson State Univ, Sch Hlth Sci, Jackson, MS USA. [Hansel, N. N.] Johns Hopkins, Dept Med, Baltimore, MD USA. [Kumar, R.] Northwestern Univ, Childrens Mem Hosp, Div Allergy & Clin Immunol, Dept Pediat, Chicago, IL 60614 USA. [Larkin, E. K.] Vanderbilt Univ, Div Allergy Pulm & Crit Care, Nashville, TN USA. [Lange, L. A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Loehr, L. R.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [London, S. J.] Natl Inst Environm Sci, US Dept HHS, NIH, Res Triangle Pk, NC USA. [O'Connor, G. T.] Boston Univ, Sch Med, Dept Med, Sect Pulm Allergy & Crit Care Med, Boston, MA 02118 USA. [Papanicolaou, G.] NHLBI, Bethesda, MD 20892 USA. [Petrini, M. F.] Univ Mississippi, Med Ctr, Dept Med, Div Pulm Crit Care & Sleep Med, Jackson, MS 39216 USA. [Rabinowitz, D.] Columbia Univ, Dept Stat, New York, NY 10032 USA. [Redline, S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Thyagarajan, B.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Tracy, R. P.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Tracy, R. P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Wilk, J. B.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Wilk, J. B.] Harvard Univ, Sch Med, Boston, MA USA. [White, W. B.] Tougaloo Coll, Jackson, MS USA. [Rich, S. S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Barr, R. G.] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA. RP Oelsner, EC (reprint author), Columbia Univ, Dept Med, Coll Phys & Surg, Med Ctr, 630 West 168th St,PH 9 East Room 105, New York, NY 10032 USA. EM eco7@columbia.edu RI Buxbaum, Sarah/E-1970-2013; OI Buxbaum, Sarah/0000-0002-4886-3564; O'Connor, George/0000-0002-6476-3926; Pottinger, Tess/0000-0003-0647-5712; Allison, Matthew/0000-0003-0777-8272; London, Stephanie/0000-0003-4911-5290 FU Division of Intramural Research, NIEHS, NIH, DHHS; National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; NIH/NHLBI [ARIC: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN 268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01-HL-087641, R01-HL-059367, R01-HL-086694]; NIH/NHGRI [U01-HG-004402]; National Institutes of Health [HHSN 268200625226C]; CARDIA [HHS-N2-68201200036-C, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095, N01-HC-45204, N01-HC-45205, N01-HC-05187, N01-HC-45134, N01-HC-95100]; CFS [R01-HL-46380-01-16]; CHS [N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-75150, N01-HC-45133, N01-HC-55222, U01-HL-080295]; FHS [N01-HC-25195]; JHS [N01-HC-95170, N01-HC-95171, N01-HC-95172]; MESA [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01-HC-65226, RC1-HL-100543, R01-HL-077612, N01-HC-95159-HC-95169, RR-024156, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL071258, R01-HL-071259]; EPA [RD-831697]; [U01-HL-075572-01]; [R01-HL-70825]; [R01-HL-53560]; [AG-023629]; [AG-15928]; [AG-20098]; [AG-027058] FX The authors report no declarations of interest with the following exception: Dr. Barr was reimbursed for conference travel by Boehringer Ingelheim, and Cenetra Health provided in-kind donation for an NIH-sponsored clinical trial. Dr. London is supported by the Division of Intramural Research, NIEHS, NIH, DHHS. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The NHLBI cohorts were funded by contracts from NIH/NHLBI: ARIC: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN 268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C, R01-HL-087641, R01-HL-059367 and R01-HL-086694; NIH/NHGRI contract U01-HG-004402 and National Institutes of Health contract HHSN 268200625226C; carotid MRI data was funded by U01-HL-075572-01; neurocognitive data is collected by U01-HL-096812, HL-096814, HL-096899, HL-096902 and HL-096917, with previous brain MRI examinations funded by R01-HL-70825; CARDIA: HHS-N2-68201200036-C, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095, N01-HC-45204, N01-HC-45205, N01-HC-05187, N01-HC-45134, N01-HC-95100; the Young Adult Longitudinal Trends in Antioxidants (YALTA) ancillary study was funded by R01-HL-53560; CFS: R01-HL-46380-01-16; CHS: N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-75150, N01-HC-45133, N01-HC-55222, U01-HL-080295; AG-023629, AG-15928, AG-20098 and AG-027058; FHS: N01-HC-25195; JHS: N01-HC-95170, N01-HC-95171, N01-HC-95172; MESA: N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N01-HC-65226, RC1-HL-100543, R01-HL-077612, N01-HC-95159-HC-95169 and RR-024156. R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL071258, R01-HL-071259, EPA grant RD-831697. NR 45 TC 7 Z9 8 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD MAY PY 2013 VL 18 IS 3 BP 196 EP 203 DI 10.3109/1354750X.2012.762805 PG 8 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 130NX UT WOS:000317926200002 PM 23557128 ER PT J AU Nguyen, DN Heaphy, CM de Wilde, RF Orr, BA Odia, Y Eberhart, CG Meeker, AK Rodriguez, FJ AF Nguyen, Doreen N. Heaphy, Christopher M. de Wilde, Roeland F. Orr, Brent A. Odia, Yazmin Eberhart, Charles G. Meeker, Alan K. Rodriguez, Fausto J. TI Molecular and Morphologic Correlates of the Alternative Lengthening of Telomeres Phenotype in High-Grade Astrocytomas SO BRAIN PATHOLOGY LA English DT Article DE ALT; ATRX; DAXX; glioblastoma; glioma; telomeres ID HUMAN GLIOBLASTOMA; IDH1 MUTATIONS; HISTONE H3.3; HUMAN CANCER; ATRX; GLIOMAS; TUMORS; OLIGODENDROGLIOMAS; DIFFERENTIATION; MECHANISM AB Recent studies suggest that the telomere maintenance mechanism known as alternative lengthening of telomeres (ALT) is relatively more common in specific glioma subsets and strongly associated with ATRX mutations. We retrospectively examined 116 high-grade astrocytomas (32 pediatric glioblastomas, 65 adult glioblastomas, 19 anaplastic astrocytomas) with known ALT status using tissue microarrays to identify associations with molecular and phenotypic features. Immunohistochemistry was performed using antibodies against ATRX, DAXX, p53 and IDH1R132H mutant protein. EGFR amplification was evaluated by fluorescence in situ hybridization (FISH). Almost half of fibrillary and gemistocytic astrocytomas (44%) demonstrated ALT. Conversely all gliosarcomas (n=4), epithelioid (n=2), giant cell (n=2) and adult small cell astrocytomas (n=7) were ALT negative. The ALT phenotype was positively correlated with the presence of round cells (P=0.002), microcysts (P<0.0002), IDH1 mutant protein (P<0.0001), ATRX protein loss (P<0.0001), strong P53 immunostaining (P<0.0001) and absence of EGFR amplification (P=0.004). There was no significant correlation with DAXX expression. We conclude that ALT represents a specific phenotype in high-grade astrocytomas with distinctive pathologic and molecular features. Future studies are required to clarify the clinical and biological significance of ALT in high-grade astrocytomas. C1 [Nguyen, Doreen N.; Heaphy, Christopher M.; de Wilde, Roeland F.; Eberhart, Charles G.; Meeker, Alan K.; Rodriguez, Fausto J.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Orr, Brent A.; Eberhart, Charles G.] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA. [Odia, Yazmin] NIH, Neurooncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Meeker, Alan K.; Rodriguez, Fausto J.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Rodriguez, FJ (reprint author), Johns Hopkins Univ Hosp, Div Neuropathol, Sheikh Zayed Tower,Room M2101,1800 Orleans St, Baltimore, MD 21231 USA. EM frodrig4@jhmi.edu FU Children's Cancer Foundation FX The work has been supported in part by the Children's Cancer Foundation. NR 27 TC 34 Z9 34 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD MAY PY 2013 VL 23 IS 3 BP 237 EP 243 DI 10.1111/j.1750-3639.2012.00630.x PG 7 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 129TP UT WOS:000317865800001 PM 22928601 ER PT J AU Zhang, L Sun, ZJ Bian, YS Kulkarni, AB AF Zhang, Lu Sun, Zhi-Jun Bian, Yansong Kulkarni, Ashok B. TI MicroRNA-135b acts as a tumor promoter by targeting the hypoxia-inducible factor pathway in genetically defined mouse model of head and neck squamous cell carcinoma SO CANCER LETTERS LA English DT Article DE Head and neck cancer; Mouse model; MicroRNA; Hypoxia ID ADENOID CYSTIC CARCINOMA; COLORECTAL-CANCER; TGF-BETA; MAMMALIAN TARGET; EXPRESSION; MIR-21; ACTIVATION; RECEPTOR; TONGUE; INFLAMMATION AB Here in, we investigated the mechanism underlying overexpression of miR-135b in the human head and neck squamous cell carcinoma (HNSCC) cell lines and in the HNSCC mouse model. Exogenous expression of miR-135b in these cell lines increased cell proliferation, migration, and colony formation. Gene silencing analysis revealed that miR-135b affects a regulator that inhibits hypoxia-inducible factor (HIF). Increased miR-135b expression was positively correlated with HIF-1 alpha expression and microvessel density in the HNSCC model. Thus, our data demonstrate that miR-135b acts as a tumor promoter by promoting cancer cell proliferation, colony formation, survival, and angiogenesis through activation of HIF-1 alpha in HNSCC. Published by Elsevier Ireland Ltd. C1 [Zhang, Lu; Sun, Zhi-Jun; Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Zhang, Lu; Sun, Zhi-Jun] Wuhan Univ, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430079, Peoples R China. [Zhang, Lu; Sun, Zhi-Jun] Wuhan Univ, Sch & Hosp Stomatol, Minist Educ, Key Lab Oral Biomed, Wuhan 430079, Peoples R China. [Bian, Yansong] Natl Inst Deafness & Other Communicat Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Kulkarni, AB (reprint author), NIDCR, Funct Genom Sect, LCDB, NIH, 30 Convent Dr,Bldg 30,Room 130, Bethesda, MD 20892 USA. EM zhijundejia@yahoo.com.cn; ak40m@nih.gov FU Intramural Research Programs of the National Institute of Dental and Craniofacial Research, NIH [ZIA-DE-000698]; National Natural Science Foundation of China [81072203, 81272963] FX We thank Dr. Carter Van Waes and Dr. Hynda Kleinman for critical reading of the manuscript, and Shelagh Johnson for expert editorial assistance. This work was supported by Intramural Research Programs of the National Institute of Dental and Craniofacial Research, NIH to ABK (ZIA-DE-000698), and National Natural Science Foundation of China to ZJS (81072203, 81272963). NR 52 TC 37 Z9 40 U1 0 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD MAY 1 PY 2013 VL 331 IS 2 BP 230 EP 238 DI 10.1016/j.canlet.2013.01.003 PG 9 WC Oncology SC Oncology GA 128WU UT WOS:000317801200013 PM 23340180 ER PT J AU Wang, YQ Geng, FJ Hu, YZ Du, FL Chen, FY AF Wang, Yunqi Geng, Fengji Hu, Yuzheng Du, Fenglei Chen, Feiyan TI Numerical processing efficiency improved in experienced mental abacus children SO COGNITION LA English DT Article DE Numerical processing efficiency; Mental abacus; Numerical; Stroop paradigm; Congruity effect; Interference; Facilitation ID NUMBER BOARD GAMES; INDIVIDUAL-DIFFERENCES; MAGNITUDE; MATHEMATICS; REPRESENTATION; PRESCHOOLERS; SKILL; DISCRIMINATION; INFORMATION; PERFORMANCE AB Experienced mental abacus (MA) users are able to perform mental arithmetic calculations with unusual speed and accuracy. However, it remains unclear whether their extraordinary gains in mental arithmetic ability are accompanied by an improvement in numerical processing efficiency. To address this question, the present study, using a numerical Stroop paradigm, examined the numerical processing efficiency of experienced MA children, MA beginners and their respective peers. The results showed that experienced MA children were less influenced than their peers by physical size information when intentionally processing numerical magnitude information, but they were more influenced than their peers by numerical magnitude information when intentionally processing physical size information. By contrast, MA beginners and peers showed no differences in the reciprocal influences between the two conflicting dimensions. These findings indicate that substantial gains in numerical processing efficiency could be achieved through long-term intensive MA training. Implications for numerical magnitude representations and for training students with mathematical learning disabilities are discussed. (C) 2013 Elsevier B.V. All rights reserved. C1 [Wang, Yunqi; Geng, Fengji; Du, Fenglei; Chen, Feiyan] Zhejiang Univ, Hangzhou 310027, Peoples R China. [Hu, Yuzheng] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Chen, FY (reprint author), Zhejiang Univ, Bio X Lab, Dept Phys, Hangzhou 310027, Peoples R China. EM chenfy@zju.edu.cn NR 50 TC 11 Z9 12 U1 0 U2 30 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0010-0277 J9 COGNITION JI Cognition PD MAY PY 2013 VL 127 IS 2 BP 149 EP 158 DI 10.1016/j.cognition.2012.12.004 PG 10 WC Psychology, Experimental SC Psychology GA 130TS UT WOS:000317943600001 PM 23454790 ER PT J AU Ortiz, JR Rudd, KE Clark, DV Jacob, ST West, TE AF Ortiz, Justin R. Rudd, Kristina E. Clark, Danielle V. Jacob, Shevin T. West, T. Eoin TI Clinical Research During a Public Health Emergency: A Systematic Review of Severe Pandemic Influenza Management SO CRITICAL CARE MEDICINE LA English DT Review DE clinical trial; critical care; developing countries; influenza; review ID RESPIRATORY-DISTRESS-SYNDROME; H1N1 2009; AFRICAN CHILDREN; CARE; MORTALITY; INFECTION; CORTICOSTEROIDS; METAANALYSIS; ELABORATION; EXPLANATION AB Objective: Rigorous evaluation of clinical interventions in the setting of a public health emergency is necessary to identify best practices, to develop clinical management guidelines, and to inform resource allocation. The 2009 influenza A (H1N1) pandemic necessitated care of critically ill patients around the world. To inform the World Health Organization Public Health Research Agenda for Influenza, we conducted a systematic review to identify clinical interventions other than antiviral therapies that would benefit severely ill 2009 H1N1 influenza patients (adults and children) in both high- and low-resource settings. Data Sources: PubMed, EMBASE, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews; hand search of abstracts from six professional society annual conferences and bibliographies of clinical review articles; and personal communication with leaders in the field. Study Selection: English language; human studies; citations added to databases from January 1, 2009 (Cochrane databases) or March 15, 2009 (PubMed and EMBASE) through January 31, 2012; randomized controlled trials, prospective cohort studies, or systematic reviews/meta-analyses of non-antiviral clinical interventions in hospitalized 2009 influenza A (H1N1) patients. Data Extraction: The search identified 2,452 articles. Thirty-six potentially relevant articles were read. Seven articles met criteria. All were observational studies. Data Synthesis: One study found benefit of convalescent plasma infusion, three studies found no benefit of corticosteroids, and three studies had mixed results on the benefit of extracorporeal lung support. No study was applicable to health care delivery in low-resource settings. Conclusions: There is a paucity of high quality clinical research to inform clinical care of severe H1N1 influenza, and we found no beneficial interventions appropriate for low-resource settings. This may be due to the logistical difficulties of conducting clinical research in response to a public health emergency. Our investigation underscores the need for the development of outbreak-ready research capacity in both high- and low-resource settings. (Crit Care Med 2013; 41: 1345-1352) C1 [Ortiz, Justin R.; Rudd, Kristina E.; Jacob, Shevin T.; West, T. Eoin] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Ortiz, Justin R.; Rudd, Kristina E.; Jacob, Shevin T.; West, T. Eoin] Univ Washington, Int Resp & Severe Illness Ctr INTERSECT, Seattle, WA 98195 USA. [Clark, Danielle V.] NIAID, Integrated Res Facil, NIH, Frederick, MD USA. RP Ortiz, JR (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM jrortiz@uw.edu OI West, T Eoin/0000-0001-5503-7204 FU World Health Organization; Robert Wood Johnson Harold Amos Medical Faculty Development Program [67423] FX This study was supported, in part, by the World Health Organization. Dr. Ortiz is supported by the Robert Wood Johnson Harold Amos Medical Faculty Development Program (Grant 67423). NR 38 TC 11 Z9 11 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2013 VL 41 IS 5 BP 1345 EP 1352 DI 10.1097/CCM.0b013e3182771386 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 126ZB UT WOS:000317661000038 PM 23399939 ER PT J AU Decker, BK Powers, JH AF Decker, Brooke K. Powers, John H. TI Using the Rate of Bacterial Clearance Determined by Real-Time Polymerase Chain Reaction to Evaluate Antibiotic Effectiveness in Acinetobacter baumannii Bacteremia SO CRITICAL CARE MEDICINE LA English DT Letter C1 [Decker, Brooke K.; Powers, John H.] NIH, Bethesda, MD 20892 USA. [Powers, John H.] Sci Applicat Int Corp, Frederick, MD USA. RP Decker, BK (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Decker M.D., Brooke K/0000-0002-3404-9115 FU PHS HHS [HHSN261200800001E] NR 4 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAY PY 2013 VL 41 IS 5 BP E47 EP E47 DI 10.1097/CCM.0b013e318283c34a PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 126ZB UT WOS:000317661000002 PM 23591227 ER PT J AU Kopp, JB AF Kopp, Jeffrey B. TI Rethinking hypertensive kidney disease: arterionephrosclerosis as a genetic, metabolic, and inflammatory disorder SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE apolipoprotein L1; arterionephrosclerosis; hypertensive kidney disease ID STAGE RENAL-DISEASE; IDIOPATHIC NODULAR GLOMERULOSCLEROSIS; AFRICAN-AMERICANS; ALLOGRAFT SURVIVAL; BLOOD-PRESSURE; NEPHROSCLEROSIS; VARIANTS; DAMAGE; AGE; AUTOREGULATION AB Purpose of review Hypertension is the attributed cause of approximately 30% of end-stage kidney disease cases in the United States, but there has been controversy as to whether benign hypertension is a cause of chronic kidney disease. Recent findings The histology of chronic kidney disease attributed to nonmalignant hypertension is arterionephrosclerosis, with pathology in the terminal branches of the interlobular arteries, together with global glomerulosclerosis. The identification of coding region variants in APOL1, encoding apolipoprotein L1, has opened a new perspective on this debate. These variants are restricted to populations of recent African descent and are strongly associated with clinically diagnosed arterionephrosclerosis, particularly when there is moderate-grade or high-grade proteinuria or progression to more advanced levels of kidney dysfunction. Nevertheless, not all African Americans with hypertension who progress to end-stage kidney disease have two APOL1 risk variants, and individuals of European and Asian descent also manifest arterionephrosclerosis. Further, we do not understand the mechanisms by which APOL1 initiates pathology in the renal microcirculation. Summary APOL1 nephropathy comprises a disease spectrum (perhaps with distinct endophenotypes), including focal segmental glomerulosclerosis, collapsing glomerulopathy, and arterionephrosclerosis. The terms hypertensive kidney disease and hypertensive nephrosclerosis have outlived their usefulness. It may be time to use the established, etiologically neutral term, arterionephrosclerosis, to consider whether this is a disease rather than a pathologic description, and to determine the causal role of various clinical correlates including aging, obesity, hyperlipidemia, smoking, chronic inflammation, and oxidative stress. C1 [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDK, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural Research Program, NIDDK, NIH FX The work was supported by the Intramural Research Program, NIDDK, NIH. The author gratefully acknowledges helpful discussions in this field of study with thoughtful and experienced colleagues, Agnes Fogo, Charles Alpers, Richard Tracy, and Barry Freedman, and the critical reviews of the manuscript by Agnes Fogo, Cheryl Winkler, and Jurgen Schnermann. The author notes the recent death of Dr. Gary S. Hill, a distinguished renal pathologist whose many scientific contributions include important papers on arterionephrosclerosis referenced here. NR 49 TC 16 Z9 17 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAY PY 2013 VL 22 IS 3 BP 266 EP 272 DI 10.1097/MNH.0b013e3283600f8c PG 7 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 126YK UT WOS:000317658800003 PM 23470819 ER PT J AU Chen, WZ Ying, TL Dimitrov, DS AF Chen, Weizao Ying, Tianlei Dimitrov, Dimiter S. TI Antibody-based candidate therapeutics against HIV-1: implications for virus eradication and vaccine design SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE broadly neutralizing monoclonal antibodies; eradication; HIV-1; prophylactics; therapeutics; vaccines ID HUMAN-IMMUNODEFICIENCY-VIRUS; BROADLY NEUTRALIZING ANTIBODIES; HUMAN MONOCLONAL-ANTIBODIES; ACTIVE ANTIRETROVIRAL THERAPY; CORECEPTOR BINDING-SITE; CD4(+) T-CELLS; ENVELOPE GLYCOPROTEINS; LATENT HIV-1; IN-VITRO; MATURATION PATHWAYS AB Introduction: The currently available anti-HIV-1 drugs can control the infection but do not eradicate the virus. Their long-term use can lead to side effects and resistance to therapy. Therefore, eradication of the virus has been a major goal of research. Biological therapeutics including broadly neutralizing monoclonal antibodies (bnAbs) are promising tools to reach this goal. They could also help design novel vaccine immunogens potentially capable of eliciting bnAbs targeting the HIV-1 envelope glycoproteins (Envs). Areas covered: We review HIV-1 bnAbs and their potential as candidate prophylactics and therapeutics used individually, in combination, or as bispecific fusion proteins. We also discuss their potential use in the 'activation-elimination' approach for HIV-1 eradication in infected patients receiving antiretroviral treatment as well as current vaccine design efforts based on understanding of interactions of candidate vaccine immunogens with matured bnAbs and their putative germline predecessors, and related antibody maturation pathways. Expert opinion: Exploration of HIV-1 bnAbs has provided and will continue to provide useful knowledge that helps develop novel types of biotherapeutics and vaccines. It is possible that bnAb-based candidate therapeutics could help eradicate HIV-1. Development of vaccine immunogens capable of eliciting potent bnAbs in humans remains a fundamental challenge. C1 [Chen, Weizao; Ying, Tianlei; Dimitrov, Dimiter S.] NCI, NIH, Frederick Natl Lab Canc Res, Prot Interact Grp, Frederick, MD 21702 USA. RP Chen, WZ (reprint author), NCI, NIH, Frederick Natl Lab Canc Res, Prot Interact Grp, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov FU Intramural AIDS Targeted Antiviral Program of the National Institutes of Health (NIH); Intramural Research Program of the NIH, National Cancer Institute FX This project was supported by the Intramural AIDS Targeted Antiviral Program of the National Institutes of Health (NIH) and the Intramural Research Program of the NIH, National Cancer Institute. The authors have no other competing interests to declare. NR 115 TC 7 Z9 7 U1 0 U2 25 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2013 VL 13 IS 5 BP 657 EP 671 DI 10.1517/14712598.2013.761969 PG 15 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 124SH UT WOS:000317485600004 PM 23293858 ER PT J AU O'Sullivan, CC Swain, SM AF O'Sullivan, Ciara C. Swain, Sandra M. TI Pertuzumab: evolving therapeutic strategies in the management of HER2-overexpressing breast cancer SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Article DE anti-HER2/neu-targeted therapy; breast cancer; pertuzumab; trastuzumab ID RANDOMIZED PHASE-II; DIMERIZATION INHIBITOR; OVARIAN-CANCER; OPEN-LABEL; CLINICAL ACTIVITY; MONOCLONAL-ANTIBODY; 1ST-LINE TREATMENT; PLUS TRASTUZUMAB; SINGLE-AGENT; CELL-LINES AB Introduction: HER2 overexpression or amplification is present in approximately one-fifth of breast cancers and historically was associated with aggressive disease and poorer prognosis. The introduction of the humanized monoclonal antibody trastuzumab dramatically improved disease-free survival (DFS) and overall survival (OS) in this subgroup. As the majority of patients with metastatic disease ultimately develop resistance to trastuzumab, a need exists for more effective targeted therapies. Pertuzumab is an anti-HER2/neu-targeted therapy in the late stages of clinical development. The combination of pertuzumab, trastuzumab and docetaxel has been found to have an OS benefit in patients with HER2 positive metastatic breast cancer (MBC) when used in the first-line setting. This reflects a new standard of care, and pertuzumab was recently approved for this indication by the Food and Drug Administration (FDA). The efficacy of pertuzumab and trastuzumab in conjunction with chemotherapy is currently being evaluated in the adjuvant setting. Areas covered: This article provides an overview of preclinical investigations in addition to reviewing pertinent Phase I, Phase II and Phase III clinical trials. Expert opinion: Pertuzumab, in combination with the humanized monoclonal antibody trastuzumab, and docetaxel is a standard of care for patients with previously untreated metastatic breast cancer based on the CLEOPATRA study showing a survival benefit. There is no increase in cardiac toxicity with the combined HER2-targeted therapy. Future issues will address appropriate sequencing and combination with other anti-HER2-targeted therapies and/or chemotherapy. C1 [O'Sullivan, Ciara C.] NIH, Med Oncol Branch, Bethesda, MD 20892 USA. [Swain, Sandra M.] Medstar Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. RP Swain, SM (reprint author), Medstar Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. EM Sandra.m.swain@medstar.net OI Swain, Sandra/0000-0002-1320-3830 FU Genentech/Roche FX CC O'Sullivan has no competing interests, SM Swain has received uncompensated advisory board and research funding from Genentech/Roche. NR 70 TC 2 Z9 4 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2013 VL 13 IS 5 BP 779 EP 790 DI 10.1517/14712598.2013.783007 PG 12 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 124SH UT WOS:000317485600011 PM 23530718 ER PT J AU Olanich, ME Barr, FG AF Olanich, Mary E. Barr, Frederic G. TI A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE fusion gene; PAX3-FOXO1; rhabdomyosarcoma; sarcoma; therapeutic target; translocation ID CHILDRENS-ONCOLOGY-GROUP; PAX3-FKHR FUSION PROTEIN; SOFT-TISSUE SARCOMA; EARLY MYOGENIC DIFFERENTIATION; GROWTH SUPPRESSIVE ACTIVITIES; FOXO TRANSCRIPTION FACTORS; MUSCLE PROGENITOR CELLS; CANNABINOID RECEPTOR 1; IN-SITU HYBRIDIZATION; EMBRYONAL RHABDOMYOSARCOMA AB Introduction: Expression of fusion oncoproteins generated by recurrent chromosomal translocations represents a major tumorigenic mechanism characteristic of multiple cancers, including one-third of all sarcomas. Oncogenic fusion genes provide novel targets for therapeutic intervention. The PAX3-FOXO1 oncoprotein in alveolar rhabdomyosarcoma (ARMS) is presented as a paradigm to examine therapeutic strategies for targeting sarcoma-associated fusion genes. Areas covered: This review discusses the role of PAX3-FOXO1 in ARMS tumors. Besides evaluating various approaches to molecularly target PAX3-FOXO1 itself, this review highlights therapeutically attractive downstream genes activated by PAX3-FOXO1. Expert opinion: Oncogenic fusion proteins represent desirable therapeutic targets because their expression is specific to tumor cells, but these fusions generally characterize rare malignancies. Full development and testing of potential drugs targeted to these fusions are complicated by the small numbers of patients in these disease categories. Although efforts to develop targeted therapies against fusion proteins should continue, molecular targets that are applicable to a broader tumor landscape should be pursued. A shift of the traditional paradigm to view therapeutic intervention as target-specific rather than tumor-specific will help to circumvent the challenges posed by rare tumors and maximize the possibility of developing successful new treatments for patients with these rare translocation-associated sarcomas. C1 [Olanich, Mary E.] NCI, NIH, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. [Barr, Frederic G.] NCI, NIH, Ctr Canc Res, Lab Pathol,Canc Mol Pathol Sect, Bethesda, MD 20892 USA. RP Barr, FG (reprint author), NCI, NIH, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. EM barrfg@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX This paper has been funded by the Intramural Research Program of the National Cancer Institute. NR 197 TC 13 Z9 13 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD MAY PY 2013 VL 17 IS 5 BP 607 EP 623 DI 10.1517/14728222.2013.772136 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 130RA UT WOS:000317935400012 PM 23432728 ER PT J AU Budhu, A Roessler, S Zhao, XL Yu, ZP Forgues, M Ji, JF Karoly, E Qin, LX Ye, QH Jia, HL Fan, J Sun, HC Tang, ZY Wang, XW AF Budhu, Anuradha Roessler, Stephanie Zhao, Xuelian Yu, Zhipeng Forgues, Marshonna Ji, Junfang Karoly, Edward Qin, Lun-Xiu Ye, Qing-Hai Jia, Hu-Liang Fan, Jia Sun, Hui-Chuan Tang, Zhao-You Wang, Xin Wei TI Integrated Metabolite and Gene Expression Profiles Identify Lipid Biomarkers Associated With Progression of Hepatocellular Carcinoma and Patient Outcomes SO GASTROENTEROLOGY LA English DT Article DE HpSC-HCC; MH-HCC; Fatty Acid; Stem Cell ID CANCER STEM-CELLS; STEAROYL-COA DESATURASE-1; IDENTIFICATION; EPCAM; HEPATOCARCINOGENESIS; MECHANISMS; PREDICTION; PALMITATE; SIGNATURE; METFORMIN AB BACKGROUND & AIMS: We combined gene expression and metabolic profiling analyses to identify factors associated with outcomes of patients with hepatocellular carcinoma (HCC). METHODS: We compared metabolic and gene expression patterns between paired tumor and nontumor tissues from 30 patients with HCC, and validated the results using samples from 356 patients with HCC. A total of 469 metabolites were measured using liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry. Metabolic and genomic data were integrated, and Kaplan-Meier and Cox proportional hazards analyses were used to associate specific patterns with patient outcomes. Associated factors were evaluated for their effects on cancer cells in vitro and tumor formation in nude mice. RESULTS: We identified 28 metabolites and 169 genes associated with aggressive HCC. Lipid metabolites of stearoyl-CoA-desaturase (SCD) activity were associated with aberrant palmitate signaling in aggressive HCC samples. Expression of gene products associated with these metabolites, including SCD, were associated independently with survival times and tumor recurrence in the test and validation sets. Combined expression of SCD and alpha-fetoprotein were associated with outcomes of patients with early-stage HCC. Levels of monounsaturated palmitic acid, the product of SCD activity, were increased in aggressive HCCs; monounsaturated palmitic acid increased migration and invasion of cultured HCC cells and colony formation by HCC cells. HCC cells that expressed small interfering RNA against SCD had decreased cell migration and colony formation in culture and reduced tumorigenicity in mice. CONCLUSIONS: By using a combination of gene expression and metabolic profile analysis, we identified a lipogenic network that involves SCD and palmitate signaling and was associated with HCC progression and patient outcomes. The microarray platform and data have been submitted to the Gene Expression Omnibus public database at NCBI following MIAME guidelines. Accession numbers: GPL4700 (platform), and GSE6857 (samples). C1 [Budhu, Anuradha; Roessler, Stephanie; Zhao, Xuelian; Yu, Zhipeng; Forgues, Marshonna; Ji, Junfang; Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Karoly, Edward] Metabolon Inc, Durham, NC USA. [Qin, Lun-Xiu; Ye, Qing-Hai; Jia, Hu-Liang; Fan, Jia; Sun, Hui-Chuan; Tang, Zhao-You] Fudan Univ, Liver Canc Inst, Shanghai 200433, Peoples R China. [Qin, Lun-Xiu; Ye, Qing-Hai; Jia, Hu-Liang; Fan, Jia; Sun, Hui-Chuan; Tang, Zhao-You] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. RP Wang, XW (reprint author), 37 Convent Dr,Bldg 37,Room 3044A, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009; Fan, Jia/C-6689-2017 FU Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute [Z01-BC 010313, Z01-BC010876] FX Supported in part by grants (Z01-BC 010313 and Z01-BC010876) from the Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute. NR 41 TC 36 Z9 38 U1 4 U2 38 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 MAY PY 2013 VL 144 IS 5 BP 1066 EP + DI 10.1053/j.gastro.2013.01.054 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 129BR UT WOS:000317813900035 PM 23376425 ER PT J AU Li, CH To, KF Tong, JHM Xiao, ZG Xia, T Lai, PBS Chow, SC Zhu, YX Chan, SL Marquez, VE Chen, YC AF Li, Chi Han To, Ka-Fai Tong, Joanna Hung-Man Xiao, Zhangang Xia, Tian Lai, Paul B. S. Chow, Sheung Ching Zhu, Yin-Xin Chan, Stephen L. Marquez, Victor E. Chen, Yangchao TI Enhancer of Zeste Homolog 2 Silences MicroRNA-218 in Human Pancreatic Ductal Adenocarcinoma Cells by Inducing Formation of Heterochromatin SO GASTROENTEROLOGY LA English DT Article DE Pancreatic Cancer; Gene Regulation; Epigenetic; Messenger RNA Processing ID HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; IN-VIVO; DE-NOVO; EXPRESSION; METHYLATION; GENE; ASSOCIATION; PROGRESSION; METASTASIS AB BACKGROUND & AIMS: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is overexpressed by pancreatic ductal adenocarcinoma (PDAC) cells and increases their aggressiveness. We identified microRNAs (miRs) that are regulated by EZH2 and studied their functions in PDAC cells. METHODS: We performed miR profile analysis of PDAC cells incubated with EZH2 inhibitor 3-deazaneplanocin A, and pancreatic ductal epithelial cells that overexpressed EZH2. Expression levels of miRs and the targets of miRs were analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. We expressed different forms of EZH2 to analyze functional domains and used small interfering RNAs to reduce its level in PDAC cells. RESULTS: Expression of miR-218 was repressed by EZH2 in PDAC cells. Levels of miR-218 were significantly reduced in primary PDAC tumor samples compared with paired, adjacent nontumor tissue. Overexpression of miR-218 in SW1990 cells reduced their proliferation and tumor formation and metastasis in nude mice. Loss of miR-218 from SW1990 cells increased levels of UDP-glycosyltransferase 8 and miR-218 was found to bind to its 3'-UTR. Levels of UDP-glycosyltransferase protein and messenger RNA were associated with the metastatic potential of PDAC cell lines and progression of tumors in patients. EZH2 was found to silence miR-218 by binding to its promoter, promoting heterochromatin formation, and recruiting the DNAs methyltransferase 1, 3A, and 3B. CONCLUSIONS: EZH2 is up-regulated in PDAC samples from patients and silences miR-218. MicroRNA-218 prevents proliferation of PDAC cells in culture, and tumor growth and metastasis in nude mice. MicroRNA-218 reduces levels of UDP-glycosyltransferase, which is associated with the metastatic potential of PDAC tumors in mice and progression of human PDAC. C1 [Li, Chi Han; Xiao, Zhangang; Xia, Tian; Chow, Sheung Ching; Zhu, Yin-Xin; Chen, Yangchao] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [To, Ka-Fai; Tong, Joanna Hung-Man] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China. [Lai, Paul B. S.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Shatin, Hong Kong, Peoples R China. [Chan, Stephen L.] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Shatin, Hong Kong, Peoples R China. [Marquez, Victor E.] NCI, Ctr Canc Res, Chem Biol Lab, Frederick, MD 21701 USA. [Chen, Yangchao] Chinese Univ Hong Kong, Shenzhen Res Inst, Shenzhen, Peoples R China. RP Chen, YC (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. EM frankch@cuhk.edu.hk RI Lai, Paul/K-8556-2015; Chan, Stephen L./I-3197-2016 OI Lai, Paul/0000-0002-9469-6728; FU Research Grants Council-General Research Fund of Hong Kong Special Administrative Region, China [CUHK462109, CUHK462211]; National Natural Science Foundation of China [81101888]; Shenzhen Basic Research Program [JC201105201092A]; CUHK; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by grants from the Research Grants Council-General Research Fund of Hong Kong Special Administrative Region, China (CUHK462109 and CUHK462211), National Natural Science Foundation of China (81101888), Shenzhen Basic Research Program (JC201105201092A), Direct Grant from CUHK to YC. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 40 TC 27 Z9 27 U1 3 U2 24 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 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2013 VL 144 IS 5 BP 1086 EP + DI 10.1053/j.gastro.2013.01.058 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 129BR UT WOS:000317813900037 PM 23395645 ER PT J AU Gunay-Aygun, M Gahl, WA AF Gunay-Aygun, Meral Gahl, William A. TI Autosomal-Recessive Polycystic Kidney Disease Gets More Complex Reply SO GASTROENTEROLOGY LA English DT Letter ID CONGENITAL HEPATIC-FIBROSIS; PKHD1 MUTATIONS C1 [Gunay-Aygun, Meral] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Intramural Program, Off Rare Dis, NIH, Bethesda, MD 20892 USA. RP Gunay-Aygun, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NR 8 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2013 VL 144 IS 5 BP 1156 EP 1157 DI 10.1053/j.gastro.2013.03.041 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 129BR UT WOS:000317813900049 PM 23528665 ER PT J AU Li, QZ Li, ZB Zheng, G Gao, GM Yu, K AF Li, Qizhai Li, Zhengbang Zheng, Gang Gao, Guimin Yu, Kai TI Rank-Based Robust Tests for Quantitative-Trait Genetic Association Studies SO GENETIC EPIDEMIOLOGY LA English DT Article DE Association study; genetic models; nonparametric; rank; robust ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; NUISANCE PARAMETER; TREND TESTS; DISEQUILIBRIUM; LOCI AB Standard linear regression is commonly used for genetic association studies of quantitative traits. This approach may not be appropriate if the trait, on its original or transformed scales, does not follow a normal distribution. A rank-based nonparametric approach that does not rely on any distributional assumptions can be an attractive alternative. Although several nonparametric tests exist in the literature, their performance in the genetic association setting is not well studied. We evaluate various nonparametric tests for the analysis of quantitative traits and propose a new class of nonparametric tests that have robust performance for traits with various distributions and under different genetic models. We demonstrate the advantage of our proposed methods through simulation study and real data applications. C1 [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Li, Zhengbang] Cent China Normal Univ, Wuhan, Peoples R China. [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Gao, Guimin] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA USA. [Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Li, QZ (reprint author), Chinese Acad Sci, Acad Math & Syst Sci, Zhongguancun East Rd 55, Beijing 100190, Peoples R China. EM liqz@amss.ac.cn FU National Science Foundation of China [61134013]; National Institutes of Health [NO1-AR-22263, RO1-AR-44422] FX We are very grateful to Dr. B. J. Stone, the associate editor, and three anonymous referees for their insightful comments. The work of Q. Li is supported in part by the National Science Foundation of China (Grant No. 61134013). This work is based on the data (GAW16) that were gathered with the support of grants from the National Institutes of Health (NO1-AR-22263 and RO1-AR-44422, Peter K. Gregersen, PI) and the National Arthritis Foundation. NR 28 TC 4 Z9 5 U1 1 U2 14 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 MAY PY 2013 VL 37 IS 4 BP 358 EP 365 DI 10.1002/gepi.21723 PG 8 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 129PV UT WOS:000317854800005 PM 23526350 ER PT J AU Hamilton, AS Miller, MF Arora, NK Bellizzi, KM Rowland, JH AF Hamilton, Ann S. Miller, Melissa F. Arora, Neeraj K. Bellizzi, Keith M. Rowland, Julia H. TI Predictors of Use of Complementary and Alternative Medicine by Non-Hodgkin Lymphoma Survivors and Relationship to Quality of Life SO INTEGRATIVE CANCER THERAPIES LA English DT Article DE non-Hodgkin lymphoma; cancer survivors; complementary and alternative medicine; perceived control; mental health ID BREAST-CANCER; PSYCHOLOGICAL DISTRESS; LONG-TERM; THERAPIES; ONCOLOGY; WOMEN; PREVALENCE; DISEASE AB Hypotheses. This study hypothesized that non-Hodgkin lymphoma (NHL) patients who used complementary and alternative medicine (CAM) would have higher health-related quality of life (HRQOL) and a greater perceived sense of control than nonusers. However, since CAM may predict HRQOL, and perceived control may be both associated with CAM use as well as being an independent predictor of HRQOL, the authors also sought to test whether perceived control mediated the relationship between CAM use and HRQOL. Study design. This was a cross-sectional study design. NHL survivors diagnosed between June 1, 1998 and August 31, 2001 were selected from the population-based SEER (Surveillance, Epidemiology, and End Results) cancer registry for Los Angeles County and were mailed a survey in 2003 that assessed CAM use and predictors of CAM use. The response rate was 54.8%; 319 provided complete data for analysis. Methods. Categories of CAM were defined according to the National Center for Complementary and Alternative Medicine guidelines. The authors measured survivors' cancer-related control using the Perceived Personal Control scale, a 4-question scale that was adapted from previously validated scales. HRQOL was measured using the mental component summary and physical component summary scores from the SF-36 v2.0. Bivariate and multivariable logistic and linear regression models were used to assess factors associated with CAM use and the association of CAM use with psychosocial health outcomes, respectively. Results. Sixty-one percent of respondents reported using at least one CAM modality within the past 4 weeks, and 40% did so after excluding personal prayer and support groups. Younger age and higher education were significantly associated with greater CAM use as were higher perception of cancer-related control (P = .004) and more positive mental functioning (P = .016). Perception of control significantly mediated the association between CAM use and mental functioning (P < .001). Conclusions. CAM use may be related to more positive mental health-related quality of life by increasing patients' perception of perceived control over their health; however, cause and effect cannot be determined. Physicians should be aware that cancer survivors have a need to take an active role in improving their health. C1 [Hamilton, Ann S.] Univ So Calif, Los Angeles, CA 90089 USA. [Miller, Melissa F.] Uniting Wellness Communities & Gildas Club Worldw, Fairfax, VA USA. [Arora, Neeraj K.; Rowland, Julia H.] NCI, Bethesda, MD 20892 USA. [Bellizzi, Keith M.] Univ Connecticut, Storrs, CT USA. RP Hamilton, AS (reprint author), Univ So Calif, Sch Med, 2001 N Soto St,SSB 318E MC9239, Los Angeles, CA 90089 USA. EM ahamilt@med.usc.edu FU California Department of Health Services (CADHS) [103885]; National Cancer Institutes (NCI) Surveillance, Epidemiology and End Results Program [N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries [U55/CCR921930-02] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The collection of cancer incidence data used in this study was supported by the California Department of Health Services (CADHS) as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institutes (NCI) Surveillance, Epidemiology and End Results Program under contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute (PHI); and the Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the PHI. NR 45 TC 7 Z9 7 U1 0 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1534-7354 J9 INTEGR CANCER THER JI Integr. Cancer Ther. PD MAY PY 2013 VL 12 IS 3 BP 225 EP 235 DI 10.1177/1534735412449733 PG 11 WC Oncology; Integrative & Complementary Medicine SC Oncology; Integrative & Complementary Medicine GA 127GC UT WOS:000317684700005 PM 22791309 ER PT J AU Mueller, MB Fischer, M Zellner, J Berner, A Dienstknecht, T Kujat, R Prantl, L Nerlich, M Tuan, RS Angele, P AF Mueller, Michael B. Fischer, Maria Zellner, Johannes Berner, Arne Dienstknecht, Thomas Kujat, Richard Prantl, Lukas Nerlich, Michael Tuan, Rocky S. Angele, Peter TI Effect of parathyroid hormone-related protein in an in vitro hypertrophy model for mesenchymal stem cell chondrogenesis SO INTERNATIONAL ORTHOPAEDICS LA English DT Article ID PROGENITOR CELLS; CHONDROCYTE HYPERTROPHY; GROWTH-PLATE; DIFFERENTIATION; MARROW; MATURATION; PTHRP; EXPRESSION; TGF-BETA-1; CULTURE AB Mesenchymal stem cells (MSCs) express markers of hypertrophic chondrocytes during chondrogenic differentiation. We tested the suitability of parathyroid hormone-related protein (PTHrP), a regulator of chondrocyte hypertrophy in embryonic cartilage development, for the suppression of hypertrophy in an in vitro hypertrophy model of chondrifying MSCs. Chondrogenesis was induced in human MSCs in pellet culture for two weeks and for an additional two weeks cultures were either maintained in standard chondrogenic medium or transferred to a hypertrophy-enhancing medium. PTHrP(1-40) was added to the medium throughout the culture period at concentrations from 1 to 1,000 pM. Pellets were harvested on days one, 14 and 28 for biochemical and histological analysis. Hypertrophic medium clearly enhanced the hypertrophic phenotype, with increased cell size, and strong alkaline phosphatase (ALP) and type X collagen staining. In chondrogenic medium, 1-100 pM PTHrP(1-40) did not inhibit chondrogenic differentiation, whereas 1,000 pM PTHrP(1-40) significantly reduced chondrogenesis. ALP activity was dose-dependently reduced by PTHrP(1-40) at 10-1,000 pM in chondrogenic conditions. Under hypertrophy-enhancing conditions, PTHrP(1-40) did not inhibit the induction of the hypertrophy. At the highest concentration (1,000 pM) in the hypertrophic group, aggregates were partially dedifferentiated and differentiated areas of these aggregates maintained their hypertrophic appearance. PTHrP(1-40) treatment dose-dependently reduced ALP expression in MSC pellets cultured under standard chondrogenic conditions and is thus beneficial for the maintenance of the chondrogenic phenotype in this medium condition. When cultured under hypertrophy-enhancing conditions, PTHrP(1-40) could not diminish the induced enhancement of hypertrophy in the MSC pellets. C1 [Mueller, Michael B.; Fischer, Maria; Zellner, Johannes; Berner, Arne; Dienstknecht, Thomas; Kujat, Richard; Prantl, Lukas; Nerlich, Michael; Angele, Peter] Univ Regensburg, Med Ctr, Dept Trauma Surg, D-93042 Regensburg, Germany. [Mueller, Michael B.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Pittsburgh, PA 15261 USA. [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Ctr Cellular & Mol Engn, Pittsburgh, PA USA. RP Mueller, MB (reprint author), Univ Regensburg, Med Ctr, Dept Trauma Surg, Franz Josef Str Allee 11, D-93042 Regensburg, Germany. EM michaelbmueller@web.de OI Zellner, Johannes/0000-0001-5385-9378 FU AO Research Fund [S-07-3M]; DFG [MU-2318/1]; Intramural Research Program of NIAMS, NIH [AR Z01 41131] FX Supported by AO Research Fund (S-07-3M), DFG (MU-2318/1) and the Intramural Research Program of NIAMS, NIH (AR Z01 41131). NR 26 TC 14 Z9 15 U1 4 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 J9 INT ORTHOP JI Int. Orthop. PD MAY PY 2013 VL 37 IS 5 BP 945 EP 951 DI 10.1007/s00264-013-1800-1 PG 7 WC Orthopedics SC Orthopedics GA 128DW UT WOS:000317750300026 PM 23371427 ER PT J AU Wilmshurst, JM Cross, JH Newton, C Kakooza, AM Wammanda, RD Mallewa, M Samia, P Venter, A Hirtz, D Chugani, H AF Wilmshurst, Jo M. Cross, J. Helen Newton, Charles Kakooza, Angelina M. Wammanda, Robinson D. Mallewa, Macpherson Samia, Pauline Venter, Andre Hirtz, Deborah Chugani, Harry TI Children With Epilepsy in Africa: Recommendations From the International Child Neurology Association/African Child Neurology Association Workshop SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE epilepsy; Africa; training; resources; traditional healers; antiepileptic drugs ID TREATMENT GAP; RISK-FACTORS; TRADITIONAL HEALERS; TANZANIAN CHILDREN; DEVELOPING-WORLD; KENYAN COAST; CARE; INTERVENTION; COMMISSION; PREVALENCE AB This article presents key findings from the International Child Neurology Association/African Child Neurology Association Workshop. The viability of international guidelines for the management of children with epilepsy should be reviewed within each African country, and adapted to comply with the regional capacity. Such recommendations can be used to lobby for resources. More training centers should be developed in Africa, so that specialists can be trained within Africa, in skills relevant to the continent, in collaboration with "out of Africa" visiting-specialists to develop the concept of "train the trainers." At least 1 child neurology specialist per 100 000 of the population is required. Specific to Africa are the challenges from stigma, prejudice, and misconceptions. "Epilepsy teams," inclusive of the traditional healers, would enable management of increased numbers of children, and challenge policy such that it is the right of the child with epilepsy to have reliable access to appropriate antiepileptic drugs, support, and health care equity between the rural and urban settings. C1 [Wilmshurst, Jo M.] Univ Cape Town, Sch Child & Adolescent Hlth, Red Cross Childrens Hosp, Dept Pediat Neurol, ZA-7700 Rondebosch, South Africa. [Cross, J. Helen] Great Ormond St Hosp Children NHS Fdn Trust, UCL Inst Child Hlth, London, England. [Cross, J. Helen] Young Epilepsy, Lingfield, Surrey, England. [Newton, Charles] Kenya Govt Med Res Ctr, Ctr Geog Med Res Coast, Kilifi, Kenya. [Newton, Charles] Wellcome Trust Res Programme, Kilifi, Kenya. [Kakooza, Angelina M.] UCL Inst Child Hlth, Neurosci Unit, London, England. [Kakooza, Angelina M.] Makerere Univ Coll Hlth Sci, Mulago Hosp, Dept Pediat & Child Hlth, Kampala, Uganda. [Wammanda, Robinson D.] Ahmadu Bello Univ, Teaching Hosp, Pediat Neurol Unit, Dept Pediat, Zaria, Nigeria. [Mallewa, Macpherson] Queen Elizabeth Cent Hosp, Coll Med, Dept Pediat & Child Hlth, Blantyre, Malawi. [Samia, Pauline] Aga Khan Univ Hosp, Nairobi, Kenya. [Venter, Andre] Univ Free State, Dept Paediat & Child Hlth, Bloemfontein, South Africa. [Hirtz, Deborah] NINDS, Off Clin Res, NIH, Rockville, MD USA. [Chugani, Harry] Childrens Hosp Michigan, Detroit, MI 48201 USA. RP Wilmshurst, JM (reprint author), Univ Cape Town, Sch Child & Adolescent Hlth, Red Cross Childrens Hosp, Dept Pediat Neurol, ZA-7700 Rondebosch, South Africa. EM jo.wilmshurst@uct.ac.za OI Newton, Charles/0000-0002-6999-5507 FU World Federation of Neurology; National Institute of Neurological Disorders and Stroke, National Institutes of Health [NIH 3 R13 NS077658]; Japanese Child Neurology Society; Child Neurology Society, Children's Hospital of Michigan; Segawa Foundation FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for the meeting was raised from grants from the World Federation of Neurology, the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH 3 R13 NS077658), the Japanese Child Neurology Society, the Child Neurology Society, Children's Hospital of Michigan, and the Segawa Foundation. Sanofi-Aventis donated pens, writing pads, folders, and name tags for the meeting. The delegates' costs were covered for the meeting. The speakers covered their own travel expenses. NR 51 TC 11 Z9 11 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD MAY PY 2013 VL 28 IS 5 BP 633 EP 644 DI 10.1177/0883073813482974 PG 12 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 127FW UT WOS:000317683900011 PM 23539548 ER PT J AU Dreger, DL Parker, HG Ostrander, EA Schmutz, SM AF Dreger, Dayna L. Parker, Heidi G. Ostrander, Elaine A. Schmutz, Sheila M. TI Identification of a Mutation that Is Associated with the Saddle Tan and Black-and-Tan Phenotypes in Basset Hounds and Pembroke Welsh Corgis SO JOURNAL OF HEREDITY LA English DT Article DE Agouti; black and tan; canid; coat color; pigmentation; RALY ID YELLOW A(Y) MUTATION; COAT COLOR; AGOUTI GENE; ASIP GENE; NONAGOUTI MUTATION; DOMESTIC DOGS; EXPRESSION; TYRP1; TRANSCRIPTS; EXTENSION AB The causative mutation for the black-and-tan (a(t)) phenotype in dogs was previously shown to be a SINE, insertion in the 5' region of Agouti Signaling Protein (ASIP). Dogs with the black-and-tan phenotype, as well as dogs with the saddle tan phenotype, genotype as a(t)/_ at this locus. We have identified a 16-bp duplication (g.1875_1890dupCCCCAGGTCAGAGTTT) in an intron of bnRNP associated with lethal yellow (RALY), which segregates with the black-and-tan phenotype in a group of 99 saddle tan and black-and-tan Basset Hounds and Pembroke Welsh Corgis. In these breeds, all dogs with the saddle tan phenotype had RALY genotypes of +/+ or +/dup, whereas dogs with the black-and-tan phenotype were homozygous for the duplication. The presence of an a(y)/_ fawn or e/e red genotype is epistatic to the +/_ saddle tan genotype. Genotypes from 10 wolves and 1 coyote indicated that the saddle tan (+) allele is the ancestral allele, suggesting that black-and-tan is a modification of saddle tan. An additional 95 dogs from breeds that never have the saddle tan phenotype have all three of the possible RALY genotypes. We suggest that a multi-gene interaction involving ASIP, RALY, MC1R, DEFB103, and a yet-unidentified modifier gene is required for expression of saddle tan. C1 [Dreger, Dayna L.; Schmutz, Sheila M.] Univ Saskatchewan, Dept Anim & Poultry Sci, Saskatoon, SK S7N 5A8, Canada. [Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Dreger, DL (reprint author), Univ Saskatchewan, Dept Anim & Poultry Sci, 5 Campus Dr, Saskatoon, SK S7N 5A8, Canada. EM dayna.dreger@nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Natural Science and Engineering Council of Canada [464048-2010]; National Human Genome Research Institute FX This work was supported by Natural Science and Engineering Council of Canada Discovery grant to S.M.S. (464048-2010). E.A.O. and H.G.P. are supported by the Intramural Program of the National Human Genome Research Institute. NR 30 TC 3 Z9 3 U1 1 U2 18 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD MAY-JUN PY 2013 VL 104 IS 3 BP 399 EP 406 DI 10.1093/jhered/est012 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 130BK UT WOS:000317887500009 PM 23519866 ER PT J AU Biragyn, A Bodogai, M Olkhanud, PB Denny-Brown, SR Puri, N Ayukawa, K Kanegasaki, S Hogaboam, CM Wejksza, K Lee-Chang, C AF Biragyn, Arya Bodogai, Monica Olkhanud, Purevdorj B. Denny-Brown, Sinan R. Puri, Nitin Ayukawa, Koichi Kanegasaki, Shiro Hogaboam, Cory M. Wejksza, Katarzyna Lee-Chang, Catalina TI Inhibition of Lung Metastasis by Chemokine CCL17-mediated In Vivo Silencing of Genes in CCR4(+) Tregs SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE chemokine; Tregs; metastasis; siRNA delivery; IL10; FoxP3 ID REGULATORY T-CELLS; BREAST-CANCER METASTASIS; PERIPHERAL-BLOOD; SUPPRESSOR-CELLS; CUTTING EDGE; BONE-MARROW; INFLAMMATION; EXPRESSION; RECEPTORS; EFFECTOR AB Despite significant attractiveness of antisense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides through their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4(+) cells, in particular FoxP3(+) regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL10 or FoxP3 in CCR4(+) Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells. C1 [Biragyn, Arya; Bodogai, Monica; Olkhanud, Purevdorj B.; Denny-Brown, Sinan R.; Wejksza, Katarzyna; Lee-Chang, Catalina] NIA, Immunotherapeut Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Puri, Nitin] Life Technol, Amb Prod, Austin, TX USA. [Ayukawa, Koichi; Kanegasaki, Shiro] Effector Cell Inst Inc, Kawasaki, Kanagawa, Japan. [Hogaboam, Cory M.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. RP Biragyn, A (reprint author), NIA, Immunotherapeut Sect, Lab Mol Biol & Immunol, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI hogaboam, cory /M-3578-2014 FU Intramural Research Program of the National Institute on Aging, NIH FX Supported by the Intramural Research Program of the National Institute on Aging, NIH. This work is fully executed by employees of the US government. NR 41 TC 11 Z9 12 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD MAY PY 2013 VL 36 IS 4 BP 258 EP 267 DI 10.1097/CJI.0b013e318294357c PG 10 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 130ZH UT WOS:000317959200004 PM 23603860 ER PT J AU Reuland, SN Smith, SM Bemis, LT Goldstein, NB Almeida, AR Partyka, KA Marquez, VE Zhang, QH Norris, DA Shellman, YG AF Reuland, Steven N. Smith, Shilo M. Bemis, Lynne T. Goldstein, Nathaniel B. Almeida, Adam R. Partyka, Katie A. Marquez, Victor E. Zhang, Qinghong Norris, David A. Shellman, Yiqun G. TI MicroRNA-26a Is Strongly Downregulated in Melanoma and Induces Cell Death through Repression of Silencer of Death Domains (SODD) SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID NASOPHARYNGEAL CARCINOMA; TRANSCRIPTION FACTOR; MALIGNANT-MELANOMA; CANCER; MIR-26A; APOPTOSIS; EZH2; TUMORIGENESIS; EXPRESSION; TARGETS AB Melanoma is an aggressive cancer that metastasizes rapidly and is refractory to conventional chemotherapies. Identifying microRNAs (miRNAs) that are responsible for this pathogenesis is therefore a promising means of developing new therapies. We identified miR-26a through microarray and quantitative reverse-transcription PCR (qRT-PCR) experiments as an miRNA that is strongly downregulated in melanoma cell lines as compared with primary melanocytes. Treatment of cell lines with miR-26a mimic caused significant and rapid cell death compared with a negative control in most melanoma cell lines tested. In surveying targets of miR-26a, we found that protein levels of SMAD1 (mothers against decapentaplegic homolog 1) and BAG-4/SODD were strongly decreased in sensitive cells treated with miR-26a mimic as compared with the control. The luciferase reporter assays further demonstrated that miR-26a can repress gene expression through the binding site in the 3' untranslated region (3'UTR) of SODD (silencer of death domains). Knockdown of these proteins with small interfering RNA (siRNA) showed that SODD has an important role in protecting melanoma cells from apoptosis in most cell lines sensitive to miR-26a, whereas SMAD1 may have a minor role. Furthermore, transfecting cells with a miR-26a inhibitor increased SODD expression. Our findings indicate that miR-26a replacement is a potential therapeutic strategy for metastatic melanoma, and that SODD, in particular, is a potentially useful therapeutic target. C1 [Reuland, Steven N.; Smith, Shilo M.; Goldstein, Nathaniel B.; Almeida, Adam R.; Partyka, Katie A.; Zhang, Qinghong; Norris, David A.; Shellman, Yiqun G.] Univ Colorado Denver, Sch Med, Dept Dermatol, Aurora, CO 80045 USA. [Bemis, Lynne T.] Univ Minnesota, Med Sch Duluth, Dept Biomed Sci, Duluth, MN 55812 USA. [Marquez, Victor E.] NCI Frederick, Ctr Canc Res, Chem Biol Lab, Frederick, MD USA. [Norris, David A.] Dept Vet Affairs Med Ctr, Dermatol Sect, Denver, CO USA. RP Shellman, YG (reprint author), Univ Colorado Denver, Sch Med, Dept Dermatol, Aurora, CO 80045 USA. EM Yiqun.Shellman@ucdenver.edu FU NIAMS [R01AR26427-18]; Veterans Administration merit grant from the Department of Veterans Affairs (Veterans Health Administration; Office of Research and Development, Biomedical Laboratory Research and Development); NIH [5T32AR007411-29, P30 CA 046934]; Southwestern Skin Cancer SPORE Pilot project; Intramural Research Program of the NIH, National Cancer Institute for Cancer Research; Bifeng Gao at the University of Colorado Microarray Core FX This work was supported in part by NIAMS grant R01AR26427-18 to DAN; by a Veterans Administration merit grant from the Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development) to DAN; by NIH training grant 5T32AR007411-29 to SNR (PI: DAN); by a Southwestern Skin Cancer SPORE Pilot project to YGS; and by the Intramural Research Program of the NIH, National Cancer Institute for Cancer Research, to VEM. We thank Karen Helm, Christine Childs, and Alistaire S Acosta at the University of Colorado Cancer Center Flow Cytometry Core (supported by NIH grant P30 CA 046934) and Bifeng Gao at the University of Colorado Microarray Core for their expert technical assistance. NR 46 TC 25 Z9 28 U1 0 U2 33 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 MAY PY 2013 VL 133 IS 5 BP 1286 EP 1293 DI 10.1038/jid.2012.400 PG 8 WC Dermatology SC Dermatology GA 127KV UT WOS:000317698800025 PM 23190898 ER PT J AU Callahan, A Anderson, WF Patel, S Barnholtz-Sloan, JS Bordeaux, JS Tucker, MA Gerstenblith, MR AF Callahan, A. Anderson, W. F. Patel, S. Barnholtz-Sloan, J. S. Bordeaux, J. S. Tucker, M. A. Gerstenblith, M. R. TI Epidemiology of anorectal melanoma in the United States: 1992-2009 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Callahan, A.; Patel, S.; Barnholtz-Sloan, J. S.; Bordeaux, J. S.; Gerstenblith, M. R.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Anderson, W. F.; Tucker, M. A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Patel, S.; Bordeaux, J. S.; Gerstenblith, M. R.] Univ Hosp Cleveland, Case Med Ctr, Dept Dermatol, Cleveland, OH 44106 USA. [Barnholtz-Sloan, J. S.; Bordeaux, J. S.; Gerstenblith, M. R.] Case Comprehens Canc Ctr, Cleveland, OH USA. RI Tucker, Margaret/B-4297-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 581 BP S99 EP S99 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900578 ER PT J AU Carson, P Yufit, T Falanga, V AF Carson, P. Yufit, T. Falanga, V. TI Development of a GMP facility for cell therapy of chronic non-healing wounds SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Carson, P.; Yufit, T.; Falanga, V.] Roger Williams Canc Med Ctr, Providence, RI USA. [Falanga, V.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Carson, P.; Yufit, T.; Falanga, V.] Roger Williams Canc Med Ctr, NIH Ctr Biomed Res Excellence, Providence, RI USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 933 BP S159 EP S159 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901224 ER PT J AU Chaudhary, SC Walsh, SB Tang, XW Kim, AL Kurundkar, D Srivastva, RK Weng, Z Bickers, DR Elmets, CA Kopelovich, L Athar, M AF Chaudhary, S. C. Walsh, S. B. Tang, X. W. Kim, A. L. Kurundkar, D. Srivastva, R. K. Weng, Z. Bickers, D. R. Elmets, C. A. Kopelovich, L. Athar, M. TI mTOR, a potential molecular target for the chemoprevention of non-melanoma skin cancer in organ transplant recipients SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Chaudhary, S. C.; Walsh, S. B.; Kurundkar, D.; Srivastva, R. K.; Weng, Z.; Elmets, C. A.; Athar, M.] UAB, Birmingham, AL USA. [Tang, X. W.; Kim, A. L.; Bickers, D. R.] Columbia Univ, New York, NY 10027 USA. [Kopelovich, L.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 429 BP S73 EP S73 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900426 ER PT J AU Colmont, CS BenKetha, A Errington, R Yee, C Udey, MC Patel, GK AF Colmont, C. S. BenKetha, A. Errington, R. Yee, C. Udey, M. C. Patel, G. K. TI Human basal cell carcinoma tumor-initiating cells are resistant to etoposide killing SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Colmont, C. S.; BenKetha, A.; Errington, R.] Cardiff Univ, Sch Med, Cardiff CF10 3AX, S Glam, Wales. [Yee, C.; Udey, M. C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Patel, G. K.] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 437 BP S74 EP S74 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900434 ER PT J AU Daily, K Coxon, A Williams, JS Lee, C Coit, DG Busam, KJ Brownell, I AF Daily, K. Coxon, A. Williams, J. S. Lee, C. Coit, D. G. Busam, K. J. Brownell, I. TI UISO cell line is not representative of Merkel cell carcinoma tumors SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Daily, K.; Coxon, A.; Williams, J. S.; Lee, C.; Brownell, I.] NCI, NIH, Bethesda, MD 20892 USA. [Coit, D. G.; Busam, K. J.; Brownell, I.] Mem Sloan Kettering, New York, NY USA. RI Lee, Chyi-Chia/I-1938-2013 OI Lee, Chyi-Chia/0000-0002-5306-7781 NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 418 BP S71 EP S71 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900415 ER PT J AU Demehri, S Yockey, LJ Visness, CM Jaffee, KF Turkoz, A Wood, RA O'Connor, GT Kattan, M Gern, JE Gergen, PJ Holtzman, M Bloomberg, G Kopan, R AF Demehri, S. Yockey, L. J. Visness, C. M. Jaffee, K. F. Turkoz, A. Wood, R. A. O'Connor, G. T. Kattan, M. Gern, J. E. Gergen, P. J. Holtzman, M. Bloomberg, G. Kopan, R. TI Circulating TSLP associates with decreased wheezing in non-atopic children SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Demehri, S.; Yockey, L. J.; Turkoz, A.; Kopan, R.] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA. [Visness, C. M.; Jaffee, K. F.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [O'Connor, G. T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Kattan, M.] Columbia Univ, Sch Med, New York, NY USA. [Wood, R. A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gern, J. E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Gergen, P. J.] NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Holtzman, M.; Bloomberg, G.] Washington Univ, Sch Med, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1015 BP S173 EP S173 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901306 ER PT J AU Ebsen, D Dieck, KT Wakamatsu, K Jain, A Mahns, A Ito, S Hearing, V Wenck, H Stab, F Kolbe, L AF Ebsen, D. Dieck, K. Tom Wakamatsu, K. Jain, A. Mahns, A. Ito, S. Hearing, V. Wenck, H. Staeb, F. Kolbe, L. TI The TRPA1 agonist allyl isothiocyanate, an inducer of neurogenic inflammation, acts as a model substance for the investigation of postinflammatory hyperpigmentation, leading to increased melanin levels in vivo and in vitro SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Ebsen, D.; Hearing, V.] NCI, Pigment Cell Biol Sect, NIH, Bethesda, MD 20892 USA. [Dieck, K. Tom; Jain, A.; Mahns, A.; Wenck, H.; Staeb, F.; Kolbe, L.] Beiersdorf AG, Skin Res Ctr, R&D, Hamburg, Germany. [Wakamatsu, K.; Ito, S.] Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Toyoake, Aichi, Japan. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1425 BP S242 EP S242 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901715 ER PT J AU Gaiser, T Gaiser, MR Hirsch, D Kemmerling, R Davis, S Meltzer, PS Ried, T AF Gaiser, T. Gaiser, M. R. Hirsch, D. Kemmerling, R. Davis, S. Meltzer, P. S. Ried, T. TI Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Gaiser, T.; Hirsch, D.; Davis, S.; Meltzer, P. S.; Ried, T.] NIH, Genet Branch, Bethesda, MD 20892 USA. [Kemmerling, R.] Paracelsus Med Univ, Inst Pathol, Salzburg, Austria. [Gaiser, M. R.] Heidelberg Univ, Dept Dermatol, Heidelberg, Germany. [Gaiser, T.] Univ Med Ctr Mannheim, Inst Pathol, Mannheim, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 326 BP S56 EP S56 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900325 ER PT J AU Harden, JL Pierson, K Suarez-Farinas, M Chiricozzi, A Goldbach-Mansky, R Bowcock, A Lowes, MA AF Harden, J. L. Pierson, K. Suarez-Farinas, M. Chiricozzi, A. Goldbach-Mansky, R. Bowcock, A. Lowes, M. A. TI Dermal CARD14 expression in psoriasis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Harden, J. L.; Pierson, K.; Suarez-Farinas, M.; Chiricozzi, A.; Lowes, M. A.] Rockefeller Univ, Dept Invest Dermatol, New York, NY 10021 USA. [Chiricozzi, A.] Univ Roma Tor Vergata, Dept Dermatol, Rome, Italy. [Goldbach-Mansky, R.] NIAMS, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD USA. [Bowcock, A.] Washington Univ, Sch Med, Div Human Genet, Dept Genet, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 150 BP S25 EP S25 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900150 ER PT J AU Heil, PM Markello, TC Carleson-Donohoe, H Gahl, WA Tifft, CJ AF Heil, P. M. Markello, T. C. Carleson-Donohoe, H. Gahl, W. A. Tifft, C. J. TI Adducted thumb - clubfoot syndrome (Ehlers-Danlos-type VIb; dermatan-4-O-sulfotransferase-deficiency) in an American patient SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Heil, P. M.; Markello, T. C.; Carleson-Donohoe, H.; Gahl, W. A.; Tifft, C. J.] NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 860 BP S146 EP S146 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901154 ER PT J AU Hollo, P Nemeth, K Jokai, H Harsing, J Soos, G Karpati, S AF Hollo, P. Nemeth, K. Jokai, H. Harsing, J. Soos, G. Karpati, S. TI Therapeutic benefit of topically applied ascorbic acid in basal cell carcinoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Hollo, P.; Nemeth, K.; Jokai, H.; Harsing, J.; Soos, G.; Karpati, S.] Semmelweis Univ, Dept Dermatovenerol & Dermatooncol, H-1085 Budapest, Hungary. [Nemeth, K.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1084 BP S184 EP S184 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901376 ER PT J AU Kim, J Ogawa, Y Palazzo, E Udey, M Morasso, M AF Kim, J. Ogawa, Y. Palazzo, E. Udey, M. Morasso, M. TI Characterization of inflammation in keratinocyte DIx3-deficient murine skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Kim, J.; Palazzo, E.; Morasso, M.] NIAMS NIH, Dev Skin Biol Unit, Bethesda, MD USA. [Ogawa, Y.; Udey, M.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RI Palazzo, Elisabetta/J-5287-2016 OI Palazzo, Elisabetta/0000-0002-0812-5524 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 114 BP S19 EP S19 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900115 ER PT J AU Kiss, A Koppel, AC Kissling, GE Efimova, T AF Kiss, A. Koppel, A. C. Kissling, G. E. Efimova, T. TI Loss of p38 delta mitogen-activated protein kinase (MAPK) expression reveals a stage-specific regulation of skin inflammation and malignant progression in a two-stage chemical skin carcinogenesis model SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Kiss, A.; Koppel, A. C.; Efimova, T.] Washington Univ, Sch Med, St Louis, MO USA. [Kissling, G. E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 425 BP S72 EP S72 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900422 ER PT J AU Kuschal, C DiGiovanna, JJ Khan, SG Gatti, RA Kraemer, KH AF Kuschal, C. DiGiovanna, J. J. Khan, S. G. Gatti, R. A. Kraemer, K. H. TI Effect of aminoglycosides and non-aminoglycosides on readthrough of stop codons in xeroderma pigmentosum group C cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Kuschal, C.; DiGiovanna, J. J.; Khan, S. G.; Kraemer, K. H.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Gatti, R. A.] Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 822 BP S139 EP S139 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901114 ER PT J AU Li, L Ansbro, MR Yuspa, SH AF Li, L. Ansbro, M. R. Yuspa, S. H. TI Development of a preclinical model for P-glycoprotein based skin absorptive transport for topical drug delivery-a case study with cyclosporin A SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Li, L.; Ansbro, M. R.; Yuspa, S. H.] NCI, LCBG, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1097 BP S186 EP S186 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901386 ER PT J AU Li, S Rajesh, S Klover, P Dalgard, C Wang, J Thangapazham, R Moss, J Darling, T AF Li, S. Rajesh, S. Klover, P. Dalgard, C. Wang, J. Thangapazham, R. Moss, J. Darling, T. TI ANGPTL4 is a paracrine factor in tuberous sclerosis tumorigenesis with a potential role in lymphangiogenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Li, S.; Rajesh, S.; Klover, P.; Wang, J.; Thangapazham, R.; Darling, T.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Dalgard, C.] USU, APG, Bethesda, MD USA. [Moss, J.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 905 BP S154 EP S154 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901198 ER PT J AU Li, W Qureshi, A Goldstein, A Giovannucci, E Stampfer, M Han, J AF Li, W. Qureshi, A. Goldstein, A. Giovannucci, E. Stampfer, M. Han, J. TI Personal history of prostate cancer and increased risk of incident melanoma in US men SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Li, W.; Qureshi, A.; Giovannucci, E.; Stampfer, M.; Han, J.] Harvard Univ, Sch Med, Boston, MA USA. [Li, W.; Goldstein, A.] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 526 BP S90 EP S90 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900523 ER PT J AU Masaki, T Wang, Y DiGiovanna, JJ Lee, CR Khan, SG Raffeld, M Hornyak, TJ Darling, TN Kraemer, KH AF Masaki, T. Wang, Y. DiGiovanna, J. J. Lee, C. R. Khan, S. G. Raffeld, M. Hornyak, T. J. Darling, T. N. Kraemer, K. H. TI High frequency of PTEN mutations in pre-malignant and malignant pigmented lesions in xeroderma pigmentosum SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Masaki, T.; Wang, Y.; DiGiovanna, J. J.; Khan, S. G.; Hornyak, T. J.; Kraemer, K. H.] NCI, Dermatol Branch, Bethesda, MD 20892 USA. [Darling, T. N.] USUHS, Bethesda, MD USA. [Masaki, T.] Kobe Univ, Kobe, Hyogo 657, Japan. [Lee, C. R.; Raffeld, M.] NCI, Bethesda, MD 20892 USA. [Wang, Y.] Peking Univ, Hosp 1, Beijing, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 398 BP S68 EP S68 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900396 ER PT J AU Mehta, NN Dagur, PK Stansky, E Rose, S Biancotto, A Sonti, K Playford, M McCoy, JP AF Mehta, N. N. Dagur, P. K. Stansky, E. Rose, S. Biancotto, A. Sonti, K. Playford, M. McCoy, J. P. TI CD146 expression identifies Th17 and Tc17 subsets in psoriatic blood and skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Mehta, N. N.; Dagur, P. K.; Stansky, E.; Rose, S.; Biancotto, A.; Sonti, K.; Playford, M.; McCoy, J. P.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 264 BP S44 EP S44 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900264 ER PT J AU Ming, M Soltani, K Shea, CR Li, X He, Y AF Ming, M. Soltani, K. Shea, C. R. Li, X. He, Y. TI Keratinocyte-specific deletion in mice reveals gene dosage-dependent role for SIRT1 in UVB-induced skin tumorigenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Ming, M.; Soltani, K.; Shea, C. R.; He, Y.] Univ Chicago, Chicago, IL 60637 USA. [Li, X.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1228 BP S209 EP S209 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901521 ER PT J AU Miyagawa, F Zhang, H Katz, SI Asada, H AF Miyagawa, F. Zhang, H. Katz, S. I. Asada, H. TI IRF8 and IRF4 may work cooperatively in CD8T cell effector differentiation SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Miyagawa, F.; Asada, H.] Nara Med Univ, Kashihara, Nara 634, Japan. [Miyagawa, F.; Zhang, H.; Katz, S. I.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 050 BP S9 EP S9 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900051 ER PT J AU Namiki, T Valencai, JC Coelho, SG Yin, L Kawaguchi, M Vieira, WD Kaneko, Y Tanemura, A Katayama, I Kawakami, Y Yokozeki, H Hearing, VJ AF Namiki, T. Valencai, J. C. Coelho, S. G. Yin, L. Kawaguchi, M. Vieira, W. D. Kaneko, Y. Tanemura, A. Katayama, I. Kawakami, Y. Yokozeki, H. Hearing, V. J. TI Nuak2 amplification coupled with Pten deficiency confers tumorigenicity to melanomas via cdk2 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Namiki, T.; Valencai, J. C.; Coelho, S. G.; Yin, L.; Kawaguchi, M.; Vieira, W. D.; Hearing, V. J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kaneko, Y.] Saitama Canc Ctr, Res Inst Clin Oncol, Saitama, Japan. [Tanemura, A.; Katayama, I.] Osaka Univ, Grad Sch Med, Dept Dermatol, Osaka, Japan. [Kawakami, Y.] Keio Univ, Sch Med, Inst Adv Med Res, Tokyo, Japan. [Yokozeki, H.] Tokyo Med & Dent Univ, Grad Sch, Dept Dermatol, Tokyo, Japan. [Yokozeki, H.] Fac Med, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 369 BP S63 EP S63 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900367 ER PT J AU Oh, J Conlan, S Freeman, A Program, N Candotti, F Holland, SM Segre, JA Kong, HH AF Oh, J. Conlan, S. Freeman, A. Program, N. Candotti, F. Holland, S. M. Segre, J. A. Kong, H. H. TI Altered skin microbiome profiles in patients with primary immunodeficiency and eczema SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Oh, J.; Conlan, S.; Program, N.; Candotti, F.; Segre, J. A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Freeman, A.; Holland, S. M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Kong, H. H.] NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1191 BP S202 EP S202 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901481 ER PT J AU Oh, J Conlan, S Polley, E Segre, JA Kong, HH AF Oh, J. Conlan, S. Polley, E. Segre, J. A. Kong, H. H. TI Microbial skin and nares communities are markedly different in children and adults SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Oh, J.; Conlan, S.; Segre, J. A.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Polley, E.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Kong, H. H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1182 BP S200 EP S200 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901473 ER PT J AU Okiyama, N Katz, SI AF Okiyama, N. Katz, S. I. TI Programmed cell death1 (PD-1) regulates the effector function of autoimmune CD8 T cells and protects against immune-related disease SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Okiyama, N.; Katz, S. I.] NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 BP S1 EP S1 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900005 ER PT J AU Ouchi, T Udey, MC AF Ouchi, T. Udey, M. C. TI Regulation of Claudin-1 expression in Langerhans cells by EpCAM SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Ouchi, T.; Udey, M. C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 037 BP S7 EP S7 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900038 ER PT J AU Palazzo, E Valentina, P Anna, G Radoja, N Blumenberg, M Kim, J Ryscavage, A Cataisson, C Morasso, M AF Palazzo, E. Valentina, P. Anna, G. Radoja, N. Blumenberg, M. Kim, J. Ryscavage, A. Cataisson, C. Morasso, M. TI Dlx3 as a cell cycle modulator during keratinocyte differentiation and tumor development SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Palazzo, E.; Valentina, P.; Anna, G.; Radoja, N.; Kim, J.; Morasso, M.] NIAMS, Dev Biol Sect Unit, NIH, Bethesda, MD USA. [Ryscavage, A.; Cataisson, C.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Blumenberg, M.] NYU, Dept Dermatol, New York, NY 10016 USA. RI Palazzo, Elisabetta/J-5287-2016 OI Palazzo, Elisabetta/0000-0002-0812-5524 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 624 BP S106 EP S106 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900621 ER PT J AU Park, H Readio, N Jin, G Asfaha, S Singh, A Singh, A Yang, X Patterson, KS Trempus, CS Wang, TC Morris, RJ AF Park, H. Readio, N. Jin, G. Asfaha, S. Singh, A. Singh, A. Yang, X. Patterson, K. S. Trempus, C. S. Wang, T. C. Morris, R. J. TI Bone marrow-derived epithelial cells as well as hair follicle bulge-derived cells contribute to skin tumors and ulcer-associated dysplasia mediated by tumor promotion in the mouse SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Readio, N.; Singh, A.; Singh, A.; Morris, R. J.] Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. [Park, H.; Jin, G.; Asfaha, S.; Yang, X.; Patterson, K. S.; Wang, T. C.; Morris, R. J.] Columbia Univ, New York, NY USA. [Trempus, C. S.] NIEHS, Matrix Biol Grp, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 430 BP S73 EP S73 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900427 ER PT J AU Purwar, R Solt, L Jetton, A Burris, T Kuchroo, VK Clark, R Kupper, T AF Purwar, R. Solt, L. Jetton, A. Burris, T. Kuchroo, V. K. Clark, R. Kupper, T. TI Genetic or chemical ROR gamma blockade profoundly suppresses hapten mediated contact hypersensitivity responses SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Purwar, R.; Kuchroo, V. K.; Clark, R.; Kupper, T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Solt, L.; Burris, T.] Scripps Res Inst, Jupiter, FL USA. [Jetton, A.] NIEHS, NIH, Triangle Res Pk, NC USA. RI Burris, Thomas/B-3886-2016 OI Burris, Thomas/0000-0003-2922-4449 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 088 BP S15 EP S15 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900089 ER PT J AU Qian, Y Jeong, JS Valenzuela, JG Evangelista, F Aoki, V Hans, G Rivitti, EA Diaz, LA AF Qian, Y. Jeong, J. S. Valenzuela, J. G. Evangelista, F. Aoki, V. Hans, G. Rivitti, E. A. Diaz, L. A. TI A non-infectious sand fly salivary gland protein is likely involved in the development and clonal selection of anti-Dsg1 autoantibodies in Fogo Selvagem SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Qian, Y.; Jeong, J. S.; Evangelista, F.; Diaz, L. A.] Univ N Carolina, Chapel Hill, NC USA. [Valenzuela, J. G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Aoki, V.; Rivitti, E. A.] Univ Sao Paulo, Sao Paulo, Brazil. [Hans, G.] Univ Mato Grosso Sul, Campo Grande, Brazil. NR 0 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 262 BP S44 EP S44 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900262 ER PT J AU Roediger, B Kyle, R Yip, K Guy, T Sumaria, N Mitchell, A Jain, R Forbes-Blom, E Chen, X Tong, P Bolton, H Paul, W de St Groth, BF Grimbaldeston, M Le Gros, G Weninger, W AF Roediger, B. Kyle, R. Yip, K. Guy, T. Sumaria, N. Mitchell, A. Jain, R. Forbes-Blom, E. Chen, X. Tong, P. Bolton, H. Paul, W. de St Groth, B. Fazekas Grimbaldeston, M. Le Gros, G. Weninger, W. TI Regulation of cutaneous inflammation by skin-resident type 2 innate lymphoid cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Roediger, B.; Sumaria, N.; Mitchell, A.; Jain, R.; Tong, P.; Bolton, H.; de St Groth, B. Fazekas; Weninger, W.] Centenary Inst, Sydney, NSW, Australia. [Kyle, R.; Forbes-Blom, E.; Le Gros, G.] Malaghan Inst Med Res, Wellington, New Zealand. [Yip, K.; Grimbaldeston, M.] Ctr Canc Biol, Adelaide, SA, Australia. [Chen, X.] NIH, Bethesda, MD 20892 USA. [Weninger, W.] Univ Sydney, Discipline Dermatol, Sydney, NSW 2006, Australia. [Weninger, W.] Royal Prince Alfred Hosp, Dept Dermatol, Sydney, NSW, Australia. NR 0 TC 0 Z9 0 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1177 BP S200 EP S200 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901468 ER PT J AU Rose, S Sonti, K Dagur, P Playford, M Lee, P Celi, FS Mehta, NN AF Rose, S. Sonti, K. Dagur, P. Playford, M. Lee, P. Celi, F. S. Mehta, N. N. TI Characterization of adipose tissue inflammation may link psoriasis and cardiometabolic disease SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Rose, S.; Sonti, K.; Dagur, P.; Playford, M.; Lee, P.; Celi, F. S.; Mehta, N. N.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1077 BP S183 EP S183 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901367 ER PT J AU Takeshita, J Saboury, B Salavati, A Torigian, DA Van Voorhees, AS Mehta, NN Alavi, A Gelfand, JM AF Takeshita, J. Saboury, B. Salavati, A. Torigian, D. A. Van Voorhees, A. S. Mehta, N. N. Alavi, A. Gelfand, J. M. TI 18-Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) as a novel tool for quantification of psoriasis disease activity: Proof of concept from the Vascular Inflammation in Psoriasis (VIP) trial SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Takeshita, J.; Saboury, B.; Salavati, A.; Torigian, D. A.; Van Voorhees, A. S.; Alavi, A.; Gelfand, J. M.] Univ Penn, Philadelphia, PA 19104 USA. [Mehta, N. N.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1041 BP S177 EP S177 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901331 ER PT J AU Tsuji, G Okiyama, N Villarroel, V Katz, SI AF Tsuji, G. Okiyama, N. Villarroel, V. Katz, S. I. TI Tubacin, a histone deacetylase 6 inhibitor, suppresses contact sensitivity via impairment of the immune synapse SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Tsuji, G.; Okiyama, N.; Villarroel, V.; Katz, S. I.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 066 BP S11 EP S11 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900067 ER PT J AU Uchiyama, A Yamada, K Uehara, A Ogino, S Udey, MC Ishikawa, O Motegi, S AF Uchiyama, A. Yamada, K. Uehara, A. Ogino, S. Udey, M. C. Ishikawa, O. Motegi, S. TI The regulation of skin wound healing by MFG-E8 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Uchiyama, A.; Yamada, K.; Uehara, A.; Ogino, S.; Ishikawa, O.; Motegi, S.] Gunma Univ, Grad Sch Med, Dept Dermatol, Maebashi, Gumma 371, Japan. [Udey, M. C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 1474 BP S251 EP S251 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698901765 ER PT J AU Villarroel, VA Okiyama, N Tsuji, G Linton, J Katz, SI AF Villarroel, V. A. Okiyama, N. Tsuji, G. Linton, J. Katz, S. I. TI Pathodynamics of CD8 T-cell trafficking in a murine model of graft-versus-host disease (GvHD), implicate the CXCR3 axis as a crucial organizer of cutaneous inflammation and injury SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Villarroel, V. A.; Okiyama, N.; Tsuji, G.; Linton, J.; Katz, S. I.] NCI, Derm Branch, CCR, NIH, Beth, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 BP S4 EP S4 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900024 ER PT J AU Yuspa, SH Liu, F Wright, L Zhuang, A Merlino, G Cataisson, C AF Yuspa, S. H. Liu, F. Wright, L. Zhuang, A. Merlino, G. Cataisson, C. TI Enhanced MET signaling in mouse epidermis activates EGFR and initiates squamous carcinogenesis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT International Investigative Dermatology Meeting CY MAY 08-11, 2013 CL Edinburgh, SCOTLAND SP European Soc Dermatol Res, Japanese Soc Investigat Dermatol, Soc Investigat Dermatol C1 [Yuspa, S. H.; Liu, F.; Wright, L.; Zhuang, A.; Merlino, G.; Cataisson, C.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2013 VL 133 SU 1 MA 385 BP S65 EP S65 PG 1 WC Dermatology SC Dermatology GA 127KW UT WOS:000317698900383 ER PT J AU Wynn, JL Hansen, NI Das, A Cotten, CM Goldberg, RN Sanchez, PJ Bell, EF Van Meurs, KP Carlo, WA Laptook, AR Higgins, RD Benjamin, DK Stoll, BJ AF Wynn, James L. Hansen, Nellie I. Das, Abhik Cotten, C. Michael Goldberg, Ronald N. Sanchez, Pablo J. Bell, Edward F. Van Meurs, Krisa P. Carlo, Waldemar A. Laptook, Abbot R. Higgins, Rosemary D. Benjamin, Daniel K., Jr. Stoll, Barbara J. CA Eunice Kennedy Shriver Natl Inst TI Early Sepsis Does Not Increase the Risk of Late Sepsis in Very Low Birth Weight Neonates SO JOURNAL OF PEDIATRICS LA English DT Article ID LATE-ONSET SEPSIS; INNATE IMMUNITY; PRETERM INFANTS; VACCINATION; OUTCOMES; NEWBORN; FAILURE AB Objective To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS). Study design Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained <= 72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for >= 5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates. Results Of 34 396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047]. Conclusions Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function. (J Pediatr 2013;162:942-8). C1 [Wynn, James L.] Vanderbilt Univ, Dept Pediat, Nashville, TN 37232 USA. [Hansen, Nellie I.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Cotten, C. Michael; Goldberg, Ronald N.; Benjamin, Daniel K., Jr.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Sanchez, Pablo J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Bell, Edward F.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Van Meurs, Krisa P.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Van Meurs, Krisa P.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Div Neonatol, Birmingham, AL USA. [Laptook, Abbot R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. RP Wynn, JL (reprint author), Vanderbilt Univ, Dept Pediat, 2215 B Garland Ave,1125 MRB4 Light Hall, Nashville, TN 37232 USA. EM james.wynn@vanderbilt.edu FU FDA HHS [1R01FD003519-01]; NCATS NIH HHS [UL1 TR000041, UL1 TR000454]; NCRR NIH HHS [M01 RR125, M01 RR16587, M01 RR32, M01 RR39, M01 RR44, M01 RR54, M01 RR59, M01 RR6022, M01 RR633, M01 RR64, M01 RR70, M01 RR7122, M01 RR750, M01 RR80, M01 RR997, UL1 RR24139]; NICHD NIH HHS [U10 HD40521, 1K24HD058735-01, 1R01HD057956-02, 1U10-HD45962-06, HHSN275201000003I, U10 HD021364, U10 HD053109, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, U10 HD53124, U10HD21415]; PHS HHS [8084, HHSN267200700051C, NCRR UL1024160] NR 25 TC 7 Z9 9 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2013 VL 162 IS 5 BP 942 EP U92 DI 10.1016/j.jpeds.2012.11.027 PG 10 WC Pediatrics SC Pediatrics GA 129JW UT WOS:000317836300016 PM 23295144 ER PT J AU Himes, SK Stroud, LR Scheidweiler, KB Niaura, RS Huestis, MA AF Himes, Sarah K. Stroud, Laura R. Scheidweiler, Karl B. Niaura, Raymond S. Huestis, Marilyn A. TI Prenatal Tobacco Exposure, Biomarkers for Tobacco in Meconium, and Neonatal Growth Outcomes SO JOURNAL OF PEDIATRICS LA English DT Article ID MATERNAL CIGARETTE-SMOKING; CANNABIS EXPOSURE; PREGNANCY; METABOLITES; NICOTINE; WOMEN; COMMUNITY; BEHAVIOR; DRUGS; ABUSE AB Objective To assess relationships between marker concentrations of tobacco in meconium and weekly self-reported maternal cigarette consumption, and prediction of neonatal growth outcomes. Study design Pregnant mothers (n = 119) from a longitudinal maternal smoking and infant neurobehavioral study (Behavior and Mood in Babies and Mothers [BAM BAM]) provided daily tobacco smoking histories. Nicotine, cotinine, and trans-3'-hydroxycotinine concentrations were quantified in 111 neonatal meconium specimens by liquid chromatography-tandem mass spectrometry. Results Median self-reported third trimester smoking was 5.9 cigarettes per day among smokers. Meconium samples from infants born to non-smokers (n = 42) were negative for tobacco markers, while specimens from self-reported smokers (n = 41) were positive for (median, range) nicotine (50.1 ng/g, 3.9-294), cotinine (73.9 ng/g, 6.4-329), and trans-3'-hydroxycotinine (124.5 ng/g, 10.2-478). Quitters (n = 28) self-reported stopping smoking at gestational weeks 2-39. Four meconium specimens from quitters were positive for tobacco biomarkers. Reduced birth weight, length, and head circumference significantly correlated with presence of meconium markers but not with individual or total marker concentrations. Among quitters and smokers, reduced infant birth weight, head circumference, and gestational age correlated with total and average daily cigarette consumption in the second and third trimesters. Conclusion Smoking cessation or reduction during pregnancy improved neonatal outcomes. The window of detection for tobacco in meconium appears to be the third trimester; however, low exposure in this trimester failed to be detected. These results will aid physicians in educating women who are pregnant or thinking about becoming pregnant on the negative consequences of smoking during pregnancy. In addition, infants at risk can be identified at birth to assist early intervention efforts. (J Pediatr 2013;162:970-5). C1 [Himes, Sarah K.; Scheidweiler, Karl B.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Stroud, Laura R.] Brown Univ, Miriam Hosp, Dept Psychiat & Human Behav, Alpert Med Sch,Ctr Behav Med, Providence, RI USA. [Stroud, Laura R.] Brown Univ, Miriam Hosp, Dept Psychiat & Human Behav, Alpert Med Sch,Ctr Prevent Med, Providence, RI USA. [Niaura, Raymond S.] Legacy Fdn, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institutes of Health [R01 DA019558]; National Institute on Drug Abuse FX Funded by National Institutes of Health (R01 DA019558) and the Intramural Research Program, National Institute on Drug Abuse. The authors declare no conflicts of interest. NR 30 TC 13 Z9 13 U1 0 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD MAY PY 2013 VL 162 IS 5 BP 970 EP 975 DI 10.1016/j.jpeds.2012.10.045 PG 6 WC Pediatrics SC Pediatrics GA 129JW UT WOS:000317836300022 PM 23211926 ER PT J AU Nguyen, TV Cowen, EW Leslie, KS AF Nguyen, Tien V. Cowen, Edward W. Leslie, Kieron S. TI Autoinflammation: From monogenic syndromes to common skin diseases SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE anakinra; autoinflammation; common dermatoses; inflammasomes; interleukin-1 beta; periodic fevers ID FAMILIAL MEDITERRANEAN FEVER; INTERLEUKIN-1 RECEPTOR ANTAGONIST; JUVENILE IDIOPATHIC ARTHRITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; MEVALONATE KINASE-DEFICIENCY; PERIODIC SYNDROME TRAPS; WIDESPREAD GRANULOMATOUS DERMATITIS; RECURRENT MULTIFOCAL OSTEOMYELITIS; HYPERIMMUNOGLOBULINEMIA-D SYNDROME; ATYPICAL NEUTROPHILIC DERMATOSIS AB Autoinflammation is characterized by aberrant regulation of the innate immune system and often manifests as periodic fevers and systemic inflammation involving multiple organs, including the skin. Mutations leading to abnormal behavior or activity of the interleukin 1 beta (IL-1 beta)-processing inflammasome complex have been found in several rare autoinflammatory syndromes, for which anticytokine therapy such as IL-1 or tumor necrosis factor-alfa inhibition may be effective. It is becoming clear that features of autoinflammation also affect common dermatoses, some of which were previously thought to be solely autoimmune in origin (eg, vitiligo, systemic lupus erythematosus). Recognizing the pathogenetic role of autoinflammation can open up new avenues for the targeted treatment of complex, inflammatory dermatoses. (J Am Acad Dermatol 2013;68:834-53.) C1 [Nguyen, Tien V.; Leslie, Kieron S.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nguyen, Tien V.] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, San Antonio, TX 78229 USA. RP Leslie, KS (reprint author), Univ Calif San Francisco, Sch Med, Dept Dermatol, Box 0316, San Francisco, CA 94143 USA. EM Lesliek@derm.ucsf.edu NR 229 TC 10 Z9 10 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAY PY 2013 VL 68 IS 5 BP 834 EP 853 DI 10.1016/j.jaad.2012.11.002 PG 20 WC Dermatology SC Dermatology GA 129IV UT WOS:000317833500024 PM 23453357 ER PT J AU Wadiwala, MF Kamal, AK AF Wadiwala, Muhammad Faisal Kamal, Ayeesha Kamran TI My patient has intracranial stenosis, does he need an intracerebral stent? Results of the SAMMPRIS study SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, 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, Stroke Serv, Int Cerebrovasc Translat Clin Res Training Progra, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. Aga Khan Univ Hosp, Vasc Fellowship Program, Int Cerebrovasc Translat Clin Res Training Progra, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43TW008660, D43 TW008660] NR 2 TC 0 Z9 0 U1 0 U2 2 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 MAY PY 2013 VL 63 IS 5 BP 654 EP 655 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 129VR UT WOS:000317872600027 PM 23758002 ER PT J AU Aschebrook-Kilfoy, B Ward, MH Dave, BJ Smith, SM Weisenburger, DD Chiu, BCH AF Aschebrook-Kilfoy, Briseis Ward, Mary H. Dave, Bhavana J. Smith, Sonali M. Weisenburger, Dennis D. Chiu, Brian C. -H. TI Dietary nitrate and nitrite intake and risk of non-Hodgkin lymphoma SO LEUKEMIA & LYMPHOMA LA English DT Article DE Non-Hodgkin lymphoma; nitrate; nitrite; diet ID DRINKING-WATER NITRATE; N-NITROSO COMPOUNDS; T(14/18)-DEFINED SUBTYPES; HISTORY QUESTIONNAIRE; CANCER; VEGETABLES; INDUCTION; HEALTH; LEVEL; WOMEN AB Although established risk factors such as immunodeficiency and viral infections may be responsible for a portion of cases of non-Hodgkin lymphoma (NHL), the vast majority of cases of NHL remain unexplained. The role of dietary nitrate and nitrite in NHL risk is of interest since they are precursors of N-nitroso compounds, and nitrosoureas have been shown to induce B- and T-cell lymphomas in animal studies. However, few studies have evaluated the potential association between consumption of nitrate and nitrite and NHL by subtype or chromosomal translocation status, and the results of these studies have been inconsistent. We estimated the dietary intake of nitrate and nitrite using a food frequency questionnaire in a population-based, case-control study of 348 cases and 470 controls conducted in Nebraska in 1999-2002. A non-significant excess risk of NHL was found among women who reported an intake of nitrite in the highest quartile compared to the lowest quartile (odds ratio [OR] = 1.6; 95% confidence interval [CI]: 0.8-2.9), particularly nitrite from animal sources (OR = 1.9; 95% CI: 1.0-3.4). No significant associations were observed for nitrate or nitrite by NHL subtype. Although there were some increases in risk that support the N-nitroso hypothesis, they were not significant and do not confer strong evidence of an association. C1 [Aschebrook-Kilfoy, Briseis; Chiu, Brian C. -H.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Smith, Sonali M.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dave, Bhavana J.] Univ Nebraska Med Ctr, Munroe Meyer Inst Genet & Rehabil, Dept Pediat, Omaha, NE USA. [Dave, Bhavana J.] Univ Nebraska Med Ctr, Munroe Meyer Inst Genet & Rehabil, Dept Pathol & Microbiol, Omaha, NE USA. [Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Aschebrook-Kilfoy, B (reprint author), Univ Chicago, Dept Hlth Studies, 5841 South Maryland Ave,N101B, Chicago, IL 60637 USA. EM brisa@uchicago.edu RI sebastianovitsch, stepan/G-8507-2013 FU American Institute for Cancer Research [99B083]; National Cancer Institute [CA94770, CA100555] FX This research was supported by a grant 99B083 from the American Institute for Cancer Research and, in part, by grants CA94770 and CA100555 from the National Cancer Institute. The authors thank Mr. Martin Bast of the Nebraska Lymphoma Study Group Registry and Tissue Bank for coordinating the patient identification and physician consent. The authors would also like to thank Smrati Jain for her work on the FISH studies. NR 33 TC 3 Z9 3 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAY PY 2013 VL 54 IS 5 BP 945 EP 950 DI 10.3109/10428194.2012.734613 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 126ZJ UT WOS:000317661900011 PM 23013327 ER PT J AU Shatzer, AN Espey, MG Chavez, M Tu, H Levine, M Cohen, JI AF Shatzer, Amber N. Espey, Michael Graham Chavez, Mayra Tu, Hongbin Levine, Mark Cohen, Jeffrey I. TI Ascorbic acid kills Epstein-Barr virus positive Burkitt lymphoma cells and Epstein-Barr virus transformed B-cells in vitro, but not in vivo SO LEUKEMIA & LYMPHOMA LA English DT Article DE Ascorbic acid; Epstein-Barr virus; Burkitt; lymphoma; reactive oxygen species; bortezomib ID NF-KAPPA-B; GENE-EXPRESSION; CANCER-CELLS; VITAMIN-C; LYMPHOPROLIFERATIVE DISEASE; ACQUIRED IMMUNODEFICIENCY; NASOPHARYNGEAL CARCINOMA; GASTRIC-CARCINOMA; HYDROGEN-PEROXIDE; HODGKINS-DISEASE AB Ascorbic acid has been shown to kill various cancer cell lines at pharmacologic concentrations. We found that Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) cells were more susceptible to ascorbic acid-induced cell killing than EBV-negative BL cells or EBV-transformed lymphoblastoid cells (LCLs). Ascorbic acid did not induce apoptosis in any of the tested cells but did induce the production of reactive oxygen species and cell death. Previously, we showed that bortezomib, a proteasome inhibitor, induces cell death in LCLs and EBV-positive BL cells. We found that ascorbic acid is strongly antagonistic for bortezomib-induced cell death in LCLs and EBV-positive BL cells. Finally, ascorbic acid did not prolong survival of severe combined immunodefiency mice inoculated with LCLs either intraperitoneally or subcutaneously. Thus, while ascorbic acid was highly effective at killing EBV-positive BL cells and LCLs in vitro, it antagonized cell killing by bortezomib and was ineffective in an animal model. C1 [Shatzer, Amber N.; Chavez, Mayra; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, Bethesda, MD 20892 USA. [Espey, Michael Graham; Tu, Hongbin; Levine, Mark] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Infect Dis Lab, 50 South Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU intramural research programs of the National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural research programs of the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 35 TC 6 Z9 6 U1 0 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD MAY PY 2013 VL 54 IS 5 BP 1069 EP 1078 DI 10.3109/10428194.2012.739686 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 126ZJ UT WOS:000317661900028 PM 23067008 ER PT J AU Ng, L Kelley, MW Forrest, D AF Ng, Lily Kelley, Matthew W. Forrest, Douglas TI Making sense with thyroid hormone-the role of T-3 in auditory development SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID TYPE-2 IODOTHYRONINE DEIODINASE; SOMATOSENSORY EVOKED-POTENTIALS; INDUCED HEARING IMPAIRMENT; INNER HAIR-CELLS; CONGENITAL HYPOTHYROIDISM; RECEPTOR-BETA; CONE PHOTORECEPTORS; ENDEMIC CRETINISM; GENE-EXPRESSION; OTOACOUSTIC EMISSIONS AB The senses are our window to the world, our interface with the habitat in which we live in and the basis for our communication with each other. Although sensory systems are not generally viewed as major targets of endocrine regulation, sensory development is profoundly influenced by thyroid hormone (T-3) signalling. In this article, we discuss this developmental role of T-3 and highlight the auditory system as the best-studied example of the interplay between systemic and local tissue mechanisms by which T-3 stimulates the onset of sensory function. Several genes that mediate the action of T-3 are known to promote sensory development in mice, including genes that encode T-3 receptors and deiodinase enzymes that amplify or deplete levels of T-3. We also discuss the current knowledge of sensory defects in human genetic disorders in which T-3 signalling is impaired. As sensory input provides the only means of acquiring information from the environment, the stimulation of sensory development is one of the most fundamental functions of T-3 signalling. Ng, L. et al. Nat. Rev. Endocrinol. 9, 296-307 (2013); published online 26 March 2013; doi:10.1038/nrendo.2013.58 C1 [Ng, Lily; Forrest, Douglas] NIDDKD, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. [Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. RP Forrest, D (reprint author), NIDDKD, Lab Endocrinol & Receptor Biol, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Deafness and other Communication Disorders FX The authors acknowledge the support of the intramural research program at the National Institute of Diabetes and Digestive and Kidney Diseases and at the National Institute on Deafness and other Communication Disorders. The authors thank Dr Francesco Celi for helpful comments. NR 129 TC 18 Z9 18 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD MAY PY 2013 VL 9 IS 5 BP 296 EP 307 DI 10.1038/nrendo.2013.58 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 130KP UT WOS:000317914700010 PM 23529044 ER PT J AU Biesecker, LG Spinner, NB AF Biesecker, Leslie G. Spinner, Nancy B. TI A genomic view of mosaicism and human disease SO NATURE REVIEWS GENETICS LA English DT Review ID MONOZYGOTIC TWINS DISCORDANT; DETECTABLE CLONAL MOSAICISM; BECKWITH-WIEDEMANN-SYNDROME; MCCUNE-ALBRIGHT SYNDROME; COPY-NUMBER-VARIATION; UNIPARENTAL DISOMY; OSTEOGENESIS IMPERFECTA; NEUROFIBROMATOSIS TYPE-1; CHROMOSOMAL MOSAICISM; ACTIVATING MUTATIONS AB Genomic technologies, including next-generation sequencing (NGS) and single-nucleotide polymorphism (SNP) microarrays, have provided unprecedented opportunities to assess genomic variation among, and increasingly within, individuals. It has long been known that cancer is a mosaic genetic disorder, but mosaicism is now apparent in a diverse range of other clinical disorders, as indicated by their tissue distributions and inheritance patterns. Recent technical advances have uncovered the causative mosaic variant underlying many of these conditions and have provided insight into the pervasiveness of mosaicism in normal individuals. Here, we discuss the clinical and molecular classes of mosaicism, their detection and the biological insights gained from these studies. C1 [Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Spinner, Nancy B.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Spinner, Nancy B.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM lesb@mail.nih.gov FU Intramural Research Program of the US National Human Genome Research Institute of the National Institutes of Health; US National Institute of Diabetes and Digestive and Kidney Diseases; US National Human Genome Research Institute; Ring 14 Association; Fred and Suzanne Biesecker Liver Center in the Research Institute at the Children's Hospital of Philadelphia FX L. G. B. is funded by the Intramural Research Program of the US National Human Genome Research Institute of the National Institutes of Health. He is an uncompensated consultant to the Illumina Corporation and receives an honorarium from the Wiley-Blackwell Corporation for editing activities. N. B. S. is funded by the US National Institute of Diabetes and Digestive and Kidney Diseases, the US National Human Genome Research Institute, the Ring 14 Association and is supported by the Fred and Suzanne Biesecker Liver Center in the Research Institute at the Children's Hospital of Philadelphia. She is grateful, as always, to L. Conlin, both for scientific discussion and for the generation of the drafts of figures included in this work. NR 95 TC 142 Z9 143 U1 5 U2 83 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD MAY PY 2013 VL 14 IS 5 BP 307 EP 320 DI 10.1038/nrg3424 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 127XQ UT WOS:000317732600009 PM 23594909 ER PT J AU Gabaldon, T Koonin, EV AF Gabaldon, Toni Koonin, Eugene V. TI Functional and evolutionary implications of gene orthology SO NATURE REVIEWS GENETICS LA English DT Article ID COMPARATIVE GENOMICS; ENZYME EVOLUTION; PROTEIN FAMILIES; PARALOGS; IDENTIFICATION; CONSERVATION; HOMOLOGY; QUEST; CLASSIFICATION; DUPLICATION AB Orthologues and paralogues are types of homologous genes that are related by speciation or duplication, respectively. Orthologous genes are generally assumed to retain equivalent functions in different organisms and to share other key properties. Several recent comparative genomic studies have focused on testing these expectations. Here we discuss the complexity of the evolution of gene-phenotype relationships and assess the validity of the key implications of orthology and paralogy relationships as general statistical trends and guiding principles. C1 [Gabaldon, Toni] Ctr Genom Regulat, Bioinformat & Genom Programme, Barcelona 08003, Spain. [Gabaldon, Toni] UPF, Barcelona 08003, Spain. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Gabaldon, T (reprint author), Ctr Genom Regulat, Bioinformat & Genom Programme, Dr Aiguader 88, Barcelona 08003, Spain. EM tgabaldon@crg.es; koonin@ncbi.nlm.nih.gov RI Gabaldon, Toni/A-7336-2008 OI Gabaldon, Toni/0000-0003-0019-1735 FU European Research Council; Spanish Ministry of Economy and Competitiveness; US Department of Health and Human Services FX T.G. is supported by funds from the European Research Council and the Spanish Ministry of Economy and Competitiveness. E. V. K. is supported by intramural funds of the US Department of Health and Human Services (to the US National Library of Medicine). NR 57 TC 101 Z9 102 U1 7 U2 65 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD MAY PY 2013 VL 14 IS 5 BP 360 EP 366 DI 10.1038/nrg3456 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 127XQ UT WOS:000317732600013 PM 23552219 ER PT J AU Alexander-Bloch, A Giedd, JN Bullmore, ET AF Alexander-Bloch, Aaron Giedd, Jay N. Bullmore, Edward T. TI Imaging structural co-variance between human brain regions SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID VOXEL-BASED MORPHOMETRY; GRAPH-THEORETICAL ANALYSIS; HUMAN CEREBRAL-CORTEX; STATE FUNCTIONAL CONNECTIVITY; LATENT VOLUMETRIC STRUCTURE; HUMAN CORTICAL DEVELOPMENT; AUTOMATED 3-D EXTRACTION; TEMPORAL-LOBE EPILEPSY; WHITE-MATTER INTEGRITY; SURFACE-BASED ANALYSIS AB Brain structure varies between people in a markedly organized fashion. Communities of brain regions co-vary in their morphological properties. For example, cortical thickness in one region influences the thickness of structurally and functionally connected regions. Such networks of structural co-variance partially recapitulate the functional networks of healthy individuals and the foci of grey matter loss in neurodegenerative disease. This architecture is genetically heritable, is associated with behavioural and cognitive abilities and is changed systematically across the lifespan. The biological meaning of this structural co-variance remains controversial, but it appears to reflect developmental coordination or synchronized maturation between areas of the brain. This Review discusses the state of current research into brain structural co-variance, its underlying mechanisms and its potential value in the understanding of various neurological and psychiatric conditions. C1 [Alexander-Bloch, Aaron; Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [Alexander-Bloch, Aaron] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Alexander-Bloch, Aaron; Bullmore, Edward T.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 0SZ, England. [Bullmore, Edward T.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge CB21 5EF, England. [Bullmore, Edward T.] GlaxoSmithKline, Clin Unit Cambridge, Cambridge CB2 0QQ, England. RP Alexander-Bloch, A (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM aalexanderbloch@gmail.com; etb23@cam.ac.uk RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; Bullmore, Edward/C-1706-2012; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Bullmore, Edward/0000-0002-8955-8283; Alexander-Bloch, Aaron/0000-0001-6554-1893 FU US National Institutes of Health (NIH) Intramural Research Program; Wellcome Trust; Medical Research Council (UK); NIH-Oxford-Cambridge Scholarship Program; NIH MD/PhD Partnership Program; UCLA Caltech Medical Scientist Training Program FX The Child Psychiatry Branch, US National Institute of Mental Health, is supported by the US National Institutes of Health (NIH) Intramural Research Program. The Behavioural and Clinical Neuroscience Institute, University of Cambridge, is supported by the Wellcome Trust and the Medical Research Council (UK). A.A.-B. is supported by the NIH-Oxford-Cambridge Scholarship Program, the NIH MD/PhD Partnership Program and the UCLA Caltech Medical Scientist Training Program. NR 220 TC 143 Z9 144 U1 9 U2 81 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 MAY PY 2013 VL 14 IS 5 BP 322 EP 336 DI 10.1038/nrn3465 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 130KK UT WOS:000317913900009 PM 23531697 ER PT J AU Mayo, LM Fraser, D Childs, E Momenan, R Hommer, DW de Wit, H Heilig, M AF Mayo, Leah M. Fraser, Diana Childs, Emma Momenan, Reza Hommer, Daniel W. de Wit, Harriet Heilig, Markus TI Conditioned Preference to a Methamphetamine-Associated Contextual Cue in Humans SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE conditioning; place preference; stimulant; amphetamine; reward ID MEASURING REWARD; METHYLPHENIDATE; AMPHETAMINE; ADDICTION; PARADIGM; BRAIN; TASK AB Classical conditioning is widely used to study motivational properties of addictive drugs in animals, but has rarely been used in humans. We established a procedure suitable for studying the neurobiology and individual determinants of classical conditioning in humans. Healthy volunteers were randomly assigned to four groups that received methamphetamine or placebo in the presence of distinctive environmental cues under paired or unpaired conditions. During each session, subjects performed tasks known to activate the ventral striatum. Tasks were performed in the presence of a distinctive context, consisting of a screen background image of a beach or mountains, accompanied by corresponding sounds. Separate groups of subjects carried out the tasks under high ($35-50) or low ($5-20) reward conditions. Within each of the two reward conditions, one group (paired) received methamphetamine (20 mg, oral) or placebo consistently associated with one of the contexts, while the other (unpaired) received drug or placebo unrelated to context. A fifth group (paired) performed the tasks with contextual cues but in the absence of monetary incentives. Before and after conditioning, participants carried out a series of forced choice tasks for the contextual cues, and change of preference over time was analyzed. All paired groups showed a significant increase in preference for the drug-associated context, with a linear trend for increase across the levels of reward. Preference was unrelated to subjective drug effects, and did not change in the unpaired group. These data support the translational utility of our conditioning procedure for studies of reward mechanisms in humans. Neuropsychopharmacology (2013) 38, 921-929; doi:10.1038/npp.2013.3; published online 27 February 2013 C1 [Mayo, Leah M.; Childs, Emma; de Wit, Harriet] Univ Chicago, Human Behav Pharmacol Lab, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. [Fraser, Diana; Momenan, Reza; Hommer, Daniel W.; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. [Fraser, Diana] Linkoping Univ, Dept Clin & Expt Med, Likoping, Sweden. RP Heilig, M (reprint author), NIAAA, 10 Ctr Dr,10-1E-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Childs, Emma/K-6775-2014; OI Childs, Emma/0000-0003-1747-5208; Heilig, Markus/0000-0003-2706-2482; de Wit, Harriet/0000-0002-7211-8994; Mayo, Leah/0000-0002-0645-4869 FU Division of Intramural Clinical and Biological Research NIAAA; Unilever; [DA02812]; [T32 DA007255] FX This research was supported by the Division of Intramural Clinical and Biological Research NIAAA (MH) and by DA02812 (HdW). Leah Mayo was supported by T32 DA007255. We want to thank Dr Melanie Schwandt for data analysis and Mrs Karen Smith for assistance with the bibliography.; HdW has received support from Unilever for a project unrelated to this research. MH is or has been the PI on Cooperative Research and Development Agreements between the NIH and Eli Lilly, Johnson & Johnson, Merck, Bristol Meyer Squibb, and GlaxoSmithKline unrelated to this project. NR 25 TC 12 Z9 12 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2013 VL 38 IS 6 BP 921 EP 929 DI 10.1038/npp.2013.3 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 126AX UT WOS:000317584600002 PM 23416857 ER PT J AU Thirunarayanan, N Nir, EA Raaka, BM Gershengorn, MC AF Thirunarayanan, Nanthakumar Nir, Eshel A. Raaka, Bruce M. Gershengorn, Marvin C. TI Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE taltirelin; thyrotropin-releasing hormone (TRH); TRH receptors; TRH analogs; CNS effects ID INCREASED DEPRESSION; ANALOGS; PITUITARY; BEHAVIOR; BINDING; SITES; BRAIN AB Thyrotropin-releasing hormone receptor type 2 (TRH-R2), not TRH-R1, has been proposed to mediate the CNS effects of TRH and its more effective analog taltirelin (TAL). Consistent with this idea, TAL exhibited higher binding affinity and signaling potency at mouse TRH-R2 than TRH-R1 in a model cell system. We used TRH-R1 knockout (R1ko), R2ko and R1/R2ko mice to determine which receptor mediates the CNS effects of TAL. There was no TRH-R1 mRNA in R1ko and R1/R2ko mice and no TRH-R2 mRNA in R2ko and R1/R2ko mice. Specific [H-3]MeTRH binding to whole brain membranes was 5% of wild type (WT) for R1ko mice, 100% for R2ko mice and 0% for R1/R2ko mice, indicating TRH-R1 is the predominant receptor expressed in the brain. In arousal assays, TAL shortened sleep time with pentobarbital sedation in WT and R2ko mice by 44 and 49% and with ketamine/xylazine sedation by 66 and 55%, but had no effect in R1ko and R1/R2ko mice. In a tail flick assay of nociception, TAL increased response latency by 65 and 70% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. In a tail suspension test of depression-like behavior, TAL increased mobility time by 49 and 37% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. Thus, in contrast to the generally accepted view that the CNS effects of TAL are mediated by TRH-R2, these effects are mediated primarily if not exclusively by TRH-R1 in mice. Neuropsychopharmacology (2013) 38, 950-956; doi:10.1038/npp.2012.256; published online 13 February 2013 C1 [Thirunarayanan, Nanthakumar; Nir, Eshel A.; Raaka, Bruce M.; Gershengorn, Marvin C.] NIDDK, Lab Endocrinol & Receptor Biol, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Lab Endocrinol & Receptor Biol, NIH, 50 South Dr,Room 4134, Bethesda, MD 20892 USA. EM MarvinG@intra.niddk.nih.gov FU NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK0011006] FX We thank Alexander Gregerov, PhD (Omeros Corporation, Seattle, WA) for generously providing the R1ko mice. This work was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), DK0011006. NR 26 TC 6 Z9 6 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2013 VL 38 IS 6 BP 950 EP 956 DI 10.1038/npp.2012.256 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 126AX UT WOS:000317584600005 PM 23303050 ER PT J AU Barbier, E Vendruscolo, LF Schlosburg, JE Edwards, S Juergens, N Park, PE Misra, KK Cheng, KJ Rice, KC Schank, J Schulteis, G Koob, GF Heilig, M AF Barbier, Estelle Vendruscolo, Leandro F. Schlosburg, Joel E. Edwards, Scott Juergens, Nathan Park, Paula E. Misra, Kaushik K. Cheng, Kejun Rice, Kenner C. Schank, Jesse Schulteis, Gery Koob, George F. Heilig, Markus TI The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE opioids; heroin; self-administration; substance P; neurokinin receptor ID SUBSTANCE-P; GENE-EXPRESSION; DRUG-ADDICTION; MICE LACKING; STRESS; REWARD; RATS; BEHAVIOR; MORPHINE; BRAIN AB Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward-and stress-related brain areas both in ShA and LgA rats compared with heroin-naive rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects. Neuropsychopharmacology (2013) 38, 976-984; doi:10.1038/npp.2012.261; published online 16 January 2013 C1 [Barbier, Estelle; Juergens, Nathan; Schank, Jesse; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Vendruscolo, Leandro F.; Schlosburg, Joel E.; Edwards, Scott; Park, Paula E.; Misra, Kaushik K.; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Cheng, Kejun; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. [Schulteis, Gery] VA San Diego Healthcare Syst, Res Serv, San Diego, CA USA. [Schulteis, Gery] Univ Calif San Diego, Med Ctr, Dept Anesthesiol, San Diego, CA 92103 USA. RP Barbier, E (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,10-1E-5330, Bethesda, MD 20892 USA. EM barbieres@mail.nih.gov RI koob, george/P-8791-2016; OI Heilig, Markus/0000-0003-2706-2482 FU National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; National Institute on Drug Abuse [DA004043]; Biomedical Laboratory Research and Development Program, Veterans Health Administration; Pearson Center for Alcoholism and Addiction Research FX We thank Dr Eric Augier for its insightful comments regarding the manuscript. This research was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism (MH) and the National Institute on Drug Abuse (KR). This work was also supported by grants from the National Institute on Drug Abuse (DA004043, GFK), a Research Career Scientist Award from the Biomedical Laboratory Research and Development Program, Veterans Health Administration (GS), and by the Pearson Center for Alcoholism and Addiction Research. This is article number 21813 from the Scripps Research Institute. NR 33 TC 17 Z9 17 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAY PY 2013 VL 38 IS 6 BP 976 EP 984 DI 10.1038/npp.2012.261 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 126AX UT WOS:000317584600008 PM 23303056 ER PT J AU Derdeyn, CP Fiorella, D Lynn, MJ Rumboldt, Z Cloft, HJ Gibson, D Turan, TN Lane, BF Janis, LS Chimowitz, MI AF Derdeyn, Colin P. Fiorella, David Lynn, Michael J. Rumboldt, Zoran Cloft, Harry J. Gibson, Daniel Turan, Tanya N. Lane, Bethany F. Janis, L. Scott Chimowitz, Marc I. CA Stenting Aggressive Med Management TI Mechanisms of Stroke After Intracranial Angioplasty and Stenting in the SAMMPRIS Trial SO NEUROSURGERY LA English DT Article DE Angioplasty and stenting; Hemorrhage; Stroke ID AGGRESSIVE MEDICAL-MANAGEMENT; CEREBRAL HYPERPERFUSION SYNDROME; PREVENTING RECURRENT STROKE; ARTERY-STENOSIS; BASILAR ARTERY; WINGSPAN STENT; COMPLICATIONS; DESIGN AB BACKGROUND: Enrollment in the Stenting and Aggressive Medical Management for the Prevention of stroke in Intracranial Stenosis (SAMMPRIS) trial was halted owing to higher-than-expected 30-day stroke rates in the stenting arm. Improvement in periprocedural stroke rates from angioplasty and stenting for intracranial atherosclerotic disease (ICAD) requires an understanding of the mechanisms of these events. OBJECTIVE: To identify the types and mechanisms of periprocedural stroke after angioplasty and stenting for ICAD. METHODS: Patients who experienced a hemorrhagic or ischemic stroke or a cerebral infarct with temporary signs within 30 days of attempted angioplasty and stenting in SAMMPRIS were identified. Study records, including case report forms, procedure notes, and imaging were reviewed. Strokes were categorized as ischemic or hemorrhagic. Ischemic strokes were categorized as perforator territory, distal embolic, or delayed stent thrombosis. Hemorrhagic strokes were categorized as subarachnoid or intra-parenchymal. Causes of hemorrhage (wire perforation, vessel rupture) were recorded. RESULTS: Three patients had an ischemic stroke after diagnostic angiography. Two of these strokes were unrelated to the procedure. Twenty-one patients had an ischemic stroke (n = 19) or cerebral infarct with temporary signs (n = 2) within 30 days of angioplasty and stenting. Most (n = 15) were perforator territory and many of these occurred after angiographically successful angioplasty and stenting of the basilar artery (n = 8). Six patients experienced a subarachnoid hemorrhage (3 from wire perforation) and 7 had a delayed intraparenchymal hemorrhage. CONCLUSION: Efforts at reducing complications from angioplasty and stenting for ICAD must focus on reducing the risks of regional perforator infarction, delayed intraparenchymal hemorrhage, and wire perforation. C1 [Derdeyn, Colin P.; Gibson, Daniel] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Derdeyn, Colin P.; Gibson, Daniel] Washington Univ, Sch Med, Dept Neurol & Neurosurg, St Louis, MO 63110 USA. [Fiorella, David] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY 11794 USA. [Lynn, Michael J.; Lane, Bethany F.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, Atlanta, GA 30322 USA. [Rumboldt, Zoran] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Cloft, Harry J.] Mayo Clin, Dept Radiol, Rochester, MN 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), 510 South Kingshighway Blvd, St Louis, MO 63110 USA. EM derdeync@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 [UL1RR029882]; University of Florida [UL1RR029889]; University of Cincinnati [UL1RR029890]; University of California, San Francisco [UL1RR024131]; AstraZeneca; NINDS [U01 NS058728, P50 55977, R01 NS051631]; SAMMPRIS grant 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, sitemonitoring, and study auditing. This research was also supported by the Investigator-Sponsored Study Program of AstraZeneca that donates rosuvastatin (Crestor) to study patients. Drs Fiorella, Derdeyn, Turan, Janis, and Chimowitz, Michael Lynn, MS, and Bethany Lane, RN, serve on the Executive Committee of the SAMMPRIS trial that is funded by the NINDS (grant U01 NS058728). All receive salary support from the SAMMPRIS grant. All other authors were investigators in SAMMPRIS and were reimbursed from the SAMMPRIS grant for their effort. Dr Derdeyn receives grant support from the NINDS (P50 55977; R01 NS051631). He is also on the Scientific Advisory Board for W. L Gore and Associates and is the Chair of the Scientific Advisory Board for Pulse Therapeutics. Dr Fiorella has received institutional research support from Seimens Medical Imaging and Microvention, consulting fees from Codman/Johnson and Johnson, NFocus, W. L. Gore and Associates, and EV3/Covidien, and royalties from Codman/Johnson and Johnson. He has received honoraria from Scientia and has ownership interest in CVSL and Vascular Simulations. M. J. Lynn, MS, receives grant support from the National Eye Institute. He is the principal investigator of the Coordinating Center for Infant Aphakia Treatment Study (EY013287) and a coinvestigator on the Core Grant for Vision Research (EY006360). Dr Cloft has received research support for the SAPPHIRE Carotid Stent registry. B. F. Lane, RN, has received consulting fees from Microvention Terumo. Dr Turan is a past recipient of funding from the American Academy of Neurology (AAN) Foundation Clinical Research Training Fellowship and is the current recipient of a K23 grant from NIH/NINDS (1K23NS069668-01A1). She has also served as an expert witness in medical legal cases. Dr Janis is a program director at the NINDS. Dr Chimowitz has received research grants from NINDS to fund the WASID trial (1 R01 NS36643) and to fund other research on intracranial stenosis (1 K24 NS050307 and 1 R01 NS051688). He currently serves on the stroke adjudication committee of an industry-funded osteoporosis drug trial (Merck and Co, Inc) and on the DSMB of another industry-funded patent foramen ovale closure trial (W. L. Gore and Associates) and is compensated for those activities. He has also served as an expert witness in medical legal cases. NR 17 TC 36 Z9 37 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAY PY 2013 VL 72 IS 5 BP 777 EP 795 DI 10.1227/NEU.0b013e318286fdc8 PG 19 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 130KS UT WOS:000317915100024 PM 23328689 ER PT J AU Colegate, SM Gardner, DR Davis, TZ Betz, JM Panter, KE AF Colegate, Steven M. Gardner, Dale R. Davis, T. Zane Betz, Joseph M. Panter, Kip E. TI Dehydropyrrolizidine Alkaloids in Two Cryptantha Species: Including Two New Open Chain Diesters One of Which is Amphoteric SO PHYTOCHEMICAL ANALYSIS LA English DT Article DE HPLCMS: amphoteric pyrrolizidine alkaloid; cryptanthine; dehydropyrrolizidine alkaloids; echimidine; echiuplatine; winged cryptantha; Cryptantha inequata; Cryptantha utahensis; scented catseye ID PYRROLIZIDINE ALKALOIDS; N-OXIDES; BIOSYNTHESIS; SPECTROSCOPY; LYCOPSAMINE; POLLEN; ACID; MS AB Introduction A livestock poisoning outbreak near Kingman, Arizona, USA, potentially linked to dehydropyrrolizidine alkaloids, prompted an evaluation of some local plants for the presence of these hepatotoxic alkaloids. Objective To qualitatively and quantitatively examine two species of Cryptantha, a Boraginaceous genus previously shown to produce potentially toxic pyrrolizidine alkaloids, collected from the vicinity of Kingman, Arizona. Method Plant extracts were analysed using HPLCelectrospray ionisation (+)MS and MS/MS to determine the presence of dehydropyrrolizidine alkaloid esters. Identities were confirmed by comparison of chromatographic and MS data with authenticated standards and, in the case of the previously undescribed alkaloids, using one- and two-dimensional NMR spectroscopy and high-resolution mass measurement. Results Cryptantha inequata and C. utahensis were shown to produce retronecine-based dehydropyrrolizidine alkaloids at approximately 0.05% and 0.09% w/w respectively. Cryptantha inequata produced mainly echimidine, acetylechimidine and echiuplatine; dehydropyrrolizidine alkaloids that were previously associated with Echium plantagineum. The previously undescribed structure of echiuplatine was elucidated as an amphoteric, open chain diester with angelic acid and 3-hydroxy-3-methylglutaric acid. Along with lycopsamine, intermedine and dihydroxyechiumine, C. utahensis produced cryptanthine, a previously undescribed open chain diester alkaloid esterified with angelic acid and 2,3-dihydroxy-2-methylbutanoic acid. All pyrrolizidine alkaloids detected were present in the plants mainly as their N-oxides. Conclusion The retronecine-based alkaloids detected in both Cryptantha species herein investigated aligns them within the Krynitzkia subgenus. The dehydropyrrolizidine alkaloids detected are expected to be toxic but the low levels in the plants potentially mitigate the risk. The identification of the amphoteric echiuplatine provides a cautionary note with respect to the analysis of total dehydropyrrolizidine alkaloid content. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Colegate, Steven M.; Gardner, Dale R.; Davis, T. Zane; Panter, Kip E.] ARS, USDA, Poisonous Plant Res Lab, Logan, UT USA. [Betz, Joseph M.] NIH, Off Dietary Supplements, Bethedsa, MD USA. RP Colegate, SM (reprint author), ARS, USDA, Poisonous Plant Res Lab, Logan, UT USA. EM steven.colegate@ars.usda.gov NR 27 TC 6 Z9 6 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0958-0344 J9 PHYTOCHEM ANALYSIS JI Phytochem. Anal. PD MAY-JUN PY 2013 VL 24 IS 3 BP 201 EP 212 DI 10.1002/pca.2400 PG 12 WC Biochemical Research Methods; Plant Sciences; Chemistry, Analytical SC Biochemistry & Molecular Biology; Plant Sciences; Chemistry GA 131OO UT WOS:000318003200002 PM 23070903 ER PT J AU Machiela, MJ Chen, C Liang, LM Diver, WR Stevens, VL Tsilidis, KK Haiman, CA Chanock, SJ Hunter, DJ Kraft, P AF Machiela, Mitchell J. Chen, Constance Liang, Liming Diver, W. Ryan Stevens, Victoria L. Tsilidis, Konstantinos K. Haiman, Christopher A. Chanock, Stephen J. Hunter, David J. Kraft, Peter CA Breast Prostate Canc Cohort TI One thousand genomes imputation in the national cancer institute breast and prostate cancer cohort consortium aggressive prostate cancer genome-wide association study SO PROSTATE LA English DT Article DE rare variants; association; fine mapping ID SUSCEPTIBILITY LOCUS; GENETIC ASSOCIATION; COMMON VARIANT; RARE VARIANTS; RISK; SEQUENCE; POWER; DISCRIMINATE; GENOTYPES; 11Q13 AB BACKGROUND Genotype imputation substantially increases available markers for analysis in genome-wide association studies (GWAS) by leveraging linkage disequilibrium from a reference panel. We sought to (i) investigate the performance of imputation from the August 2010 release of the 1000 Genomes Project (1000GP) in an existing GWAS of prostate cancer, (ii) look for novel associations with prostate cancer risk, (iii) fine-map known prostate cancer susceptibility regions using an approximate Bayesian framework and stepwise regression, and (iv) compare power and efficiency of imputation and de novo sequencing. METHODS We used 2,782 aggressive prostate cancer cases and 4,458 controls from the NCI Breast and Prostate Cancer Cohort Consortium aggressive prostate cancer GWAS to infer 5.8 million well-imputed autosomal single nucleotide polymorphisms (SNPs). RESULTS Imputation quality, as measured by correlation between imputed and true allele counts, was higher among common variants than rare variants. We found no novel prostate cancer associations among a subset of 1.2 million well-imputed low-frequency variants. At a genome-wide sequencing cost of $2,500, imputation from SNP arrays is a more powerful strategy than sequencing for detecting disease associations of SNPs with minor allele frequencies (MAF) above 1%. CONCLUSIONS 1000GP imputation provided dense coverage of previously identified prostate cancer susceptibility regions, highlighting its potential as an inexpensive first-pass approach to fine mapping in regions such as 5p15 and 8q24. Our study shows 1000GP imputation can accurately identify low-frequency variants and stresses the importance of large sample size when studying these variants. Prostate 73: 677689, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Machiela, Mitchell J.; Chen, Constance; Liang, Liming; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Machiela, Mitchell J.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Diver, W. Ryan; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Tsilidis, Konstantinos K.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Tsilidis, Konstantinos K.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. RP Kraft, P (reprint author), 655 Huntington Ave,Bldg 2 Room 207, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Machiela, Mitchell/F-9781-2013 OI Machiela, Mitchell/0000-0001-6538-9705 FU US National Institutes of Health, National Cancer Institute [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics [T32-CA09001, T32-GM074897] FX Grant sponsor: US National Institutes of Health, National Cancer Institute; Grant numbers: U01-CA98233-07; U01-CA98710-06; U01-CA98216-06; U01-CA98758-07; Grant sponsor: NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics; Grant numbers: T32-CA09001. T32-GM074897.; Special thanks to the participants and study staff from each study NCI BPC3 study. In particular, we would like to acknowledge the contributions from Demetrius Albanes (Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland), Gerald L. Andriole (Division of Urologic Surgery, School of Medicine, Washington University, St. Louis, Missouri), Sonja I. Berndt (Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland), H. Bas Bueno-de-Mesquita (National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands), Brian Henderson (Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California), Mattias Johansson (International Agency for Research on Cancer (IARC), Lyon, France; Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea ~ University, Umea ~, Sweden), Loic Le Marchand University of Hawaii Cancer Center, Honolulu, Hawaii), Sara Lindstrom (Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts), J. Ramon Quiros (Public Health Directorate, Asturias, Spain), Susan M. Gapstur (Epidemiology Research Program, American Cancer Society, Atlanta, Georgia), J. Michael Gaziano (Division of Aging, Brigham and Women's Hospital, Boston, Massachusetts; Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, Massachusetts), Edward Giovannucci (Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), Salvatore Panico (Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy), Frederick Schumacher (Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California), Meir J. Stampferz (Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), Anne Tjonneland (Institute of Cancer Epidemiology, Danish Cancer Society), Ruth Travis (Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom), Dimitrios Trichopoulos (Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Hellenic Health Foundation; Bureau of Epidemiologic Research of the Academy of Athens) Jarmo Virtamo (Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland), Walter C. Willett (Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts), and Meredith Yeager (Core Genotype Facility, National Cancer Institute, National Institutes of Health, Gaithersburg, Maryland). This work was supported by the US National Institutes of Health, National Cancer Institute (cooperative agreements U01-CA98233-07 to David J. Hunter, U01-CA98710-06 to Susan M. Gapstur, U01-CA98216-06 to Elio Riboli and Rudolf Kaaks, and U01-CA98758-07 to Brian E.; Henderson, and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics) as well as support from T32-CA09001 and T32-GM074897. NR 43 TC 4 Z9 4 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY PY 2013 VL 73 IS 7 BP 677 EP 689 DI 10.1002/pros.22608 PG 13 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 130PL UT WOS:000317930600001 PM 23255287 ER PT J AU Geybels, MS Hutter, CM Kwon, EM Ostrander, EA Fu, R Feng, ZD Stanford, JL Peters, U AF Geybels, Milan S. Hutter, Carolyn M. Kwon, Erika M. Ostrander, Elaine A. Fu, Rong Feng, Ziding Stanford, Janet L. Peters, Ulrike TI Variation in selenoenzyme genes and prostate cancer risk and survival SO PROSTATE LA English DT Article DE prostate cancer; risk; mortality; selenoenzyme genes; genetic variation ID SELENOPROTEIN-P; SELENIUM SUPPLEMENTATION; OXIDATIVE STRESS; HUMAN HEALTH; PREVENTION; TRIAL; POLYMORPHISMS; GPX1 AB BACKGROUND While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival. METHODS We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based casecontrol study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n=2), GPX2 (n=4), GPX3 (n=6), GPX4 (n=6), SEP15 (n=4), SEPP1 (n=6), and TXNRD1 (n=7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively. RESULTS Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.440.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4, and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons. CONCLUSIONS We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets. Prostate 73: 734742, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Geybels, Milan S.] Maastricht Univ, Dept Epidemiol, GROW Sch Oncol & Dev Biol, Maastricht, Netherlands. [Hutter, Carolyn M.; Fu, Rong; Feng, Ziding; Stanford, Janet L.; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Hutter, Carolyn M.; Stanford, Janet L.; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Kwon, Erika M.] Johns Hopkins Univ, Sch Med, Program Human Genet & Mol Biol, Baltimore, MD USA. [Fu, Rong; Feng, Ziding] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M4-B874, Seattle, WA 98109 USA. EM upeters@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute [R01-CA056678, R01-CA092579, R03-CA137799, P50-CA097186, R01-CA120582]; Dutch Cancer Society (Fred Hutchinson Cancer Research Center) [UM 2009-4556]; Intramural Program of the National Human Genome Research Institute FX Grant sponsor: National Cancer Institute; Grant numbers: R01-CA056678; R01-CA092579; R03-CA137799; P50-CA097186; R01-CA120582; Grant sponsor: Dutch Cancer Society (Fred Hutchinson Cancer Research Center); Grant number: UM 2009-4556; Grant sponsor: Intramural Program of the National Human Genome Research Institute. NR 30 TC 15 Z9 17 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY PY 2013 VL 73 IS 7 BP 734 EP 742 DI 10.1002/pros.22617 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 130PL UT WOS:000317930600007 PM 23143801 ER PT J AU Radke, AK Holtz, NA Gewirtz, JC Carroll, ME AF Radke, Anna K. Holtz, Nathan A. Gewirtz, Jonathan C. Carroll, Marilyn E. TI Reduced emotional signs of opiate withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake SO PSYCHOPHARMACOLOGY LA English DT Article DE CPA; Morphine; Rat; Saccharin preference; Startle; Withdrawal; Selective breeding ID CONDITIONED PLACE AVERSION; PRECIPITATED MORPHINE-WITHDRAWAL; ACOUSTIC STARTLE REACTIVITY; ACUTE ALCOHOL-WITHDRAWAL; NUCLEUS-ACCUMBENS SHELL; ACUTE OPIOID DEPENDENCE; SEX-DIFFERENCES; PHYSICAL-DEPENDENCE; ETHANOL WITHDRAWAL; DRUG-ABUSE AB Rats bred for high (HiS) and low (LoS) saccharin intake exhibit divergent behavioral responses to multiple drugs of abuse, with HiS rats displaying greater vulnerability to drug taking. Previous research indicates that this effect may be due to increased sensitivity to reward in HiS rats and to the aversive effects of acute drug administration in LoS rats. The current study investigated whether HiS and LoS rats also exhibit different behavioral signs of withdrawal following one or repeated opiate exposures. Emotional signs of opiate withdrawal were assessed with potentiation of the acoustic startle reflex and conditioned place aversion (CPA) in male and female HiS and LoS rats. Startle was measured before and 4 h after a 10-mg/kg injection of morphine on days 1, 2, and 7 of opiate exposure. CPA was induced with a 2-day, naloxone-precipitated conditioning paradigm. Somatic signs of withdrawal and weight loss were also measured. Male and female LoS rats exhibited lower startle potentiation than HiS rats on the seventh day of morphine exposure. LoS male rats also failed to develop a CPA to morphine withdrawal. No differences in physical withdrawal signs were observed between HiS and LoS rats, but males of both lines had more physical signs of withdrawal than females. These results suggest that LoS rats are less vulnerable to the negative emotional effects of morphine withdrawal than HiS rats. A less severe withdrawal syndrome may contribute to decreased levels of drug taking in the LoS line. C1 [Radke, Anna K.; Holtz, Nathan A.; Carroll, Marilyn E.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Gewirtz, Jonathan C.] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. [Gewirtz, Jonathan C.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Radke, Anna K.] NIAAA, NIH, Rockville, MD 20852 USA. RP Radke, AK (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20852 USA. EM anna.radke@nih.gov FU NIDA [K05 DA015267, P20 DA024196]; University of Minnesota FX We thank Sofiya Hupalo and Jacob Leslie for technical assistance, Gail Towers for animal husbandry, Dr. Mark Thomas for the use of the place-conditioning apparatus, and Dr. Andrew Harris for assistance measuring somatic withdrawal signs. This work was funded by NIDA grants K05 DA015267 and P20 DA024196 (MEC) and the University of Minnesota (JCG). NR 95 TC 11 Z9 11 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2013 VL 227 IS 1 BP 117 EP 126 DI 10.1007/s00213-012-2945-0 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 129QW UT WOS:000317858000011 PM 23254375 ER PT J AU Katz, JL Bergman, J AF Katz, Jonathan L. Bergman, Jack TI Obituary: Peter B. Dews (1922-2012) SO PSYCHOPHARMACOLOGY LA English DT Biographical-Item C1 [Katz, Jonathan L.] NIDA, Intramural Res Program, Baltimore, MD USA. [Bergman, Jack] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA USA. RP Katz, JL (reprint author), NIDA, Intramural Res Program, Baltimore, MD USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2013 VL 227 IS 1 BP 193 EP 194 DI 10.1007/s00213-013-3055-3 PG 2 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 129QW UT WOS:000317858000017 ER PT J AU Eaton, NR Keyes, KM Krueger, RF Noordhof, A Skodol, AE Markon, KE Grant, BF Hasin, DS AF Eaton, Nicholas R. Keyes, Katherine M. Krueger, Robert F. Noordhof, Arjen Skodol, Andrew E. Markon, Kristian E. Grant, Bridget F. Hasin, Deborah S. TI Ethnicity and psychiatric comorbidity in a national sample: evidence for latent comorbidity factor invariance and connections with disorder prevalence SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Comorbidity; Ethnicity; Internalizing; Externalizing; Prevalence; Disparities ID COMMON MENTAL-DISORDERS; ALCOHOL-USE DISORDER; INTERVIEW SCHEDULE AUDADIS; ENVIRONMENTAL RISK-FACTORS; MAJOR DEPRESSIVE DISORDER; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; DSM-III-R; EPIDEMIOLOGIC SURVEY; UNITED-STATES AB Prevalence rates, and bivariate comorbidity patterns, of many common mental disorders differ significantly across ethnic groups. While studies have examined multivariate comorbidity patterns by gender and age, no studies to our knowledge have examined such patterns by ethnicity. Such an investigation could aid in understanding the nature of ethnicity-related health disparities in mental health and is timely given the likely implementation of multivariate comorbidity structures (i.e., internalizing and externalizing) to frame key parts of DSM-5. We investigated whether multivariate comorbidity of 11 common mental disorders, and their associated latent comorbidity factors, differed across five ethnic groups in a large, nationally representative sample (n = 43,093). We conducted confirmatory factor analyses and factorial invariance analyses in White (n = 24,507), Hispanic/Latino (n = 8,308), Black (n = 8,245), Asian/Pacific Islander (n = 1,332), and American Indian/Alaska Native (n = 701) individuals. Results supported a two-factor internalizing-externalizing comorbidity factor model in both lifetime and 12-month diagnoses. This structure was invariant across ethnicity, but factor means differed significantly across ethnic groups. These findings, taken together, indicated that observed prevalence rate differences between ethnic groups reflect ethnic differences in latent internalizing and externalizing factor means. We discuss implications for classification (DSM-5 and ICD-11 meta-structure), health disparities research, and treatment. C1 [Eaton, Nicholas R.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Keyes, Katherine M.; Skodol, Andrew E.; Hasin, Deborah S.] Columbia Univ, New York, NY 10032 USA. [Krueger, Robert F.] Univ Minnesota, Minneapolis, MN 55455 USA. [Noordhof, Arjen] Univ Amsterdam, Dept Psychol, NL-1018 XA Amsterdam, Netherlands. [Skodol, Andrew E.] Univ Arizona, Phoenix, AZ 85016 USA. [Markon, Kristian E.] Univ Iowa, Iowa City, IA 52242 USA. [Grant, Bridget F.] NIAAA, NIH, LEB, Bethesda, MD 20892 USA. RP Eaton, NR (reprint author), SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. EM nreaton@gmail.com FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); NIAAA, National Institutes of Health; National Institute on Drug Abuse FX U01AA018111, R01DA018652, and K05AA014223 (Hasin). The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and funded, in part, by the Intramural Program, NIAAA, National Institutes of Health, with additional support from the National Institute on Drug Abuse. NR 61 TC 20 Z9 20 U1 3 U2 23 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD MAY PY 2013 VL 48 IS 5 BP 701 EP 710 DI 10.1007/s00127-012-0595-5 PG 10 WC Psychiatry SC Psychiatry GA 127GB UT WOS:000317684500003 PM 23052426 ER PT J AU Le, AD Funk, D Coen, K Li, ZX Shaham, Y AF Le, A. D. Funk, Douglas Coen, Kathleen Li, Zhaoxia Shaham, Yavin TI Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats SO ADDICTION BIOLOGY LA English DT Article DE Alcohol self-administration; CRF receptors; d-Phe CRF; median raphe nucleus; reinstatement; stress ID STRESS-INDUCED REINSTATEMENT; INDUCED INCREASES; RECEPTORS; BRAIN AB The pharmacological stressor yohimbine increases ongoing alcohol self-administration and reinstates alcohol seeking in rats. This effect is attenuated by systemic injections of a corticotropin-releasing factor (CRF) antagonist. The brain sites involved in CRF's role in yohimbine-induced alcohol taking and seeking are unknown. We report that injections of the CRF receptor antagonist d-Phe CRF into the median raphe nucleus (MRN) attenuated yohimbine-induced reinstatement of alcohol seeking but had no effect on yohimbine-induced increases in alcohol intake during ongoing self-administration. Results indicate an important role of MRN CRF receptors in yohimbine-induced reinstatement of alcohol seeking but not yohimbine-induced increases in alcohol intake. C1 [Le, A. D.; Funk, Douglas; Coen, Kathleen; Li, Zhaoxia] Ctr Addict & Mental Hlth, Neurobiol Alcohol Lab, Toronto, ON M5S 2S1, Canada. [Le, A. D.] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A1, Canada. [Le, A. D.] Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD USA. RP Le, AD (reprint author), Ctr Addict & Mental Hlth, Neurobiol Alcohol Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM anh_le@camh.net RI shaham, yavin/G-1306-2014 FU NIAAA [AA13108] FX This work was supported by a grant from the NIAAA (AA13108) to A.D.L. NR 14 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAY PY 2013 VL 18 IS 3 BP 448 EP 451 DI 10.1111/j.1369-1600.2011.00374.x PG 4 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 123ZG UT WOS:000317431500006 PM 21967606 ER PT J AU Zhang, LS Kerich, M Schwandt, ML Rawlings, RR McKellar, JD Momenan, R Hommer, DW George, DT AF Zhang, Lishu Kerich, Mike Schwandt, Melanie L. Rawlings, Robert R. McKellar, Joshua D. Momenan, Reza Hommer, Daniel W. George, David T. TI Smaller right amygdala in Caucasian alcohol-dependent male patients with a history of intimate partner violence: a volumetric imaging study SO ADDICTION BIOLOGY LA English DT Article DE Aggression; alcohol; amygdala; domestic violence; imaging; intimate partner violence ID BORDERLINE PERSONALITY-DISORDER; CONGENITAL ADRENAL-HYPERPLASIA; DOMESTIC VIOLENCE; SEROTONIN TRANSPORTER; BRAIN VOLUMES; SELECT GROUP; AGGRESSION; POLYMORPHISM; BEHAVIOR; CORTEX AB Studies have shown that various brain structure abnormalities are associated with chronic alcohol abuse and impulsive aggression. However, few imaging studies have focused on violent individuals with a diagnosis of alcohol dependence. The present study used volumetric magnetic resonance imaging (MRI) to compare the volumes of different structural components of prefrontal cortex and six subcortical structures in perpetrators of intimate partner violence with alcohol dependence (IPV-ADs), non-violent alcohol-dependent patients (non-violent ADs) and healthy controls (HCs). Caucasian men (n=54), ages 2455, who had participated in National Institutes of Alcohol Abuse and Alcoholism treatment programs, were grouped together as IPV-ADs (n=27), non-violent ADs (n=14) and HCs (n=13). The MRI scan was performed at least 3 weeks from the participant's last alcohol use. T1-weighted images were used to measure the volumes of intracranial space, gray and white matter, orbitofrontal cortex, medial prefrontal cortex, lateral prefrontal cortex, and six subcortical structures. Results revealed that IPV-ADs, compared with non-violent ADs and HCs, had a significant volume reduction in the right amygdala. No significant volumetric difference was found in other structures. This finding suggests that structural deficits in the right amygdala may underlie impulsive types of aggression often seen in alcohol-dependent patients with a history of IPV. It adds to a growing literature suggesting that there are fundamental differences between alcohol-dependent patients with and without IPV. C1 [Zhang, Lishu; Kerich, Mike; Schwandt, Melanie L.; Rawlings, Robert R.; McKellar, Joshua D.; Momenan, Reza; Hommer, Daniel W.; George, David T.] NIAAA, Clin Res Ctr, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP George, DT (reprint author), NIAAA, Clin Res Ctr, Lab Clin & Translat Studies, 10 Ctr Dr,Room 10-CRC-1-5330, Bethesda, MD 20892 USA. EM ted.george@mail.nih.gov RI Schwandt, Melanie/L-9866-2016 FU NIAAA Intramural Research Program FX Special thanks are due to Monte J. Phillips, BA, for helping us in reviewing and editing the manuscript. The study was funded by the NIAAA Intramural Research Program. NR 53 TC 6 Z9 6 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAY PY 2013 VL 18 IS 3 BP 537 EP 547 DI 10.1111/j.1369-1600.2011.00381.x PG 11 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 123ZG UT WOS:000317431500015 PM 21995346 ER PT J AU Bruce, D Kahana, S Harper, GW Fernandez, MI AF Bruce, Douglas Kahana, Shoshana Harper, Gary W. Fernandez, M. Isabel CA ATN TI Alcohol use predicts sexual risk behavior with HIV-negative or partners of unknown status among young HIV-positive men who have sex with men SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE MSM; HIV-positive; youth; alcohol; sexual risk behavior; secondary prevention ID SUBSTANCE USE; DRUG-USE; GAY AB Although the relationship between substance use and heightened sexual risk behaviors have been documented in samples of young men who have sex with men (YMSM) and HIV-positive adult men who have sex with men (MSM), there is a dearth of research on the role of substance use in the sexual risk behaviors of HIV-positive YMSM. We examined associations between alcohol and other drug use with sexual risk behaviors among a sample of HIV-positive YMSM (N=200). There were no significant predictors of either receptive or insertive unprotected anal intercourse (UAI) with HIV-positive partners among the substance use variables. Failure to use a condom after drinking alcohol (=2.00, p<0.01) was significantly associated with insertive UAI with HIV-negative partners or partners of unknown status. Failure to use a condom after drinking alcohol (=1.36, p<0.05) and age (=0.35, p<0.05) were significantly associated with receptive UAI with HIV-negative partners or partners of unknown status. Findings from this article underscore the role of alcohol in facilitating UAI among HIV-positive YMSM and their HIV-negative and status-unknown partners. C1 [Bruce, Douglas] Depaul Univ, Master Publ Hlth Program, Chicago, IL 60604 USA. [Kahana, Shoshana] NIDA, Bethesda, MD 20892 USA. [Harper, Gary W.] Depaul Univ, Master Publ Hlth Program, Dept Psychol, Chicago, IL 60604 USA. [Fernandez, M. Isabel] N Bayshore DR, Miami, FL USA. [Fernandez, M. Isabel] Nova SE Univ, COM, Miami, FL USA. RP Bruce, D (reprint author), Depaul Univ, Master Publ Hlth Program, Chicago, IL 60604 USA. EM dbruce1@depaul.edu FU NICHD NIH HHS [5U01HD40474, 5U01HD40533, U01 HD040474, U01 HD040533]; NIMH NIH HHS [K01 MH089838, K01MH089838] NR 21 TC 19 Z9 19 U1 1 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD MAY 1 PY 2013 VL 25 IS 5 BP 559 EP 565 DI 10.1080/09540121.2012.720363 PG 7 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 122BW UT WOS:000317291300004 PM 22971018 ER PT J AU Chang, LW Kagaayi, J Nakigozi, G Serwada, D Quinn, TC Gray, RH Bollinger, RC Reynolds, SJ Holtgrave, D AF Chang, Larry W. Kagaayi, Joseph Nakigozi, Gertrude Serwada, David Quinn, Thomas C. Gray, Ronald H. Bollinger, Robert C. Reynolds, Steven J. Holtgrave, David TI Cost analyses of peer health worker and mHealth support interventions for improving AIDS care in Rakai, Uganda SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE cost analysis; mHealth; community health workers; Uganda; antiretroviral treatment ID CLUSTER-RANDOMIZED TRIAL; HIV AB A cost analysis study calculates resources needed to deliver an intervention and can provide useful information on affordability for service providers and policy-makers. We conducted cost analyses of both a peer health worker (PHW) and a mHealth (mobile phone) support intervention. Excluding supervisory staffing costs, total yearly costs for the PHW intervention was $8475, resulting in a yearly cost per patient of $8.74, per virologic failure averted cost of $189, and per patient lost to follow-up averted cost of $1025. Including supervisory staffing costs increased total yearly costs to $14,991. Yearly costs of the mHealth intervention were an additional $1046, resulting in a yearly cost per patient of $2.35. In a threshold analysis, the PHW intervention was found to be cost saving if it was able to avert 1.50 patients per year from switching to second-line antiretroviral therapy. Other AIDS care programs may find these intervention costs affordable. C1 [Chang, Larry W.; Bollinger, Robert C.; Reynolds, Steven J.] Johns Hopkins Sch Med, Div Infect Dis, Dept Med, Baltimore, MD USA. [Kagaayi, Joseph; Nakigozi, Gertrude; Serwada, David] Rakai Hlth Sci Program, Entebbe, Uganda. [Quinn, Thomas C.; Reynolds, Steven J.] NIAID, Immunoregulat Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Gray, Ronald H.; Holtgrave, David] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Chang, LW (reprint author), Johns Hopkins Sch Med, Div Infect Dis, Dept Med, Baltimore, MD USA. EM lchang8@jhmi.edu RI Emchi, Karma/Q-1952-2016 FU Intramural NIH HHS [ZIA AI000361-30]; NIAID NIH HHS [2T32-AI07291, T32 AI007291]; NIMH NIH HHS [K23 MH086338, 1K23MH086338-01A2] NR 16 TC 7 Z9 7 U1 1 U2 13 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD MAY 1 PY 2013 VL 25 IS 5 BP 652 EP 656 DI 10.1080/09540121.2012.722600 PG 5 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 122BW UT WOS:000317291300018 PM 22971113 ER PT J AU Unruh, ML Larive, B Chertow, GM Eggers, PW Garg, AX Gassman, J Tarallo, M Finkelstein, FO Kimmel, PL AF Unruh, Mark L. Larive, Brett Chertow, Glenn M. Eggers, Paul W. Garg, Amit X. Gassman, Jennifer Tarallo, Maria Finkelstein, Fredric O. Kimmel, Paul L. CA FHN Trials Grp TI Effects of 6-Times-Weekly Versus 3-Times-Weekly Hemodialysis on Depressive Symptoms and Self-reported Mental Health: Frequent Hemodialysis Network (FHN) Trials SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Hemodialysis; daily hemodialysis; nocturnal hemodialysis; depression; health-related quality of life; clinical trial ID QUALITY-OF-LIFE; STAGE RENAL-DISEASE; PERITONEAL-DIALYSIS PATIENTS; RANDOMIZED-TRIALS; HOME HEMODIALYSIS; MAJOR DEPRESSION; CLINICAL-TRIAL; 3 TIMES; MORTALITY; OUTCOMES AB Background: Patients undergoing maintenance hemodialysis frequently exhibit poor mental health. We studied the effects of frequent in-center and nocturnal hemodialysis on depressive symptoms and self-reported mental health. Study Design: 1-year randomized controlled clinical trials. Setting & Participants: Hemodialysis centers in the United States and Canada. 332 patients were randomly assigned to frequent (6-times-weekly) compared with conventional (3-times-weekly) hemodialysis in the Frequent Hemodialysis Network (FHN) Daily (n = 245) and Nocturnal (n = 87) Trials. Intervention: The Daily Trial was a trial of frequent (6-times-weekly) compared with conventional (3-times-weekly) in-center hemodialysis. The Nocturnal Trial assigned patients to either frequent nocturnal (6-times-weekly) hemodialysis or conventional (3-times-weekly) hemodialysis. Outcomes: Self-reported depressive symptoms and mental health. Measurements: Beck Depression Inventory and the mental health composite score and emotional subscale of the RAND 36-Item Health Survey at baseline and 4 and 12 months. The mental health composite score is derived by summarizing these domains of the RAND 36-Item Health Survey: emotional, role emotional, energy/fatigue, and social functioning scales. Results: In the Daily Trial, participants randomly assigned to frequent compared with conventional in-center hemodialysis showed no significant change over 12 months in adjusted mean Beck Depression Inventory score (-1.9 +/- 0.7 vs -0.6 +/- 0.7; P = 0.2), but experienced clinically significant improvements in adjusted mean mental health composite (3.7 +/- 0.9 vs 0.2 +/- 1.0; P = 0.007) and emotional subscale (5.2 +/- 1.6 vs -0.3 +/- 1.7; P = 0.01) scores. In the Nocturnal Trial, there were no significant changes in the same metrics in participants randomly assigned to nocturnal compared with conventional hemodialysis. Limitations: Trial interventions were not blinded. Conclusions: Frequent in-center hemodialysis, as compared with conventional in-center hemodialysis, improved self-reported general mental health. Changes in self-reported depressive symptoms were not statistically significant. We were unable to conclude whether nocturnal hemodialysis yielded similar effects. Am J Kidney Dis. 61(5): 748-758. (C) 2013 by the National Kidney Foundation, Inc. C1 [Unruh, Mark L.] Univ New Mexico, Sch Med, Div Nephrol, Albuquerque, NM 87131 USA. [Larive, Brett; Gassman, Jennifer] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Eggers, Paul W.; Kimmel, Paul L.] NIDDK, Bethesda, MD USA. [Garg, Amit X.] Univ Western Ontario, Dept Med, Div Nephrol, London, ON, Canada. [Tarallo, Maria] NYU, Langone Med Ctr, New York, NY USA. [Finkelstein, Fredric O.] Yale Univ, Hosp St Raphaels, New Haven, CT USA. RP Unruh, ML (reprint author), Univ New Mexico, Sch Med, MSC 10-5550,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM mlunruh@salud.unm.edu FU National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases, Center for Medicare and Medicaid Services; NIH Research Foundation; Amgen; Baxter; Dialysis Clinics; DaVita; Dialysis Clinics Inc (DCI); Fresenius Medical Care; Renal Advantage; Renal Research Institute; Satellite Healthcare; Fresenius; DCI FX The FHN trials were supported by the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases, Center for Medicare and Medicaid Services, and the NIH Research Foundation. Contributors to the NIH Foundation in support of the FHN trials included Amgen, Baxter, and Dialysis Clinics. Additional support was provided by DaVita, Dialysis Clinics Inc (DCI), Fresenius Medical Care, Renal Advantage, Renal Research Institute, and Satellite Healthcare. The corporate study sponsors did not participate in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.; Dr Chertow has been on the Board of Directors for Satellite Healthcare and the Scientific Advisory Board for DaVita. Dr Garg has been a coinvestigator on investigator-initiated research sponsored by Fresenius. Dr Unruh has received research support from Baxter, Satellite Healthcare, and DCI. NR 48 TC 18 Z9 18 U1 3 U2 19 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAY PY 2013 VL 61 IS 5 BP 748 EP 758 DI 10.1053/j.ajkd.2012.11.047 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 121WV UT WOS:000317276600016 PM 23332990 ER PT J AU Amano, M Tojo, Y Salcedo-Gomez, PM Campbell, JR Das, D Aoki, M Xu, CX Rao, KV Ghosh, AK Mitsuya, H AF Amano, Masayuki Tojo, Yasushi Salcedo-Gomez, Pedro Miguel Campbell, Joseph Richard Das, Debananda Aoki, Manabu Xu, Chun-Xiao Rao, Kalapala Venkateswara Ghosh, Arun K. Mitsuya, Hiroaki TI GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL THERAPY; EXPERIENCED PATIENTS; TREATMENT-NAIVE; DESIGN; DIMERIZATION; P-2-LIGANDS; INFECTION; SELECTION; PROTEINS AB We report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0005 to 0.0007 mu M) with minimal cytotoxicity (50% cytotoxic concentration [CC50], 44.6 mu M). GRL-0519 blocked the infectivity and replication of HIV-1(NL4-3) variants selected by up to a 5 mu M concentration of ritonavir, lopinavir, or atazanavir (EC50, 0.0028 to 0.0033 mu M). GRL-0519 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2(ROD). The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2' binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PI-resistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics. C1 [Amano, Masayuki; Tojo, Yasushi; Salcedo-Gomez, Pedro Miguel; Campbell, Joseph Richard; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 860, Japan. [Amano, Masayuki; Tojo, Yasushi; Salcedo-Gomez, Pedro Miguel; Campbell, Joseph Richard; Aoki, Manabu; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 860, Japan. [Aoki, Manabu] Kumamoto Hlth Sci Univ, Dept Med Technol, Kumamoto, Japan. [Xu, Chun-Xiao; Rao, Kalapala Venkateswara; Ghosh, Arun K.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Xu, Chun-Xiao; Rao, Kalapala Venkateswara; Ghosh, Arun K.] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Das, Debananda; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Mitsuya, H (reprint author), Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 860, Japan. EM hm21q@nih.gov RI Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU Grant for Global Education and Research Center Aiming at the Control of AIDS (Global Center of Excellence, supported by Monbu-Kagakusho); Ministry of Health, Welfare, and Labor of Japan; Intramural Research Program of the Center for Cancer Research; Monbu-Kagakusho; National Cancer Institute, National Institutes of Health; National Institutes of Health [GM53386] FX This work was supported in part by a Grant for Global Education and Research Center Aiming at the Control of AIDS (Global Center of Excellence, supported by Monbu-Kagakusho); Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan; a Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo, no. 78; Kumamoto University) of Monbu-Kagakusho (H.M.); the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (H.M.); and by a grant from the National Institutes of Health (GM53386; A.K.G.). NR 38 TC 12 Z9 13 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2013 VL 57 IS 5 BP 2036 EP 2046 DI 10.1128/AAC.02189-12 PG 11 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 124ME UT WOS:000317467600006 PM 23403426 ER PT J AU Warpeha, KM Park, YD Williamson, PR AF Warpeha, Katherine M. Park, Yoon-Dong Williamson, Peter R. TI Susceptibility of Intact Germinating Arabidopsis thaliana to Human Fungal Pathogens Cryptococcus neoformans and C. gattii SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID BLUE-LIGHT; G-PROTEIN; ETIOLATED ARABIDOPSIS; VANCOUVER-ISLAND; VIRULENCE; INFECTION; LACCASE; PHENYLALANINE; MACROPHAGES; ASSOCIATION AB The fungus Cryptococcus contributes a large global burden of infectious death in both HIV-infected and healthy individuals. As Cryptococcus is an opportunistic pathogen, much of the evolutionary pressure shaping virulence occurs in environments in contact with plants and soil. The present studies investigated inoculation of intact seeds of the common weed Arabidopsis thaliana with fungal cells over a 21-day period. C. gattii was the more virulent plant pathogen, resulting in disrupted germination as well as increased stem lodging, fungal burden, and plant tissue colocalization. C. neoformans was a less virulent plant pathogen but exhibited prolonged tissue residence within the cuticle and vascular spaces. Arabidopsis mutants of the PRN1 gene, which is involved in abiotic and biotic signaling affecting phenylalanine-derived flavonoids, showed altered susceptibility to cryptoccocal infections, suggesting roles for this pathway in cryptococcal defense. The fungal virulence factor laccase was also implicated in plant pathogenesis, as a cryptococcal lac1 Delta strain was less virulent than wild-type fungi and was unable to colonize seedlings. In conclusion, these studies expand knowledge concerning the ecological niche of Cryptococcus by demonstrating the pathogenic capacity of the anamorphic form of cryptococcal cells against healthy seedlings under physiologically relevant conditions. In addition, an important role of laccase in plant as well as human virulence may suggest mechanisms for laccase retention and optimization during evolution of this fungal pathogen. C1 [Warpeha, Katherine M.] Univ Illinois, Dept Biol Sci, Chicago, IL 60680 USA. [Park, Yoon-Dong; Williamson, Peter R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Williamson, Peter R.] Univ Illinois, Coll Med, Dept Med, Sect Infect Dis Immunol & Int Med, Chicago, IL USA. RP Warpeha, KM (reprint author), Univ Illinois, Dept Biol Sci, Chicago, IL 60680 USA. EM kwarpeha@uic.edu; williamsonpr@mail.nih.gov FU United States Public Health Service grants [NIH-AI38258, NIH-A14599]; NIH, NIAID; Veterans Health Administration; University of Illinois at Chicago FX This work was supported, in part, by United States Public Health Service grants NIH-AI38258 and NIH-A14599 and the intramural research program of the NIH, NIAID, as well as a Merit Review grant from the Veterans Health Administration to P. R. W. This work was also supported by University of Illinois at Chicago start-up funds in support of K.M.W. NR 56 TC 11 Z9 11 U1 0 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD MAY PY 2013 VL 79 IS 9 BP 2979 EP 2988 DI 10.1128/AEM.03697-12 PG 10 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 124OT UT WOS:000317474800015 PM 23435895 ER PT J AU Pan, WL Wong, JH Fang, EF Chan, YS Ye, XJ Ng, TB AF Pan, Wen Liang Wong, Jack Ho Fang, Evandro Fei Chan, Yau Sang Ye, Xiu Juan Ng, Tzi Bun TI Differential inhibitory potencies and mechanisms of the type I ribosome inactivating protein marmorin on estrogen receptor (ER)-positive and ER-negative breast cancer cells SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Marmorin; Ribosome inactivating protein; Breast cancer; Apoptosis; Estrogen receptor alpha; Endoplasmic reticulum stress ID MUSHROOM HYPSIZIGUS-MARMOREUS; REVERSE-TRANSCRIPTASE; ENDOPLASMIC-RETICULUM; ANTITUMOR-ACTIVITY; APOPTOSIS; EXPRESSION; VITRO; CARCINOMA; DAMAGE; LECTIN AB Breast cancer is the second most common cancer with a high incidence rate worldwide. One of the promising therapeutic approaches on breast cancer is to use the drugs that target the estrogen receptor (ER). In the present investigation, marmorin, a type I ribosome inactivating protein from the mushroom Hypsizigus marmoreus, inhibited the survival of breast cancer in vitro and in vivo. It evinced more potent cytotoxicity toward estrogen receptor (ER)-positive MCF7 breast cancer cells than ER-negative MDA-MB-231 cells. Further study disclosed that marmorin undermined the expression level of estrogen receptor alpha (ER alpha) and significantly inhibited the proliferation of MCF7 cells induced by 17 beta-estradiol. Knockdown of ER alpha in MCF7 cells significantly attenuated the inhibitory effect of marmorin on proliferation, suggesting that the ER alpha-mediated pathway was implicated in the suppressive action of marmorin on ER-positive breast cancer cells. Moreover, marmorin induced time-dependent apoptosis in both MCF7 and MDA-MB-231 cells. It brought about G2/M-phase arrest, mitochondrial membrane potential depolarization and caspase-9 activation in MCF7 cells, and to a lesser extent in MDA-MB-231 cells. Marmorin triggered the death receptor apoptotic pathway (e.g. caspase-8 activation) and endoplasmic reticulum stress (ERS, as evidenced by phosphorylation of PERK and IRE1 alpha, cleavage of caspase-12, and up-regulation of CHOP expression) in both MCF7 and MDA-MB-231 cells. In summary, marmorin exhibited inhibitory effect on breast cancer partially via diminution of ERa and apoptotic pathways mediated by mitochondrial, death receptor and ERS. The results advocate that marmorin is a potential candidate for breast cancer therapy. (C) 2012 Elsevier B.V. All rights reserved. C1 [Pan, Wen Liang; Wong, Jack Ho; Chan, Yau Sang; Ng, Tzi Bun] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Fang, Evandro Fei] NIA, NIH, Baltimore, MD 21224 USA. [Ye, Xiu Juan] Fujian Agr & Forestry Univ, Inst Plant Virol, Key Lab Plant Virol Fujian Prov, Fuzhou, Peoples R China. RP Ng, TB (reprint author), Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. EM b021770@mailserv.cuhk.edu.hk NR 43 TC 9 Z9 10 U1 0 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 EI 0006-3002 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAY PY 2013 VL 1833 IS 5 BP 987 EP 996 DI 10.1016/j.bbamcr.2012.12.013 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 123FT UT WOS:000317374500004 PM 23274857 ER PT J AU Volkow, ND Wang, GJ Tomasi, D Baler, RD AF Volkow, Nora D. Wang, Gene-Jack Tomasi, Dardo Baler, Ruben D. TI The Addictive Dimensionality of Obesity SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Dopamine; drug addiction; obesity; prefrontal cortex; reward; self-control ID VENTRAL TEGMENTAL AREA; BODY-MASS INDEX; DOPAMINE D2 RECEPTORS; HIGH-CALORIE FOODS; NUCLEUS-ACCUMBENS; DORSAL STRIATUM; SUBSTANCE USE; ORBITOFRONTAL CORTEX; PREFRONTAL CORTEX; GENETIC-VARIATION AB Our brains are hardwired to respond and seek immediate rewards. Thus, it is not surprising that many people overeat, which in some can result in obesity, whereas others take drugs, which in some can result in addiction. Though food intake and body weight are under homeostatic regulation, when highly palatable food is available, the ability to resist the urge to eat hinges on self-control. There is no homeostatic regulator to check the intake of drugs (including alcohol); thus, regulation of drug consumption is mostly driven by self-control or unwanted effects (i.e., sedation for alcohol). Disruption in both the neurobiological processes that underlie sensitivity to reward and those that underlie inhibitory control can lead to compulsive food intake in some individuals and compulsive drug intake in others. There is increasing evidence that disruption of energy homeostasis can affect the reward circuitry and that overconsumption of rewarding food can lead to changes in the reward circuitry that result in compulsive food intake akin to the phenotype seen with addiction. Addiction research has produced new evidence that hints at significant commonalities between the neural substrates underlying the disease of addiction and at least some forms of obesity. This recognition has spurred a healthy debate to try and ascertain the extent to which these complex and dimensional disorders overlap and whether or not a deeper understanding of the crosstalk between the homeostatic and reward systems will usher in unique opportunities for prevention and treatment of both obesity and drug addiction. C1 [Volkow, Nora D.; Baler, Ruben D.] NIDA, NIH, Bethesda, MD 20892 USA. [Volkow, Nora D.; Tomasi, Dardo] NIAAA, NIH, Bethesda, MD 90034 USA. [Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd,Mail Drop Code 9581,Suite 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI Tomasi, Dardo/J-2127-2015 FU National Institutes of Health (Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse) FX This research was supported by the National Institutes of Health (Intramural Research Program of the National Institute on Alcoholism and Alcohol Abuse). The authors report no biomedical financial interests or potential conflicts of interest. NR 112 TC 104 Z9 106 U1 8 U2 121 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2013 VL 73 IS 9 BP 811 EP 818 DI 10.1016/j.biopsych.2012.12.020 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 126AO UT WOS:000317583700008 PM 23374642 ER PT J AU Wise, RA AF Wise, Roy A. TI Dual Roles of Dopamine in Food and Drug Seeking: The Drive-Reward Paradox SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Addiction; drug seeking; eating; obesity; paradox; reward ID VENTRAL TEGMENTAL AREA; BRAIN-STIMULATION REWARD; MEDIAL FOREBRAIN-BUNDLE; INTRACRANIAL SELF-STIMULATION; NUCLEUS ACCUMBENS AMPHETAMINE; PIMOZIDE-INDUCED EXTINCTION; IN-VIVO MICRODIALYSIS; FREELY MOVING RATS; ELECTRICAL-STIMULATION; LATERAL HYPOTHALAMUS AB The question of whether (or to what degree) obesity reflects addiction to high-energy foods often narrows to the question of whether the overeating of these foods causes the same long-term neuroadaptations as are identified with the late stages of addiction. Of equal or perhaps greater interest is the question of whether common brain mechanisms mediate the acquisition and development of eating and drug-taking habits. The earliest evidence on this question is rooted in early studies of brain stimulation reward. Lateral hypothalamic electrical stimulation can be reinforcing in some conditions and can motivate feeding in others. That stimulation of the same brain region should be both reinforcing and drive inducing is paradoxical; why should an animal work to induce a drive-like state such as hunger? This is known as the drive-reward paradox. Insights into the substrates of the drive-reward paradox suggest an answer to the controversial question of whether the dopamine system-a system downstream from the stimulated fibers of the lateral hypothalamus-is more critically involved in wanting or in liking of various rewards including food and addictive drugs. That the same brain circuitry is implicated in the motivation for and the reinforcement by both food and addictive drugs extends the argument for a common mechanism underlying compulsive overeating and compulsive drug taking. C1 NIDA, Intramural Res Program, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Wise, RA (reprint author), NIDA, Intramural Res Program, NIH, US Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rwise@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health FX Preparation of this manuscript was supported in the form of salary by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health. NR 129 TC 35 Z9 35 U1 4 U2 97 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2013 VL 73 IS 9 BP 819 EP 826 DI 10.1016/j.biopsych.2012.09.001 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 126AO UT WOS:000317583700009 PM 23044182 ER PT J AU Kim, Y Kim, J Tae, J Roth, BL Rhim, H Keum, G Nam, G Choo, H AF Kim, Youngjae Kim, Jeeyeon Tae, Jinsung Roth, Bryan L. Rhim, Hyewhon Keum, Gyochang Nam, Ghilsoo Choo, Hyunah TI Discovery of aryl-biphenyl-2-ylmethylpiperazines as novel scaffolds for 5-HT7 ligands and role of the aromatic substituents in binding to the target receptor SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 5-HT7 receptor; Agonist; Antagonist; Biphenyl; Arylpiperazine ID RAT HYPOTHALAMUS; AGONIST; ANTAGONIST; IDENTIFICATION; DERIVATIVES; SB-269970; KETONES; POTENT AB It has been reported that 5-HT7 receptors are promising targets of depression and neuropathic pain. 5-HT7 receptor antagonists have exhibited antidepressant-like profiles, while agonists have represented potential therapeutics for pain. In the course of our ongoing efforts to discover novel 5-HT7 modulators, we designed an arylpiperazine scaffold with a substituted biphenyl-2-ylmethyl group. A series of biphenyl-2-yl-arylpiperazinylmethanes were then prepared, which showed a broad spectrum of binding affinities to the 5-HT7 receptor depending upon the substituents attached to the biphenyl and aryl functionalities. Among those synthesized compounds, the compounds 1-24 and 1-26 showed the best binding affinities to the 5-HT7 receptor with K-i values of 43.0 and 46.0 nM, respectively. Structure-activity relationship study in conjunction with molecular docking study proposed that the 5-HT7 receptor might have two distinctive hydrophobic binding sites, one specific for aromatic 2-OCH3 substituents within the arylpiperazine and the other for biphenyl methoxy group. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Kim, Youngjae; Kim, Jeeyeon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah] Korea Inst Sci & Technol, Ctr Neuromed, Seoul 136791, South Korea. [Kim, Youngjae; Choo, Hyunah] Univ Sci & Technol, Dept Biol Chem, Taejon 305350, South Korea. [Kim, Jeeyeon; Tae, Jinsung] Yonsei Univ, Dept Chem, Seoul 120749, South Korea. [Roth, Bryan L.] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Rhim, Hyewhon] Korea Inst Sci & Technol, Ctr Neurosci, Seoul 136791, South Korea. RP Nam, G (reprint author), Korea Inst Sci & Technol, Ctr Neuromed, Hwarangro 14 Gil 5, 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 National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]; Basic Science Research Program through the National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2012-0002547]; Korea Institute of Science and Technology FX Binding affinities were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012-0002547), and Korea Institute of Science and Technology. NR 29 TC 5 Z9 6 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 1 PY 2013 VL 21 IS 9 BP 2568 EP 2576 DI 10.1016/j.bmc.2013.02.038 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 123PS UT WOS:000317403200015 PM 23541835 ER PT J AU Murugan, RN Park, JE Lim, D Ahn, M Cheong, C Kwon, T Nam, KY Choi, SH Kim, BY Yoon, DY Yaffe, MB Yu, DY Lee, KS Bang, JK AF Murugan, Ravichandran N. Park, Jung-Eun Lim, Dan Ahn, Mija Cheong, Chaejoon Kwon, Taeho Nam, Ky-Youb Choi, Sun Ho Kim, Bo Yeon Yoon, Do-Young Yaffe, Michael B. Yu, Dae-Yeul Lee, Kyung S. Bang, Jeong Kyu TI Development of cyclic peptomer inhibitors targeting the polo-box domain of polo-like kinase 1 SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Polo-box domain (PBD); Cyclic peptomers; Kinase inhibitors; Solid phase peptide synthesis ID SMALL-MOLECULE INHIBITORS; PEPTOIDS; ALKYLATION; DISCOVERY AB The polo-box domain (PBD) of polo-like kinase 1 (Plk1) is essentially required for the function of Plk1 in cell proliferation. The availability of the phosphopeptide-binding pocket on PBD provides a unique opportunity to develop novel protein-protein interaction inhibitors. Recent identification of a minimal 5-residue-long phosphopeptide, PLHSpT, as a Plk1 PBD-specific ligand has led to the development of several peptide-based inhibitors, but none of them is cyclic peptide. Through the combination of single-peptoid mimics and thio-ether bridged cyclization, we successfully demonstrated for the first time two cyclic peptomers, PL-116 and PL-120, dramatically improved the binding affinity without losing mono-specificity against Plk1 PBD in comparison with the linear parental peptide, PLHSpT. These cyclic peptomers could serve as promising templates for future drug designs to inhibit Plk1 PBD. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Murugan, Ravichandran N.; Ahn, Mija; Cheong, Chaejoon; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Chung Buk 363883, Cheongwon, South Korea. [Park, Jung-Eun; Kwon, Taeho; Choi, Sun Ho; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Dept Biol & Biol Engn, Ctr Canc Res, Cambridge, MA 02139 USA. [Kwon, Taeho; Yu, Dae-Yeul] Korea Res Inst Biosci & Biotechnol, Aging Res Ctr, Taejon 305806, South Korea. [Kwon, Taeho; Yoon, Do-Young] Konkuk Univ, Dept Biosci & Biotechnol, Bio Mol Informat Ctr, Seoul 143701, South Korea. [Kwon, Taeho; Kim, Bo Yeon] Korea Res Inst Biosci & Biotechnol, World Class Inst, Ochang, South Korea. [Nam, Ky-Youb] Bioinformat & Mol Design Res Ctr, Seoul 120749, South Korea. [Choi, Sun Ho] Dong A Pharmaceut Co Ltd, Res Labs, Yongin 449905, South Korea. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 3118, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov; bangjk@kbsi.re.kr FU Korea Basic Science Institute [T33418]; National Cancer Institute; National Research Foundation of Korea (NRF)'s basic research program [2010-0019306] FX This work was supported in part by the Korea Basic Science Institute's research Grant T33418 (J. K. B.), the National Cancer Institute's Intramural Research Grant (K. S. L.), and the National Research Foundation of Korea (NRF)'s basic research program (2010-0019306) (D.Y.Y.). NR 22 TC 20 Z9 21 U1 1 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 1 PY 2013 VL 21 IS 9 BP 2623 EP 2634 DI 10.1016/j.bmc.2013.02.020 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 123PS UT WOS:000317403200020 PM 23498919 ER PT J AU Conde-Agudelo, A Papageorghiou, AT Kennedy, SH Villar, J AF Conde-Agudelo, A. Papageorghiou, A. T. Kennedy, S. H. Villar, J. TI Novel biomarkers for predicting intrauterine growth restriction: a systematic review and meta-analysis SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Review DE Biomarker; intrauterine growth restriction; meta-analysis; prediction; systematic review ID FOR-GESTATIONAL-AGE; UTERINE-ARTERY DOPPLER; MIDTRIMESTER AMNIOTIC-FLUID; MATERNAL SERUM; FETAL-GROWTH; PAPP-A; ANGIOGENIC FACTORS; EARLY-PREGNANCY; HOMOCYSTEINE CONCENTRATION; PLASMA HOMOCYSTEINE AB Background Several biomarkers for predicting intrauterine growth restriction (IUGR) have been proposed in recent years. However, the predictive performance of these biomarkers has not been systematically evaluated. Objective To determine the predictive accuracy of novel biomarkers for IUGR in women with singleton gestations. Search strategy Electronic databases, reference list checking and conference proceedings. Selection criteria Observational studies that evaluated the accuracy of novel biomarkers proposed for predicting IUGR. Data collection and analysis Data were extracted on characteristics, quality and predictive accuracy from each study to construct 2x2 tables. Summary receiver operating characteristic curves, sensitivities, specificities and likelihood ratios (LRs) were generated. Main results A total of 53 studies, including 39974 women and evaluating 37 novel biomarkers, fulfilled the inclusion criteria. Overall, the predictive accuracy of angiogenic factors for IUGR was minimal (median pooled positive and negative LRs of 1.7, range 1.019.8; and 0.8, range 0.01.0, respectively). Two small casecontrol studies reported high predictive values for placental growth factor and angiopoietin-2 only when IUGR was defined as birthweight centile with clinical or pathological evidence of fetal growth restriction. Biomarkers related to endothelial function/oxidative stress, placental protein/hormone, and others such as serum levels of vitamin D, urinary albumin:creatinine ratio, thyroid function tests and metabolomic profile had low predictive accuracy. Conclusions None of the novel biomarkers evaluated in this review are sufficiently accurate to recommend their use as predictors of IUGR in routine clinical practice. However, the use of biomarkers in combination with biophysical parameters and maternal characteristics could be more useful and merits further research. C1 [Conde-Agudelo, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Conde-Agudelo, A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Papageorghiou, A. T.; Kennedy, S. H.; Villar, J.] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Womens Ctr, Oxford OX3 9DU, England. [Papageorghiou, A. T.; Kennedy, S. H.; Villar, J.] Green Templeton Coll, Oxford Maternal & Perinatal Hlth Inst, Oxford, England. RP Villar, J (reprint author), Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Womens Ctr, Oxford OX3 9DU, England. EM jose.villar@obs-gyn.ox.ac.uk FU Oxford Partnership Comprehensive Biomedical Research Centre; Department of Health NIHR Biomedical Research Centres funding scheme FX ATP and SHK are supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health NIHR Biomedical Research Centres funding scheme. NR 88 TC 41 Z9 42 U1 2 U2 35 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD MAY PY 2013 VL 120 IS 6 BP 681 EP 694 DI 10.1111/1471-0528.12172 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 122YG UT WOS:000317353900006 PM 23398929 ER PT J AU Furuyama, K Harada, T Iwama, E Shiraishi, Y Okamura, K Ijichi, K Fujii, A Ota, K Wang, S Li, HY Takayama, K Giaccone, G Nakanishi, Y AF Furuyama, Kazuto Harada, Taishi Iwama, Eiji Shiraishi, Yoshimasa Okamura, Kyoko Ijichi, Kayo Fujii, Akiko Ota, Keiichi Wang, Shuo Li, Heyan Takayama, Koichi Giaccone, Giuseppe Nakanishi, Yoichi TI Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors SO CANCER SCIENCE LA English DT Article ID CELL LUNG-CANCER; ACQUIRED-RESISTANCE; PHASE-I; FUNCTIONAL-ANALYSIS; SOMATIC MUTATIONS; GENE-MUTATIONS; GEFITINIB; ERLOTINIB; ADENOCARCINOMA; MODELS AB The presence of epidermal growth factor receptor (EGFR) somatic mutations in non-small-cell lung cancer patients is associated with response to treatment with EGFR-tyrosine kinase inhibitors, such as gefitinib and erlotinib. More than 100 mutations in the kinase domain of EGFR have been identified. In particular there are many variations of deletion mutations in exon 19. In this study, using yellow fluorescent protein-tagged fragments of the EGFR intracellular domain, we examined the differences in sensitivity to gefitinib, erlotinib and afatinib between several exon 19 mutants and other common EGFR mutations. We also used serum of patients undergoing treatment with EGFR-tyrosine kinase inhibitors in this system. In addition, we examined the relative kinase activity of these mutants by measuring relative fluorescent intensity after immunofluorescence staining. We found that both sensitivity to EGFR-tyrosine kinase inhibitors and relative kinase activity differed among several EGFR mutations found in the same region of the kinase domain. This study underscores the importance of reporting the clinical outcome of treatment in relation to different EGFR mutations. C1 [Furuyama, Kazuto; Harada, Taishi; Iwama, Eiji; Shiraishi, Yoshimasa; Okamura, Kyoko; Ijichi, Kayo; Fujii, Akiko; Ota, Keiichi; Wang, Shuo; Li, Heyan; Takayama, Koichi; Nakanishi, Yoichi] Kyushu Univ, Chest Dis Res Inst, Grad Sch Med Sci, Fukuoka 812, Japan. [Giaccone, Giuseppe] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harada, T (reprint author), Kyushu Univ, Chest Dis Res Inst, Grad Sch Med Sci, Fukuoka 812, Japan. EM harada-t@kokyu.med.kyushu-u.ac.jp RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 30 TC 8 Z9 8 U1 0 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD MAY PY 2013 VL 104 IS 5 BP 584 EP 589 DI 10.1111/cas.12125 PG 6 WC Oncology SC Oncology GA 130FA UT WOS:000317897100010 PM 23387505 ER PT J AU Won, S Davies-Venn, C Liu, ST Bluemke, DA AF Won, Samuel Davies-Venn, Cynthia Liu, Songtao Bluemke, David A. TI Noninvasive imaging of myocardial extracellular matrix for assessment of fibrosis SO CURRENT OPINION IN CARDIOLOGY LA English DT Review DE extracellular matrix; imaging; left ventricular remodeling; magnetic resonance; myocardial fibrosis ID CARDIAC MAGNETIC-RESONANCE; ALPHA(V)BETA(3) INTEGRIN EXPRESSION; ANGIOTENSIN-II; HEART-FAILURE; VOLUME FRACTION; IN-VIVO; DILATED CARDIOMYOPATHY; COLLAGEN TURNOVER; CONTRAST AGENT; FACTOR-XIII AB Purpose of review Myocardial fibrosis is a common feature of many cardiomyopathies, including hypertrophic cardiomyopathy. Myocardial fibrosis has been shown to be reversible and treatable with timely intervention. Although early detection and assessment of fibrosis is crucial, adequate diagnostics are still in development. Recent studies have shown progress on noninvasive imaging methods of fibrosis using cardiovascular magnetic resonance (CMR) and nuclear imaging modalities. Recent findings T1 mapping and extracellular volume mapping (ECV) combined with CMR imaging are cutting edge methods that have the potential to assess interstitial myocardial fibrosis. Recent findings show that ECV measurement can be correlated to the extent of diffuse fibrosis. Comparatively, molecular imaging targets specific biomarkers in the fibrosis formation pathway and provides enhanced sensitivity for imaging early disease. Biomarkers include molecules involved in angiogenesis, ventricular remodeling, and fibrotic tissue formation, whereas collagen targeted agents can directly identify fibrotic tissue in the heart. Summary This review introduces novel methods of fibrosis imaging that utilize properties of extracellular matrix and its biomarkers. Changes in characteristics and cellular biomarkers of the extracellular space can provide significant information regarding fibrosis formation and its role in cardiomyopathy. Ultimately, these findings may improve detection and monitoring of disease and improve efficiency and effectiveness of the treatment. C1 [Won, Samuel; Davies-Venn, Cynthia; Liu, Songtao; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Won, Samuel; Davies-Venn, Cynthia; Liu, Songtao; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, Bethesda, MD USA. RP Bluemke, DA (reprint author), NIH, 10 Ctr Dr,Rm 10-1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural Research Program of the NIH, Clinical Center FX This research was supported by the Intramural Research Program of the NIH, Clinical Center. NR 73 TC 15 Z9 18 U1 0 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-4705 EI 1531-7080 J9 CURR OPIN CARDIOL JI Curr. Opin. Cardiol. PD MAY PY 2013 VL 28 IS 3 BP 282 EP 289 DI 10.1097/HCO.0b013e32835f5a2b PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 124NN UT WOS:000317471500003 PM 23549230 ER PT J AU Churchill, M Nath, A AF Churchill, Melissa Nath, Avindra TI Where does HIV hide? A focus on the central nervous system SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE astrocytes; brain; dementia; HIV; microglia; mutations; reservoirs; viral evolution ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN FETAL ASTROCYTES; CELLULAR-LOCALIZATION; CEREBROSPINAL-FLUID; MACROPHAGE-TROPISM; INFECTION; BRAIN; DEMENTIA; TISSUES; EXPRESSION AB Purpose of review To review the literature on infection and evolution of HIV within the brain in the context for understanding the nature of the brain reservoir and its consequences. Recent findings HIV-1 in the brain can evolve in separate compartments within macrophage/microglia and astrocytes. The virus adapts to the brain environment to infect these cells and brain-specific mutations can be found in nearly all genes of the virus. The virus evolves to become more neurovirulent. Summary The brain is an ideal reservoir for the HIV. The brain is a relatively immune privileged site and the blood-brain barrier prevents easy access to antiretroviral drugs. Further, the virus infects resident macrophages and astrocytes which are long-lived cells and causes minimal cytopathology in these cells. Hence as we move towards developing strategies for eradication of the virus from the peripheral reservoirs, it is critical that we pay close attention to the virus in the brain and develop strategies for maintaining it in a latent state failure of which could result in dire consequences. C1 [Churchill, Melissa] Burnet Inst, Ctr Virol, Melbourne, Vic 3004, Australia. [Churchill, Melissa] Monash Univ, Dept Microbiol, Clayton, Vic 3168, Australia. [Churchill, Melissa] Monash Univ, Dept Med, Clayton, Vic, Australia. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Churchill, M (reprint author), Burnet Inst, 85 Commercial Rd, Melbourne, Vic 3004, Australia. EM churchil@burnet.edu.au FU Intramural NIH HHS [ZIA NS003130-06, ZIA NS003130-05] NR 44 TC 42 Z9 42 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2013 VL 8 IS 3 BP 165 EP 169 DI 10.1097/COH.0b013e32835fc601 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 126DG UT WOS:000317591500002 PM 23429501 ER PT J AU Lo, B Grady, C AF Lo, Bernard Grady, Christine CA Int AIDS Soc TI Ethical considerations in HIV cure research: points to consider SO CURRENT OPINION IN HIV AND AIDS LA English DT Review DE ethics; HIV cure; research ID PREVENTION TRIALS NETWORK AB Purpose of review Research directed toward an HIV cure presents ethical as well as scientific challenges. Recent findings International guidelines, regulations, and the medical literature provide helpful guidance on protecting research participants. Summary This review presents points to consider for researchers, sponsors, oversight committees, community advisory boards, and HIV advocates to help resolve ethical challenges that are particularly complex or difficult or that are not adequately addressed by current ethical guidelines. The points to consider are: collaborative partnership among international scientists from both the private and public sectors, as well as engagement of HIV-affected communities, social value, scientific validity, fair selection of participants and study sites, a favorable and acceptable risk-benefit balance, independent scientific and ethical review, informed and voluntary consent, and respect for enrolled patients and communities. To prevent therapeutic misconception, participants' comprehension of key features of the study may need to be assessed. Participants who suffer study-related adverse events should receive appropriate medical care and compensation. If interventions are shown capable of curing HIV, sponsors and international funding agencies should plan how to make them available and affordable in resource-poor countries. C1 [Lo, Bernard] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Grady, Christine] NIH, Bethesda, MD 20892 USA. RP Lo, B (reprint author), Univ Calif San Francisco, 103 Plaza Dr, Berkeley, CA 94705 USA. EM bernie@medicine.ucsf.edu RI Barre-Sinoussi, Francoise/G-8355-2011 FU US National Institutes of Health (NIH) FX The authors have written the article on behalf of the International AIDS Society (IAS) 'Towards an HIV Cure' Working Group on Ethical Issues, and acknowledge the fruitful contribution of the group; the full list of members can be found below. The Working Group on Ethical Issues is a project of the International AIDS Society 'Towards an HIV Cure' initiative, which is in partnership with the US National Institutes of Health (NIH), although the NIH has not directly funded the research in this article. The authors would also like to thank the International AIDS Society for their support, particularly Rosanne Lamplough. NR 14 TC 23 Z9 23 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2013 VL 8 IS 3 BP 243 EP 249 DI 10.1097/COH.0b013e32835ea1c5 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 126DG UT WOS:000317591500014 PM 23422260 ER PT J AU Kawabata, A Ohta, N Seiler, G Pyle, MM Ishiguro, S Zhang, YQ Becker, KG Troyer, D Tamura, M AF Kawabata, Atsushi Ohta, Naomi Seiler, Garret Pyle, Marla M. Ishiguro, Susumu Zhang, Yong Qing Becker, Kevin G. Troyer, Deryl Tamura, Masaaki TI Naive rat umbilical cord matrix stem cells significantly attenuate mammary tumor growth through modulation of endogenous immune responses SO CYTOTHERAPY LA English DT Article DE immune response; macrophages; mammary tumor; rat umbilical cord matrix stem cells; T cells ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; JELLY-DERIVED CELLS; REGULATORY T-CELLS; BREAST-CANCER; GENE-THERAPY; INFILTRATING LYMPHOCYTES; COLORECTAL-CANCER; EPITHELIAL-CELLS; OVARIAN-CANCER; IN-VITRO AB Background aims. Un-engineered human and rat umbilical cord matrix stem cells (UCMSCs) attenuate growth of several types of tumors in mice and rats. However, the mechanism by which UCMSCs attenuate tumor growth has not been studied rigorously. Methods. The possible mechanisms of tumor growth attenuation by rat UCMSCs were studied using orthotopic Mat B III rat mammary tumor grafts in female F344 rats. Tumor-infiltrating leukocytes were identified and quantified by immunohistochemistry analysis. Potential cytokines involved in lymphocyte infiltration in the tumors were determined by microarray and Western blot analysis. The Boyden chamber migration assay was performed for the functional analysis of identified cytokines. Results. Rat UCMSCs markedly attenuated tumor growth; this attenuation was accompanied by considerable lymphocyte infiltration. Immunohistochemistry analysis revealed that most infiltrating lymphocytes in the rat UCMSC-treated tumors were CD3(+) T cells. In addition, treatment with rat UCMSCs significantly increased infiltration of CD8(+) and CD4(+) T cells and natural killer (NK) cells throughout tumor tissue. CD68(+) monocytes/macrophages and Foxp3(+) regulatory T cells were scarcely observed, only in the tumors of the phosphate-buffered saline control group. Microarray analysis of rat UCMSCs demonstrated that monocyte chemotactic protein-1 is involved in rat UCMSC-induced lymphocyte infiltration in the tumor tissues. Conclusions. These results suggest that naive rat UCMSCs attenuated mammary tumor growth at least in part by enhancing host anti-tumor immune responses. Naive UCMSCs can be used as powerful therapeutic cells for breast cancer treatment, and monocyte chemotactic protein-1 may be a key molecule to enhance the effect of UCMSCs at the tumor site. C1 [Kawabata, Atsushi; Ohta, Naomi; Seiler, Garret; Pyle, Marla M.; Ishiguro, Susumu; Troyer, Deryl; Tamura, Masaaki] Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, Manhattan, KS 66506 USA. [Zhang, Yong Qing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. RP Tamura, M (reprint author), Kansas State Univ, Coll Vet Med, Dept Anat & Physiol, Manhattan, KS 66506 USA. EM mtamura@vet.ksu.edu OI Becker, Kevin/0000-0002-6794-6656; Ohta, Naomi/0000-0001-5790-3137 FU Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research; Kansas Bioscience Authority Collaborative Cancer Research Initiative grant; Kansas State Legislative Appropriation; KSU College of Veterinary Medicine Dean's fund; NIH [P20 RR017686, P20 RR016475, P20 RR01556, R21 CA135599]; Intramural Research Program of the NIH, National Institute on Aging FX We are grateful to Mr William H. Wood III (National Institute on Aging, NIH) for his excellent technical assistance in microarray analysis. We are thankful to Mr Sivasai Balivada (Department of Anatomy & Physiology, Kansas State University) for his technical assistance in animal studies. This work was supported by Kansas State University (KSU) Terry C. Johnson Center for Basic Cancer Research, Kansas Bioscience Authority Collaborative Cancer Research Initiative grant, Kansas State Legislative Appropriation, KSU College of Veterinary Medicine Dean's fund, NIH grants P20 RR017686, P20 RR016475, P20 RR01556 and R21 CA135599 and the Intramural Research Program of the NIH, National Institute on Aging. NR 53 TC 4 Z9 5 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAY PY 2013 VL 15 IS 5 BP 586 EP 597 DI 10.1016/j.jcyt.2013.01.006 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 123EJ UT WOS:000317370900008 PM 23474329 ER PT J AU Castiello, L Mossoba, M Viterbo, A Sabatino, M Fellowes, V Foley, JE Winterton, M Halverson, DC Civini, S Jin, P Fowler, DH Stroncek, DF AF Castiello, Luciano Mossoba, Miriam Viterbo, Antonella Sabatino, Marianna Fellowes, Vicki Foley, Jason E. Winterton, Matthew Halverson, David C. Civini, Sara Jin, Ping Fowler, Daniel H. Stroncek, David F. TI Differential gene expression profile of first-generation and second-generation rapamycin-resistant allogeneic T cells SO CYTOTHERAPY LA English DT Article DE cell therapy; graft-versus-host disease; sirolimus; T lymphocytes ID DONOR TH2 CELLS; IN-VIVO; IMMUNE-RESPONSES; GRAFT-REJECTION; UP-REGULATION; ACTIVATION; PATHWAY; BIOINFORMATICS; INHIBITION; SIGNATURES AB Background aims. We completed a phase II clinical trial evaluating rapamycin-resistant allogeneic T cells (T-rapa) and now have evaluated a T-rapa product manufactured in 6 days (T-rapa(6)) rather than 12 days (T-Rapa(12)). Methods. Using gene expression microarrays, we addressed our hypothesis that the two products would express a similar phenotype. The products had similar phenotypes using conventional comparison methods of cytokine secretion and surface markers. Results. Unsupervised analysis of 34,340 genes revealed that T-rapa6 and T-rapa(12) products clustered together, distinct from culture input CD4(+) T cells. Statistical analysis of T-rapa6 products revealed differential expression of 19.3% of genes (n = 6641) compared with input CD4(+) cells; similarly, 17.8% of genes (n = 6147) were differentially expressed between T-rapa(12) products and input CD4(+) cells. Compared with input CD4(+) cells, T-rapa(6) and T-rapa(12) products were similar in terms of up-regulation of major gene families (cell cycle, stress response, glucose catabolism, DNA metabolism) and down-regulation (inflammatory response, immune response, apoptosis, transcriptional regulation). However, when directly compared, T-rapa(6) and T-rapa(12) products showed differential expression of 5.8% of genes (n = 1994; T-rapa(6) vs. T-rapa(12)). Conclusions. Second-generation T-rapa(6) cells possess a similar yet distinct gene expression profile relative to first-generation T-rapa(12) cells and may mediate differential effects after adoptive transfer. C1 [Castiello, Luciano; Viterbo, Antonella; Sabatino, Marianna; Civini, Sara; Jin, Ping; Stroncek, David F.] NCI, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Mossoba, Miriam; Fellowes, Vicki; Foley, Jason E.; Winterton, Matthew; Halverson, David C.; Fowler, Daniel H.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Castiello, L (reprint author), NIH, Dept Transfus Med, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM castiellol@cc.nih.gov RI Castiello, Luciano/K-8616-2016 OI Castiello, Luciano/0000-0001-7146-3158 FU NIH, Clinical Center; National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, Clinical Center and National Cancer Institute. We would like to thank our collaborator, Dr. Bruce Levine of the University of Pennsylvania, for his assistance with the manufacturing of the anti-CD3, anti-CD28 co-stimulation beads. NR 48 TC 3 Z9 3 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD MAY PY 2013 VL 15 IS 5 BP 598 EP 609 DI 10.1016/j.jcyt.2012.12.008 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 123EJ UT WOS:000317370900009 PM 23352462 ER PT J AU Alvarez-Downing, MM Kamal, N Inchauste, SM Khangura, SK Malech, HL Holland, SM Hughes, MS Heller, T Sherry, RM AF Alvarez-Downing, Melissa M. Kamal, Natasha Inchauste, Suzanne M. Khangura, Sajneet K. Malech, Harry L. Holland, Steven M. Hughes, Marybeth S. Heller, Theo Sherry, Richard M. TI The Role of Surgery in the Management of Patients With Refractory Chronic Granulomatous Disease Colitis SO DISEASES OF THE COLON & RECTUM LA English DT Article DE Chronic granulomatous disease; Colitis; Surgical management ID GASTROINTESTINAL MANIFESTATIONS; CROHNS-DISEASE; COMPLICATIONS AB BACKGROUND: Chronic granulomatous disease is a rare immunodeficiency complicated by dysregulated inflammation and granulomatous complications of the GI tract. The management of chronic granulomatous disease colitis presents the dilemma of an immunocompromised host requiring immunosuppressive therapy which can potentiate fatal infections. OBJECTIVE: The aim of this study was to identify the types of GI surgery performed in patients and determine the role of surgery in the management of refractory colitis. DESIGN AND SETTINGS: A retrospective single-institution chart review was performed. PATIENTS: Of 268 patients with chronic granulomatous disease treated at the National Institutes of Health between 1985 and 2011, 98 (37%) were identified as having colitis; 27 (10%) had a history of GI luminal surgery. MAIN OUTCOME MEASURES: Patient characteristics, type of GI surgery, and clinical outcomes were documented. RESULTS: A total of 62 GI luminal surgeries were performed in 27 patients with chronic granulomatous disease and colitis. All 27 had a history of perineal disease requiring intervention. Four (15%) had additional surgery performed for reasons other than colitis. Otherwise, 12 (44%) had surgery limited to the perineum, 2 (7%) had a segmental resection, and 13 (48%) underwent fecal diversion with ileostomy or colostomy. Despite local procedures, 7 (58%) patients in the perineal-only group remained symptomatic. Both patients with a segmental resection had persistent perineal disease, and 1 had a recurrent colovesicular fistula. Of the 13 ostomy patients, 11 initially received a diverting ostomy. Eight (73%) of these ultimately required additional procedures for refractory disease, and 4 (36%) developed peristomal pyoderma gangrenosum. Four patients who underwent proctocolectomy with end ileostomy, either initially (2) or as a definitive procedure (2), experienced resolution of colitis and perineal disease. LIMITATIONS: This study is limited by its retrospective design, small sample size, and highly selected patient population. CONCLUSIONS: Proctocolectomy with end ileostomy may offer a definitive treatment in a patient with refractory chronic granulomatous disease colitis given current therapeutic limitations. C1 [Alvarez-Downing, Melissa M.; Inchauste, Suzanne M.; Hughes, Marybeth S.; Sherry, Richard M.] NCI, Surg Branch, Bethesda, MD 20891 USA. [Kamal, Natasha] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Khangura, Sajneet K.; Heller, Theo] NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. [Malech, Harry L.] NIAID, Lab Host Defenses, Bethesda, MD 20892 USA. [Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Alvarez-Downing, MM (reprint author), NCI, Surg Branch, 10 Ctr Dr,Bldg 10 Hatfield CRC,Rm 3-5888, Bethesda, MD 20891 USA. EM melmalvarez@gmail.com; sherryr@mail.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU Intramural Research Programs of the National Cancer Institute, National Institute of Allergy and Infectious Diseases, Clinical Center and National Institute of Diabetes and Digestive and Kidney Diseases FX Intramural Research Programs of the National Cancer Institute, National Institute of Allergy and Infectious Diseases, Clinical Center and National Institute of Diabetes and Digestive and Kidney Diseases. NR 25 TC 4 Z9 4 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD MAY PY 2013 VL 56 IS 5 BP 609 EP 614 DI 10.1097/DCR.0b013e3182781504 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 126DB UT WOS:000317590800010 PM 23575400 ER PT J AU Grassl, A Winter, L Thalhammer, C Renz, W Kellman, P Martin, C von Knobelsdorff-Brenkenhoff, F Tkachenko, V Schulz-Menger, J Niendorf, T AF Graessl, Andreas Winter, Lukas Thalhammer, Christof Renz, Wolfgang Kellman, Peter Martin, Conrad von Knobelsdorff-Brenkenhoff, Florian Tkachenko, Valeriy Schulz-Menger, Jeanette Niendorf, Thoralf TI Design, evaluation and application of an eight channel transmit/receive coil array for cardiac MRI at 7.0 T SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Ultrahigh field MRI; Cardiovascular MRI; Transceiver array; Parallel imaging ID 7 TESLA; MAGNETIC-RESONANCE; SENSE AB The objective of this work is to design, examine and apply an eight channel transmit/receive coil array tailored for cardiac magnetic resonance imaging at 7.0 T that provides image quality suitable for clinical use, patient comfort, and ease of use. The cardiac coil array was designed to consist of a planar posterior section and a modestly curved anterior section. For radio frequency (RF) safety validation, numerical computations of the electromagnetic field (EMF) and the specific absorption rate (SAR) distribution were conducted. In vivo cardiac imaging was performed using a 2D CINE FLASH technique. For signal-to-noise ratio (SNR) assessment reconstructed images were scaled in SNR units. The parallel imaging capabilities of the coil were examined using GRAPPA and SENSE reconstruction with reduction factors of up to R = 4. The assessment of the RF characteristics yielded a maximum noise correlation of 0.33. The baseline SNR advantage at 7.0 T was put to use to acquire 2D CINE images of the heart with a spatial resolution of 1 mm x 1 mm x 4 mm. The coil array supports 1D acceleration factors of up to R = 3 without impairing image quality significantly. For un-accelerated 2D CINE FLASH acquisitions the results revealed an SNR of approximately 140 for the left ventricular blood pool. Blood/myocardium contrast was found to be approximately 90 for un-accelerated 2D CINE FLASH acquisitions. The proposed 8 channel cardiac transceiver surface coil has the capability to acquire high contrast, high spatial and temporal resolution in vivo images of the heart at 7.0 T. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Graessl, Andreas; Winter, Lukas; Thalhammer, Christof; Renz, Wolfgang; Martin, Conrad; von Knobelsdorff-Brenkenhoff, Florian; Schulz-Menger, Jeanette; Niendorf, Thoralf] Max Delbrueck Ctr Mol Med, Berlin Ultrahigh Field Facil, D-13125 Berlin, Germany. [Renz, Wolfgang] Siemens Healthcare, D-91052 Erlangen, Germany. [Kellman, Peter] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [von Knobelsdorff-Brenkenhoff, Florian; Schulz-Menger, Jeanette] HELIOS Klinikum Berlin Buch, Dept Cardiol & Nephrol, D-13125 Berlin, Germany. [von Knobelsdorff-Brenkenhoff, Florian; Tkachenko, Valeriy; Schulz-Menger, Jeanette; Niendorf, Thoralf] Charite, ECRC, D-13125 Berlin, Germany. RP Niendorf, T (reprint author), Max Delbrueck Ctr Mol Med, Berlin Ultrahigh Field Facil, Robert Roessle Str 10, D-13125 Berlin, Germany. EM Andreas.Graessl@mdc-berlin.de; Lukas.Winter@mdc-berlin.de; Christof.Thalhammer@mdc-berlin.de; Wolfgang.Renz@mdc-berlin.de; kellmanp@mail.nih.gov; Conrad.Martin@mdc-berlin.de; florian.von-knobelsdorff@charite.de; v.o.tkachenko@googlemail.com; jeanette.schulz-menger@charite.de; Thoralf.Niendorf@mdc-berlin.de RI Niendorf, Thoralf/H-7738-2013; OI Niendorf, Thoralf/0000-0001-7584-6527; Winter, Lukas/0000-0002-4381-275X NR 19 TC 16 Z9 16 U1 0 U2 18 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X EI 1872-7727 J9 EUR J RADIOL JI Eur. J. Radiol. PD MAY PY 2013 VL 82 IS 5 BP 752 EP 759 DI 10.1016/j.ejrad.2011.08.002 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 122RP UT WOS:000317335800015 PM 21920683 ER PT J AU Glymour, MM Benjamin, EJ Kosheleva, A Gilsanz, P Curtis, LH Patton, KK AF Glymour, M. Maria Benjamin, Emelia J. Kosheleva, Anna Gilsanz, Paola Curtis, Lesley H. Patton, Kristen K. TI Early life predictors of atrial fibrillation-related mortality: Evidence from the health and retirement study SO HEALTH & PLACE LA English DT Article DE Atrial fibrillation; Mortality; Residence; Geographic; Lifecourse ID LIFECOURSE SOCIAL CONDITIONS; CORONARY-HEART-DISEASE; LOW-BIRTH-WEIGHT; UNITED-STATES; STROKE BELT; CARDIOVASCULAR-DISEASE; RISK-FACTOR; 1ST STROKE; CHILDHOOD; HEIGHT AB Prior research found that Americans born in 6 southeastern states (the AF-risk zone) had elevated risk of AF-related mortality, but no mechanisms were identified. We hypothesized the association between AF-related mortality and AF-risk zone birth is explained by indicators of childhood social disadvantage or adult risk factors. In 24,323 participants in the US Health and Retirement Study, we found that birth in the AF-risk zone was significantly associated with hazard of AF-related mortality. Among whites, the relationship was specific to place of birth, rather than place of adult residence. Neither paternal education nor subjectively assessed childhood SES predicted AF-related mortality. Conventional childhood and adult cardiovascular risk factors did not explain the association between place of birth and AF-related mortality. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Glymour, M. Maria; Kosheleva, Anna; Gilsanz, Paola] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Sch Publ Hlth, Cardiol Sect,Dept Med,Dept Epidemiol, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Sch Publ Hlth, Prevent Med Sect,Dept Med,Dept Epidemiol, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Curtis, Lesley H.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Patton, Kristen K.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA USA. RP Glymour, MM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 677 Huntington Ave,Kresge 617, Boston, MA 02115 USA. EM mglymour@hsph.harvard.edu OI Benjamin, Emelia/0000-0003-4076-2336; Patton, Kristen K./0000-0002-9034-6966 FU NIH/NIA [R21AG03438501]; Harvard School of Public Health Initiative to Maximize Student Diversity (IMSD) training grant (NIH/NIGMS); National Heart Lung and Blood Institute [F31HL112613]; John L. Locke Charitable Trust; National Institute on Aging [NIA U01AG009740]; [1RC1-HL101056]; [1R01HL092577]; [1R01HL102214]; [1R01AG028321] FX Contributions of Dr. Glymour and Ms. Kosheleva to this study were supported by funding from the NIH/NIA (R21AG03438501).; Dr. Benjamin receives research support from 1RC1-HL101056; 1R01HL092577; 1R01HL102214; 1R01AG028321; Ms. Gilsanz was supported by the Harvard School of Public Health Initiative to Maximize Student Diversity (IMSD) training grant (NIH/NIGMS) and by the National Heart Lung and Blood Institute (F31HL112613). Contributions of Dr. Patton to this study were supported by funding from the John L. Locke Charitable Trust.; The Health and Retirement Study is sponsored by the National Institute on Aging (grant number NIA U01AG009740) and conducted by the University of Michigan. NR 40 TC 0 Z9 0 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 J9 HEALTH PLACE JI Health Place PD MAY PY 2013 VL 21 BP 133 EP 139 DI 10.1016/j.healthplace.2012.12.008 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 121TD UT WOS:000317266200015 PM 23454734 ER PT J AU Chu, AY Workalemahu, T Paynter, NP Rose, LM Giulianini, F Tanaka, T Ngwa, JS Qi, QB Curhan, GC Rimm, EB Hunter, DJ Pasquale, LR Ridker, PM Hu, FB Chasman, DI Qi, L AF Chu, Audrey Y. Workalemahu, Tsegaselassie Paynter, Nina P. Rose, Lynda M. Giulianini, Franco Tanaka, Toshiko Ngwa, Julius S. Qi, Qibin Curhan, Gary C. Rimm, Eric B. Hunter, David J. Pasquale, Louis R. Ridker, Paul M. Hu, Frank B. Chasman, Daniel I. Qi, Lu CA CHARGE Nutr Working Grp DietGen Consortium TI Novel locus including FGF21 is associated with dietary macronutrient intake SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; FOOD FREQUENCY QUESTIONNAIRE; INSULIN SENSITIVITY; METABOLIC SYNDROME; OBESITY; RISK; HEALTH; DISEASE; WOMEN; GENE AB Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P 10(5)) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n 38 360) and attained genome-wide significance in combined analysis (P-joint 7.9 10(9)). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake. C1 [Chu, Audrey Y.; Paynter, Nina P.; Rose, Lynda M.; Giulianini, Franco; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Workalemahu, Tsegaselassie; Qi, Qibin; Curhan, Gary C.; Rimm, Eric B.; Hunter, David J.; Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Workalemahu, Tsegaselassie; Qi, Qibin; Curhan, Gary C.; Rimm, Eric B.; Hunter, David J.; Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Pasquale, Louis R.] Brigham & Womens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Workalemahu, Tsegaselassie; Qi, Qibin; Rimm, Eric B.; Hunter, David J.; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Workalemahu, Tsegaselassie; Qi, Qibin; Rimm, Eric B.; Hunter, David J.; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Tanaka, Toshiko] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Ngwa, Julius S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Pasquale, Louis R.] Harvard Univ, Sch Med, Mass Eye & Ear Infirm, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Bldg 2,Room 323,655 Huntington Ave, Boston, MA 02115 USA. EM luqi@hsph.harvard.edu FU National Institutes of Health [DK091718, HL71981, HL073168, CA87969, CA49449, HL34594, HL088521, U01HG004399, DK080140, DK58845, DK46200, HL043851, HL080467, CA058988]; Amgen; American Heart Association Scientist Development Award [0730094N] FX The HPFS and NHS were supported by grants DK091718, HL71981, HL073168, CA87969, CA49449, HL34594, HL088521, U01HG004399, DK080140, DK58845 and DK46200 from the National Institutes of Health. The WGHS is supported by HL043851, HL080467 and CA058988 from the National Institutes of Health with collaborative scientific support and funding for genotyping provided by Amgen. L. Q. is a recipient of the American Heart Association Scientist Development Award (0730094N). NR 39 TC 31 Z9 33 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 1 PY 2013 VL 22 IS 9 BP 1895 EP 1902 DI 10.1093/hmg/ddt032 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 123ZD UT WOS:000317431100018 PM 23372041 ER PT J AU Rebeil, R Jarrett, CO Driver, JD Ernst, RK Oyston, PCF Hinnebusch, BJ AF Rebeil, Roberto Jarrett, Clayton O. Driver, James D. Ernst, Robert K. Oyston, Petra C. F. Hinnebusch, B. Joseph TI Induction of the Yersinia pestis PhoP-PhoQ Regulatory System in the Flea and Its Role in Producing a Transmissible Infection SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SALMONELLA-TYPHIMURIUM VIRULENCE; BACTERIAL SENSOR KINASE; BIOFILM FORMATION; ESCHERICHIA-COLI; PASTEURELLA-PESTIS; CAENORHABDITIS-ELEGANS; ANTIMICROBIAL PEPTIDES; POLYMYXIN-RESISTANCE; PMRA-PMRB; SURVIVAL AB Transmission of Yersinia pestis is greatly enhanced after it forms a bacterial biofilm in the foregut of the flea vector that interferes with normal blood feeding. Here we report that the ability to produce a normal foregut-blocking infection depends on induction of the Y. pestis PhoP-PhoQ two-component regulatory system in the flea. Y. pestis phoP-negative mutants achieved normal infection rates and bacterial loads in the flea midgut but produced a less cohesive biofilm both in vitro and in the flea and had a greatly reduced ability to localize to and block the flea foregut. Thus, not only is the PhoP-PhoQ system induced in the flea gut environment, but also this induction is required to produce a normal transmissible infection. The altered biofilm phenotype in the flea was not due to lack of PhoPQ-dependent or PmrAB-dependent addition of aminoarabinose to the Y. pestis lipid A, because an aminoarabinose-deficient mutant that is highly sensitive to cationic antimicrobial peptides had a normal phenotype in the flea digestive tract. In addition to enhancing transmissibility, induction of the PhoP-PhoQ system in the arthropod vector prior to transmission may preadapt Y. pestis to resist the initial encounter with the mammalian innate immune response. C1 [Rebeil, Roberto; Jarrett, Clayton O.; Driver, James D.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Ernst, Robert K.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Ernst, Robert K.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Oyston, Petra C. F.] CBS Porton Down, Def Sci & Technol Lab, Salisbury, Wilts, England. RP Hinnebusch, BJ (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. EM jhinnebusch@niaid.nih.gov FU Division of Intramural Research, NIAID, NIH; Ellison Medical Foundation (New Scholars in Global Infectious Diseases) FX This work was supported by the Division of Intramural Research, NIAID, NIH, and by the Ellison Medical Foundation (New Scholars in Global Infectious Diseases award to B.J.H.). NR 84 TC 20 Z9 22 U1 0 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2013 VL 195 IS 9 BP 1920 EP 1930 DI 10.1128/JB.02000-12 PG 11 WC Microbiology SC Microbiology GA 123SE UT WOS:000317410200009 PM 23435973 ER PT J AU Kim, T Shapiro, BA AF Kim, Taejin Shapiro, Bruce A. TI The role of salt concentration and magnesium binding in HIV-1 subtype-A and subtype-B kissing loop monomer structures SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article DE HIV-1 dimerization; HIV-1 subtype-A dimerization; HIV-1 subtype-B dimerization; Ion concentration; Magnesium binding; RNA molecular dynamics simulations ID MOLECULAR-DYNAMICS SIMULATIONS; IMMUNODEFICIENCY-VIRUS TYPE-1; DIMERIZATION INITIATION SITE; GENOMIC RNA DIMERIZATION; NMR SOLUTION STRUCTURE; IN-VITRO; STABLE DIMER; SEQUENCE; COMPLEX; OLIGONUCLEOTIDE AB The subtype-B monomers of the human immunodeficiency virus type-1 (HIV-1) have experimentally been shown to dimerize at high salt concentration or in the presence of magnesium, while the dimerization of the subtype-A monomers requires magnesium binding at the G273 or G274 phosphate groups regardless of salt concentration. We used explicit solvent molecular dynamics (MD) simulations to investigate the conformational changes in subtype-A and -B monomers in different salt concentrations, and we found that our MD simulation results are consistent with those of experiments. At low salt concentration, hairpin loop structures of both subtypes were deformed and bases in the hairpin loop were turned inside. At high salt concentrations, the subtype-B monomer maintained the hairpin loop shape and most bases in the hairpin loop pointed out, while the subtype-A monomer showed a severe deformation. We also found that the flanking bases in the subtype-B stabilize the hairpin loop, while the flanking base G273 in the subtype-A caused a significant deformation. However, a bound magnesium ion at the G273 or G274 phosphate groups controlled the behavior of the G273 base and prevented the subtype-A monomer from deformation. We also applied restraints to both subtypes to examine the role of high salt concentration or magnesium binding. While restraints were applied, both subtypes at 0M salt concentration maintained their shapes. However, when restraints were removed, they deformed significantly. Therefore, we suggest that the dimerization of both subtypes requires the proper conformation of the monomers which is induced by the appropriate salt strength and magnesium ion binding. C1 [Kim, Taejin; Shapiro, Bruce A.] Frederick Natl Lab Canc Res, Ctr Canc Res Nanobiol Program, Frederick, MD 20872 USA. RP Shapiro, BA (reprint author), Frederick Natl Lab Canc Res, Ctr Canc Res Nanobiol Program, Frederick, MD 20872 USA. EM shapirbr@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We wish to thank the National Cancer Institute's Advanced Biomedical Computing Center (ABCC) of the Frederick National Laboratory for Cancer Research for the computational support. We also thank the NIH Fellows Editorial Board for editorial assistance on a late version of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 44 TC 7 Z9 7 U1 0 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD MAY 1 PY 2013 VL 31 IS 5 BP 495 EP 510 DI 10.1080/07391102.2012.706072 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 122VC UT WOS:000317345200006 PM 22881341 ER PT J AU White, SF Brislin, S Sinclair, S Fowler, KA Pope, K Blair, RJR AF White, Stuart F. Brislin, Sarah Sinclair, Stephen Fowler, Katherine A. Pope, Kayla Blair, R. James R. TI The relationship between large cavum septum pellucidum and antisocial behavior, callous-unemotional traits and psychopathy in adolescents SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Conduct disorder; development ID FETAL-ALCOHOL-SYNDROME; CONDUCT DISORDER; BRAIN ANOMALIES; CHILDREN; SCHIZOPHRENIA; HYPERACTIVITY; OFFENDERS; AMYGDALA; BOYS; AGGRESSION AB Background: The presence of a large cavum septum pellucidum (CSP) has been previously associated with antisocial behavior/psychopathic traits in an adult community sample. Aims: The current study investigated the relationship between a large CSP and symptom severity in disruptive behavior disorders (DBD; conduct disorder and oppositional defiant disorder). Method: Structural MRI scans of youth with DBDs (N=32) and healthy comparison youth (N=27) were examined for the presence of a large CSP and if this was related to symptom severity. Results: Replicating previous results, a large CSP was associated with DBD diagnosis, proactive aggression, and level of psychopathic traits in youth. However, the presence of a large CSP was unrelated to aggression or psychopathic traits within the DBD sample. Conclusions: Early brain mal-development may increase the risk of a DBD diagnosis, but does not mark a particularly severe form of DBD within patients receiving these diagnoses. C1 [White, Stuart F.; Brislin, Sarah; Sinclair, Stephen; Fowler, Katherine A.; Pope, Kayla; Blair, R. James R.] NIMH, Unit Affect Cognit Neurosci, NIH, Bethesda, MD 20892 USA. RP White, SF (reprint author), 9000 Rockville Pike,Bldg 15 Room 300 C, Bethesda, MD 20892 USA. EM whitesf@mail.nih.gov FU Division of Intramural Research Programs; National Institute of Mental Health/NIH FX This study was supported by the Division of Intramural Research Programs and the National Institute of Mental Health/NIH. NR 41 TC 5 Z9 6 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD MAY PY 2013 VL 54 IS 5 BP 575 EP 581 DI 10.1111/j.1469-7610.2012.02603.x PG 7 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 127EN UT WOS:000317679500010 PM 22934662 ER PT J AU Hara, K Rivera, MM Koh, C Sakiani, S Hoofnagle, JH Heller, T AF Hara, Koji Rivera, Maria M. Koh, Christopher Sakiani, Sasan Hoofnagle, Jay H. Heller, Theo TI Important Factors in Reliable Determination of Hepatitis C Virus Genotype by Use of the 5 ' Untranslated Region SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID SEQUENCE-ANALYSIS; NS5B SEQUENCE; ASSAY; HCV; CLASSIFICATION; INFECTION; SUBTYPES AB Accurate genotyping of hepatitis C virus (HCV) is important for determining the optimal regimen, dose, and duration of antiviral therapy for chronic HCV infection, as well as for estimating the response rate. The 5' untranslated region (UTR) of HCV RNA is used in commercial genotyping, but the probes and the lengths of the amplicons are proprietary and vary among the assays. In this study, factors involved in the reliable determination of HCV genotypes utilizing the 5' UTR were evaluated. Serum samples from four subjects with chronic HCV infection and disparate results on commercial genotyping and four controls were analyzed. HCV RNA was extracted from serum samples, and the 5' UTR and NS5B region were sequenced. Ten clones from each region were compared to prototype sequences and analyzed for genotype assignment using five programs. The results were compared to those from commercial assays. 5' UTR sequences were sequentially shortened from either the 5' end, the 3' end, or both ends, with genotyping of the resultant fragments. Sequences were obtained for the 5' UTR in all eight subjects and for the NS5B region in five subjects. The genotype assignments were identical between the two regions in the five subjects with complete sequencing. Genotyping by sequencing gave different results than those from the commercial assays in the four experimental samples but agreed in the four controls. Shortening of the sequences affected the results, and the results for sequences of <200 bases were inaccurate. Neither the Hamming distance nor the quasispecies affected the results. Sequencing of the HCV 5' UTR provided reliable genotyping results and resolved discrepancies identified in commercial assays, but genotyping by sequencing was highly dependent upon sequence length. C1 [Hara, Koji; Rivera, Maria M.; Koh, Christopher; Sakiani, Sasan; Hoofnagle, Jay H.; Heller, Theo] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Heller, T (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. EM theoh@intra.niddk.nih.gov FU intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases [Z01 DK054514-02]; Clinical Center, National Institutes of Health, Bethesda, MD FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases (Z01 DK054514-02 LDB) and the Clinical Center, National Institutes of Health, Bethesda, MD. NR 25 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2013 VL 51 IS 5 BP 1485 EP 1489 DI 10.1128/JCM.03344-12 PG 5 WC Microbiology SC Microbiology GA 126GT UT WOS:000317602100022 PM 23467599 ER PT J AU Dize, L West, S Williams, JA Van der Pol, B Quinn, TC Gaydos, CA AF Dize, Laura West, Sheila Williams, James A. Van der Pol, Barbara Quinn, Thomas C. Gaydos, Charlotte A. TI Comparison of the Abbott m2000 RealTime CT Assay and the Cepheid GeneXpert CT/NG Assay to the Roche Amplicor CT Assay for Detection of Chlamydia trachomatis in Ocular Samples from Tanzania SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID MASS TREATMENT; INFECTION AB The GeneXpert CT/NG assay (GeneXpert) and the Abbott m2000 RealTime CT (m2000) assay were compared to Amplicor for detecting ocular Chlamydia trachomatis. Discordant specimens were tested by the Aptima CT assay. The m2000 assay sensitivity was 100% (95% confidence interval [CI], 90% to 100%), and specificity was 98.46% (95% CI, 95.2% to 99.2%); GeneXpert sensitivity was 100% (95% CI, 90% to 100%), and specificity was 100% (95% CI, 98.1% to 100%). The m2000 and GeneXpert assays appear to perform as well as the Amplicor assay. C1 [Dize, Laura; West, Sheila; Quinn, Thomas C.; Gaydos, Charlotte A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Williams, James A.; Van der Pol, Barbara] Indiana Univ Sch Med, Indianapolis, IN USA. [Van der Pol, Barbara] Indiana Univ, Sch Publ Hlth, Bloomington, IN USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Dize, L (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. EM Ldize2@jhmi.edu FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Bill and Melinda Gates Foundation; Abbott Molecular Diagnostics; BD Diagnostics; Beckman Coulter; Cepheid; Roche Molecular Diagnostics; Gen-Probe Hologic FX This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Bill and Melinda Gates Foundation.; B.V.D.P. has received honoraria, consulting fees, or research support from the following sponsors: Abbott Molecular Diagnostics, BD Diagnostics, Beckman Coulter, Cepheid, and Roche Molecular Diagnostics. C.A.G. has received honoraria or research support from the following sponsors: Abbott Molecular Diagnostics, BD Diagnostics, Gen-Probe Hologic, Cepheid, and Roche Molecular Diagnostics. NR 8 TC 14 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAY PY 2013 VL 51 IS 5 BP 1611 EP 1613 DI 10.1128/JCM.00519-13 PG 3 WC Microbiology SC Microbiology GA 126GT UT WOS:000317602100048 PM 23486714 ER PT J AU Wan, ZP Zhang, SS Fan, YL Liu, K Du, F Davey, AM Zhang, HY Han, WD Xiong, CY Liu, WL AF Wan, Zhengpeng Zhang, Shaosen Fan, Yilin Liu, Kai Du, Feng Davey, Angel M. Zhang, Huiyuan Han, Weidong Xiong, Chunyang Liu, Wanli TI B Cell Activation Is Regulated by the Stiffness Properties of the Substrate Presenting the Antigens SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HIGH EPITOPE DENSITY; RESPONSES IN-VIVO; LYMPH-NODE; IMMUNOLOGICAL SYNAPSES; SIGNAL-TRANSDUCTION; SUBCAPSULAR SINUS; PROTEIN MOLECULE; LIVING CELLS; RECEPTOR; MICROCLUSTER AB B lymphocytes are activated upon Ag sensing by BCRs. The substrate presenting the Ag can show different degrees of stiffness. It is not clear whether B cells can respond to changes in substrate stiffness. In this study we use high-resolution, high-speed live cell imaging techniques to capture the molecular events in B cell activation after the recognition of Ags tethered to polyacrylamide gel substrates with variable degrees of stiffness as quantified by Young's modulus (2.6-22.1 kPa). We show that the initiation of B cell activation is extremely sensitive to substrate stiffness. B cells exhibit much stronger activation responses when encountering Ags tethered to substrates with a high degree of stiffness as measured by the accumulation of BCR, phospho-spleen tyrosine kinase, and phosphotyrosine molecules into the B cell immunological synapse. Ags tethered to stiff substrates induce the formation of more prominent BCR and phospho-spleen tyrosine kinase microclusters with significantly enhanced colocalization as compared with Ags tethered to soft substrates. Moreover, the expression of the B cell activation marker CD69 is enhanced in B cells encountering Ags on stiffer substrates. Through time-lapse live cell imaging, we find that the different responses of B cells to substrate stiffness are only demonstrated 5 min after BCR and Ag recognition. Using a series of cytoskeleton inhibitors, we determine that the mechanosensing ability of B cells is dependent on microtubules, and only mildly linked to the actin cytoskeleton. These results suggest the importance of the mechanical properties mediated by substrate stiffness in B cell activation. The Journal of Immunology, 2013, 190: 4661-4675. C1 [Wan, Zhengpeng; Zhang, Shaosen; Fan, Yilin; Zhang, Huiyuan; Liu, Wanli] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. [Liu, Kai; Xiong, Chunyang] Peking Univ, Acad Adv Interdisciplinary Studies, Beijing 100871, Peoples R China. [Du, Feng; Xiong, Chunyang] Peking Univ, Coll Engn, Beijing 100871, Peoples R China. [Davey, Angel M.] NIAID, NIH, Bethesda, MD 20892 USA. [Han, Weidong] Chinese Peoples Liberat Army Gen Hosp, Inst Basic Med, Biotherapeut Ctr, Dept Immunol, Beijing 100853, Peoples R China. RP Liu, WL (reprint author), Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China. EM liuwanli@biomed.tsinghua.edu.cn RI Xiong, Chunyang/C-2647-2009 OI Xiong, Chunyang/0000-0002-8821-2643 FU Ministry of Science and Technology of China [2013CB933702]; National Science Foundation China [31270913, 11272015, 81230061]; Beijing Natural Science Foundation [5132016]; Ph.D. Programs Foundation of Ministry of Education of China [20120002120007]; New Century Excellent Talents in University of Ministry of Education of China [NCET-12-0299]; Tsinghua University-Gates Foundation FX This work was supported by Ministry of Science and Technology of China Grant 2013CB933702 (to C.X.), National Science Foundation China Grants 31270913 (to W.L.), 11272015 (to C.X.), and 81230061 (to W.H.), Beijing Natural Science Foundation Grant 5132016 (to W.L.), Ph.D. Programs Foundation of Ministry of Education of China Grant 20120002120007 (to W.L.), New Century Excellent Talents in University of Ministry of Education of China Grant NCET-12-0299 (to W.L.), and by the Tsinghua University-Gates Foundation. NR 61 TC 20 Z9 20 U1 0 U2 33 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2013 VL 190 IS 9 BP 4661 EP 4675 DI 10.4049/jimmunol.1202976 PG 15 WC Immunology SC Immunology GA 130IP UT WOS:000317907900030 PM 23554309 ER PT J AU Andrade, BB Hullsiek, KH Boulware, DR Rupert, A French, MA Ruxrungtham, K Montes, ML Price, H Barreiro, P Audsley, J Sher, A Lewin, SR Sereti, I AF Andrade, Bruno Bezerril Hullsiek, Katherine Huppler Boulware, David R. Rupert, Adam French, Martyn A. Ruxrungtham, Kiat Luisa Montes, Marisa Price, Huw Barreiro, Pablo Audsley, Jennifer Sher, Alan Lewin, Sharon R. Sereti, Irini CA INSIGHT Study Grp TI Biomarkers of Inflammation and Coagulation Are Associated With Mortality and Hepatitis Flares in Persons Coinfected With HIV and Hepatitis Viruses SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE hepatic flares; biomarkers; AIDS; hepatitis ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; C VIRUS; IMMUNE RECONSTITUTION; INFECTED PATIENTS; OPPORTUNISTIC DISEASE; FIBROSIS PROGRESSION; LIVER FIBROSIS; INCREASED RISK; COHORT AB Methods. We performed a retrospective cohort study of 287 HIV-positive persons coinfected with HBV and/or HCV (70 had HBV coinfection only, 207 had HCV coninfection only, and 10 had HBV and HCV coinfections) who had pre-ART plasma samples evaluated for biomarkers associated with death (within 4 years) and/or hepatitis flare (within 4 months) after ART initiation. A predictive biomarker risk score was calculated. Results. Forty-eight deaths and 50 hepatitis flares occurred. Nonsurvivors were older, had more prior AIDS-defining events, and had higher pre-ART triglycerides and aspartate transaminase levels. Detectable hyaluronic acid and higher d-dimer, interleukin 6, interleukin 8, and soluble CD14 levels were associated with death in univariate models and with a composite biomarker risk score. The risk of hepatitis flares was higher with HBV coinfection only (24.3%) and with HBV and HCV coinfection (50%) than with HCV coinfection only (13.5%). Higher levels of alanine transaminase and interleukin 10 were also associated with hepatitis flares. Conclusions. Among HIV-positive patients coinfected with HBV and/or HCV who are initiating ART, biomarkers of inflammation and coagulation are associated with an increased risk of death, whereas HBV coinfection and higher pre-ART interleukin 10 levels are associated with hepatitis flares. C1 [Andrade, Bruno Bezerril; Sher, Alan] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Sereti, Irini] NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Rupert, Adam] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Hullsiek, Katherine Huppler; Boulware, David R.] Univ Minnesota, Minneapolis, MN USA. [Ruxrungtham, Kiat] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. [Ruxrungtham, Kiat] Thai Red Cross AIDS Res Ctr, HIV NAT, Bangkok, Thailand. [Luisa Montes, Marisa] Hosp La Paz, Madrid, Spain. [Barreiro, Pablo] Hosp Carlos III, Madrid, Spain. [Price, Huw] MRC Clin Trials Unit, London, England. [French, Martyn A.] Univ Western Australia, Perth, WA 6009, Australia. [Audsley, Jennifer; Lewin, Sharon R.] Alfred Hosp, Melbourne, Vic, Australia. [Audsley, Jennifer; Lewin, Sharon R.] Monash Univ, Melbourne, Vic 3004, Australia. [Lewin, Sharon R.] Burnet Inst, Melbourne, Vic, Australia. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-07A,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Boulware, David/I-4533-2013; Andrade, Bruno/J-9111-2012; Audsley, Jennifer/H-4581-2014; OI Andrade, Bruno/0000-0001-6833-3811; Audsley, Jennifer/0000-0001-6322-3197; Lewin, Sharon Ruth/0000-0002-0330-8241; Boulware, David/0000-0002-4715-0060 FU National Institute of Allergy and Infectious Diseases (NIAID) [3 U01 AI068641-05S1, U01AI042170, U01AI046362]; NIAID Intramural Research Program; National Institutes of Health; National Research University Project of CHE; Ratchadaphiseksomphot Endowment Fund, Thailand [HR1161A]; National Science and Technology Development Agency, BIOTEC; Thai Research Fund, Thailand FX This work was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID; grants 3 U01 AI068641-05S1, U01AI042170, and U01AI046362) and the NIAID Intramural Research Program, National Institutes of Health; the National Research University Project of CHE and the Ratchadaphiseksomphot Endowment Fund, Thailand (grant HR1161A to K. R.); the National Science and Technology Development Agency, BIOTEC (grant to K. R.); and the Thai Research Fund, Thailand (to K. R.). NR 48 TC 17 Z9 17 U1 0 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2013 VL 207 IS 9 BP 1379 EP 1388 DI 10.1093/infdis/jit033 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 124AJ UT WOS:000317434600005 PM 23335804 ER PT J AU Vickers, KC Sethupathy, P Baran-Gale, J Remaley, AT AF Vickers, Kasey C. Sethupathy, Praveen Baran-Gale, Jeanette Remaley, Alan T. TI Complexity of microRNA function and the role of isomiRs in lipid homeostasis SO JOURNAL OF LIPID RESEARCH LA English DT Review DE microRNA isoform; lipid metabolism; nontemplated additions ID ELEMENT-BINDING PROTEINS; FATTY LIVER-DISEASE; HEPARAN-SULFATE PROTEOGLYCANS; SMALL RNAS; LIPOPROTEIN METABOLISM; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; CHOLESTEROL HOMEOSTASIS; CIRCULATING MICRORNAS AB MicroRNAs (miRNAs) are key posttranscriptional regulators of biological pathways that govern lipid metabolic phenotypes. Recent advances in high-throughput small RNA sequencing technology have revealed the complex and dynamic repertoire of miRNAs. Specifically, it has been demonstrated that a single genomic locus can give rise to multiple, functionally distinct miRNA isoforms (isomiR). There are several mechanisms by which isomiRs can be generated, including processing heterogeneity and posttranscriptional modifications, such as RNA editing, exonuclease-mediated nucleotide trimming, and/or nontemplated nucleotide addition (NTA). NTAs are dominant at the 3'-end of a miRNA, are most commonly uridylation or adenlyation events, and are catalyzed by one or more of several nucleotidyl transferase enzymes. 3' NTAs can affect miRNA stability and/or activity and are physiologically regulated, whereas modifications to the 5'-ends of miRNAs likely alter miRNA targeting activity. Recent evidence also suggests that the biogenesis of specific miRNAs, or small RNAs that act as miRNAs, can occur through unconventional mechanisms that circumvent key canonical miRNA processing steps. The unveiling of miRNA diversity has significantly added to our view of the complexity of miRNA function. In this review we present the current understanding of the biological relevance of isomiRs and their potential role in regulating lipid metabolism.-Vickers, K. C., P. Sethupathy, J. Baran-Gale, and A. T. Remaley. Complexity of microRNA function and the role of isomiRs in lipid homeostasis. J. Lipid Res. 2013. 54: 1182-1191. C1 [Vickers, Kasey C.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Sethupathy, Praveen; Baran-Gale, Jeanette] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20892 USA. RP Vickers, KC (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. EM kasey.c.vickers@vanderbilt.edu OI Baran-Gale, Jeanette/0000-0002-8779-328X FU National Heart, Lung, and Blood Institute intramural research program; National Institutes of Health [K22-HL-113039-01, 4R00-DK-091318-02] FX This work was supported by the National Heart, Lung, and Blood Institute intramural research program and by National Institutes of Health Grants K22-HL-113039-01 (K.C.V.) and 4R00-DK-091318-02 (P.S.). NR 139 TC 19 Z9 20 U1 0 U2 24 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD MAY PY 2013 VL 54 IS 5 BP 1182 EP 1191 DI 10.1194/jlr.R034801 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 123MO UT WOS:000317394300006 PM 23505317 ER PT J AU Molica, F Burger, F Thomas, A Staub, C Tailleux, A Staels, B Pelli, G Zimmer, A Cravatt, B Matter, CM Pacher, P Steffens, S AF Molica, Filippo Burger, Fabienne Thomas, Aurelien Staub, Christian Tailleux, Anne Staels, Bart Pelli, Graziano Zimmer, Andreas Cravatt, Benjamin Matter, Christian M. Pacher, Pal Steffens, Sabine TI Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation SO JOURNAL OF LIPID RESEARCH LA English DT Article DE restenosis; balloon injury; fatty acid amide hydrolase ID DRUG-ELUTING STENTS; CORONARY-ARTERY-DISEASE; ACID AMIDE HYDROLASE; ENDOCANNABINOID SYSTEM; KNOCKOUT MICE; ATHEROSCLEROSIS; RESTENOSIS; MIGRATION; ALPHA; MECHANISMS AB Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an inflammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of FA amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apoE knockout (apoE(-/-)) and apoE(-/-) FAAH(-/-) mice. Anandamide levels were systemically elevated in apoE(-/-) mice after balloon injury. ApoE(-/-)FAAH(-/-) mice had significantly higher baseline anandamide levels and enhanced neointima formation compared with apoE(-/-) controls. The latter effect was inhibited by treatment with CB1 antagonist AM281. Similarly, apoE(-/-) mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth-muscle cell (SMC) content, and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB1-/- SMCs or when treating apoE(-/-) or apoE(-/-)FAAH(-/-) SMCs with AM281. Macrophage in vitro adhesion and migration were marginally affected by CB1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury.-Molica, F., F. Burger, A. Thomas, C. Staub, A. Tailleux, B. Staels, G. Pelli, A. Zimmer, B. Cravatt, C. M. Matter. P. Pacher, and S. Steffens. Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation. J. Lipid Res. 2013. 54: 1360-1368. C1 [Molica, Filippo; Burger, Fabienne; Pelli, Graziano; Steffens, Sabine] Univ Hosp, Div Cardiol, Geneva, Switzerland. [Thomas, Aurelien; Staub, Christian] Univ Ctr Legal Med, Toxicol Unit, Geneva, Switzerland. [Tailleux, Anne; Staels, Bart] European Genom Inst Diabet, F-59000 Lille, France. [Tailleux, Anne; Staels, Bart] Univ Lille 2, F-59000 Lille, France. [Tailleux, Anne; Staels, Bart] INSERM, UMR 1011, F-59000 Lille, France. [Tailleux, Anne; Staels, Bart] Inst Pasteur, F-59000 Lille, France. [Zimmer, Andreas] Univ Bonn, Inst Mol Psychiat, Bonn, Germany. [Cravatt, Benjamin] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Cravatt, Benjamin] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Cravatt, Benjamin] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Matter, Christian M.] Univ Zurich, Inst Physiol, Zurich Ctr Integrat Human Physiol, CH-8006 Zurich, Switzerland. [Matter, Christian M.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Pacher, Pal] NIH, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, Bethesda, MD 20892 USA. [Steffens, Sabine] Univ Munich, Inst Cardiovasc Prevent, Munich, Germany. RP Steffens, S (reprint author), Univ Hosp, Div Cardiol, Geneva, Switzerland. EM sabine.steffens@med.uni-muenchen.de RI Zimmer, Andreas/B-8357-2009; Pacher, Pal/B-6378-2008; Filippo, Molica/A-6315-2013 OI Staels, Bart/0000-0002-3784-1503; Pacher, Pal/0000-0001-7036-8108; FU Swiss National Science Foundation [310030_130732/1]; Prevot; OPO Foundation; Swiss Life FX This work was supported by grants from the Swiss National Science Foundation (Grant #310030_130732/1), Prevot, OPO Foundation, and Swiss Life (S.S.). NR 31 TC 8 Z9 8 U1 1 U2 21 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD MAY PY 2013 VL 54 IS 5 BP 1360 EP 1368 DI 10.1194/jlr.M035147 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 123MO UT WOS:000317394300021 PM 23479425 ER PT J AU Fung, KW Jao, CS Demner-Fushman, D AF Fung, Kin Wah Jao, Chiang S. Demner-Fushman, Dina TI Extracting drug indication information from structured product labels using natural language processing SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CLINICAL DECISION-SUPPORT; ELECTRONIC HEALTH RECORDS; PHYSICIAN ORDER ENTRY; MEDICATION ERRORS; PATIENT SAFETY; NDF-RT; TERMINOLOGY; PREVENTION; RXNORM AB Objective To extract drug indications from structured drug labels and represent the information using codes from standard medical terminologies. Materials and methods We used MetaMap and other publicly available resources to extract information from the indications section of drug labels. Drugs and indications were encoded by RxNorm and UMLS identifiers respectively. A sample was manually reviewed. We also compared the results with two independent information sources: National Drug File-Reference Terminology and the Semantic Medline project. Results A total of 6797 drug labels were processed, resulting in 19 473 unique drug-indication pairs. Manual review of 298 most frequently prescribed drugs by seven physicians showed a recall of 0.95 and precision of 0.77. Inter-rater agreement (Fleiss.) was 0.713. The precision of the subset of results corroborated by Semantic Medline extractions increased to 0.93. Discussion Correlation of a patient's medical problems and drugs in an electronic health record has been used to improve data quality and reduce medication errors. Authoritative drug indication information is available from drug labels, but not in a format readily usable by computer applications. Our study shows that it is feasible to use publicly available natural language processing resources to extract drug indications from drug labels. The same method can be applied to other sections of the drug label-for example, adverse effects, contraindications. Conclusions It is feasible to use publicly available natural language processing tools to extract indication information from freely available drug labels. Named entity recognition sources (eg, MetaMap) provide reasonable recall. Combination with other data sources provides higher precision. C1 [Fung, Kin Wah; Demner-Fushman, Dina] US Natl Inst Hlth, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bethesda, MD 20894 USA. [Jao, Chiang S.] Tranformation Inc, Naperville, IL USA. RP Fung, KW (reprint author), US Natl Inst Hlth, Lister Hill Natl Ctr Biomed Commun, Natl Lib Med, Bldg 38A,Room 9S-914,8600 Rockville Pike,MSC 3826, Bethesda, MD 20894 USA. EM kfung@mail.nih.gov FU Intramural Research Program of the NIH, National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 36 TC 13 Z9 14 U1 4 U2 21 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY PY 2013 VL 20 IS 3 BP 482 EP 488 DI 10.1136/amiajnl-2012-001291 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 124PP UT WOS:000317477500013 PM 23475786 ER PT J AU Beavers, KM Hsu, FC Houston, DK Beavers, DP Harris, TB Hue, TF Kim, LJ Koster, A Penninx, BW Simonsick, EM Strotmeyer, ES Kritchevsky, SB Nicklas, BJ AF Beavers, Kristen M. Hsu, Fang-Chi Houston, Denise K. Beavers, Daniel P. Harris, Tamara B. Hue, Trisha F. Kim, Lauren J. Koster, Annemarie Penninx, Brenda W. Simonsick, Eleanor M. Strotmeyer, Elsa S. Kritchevsky, Stephen B. Nicklas, Barbara J. CA Hlth ABC Study TI The Role of Metabolic Syndrome, Adiposity, and Inflammation in Physical Performance in the Health ABC Study SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Metabolic syndrome; Physical function; Inflammation; Obesity ID C-REACTIVE PROTEIN; LOWER-EXTREMITY FUNCTION; INCIDENT MOBILITY LIMITATION; NUTRITION EXAMINATION SURVEY; BODY-COMPOSITION; OLDER-ADULTS; SUBSEQUENT DISABILITY; CARDIOVASCULAR EVENTS; MUSCLE STRENGTH; NATIONAL-HEALTH AB Background: Metabolic syndrome (MetS) and functional limitation have been linked, but whether and how specific components of MetS and associated factors, such as inflammation, drive this relationship is unknown. Methods: Data are from 2,822 men and women, aged 70-79 years, participating in the Health, Aging, and Body Composition (Health ABC) study and followed for 5 years. Presence of MetS at baseline was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Interleukin-6, C-reactive protein, and body fat mass were measured at baseline. Measures of physical performance, including 400-m walk time, 20-m walking speed, and the Health ABC physical performance battery (PPB) were obtained at baseline and examination years 2, 4, and 6. Results: A total of 1,036 (37%) individuals met criteria for MetS. MetS was associated with poorer physical performance at baseline. Effect estimates between MetS and gait speed, and components of the Health ABC PPB (standing balance and repeated sit-to-stand performance) were modestly attenuated after adjustment for inflammation. All associations were attenuated to nonsignificance after adding total body fat mass to the model. Longitudinal analyses yielded similar results. Individual MetS component analysis revealed that abdominal obesity explained the largest fraction of the variation in physical performance. Conclusions: Although inflammatory biomarkers partially accounted for the relationship between MetS and aspects of physical performance, overall findings implicate adiposity as the primary factor explaining poorer physical performance in older adults with MetS. C1 [Beavers, Kristen M.; Houston, Denise K.; Kritchevsky, Stephen B.; Nicklas, Barbara J.] Wake Forest Sch Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. [Hsu, Fang-Chi; Beavers, Daniel P.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hue, Trisha F.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco Coordinating Ctr, San Francisco, CA USA. [Kim, Lauren J.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Koster, Annemarie] Maastricht Univ, Dept Social Med, Maastricht, Netherlands. [Penninx, Brenda W.] Free Univ Amsterdam, Dept Psychiat, NL-1007 MC Amsterdam, Netherlands. [Penninx, Brenda W.] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Harbor Hosp, Baltimore, MD 21224 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Prevent Med Res Lab, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15260 USA. RP Beavers, KM (reprint author), Wake Forest Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM beaverkm@wfu.edu RI Strotmeyer, Elsa/F-3015-2014; Koster, Annemarie/E-7438-2010; Beavers, Daniel/G-5338-2016; OI Strotmeyer, Elsa/0000-0002-4093-6036; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; National Institute on Nursing Research (NINR) [R01-NR012459]; NIH, National Institute on Aging; [F32-AG039186] FX This work was supported by National Institute on Aging (NIA) grants N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, and NIA grant R01-AG028050; National Institute on Nursing Research (NINR) grant R01-NR012459; Intramural Research Program of the NIH, National Institute on Aging, as well as an individual postdoctoral fellowship (F32-AG039186) awarded to KMB. NR 37 TC 15 Z9 15 U1 1 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAY PY 2013 VL 68 IS 5 BP 617 EP 623 DI 10.1093/gerona/gls213 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 125KO UT WOS:000317538900015 PM 23109678 ER PT J AU Lund, JL Sturmer, T Harlan, LC Sanoff, HK Sandler, RS Brookhart, MA Warren, JL AF Lund, Jennifer L. Stuermer, Til Harlan, Linda C. Sanoff, Hanna K. Sandler, Robert S. Brookhart, Maurice Alan Warren, Joan L. TI Identifying Specific Chemotherapeutic Agents in Medicare Data A Validation Study SO MEDICAL CARE LA English DT Article DE validation; chemotherapy; SEER; Medicare; administrative data ID III COLON-CANCER; CELL LUNG-CANCER; ACUTE MYELOID-LEUKEMIA; ADJUVANT CHEMOTHERAPY; BREAST-CANCER; OLDER WOMEN; RECTAL-CANCER; ELDERLY-WOMEN; TREATMENT DISPARITIES; COLORECTAL-CANCER AB Background: Large health care databases are increasingly used to examine the dissemination and benefits and harms of chemotherapy treatment in routine practice, particularly among patients excluded from trials (eg, the elderly). Misclassification of chemotherapy could bias estimates of frequency and association, warranting an updated assessment. Methods: We evaluated the validity of Medicare claims to identify receipt of chemotherapy and specific agents delivered to elderly stage II/III colorectal (CRC), in situ/early-stage breast, non-small-cell lung, and ovarian cancer patients using the National Cancer Institute's Patterns of Care studies (POC) as the gold standard. The POC collected data on chemotherapy treatment by reabstracting hospital records, contacting physicians, and reviewing medical records. Patients' POC data were linked and compared with their Medicare claims for 2 to 12 months postdiagnosis. kappa, sensitivity, specificity, positive and negative predictive values and 95% confidence intervals were calculated for the receipt of any chemotherapy and specific agents. Results: Sensitivity and specificity of Medicare claims to identify any chemotherapy were high across all cancer sites. We found substantial variation in validity across agents, by site and administration modality. Capecitabine, an oral CRC treatment, was identified in claims with high specificity (98%) but low sensitivity (47%), whereas oxaliplatin, an intravenously administered CRC agent had higher sensitivity (75%) and similar specificity (97%). Conclusions: Receipt of chemotherapy and specific intravenous agents can be identified using Medicare claims, showing improvement from prior reports; yet, variation exists. Future studies should assess newly approved agents and the impact of coverage decisions for these agents under the Medicare Part D program. C1 [Lund, Jennifer L.; Stuermer, Til; Brookhart, Maurice Alan] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Harlan, Linda C.; Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Sanoff, Hanna K.] Univ Virginia, Sch Med, Div Hematol & Oncol, Charlottesville, VA 22908 USA. [Sandler, Robert S.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. RP Lund, JL (reprint author), Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, McGavran Greenberg Hall,CB 7435, Chapel Hill, NC 27599 USA. EM jlund@email.unc.edu FU national Institutes of Health [T32 DK07634] FX This research was supported in part by a grant from the national Institutes of Health (T32 DK07634). NR 45 TC 21 Z9 21 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAY PY 2013 VL 51 IS 5 BP E27 EP E34 DI 10.1097/MLR.0b013e31823ab60f PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 126WU UT WOS:000317653900001 PM 22080337 ER PT J AU Carter, LG Qi, NR De Cabo, R Pearson, KJ AF Carter, Lindsay G. Qi, Nathan R. De Cabo, Rafael Pearson, Kevin J. TI Maternal Exercise Improves Insulin Sensitivity in Mature Rat Offspring SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE PREGNANCY; RUNNING; PROGRAMMING; HYPERINSULINEMIC-EUGLYCEMIC CLAMP ID INTRAUTERINE GROWTH-RETARDATION; SIGNALING PROTEIN EXPRESSION; II DIABETES-MELLITUS; SKELETAL-MUSCLE; BIRTH-WEIGHT; DEVELOPMENTAL ORIGINS; GLUCOSE-UPTAKE; ADULT; HYPERTENSION; PREGNANCY AB CARTER, L. G., N. R. QI, R. DE CABO, AND K. J. PEARSON Maternal Exercise Improves Insulin Sensitivity in Mature Rat Offspring. Med. Sci. Sports Exerc., Vol. 45, No. 5, pp. 832-840, 2013. Purpose: Recent findings have shown that the intrauterine environment can negatively influence long-term insulin sensitivity in the offspring. Here we look at maternal voluntary exercise as an intervention to improve offspring insulin sensitivity and glucose homeostasis. Methods: Female Sprague-Dawley rats were split into sedentary and exercise groups with the exercise cohort having voluntary access to a running wheel in the cage before and during mating, pregnancy, and nursing. Female offspring were weaned into sedentary cages. Glucose tolerance tests and hyperinsulinemic-euglycemic clamp were performed in adult offspring to evaluate glucose regulation and insulin sensitivity. Results: Adult female offspring born to exercised dams had enhanced glucose disposal during glucose tolerance testing (P < 0.05) as well as increased glucose infusion rates (P < 0.01) and whole body glucose turnover rates (P G 0.05) during hyperinsulinemic-euglycemic clamp testing compared with offspring from sedentary dams. Offspring from exercised dams also had decreased insulin levels (P < 0.01) and hepatic glucose production (P < 0.05) during the clamp procedure compared with offspring born to sedentary dams. Offspring from exercised dams had increased glucose uptake in skeletal muscle (P < 0.05) and decreased heart glucose uptake (P < 0.01) compared with offspring from sedentary dams in response to insulin infusion during the clamp procedure. Conclusions: Exercise during pregnancy enhances offspring insulin sensitivity and improves offspring glucose homeostasis. This can decrease offspring susceptibility to insulin-resistant related diseases such as type 2 diabetes mellitus. Maternal exercise could be an easy, short-term, nonpharmacological method of preventing disease in future generations. C1 [Carter, Lindsay G.; Pearson, Kevin J.] Univ Kentucky, Coll Med, Grad Ctr Nutr Sci, Lexington, KY 40536 USA. [Qi, Nathan R.] Univ Michigan, Diabet Res & Training Ctr, Nutr & Obes Res Ctr, Anim Phenotyping Core, Ann Arbor, MI 48109 USA. [De Cabo, Rafael] NIA, NIH, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Pearson, KJ (reprint author), Univ Kentucky, Coll Med, Grad Ctr Nutr Sci, 900 South Limestone, Lexington, KY 40536 USA. EM kevin.pearson@uky.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU U.S. National Institutes of Health (NIH) [R01 DK090460]; University of Michigan [DK089503]; NIH [DK07778]; National Institute on Aging, NIH FX This study was supported by the U.S. National Institutes of Health (NIH) (grant no. R01 DK090460 to K.J.P.) and used core services supported by the University of Michigan (grant no. DK089503). L. G. C. was supported by an NIH training grant (no. DK07778). This research was supported in part by the Intramural Research Program of the National Institute on Aging, NIH. NR 40 TC 24 Z9 24 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2013 VL 45 IS 5 BP 832 EP 840 DI 10.1249/MSS.0b013e31827de953 PG 9 WC Sport Sciences SC Sport Sciences GA 129NH UT WOS:000317847000004 PM 23247711 ER PT J AU Alonso, N Fernandez, N Notcovich, C Monczor, F Simaan, M Baldi, A Gutkind, JS Davio, C Shayo, C AF Alonso, Natalia Fernandez, Natalia Notcovich, Cintia Monczor, Federico Simaan, May Baldi, Alberto Gutkind, J. Silvio Davio, Carlos Shayo, Carina TI Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration SO MOLECULAR PHARMACOLOGY LA English DT Article ID G-PROTEIN ACTIVATION; OPIOID RECEPTORS; DRUG DISCOVERY; BETA-ARRESTINS; H-1 RECEPTOR; INTERNALIZATION; OLIGOMERIZATION; CLATHRIN; CELLS; ROLES AB G protein-coupled receptor signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, i.e., signaling networks. In this work we present an exhaustive study of the cross-talk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and Chinese hamster ovary-transfected cells. By desensitization assays we demonstrated the existence of a crossdesensitization between both receptors independent of protein kinase A or C. H1R-agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment of 48 hours. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the cross-talk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. To evaluate potential heterodimerization of the receptors, sensitized emission fluorescence resonance energy transfer experiments were performed in human embryonic kidney 293T cells using H1R-cyan fluorescent protein and H2R-yellow fluorescent protein. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor crossdesensitization, which was mediated by G protein-coupled receptor kinase 2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands. C1 [Alonso, Natalia; Notcovich, Cintia; Baldi, Alberto; Shayo, Carina] Inst Biol & Med Expt, Lab Farmacol & Patol Mol, RA-1428 Buenos Aires, DF, Argentina. [Fernandez, Natalia; Monczor, Federico; Davio, Carlos] Univ Buenos Aires, Fac Farm & Bioquim, Catedra Quim Med, Lab Farmacol Receptores, RA-1113 Buenos Aires, DF, Argentina. [Simaan, May; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Shayo, C (reprint author), Inst Biol & Med Expt, Vta Obligado 2490, RA-1428 Buenos Aires, DF, Argentina. EM carinashayo@hotmail.com FU Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP 0344]; Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2010-237, PICT 2010-1571]; National Institutes of Health National Institute of Dental and Craniofacial Research [Z01DE00551] FX This study was supported by the Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP 0344]; and the Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2010-237] and [PICT 2010-1571]. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research [Grant Z01DE00551]. NR 44 TC 8 Z9 8 U1 0 U2 10 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAY PY 2013 VL 83 IS 5 BP 1087 EP 1098 DI 10.1124/mol.112.083394 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 125XN UT WOS:000317575500017 PM 23462507 ER PT J AU Valatas, V He, J Rivollier, A Kolios, G Kitamura, K Kelsall, BL AF Valatas, V. He, J. Rivollier, A. Kolios, G. Kitamura, K. Kelsall, B. L. TI Host-dependent control of early regulatory and effector T-cell differentiation underlies the genetic susceptibility of RAG2-deficient mouse strains to transfer colitis SO MUCOSAL IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MEDIATED INTESTINAL INFLAMMATION; DENDRITIC CELLS; RETINOIC-ACID; CROHNS-DISEASE; BOWEL-DISEASE; TH17 CELLS; REG-CELLS; IN-VIVO; IL-23 AB De novo differentiation of CD4(+) Foxp3(+) regulatory T cells (induced (i) Tregs) occurs preferentially in the gut-associated lymphoid tissues (GALT). We addressed the contribution of background genetic factors in affecting the balance of iTreg, T helper type 1 (Th1), and Th17 cell differentiation in GALT in vivo following the transfer of naive CD4(+) CD45RB(high) T cells to strains of RAG2-deficient mice with differential susceptibility to inflammatory colitis. iTregs represented up to 5% of CD4(+) T cells in mesenteric lymph nodes of less-susceptible C57BL/6RAG2(-/-) mice compared with <1% in highly susceptible C57BL/10RAG2(-/-) mice 2 weeks following T-cell transfer before the onset of colitis. Early Treg induction was correlated inversely with effector cell expansion and the severity of colitis development, was controlled primarily by host and not T-cell-dependent factors, and was strongly associated with interleukin-12 (IL-12)/23 production by host CD11c(+) CD103(+) dendritic cells. These data highlight the importance of genetic factors regulating IL-12/23 production in controlling the balance between iTreg differentiation and effector-pathogenic CD4(+) T-cell expansion in lymphopenic mice and indicate a direct role for iTregs in the regulation of colonic inflammation in vivo. C1 [Valatas, V.] Heraklion Univ Hosp, Dept Gastroenterol, Iraklion, Crete, Greece. [He, J.; Kelsall, B. L.] NIAID, Mucosal Immun Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Rivollier, A.] Lund Univ, Immunol Sect, Dept Expt Med Sci, Lund, Sweden. [Kolios, G.] Democritus Univ Thrace Dragana, Sch Med, Pharmacol Lab, Alexandroupolis, Greece. [Kitamura, K.] Kanazawa Univ Hosp, Dept Gastroenterol, Kanazawa, Ishikawa, Japan. RP Kelsall, BL (reprint author), NIAID, Mucosal Immun Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM kelsall@nih.gov RI Kolios, George/N-6641-2013; OI Kolios, George/0000-0002-2066-4782 FU Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA FX Funding for these studies was provided by the Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA. We thank Ethan Shevach and Eva Huter for their help with the scurfy mouse experiments, and Ivan Fuss for providing anti-IL12p40 antibodies. We would also like to thank the Flow Cytometry Unit, Research Technologies Branch, NIAID for their help with flow cytometric sorting. NR 53 TC 7 Z9 7 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 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD MAY PY 2013 VL 6 IS 3 BP 601 EP 611 DI 10.1038/mi.2012.102 PG 11 WC Immunology SC Immunology GA 127TX UT WOS:000317722800016 PM 23149660 ER PT J AU Sinclair, LV Rolf, J Emslie, E Shi, YB Taylor, PM Cantrell, DA AF Sinclair, Linda V. Rolf, Julia Emslie, Elizabeth Shi, Yun-Bo Taylor, Peter M. Cantrell, Doreen A. TI Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation SO NATURE IMMUNOLOGY LA English DT Article ID 4F2 HEAVY-CHAIN; TRANSFER-RNA SYNTHETASE; LYMPHOCYTE ACTIVATION; MAMMALIAN TARGET; GENE-EXPRESSION; IN-VIVO; MTOR; KINASE; MEMORY; GENERATION AB T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells. C1 [Sinclair, Linda V.; Rolf, Julia; Emslie, Elizabeth; Taylor, Peter M.; Cantrell, Doreen A.] Univ Dundee, Div Cell Signalling & Immunol, Dundee, Scotland. [Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Cellular Regulat & Metab, NIH, Bethesda, MD USA. RP Cantrell, DA (reprint author), Univ Dundee, Div Cell Signalling & Immunol, Dundee, Scotland. EM d.a.cantrell@dundee.ac.uk OI Cantrell, Doreen/0000-0001-7525-3350 FU Wellcome Trust [065975/Z/01/A, 097418/Z/11Z, WT094226]; Intramural Research Program of the National Institute Child Health and Human Development of the US National Institutes of Health FX We thank G. Holman (University of Bath) for anti-Glut1; H. Shen (University of Pennsylvania) for L. monocytogenes; L. Chen for help in the initial characterization of amino-acid transporters expressed by CTLs; members of the Biological Services Unit; R. Clarke of the Flow Cytometry Facility; and members of the D. A. C. laboratory and S. Arthur for critical reading of the manuscript. Supported by the Wellcome Trust (065975/Z/01/A and 097418/Z/11Z to D. A. C., and WT094226 to P. M. T.) and the Intramural Research Program of the National Institute Child Health and Human Development of the US National Institutes of Health. NR 41 TC 128 Z9 130 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAY PY 2013 VL 14 IS 5 BP 500 EP + DI 10.1038/ni.2556 PG 11 WC Immunology SC Immunology GA 127XL UT WOS:000317732100015 PM 23525088 ER PT J AU Silverman, JL Babineau, BA Oliver, CF Karras, MN Crawley, JN AF Silverman, Jill L. Babineau, Brooke A. Oliver, Chicora F. Karras, Michael N. Crawley, Jacqueline N. TI Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism SO NEUROPHARMACOLOGY LA English DT Article DE Social behavior; Repetitive behavior; Mouse model; Autism; Neurodevelopmental disorder; BTBR ID FRAGILE-X-SYNDROME; PLUS TF/J MOUSE; PERVASIVE DEVELOPMENTAL DISORDERS; MGLUR5 ANTAGONIST MPEP; NULL MUTANT MICE; SPECTRUM DISORDERS; LOCOMOTOR-ACTIVITY; ANXIOLYTIC-LIKE; INBRED STRAINS; D-AMPHETAMINE AB Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed. Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects. In the present studies, dose-response curves for D-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism. AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming. We then tested AMPH in B6 and BTBR on the 3-chambered social approach task. One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced. This finding replicated across multiple cohorts treated with AMPH and saline vehicle. In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task. Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. Published by Elsevier Ltd. C1 [Silverman, Jill L.; Babineau, Brooke A.; Oliver, Chicora F.; Karras, Michael N.; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Silverman, JL (reprint author), Univ Calif Davis, Sch Med, MIND Inst, Sacramento, CA 95817 USA. EM jill.silverman@ucdmc.ucdavis.edu FU National Institute of Mental Health Intramural Research Program FX The research was supported by the National Institute of Mental Health Intramural Research Program. NR 110 TC 9 Z9 9 U1 2 U2 14 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 MAY PY 2013 VL 68 SI SI BP 210 EP 222 DI 10.1016/j.neuropharm.2012.07.042 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 123EL UT WOS:000317371100016 PM 22968082 ER PT J AU Mays, JW Fassil, H Edwards, DA Pavletic, SZ Bassim, CW AF Mays, J. W. Fassil, H. Edwards, D. A. Pavletic, S. Z. Bassim, C. W. TI Oral chronic graft-versus-host disease: current pathogenesis, therapy, and research SO ORAL DISEASES LA English DT Review DE oncology; oral; pathology; immunology and microbiology; graft-versus-host disease; transplant ID BONE-MARROW-TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; REGULATORY T-CELLS; CLINICAL-TRIALS; DENDRITIC CELLS; CHRONIC GVHD; TOPICAL CYCLOSPORINE; RISK-FACTORS AB Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. In this review, we discuss the presentation, prevalence, diagnosis, and treatment of oral manifestations in chronic graft-versus-host disease (cGVHD), which is a major late complication in patients treated by allogeneic hematopoietic stem cell transplantation. We assess current general knowledge of systemic and oral cGVHD and present general treatment recommendations based on literature review and our clinical experience. Additionally, we review areas where the understanding of oral cGVHD could be improved by further research and address tools with which to accomplish the long-term goal of providing better health and quality of life to patients with cGVHD. C1 [Mays, J. W.; Edwards, D. A.; Bassim, C. W.] Natl Inst Dent & Craniofacial Res, Clin Res Core, Bethesda, MD USA. [Fassil, H.; Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Fassil, H.] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. RP Mays, JW (reprint author), NIDCR, NIH, 10 Room 1B25,10 Ctr Dr,MSC 1191, Bethesda, MD 20892 USA. EM maysjw@mail.nih.gov FU National Institutes of Health through the National Institute for Dental and Craniofacial Research; National Cancer Institute, Center for Cancer Research; Clinical Research Training Program; NIH; Pfizer Inc. FX The authors thank Dr. Francis Hakim for insightful discussion and suggestions regarding this manuscript. We are extraordinarily grateful to the patients and their families for their participation in these studies and thank the members of the NIH Study Group for continual discussion and collaboration with this patient group. This work was supported by the Intramural Research Program of the National Institutes of Health through the National Institute for Dental and Craniofacial Research and the National Cancer Institute, Center for Cancer Research. H. F. was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 109 TC 15 Z9 16 U1 2 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD MAY PY 2013 VL 19 IS 4 BP 327 EP 346 DI 10.1111/odi.12028 PG 20 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 124TT UT WOS:000317490800001 PM 23107104 ER PT J AU Louis, GMB Yeung, E Sundaram, R Laughon, SK Zhang, CL AF Louis, Germaine M. Buck Yeung, Edwina Sundaram, Rajeshwari Laughon, S. Katherine Zhang, Cuilin TI The Exposome - Exciting Opportunities for Discoveries in Reproductive and Perinatal Epidemiology SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE environment; exposome; exposure; fecundity; fertility; sensitive windows ID IN-VITRO FERTILIZATION; FOR-GESTATIONAL-AGE; TESTICULAR DYSGENESIS SYNDROME; POLYCYSTIC-OVARY-SYNDROME; BIRTH-WEIGHT; GENE-EXPRESSION; BISPHENOL-A; EXPOSURE; CANCER; ENDOMETRIOSIS AB Understanding the mechanisms that underlie successful human reproduction and development is an ambitious goal, given the many unique methodological challenges surrounding such study. These challenges are well understood by reproductive and perinatal epidemiologists and include its conditional nature, unobservable yet informative outcomes such as conception, multi-scale missing data, correlated or non-independent outcomes, interval censoring and a hierarchical data structure. Novel methodologies for overcoming these challenges and for answering critical data gaps are needed if we are to better understand the inefficiency that currently characterises human reproduction with the goal of improving population health. The exposome is an emerging paradigm that offers promise for understanding the natural history of human reproduction and development, and its many associated impairments that develop later in child- or adulthood. This novel paradigm recognises the need to identify and measure the totality of environmental (non-genetic) exposures from preconception through sensitive windows, and to identify patterns associated with healthy and adverse outcomes. The exposome accommodates research focusing on unique subpopulations, such as couples undergoing assisted reproductive technologies, so that methodological limitations such as unobservable and conditional outcomes can be better addressed. Reproductive and perinatal epidemiology is uniquely suited for proof-of-concept exposome research, given the intricate relations between fecundity, gravid health and later onset disease and the narrow and interrelated sensitive windows that characterise the conditional nature of human reproduction and development. Bold new conceptual frameworks such as the exposome are needed for designing research that may lead to discovery and improve population health. C1 [Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Yeung, Edwina; Laughon, S. Katherine; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Louis, GMB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B05, Rockville, MD 20852 USA. EM louisg@mail.nih.gov RI Yeung, Edwina/F-5992-2015; OI Yeung, Edwina/0000-0002-3851-2613; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490; Grantz, Katherine/0000-0003-0276-8534 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health FX Supported by the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institutes of Health. The authors acknowledge the input from members of the Exposome Working Group, Division of Epidemiology, Statistics and Prevention Research, NICHD for their helpful comments and suggestions regarding this paper. Members include: Drs Nansi Boghossian, Alexander McLain (now at the University of South Carolina), Pauline Mendola, Sunni Mumford, Tonja Nansel, Neil Perkins and Anna Pollack. NR 48 TC 10 Z9 10 U1 1 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2013 VL 27 IS 3 BP 229 EP 236 DI 10.1111/ppe.12040 PG 8 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 123XG UT WOS:000317424600003 ER PT J AU Ahrens, KA Schisterman, EF AF Ahrens, Katherine A. Schisterman, Enrique F. TI A Time and Place for Causal Inference Methods in Perinatal and Paediatric Epidemiology SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID MARGINAL STRUCTURAL MODELS; ACTIVE ANTIRETROVIRAL THERAPY; DOUBLY ROBUST ESTIMATION; EXPOSURE C1 [Ahrens, Katherine A.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, DESPR, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, DESPR, 6100 Execut Blvd,7B03, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI 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 FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 26 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2013 VL 27 IS 3 BP 258 EP 262 DI 10.1111/ppe.12048 PG 5 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 123XG UT WOS:000317424600006 PM 23574413 ER PT J AU Jukic, AMZ Lawlor, DA Juhl, M Owe, KM Lewis, B Liu, JH Wilcox, AJ Longnecker, MP AF Jukic, Anne Marie Z. Lawlor, Debbie A. Juhl, Mette Owe, Katrine M. Lewis, Barbara Liu, Jihong Wilcox, Allen J. Longnecker, Matthew P. TI Physical Activity During Pregnancy and Language Development in the Offspring SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE exercise; cognition; child development; physical activity ID SHORT-TERM-MEMORY; RAT PUPS; EXERCISE; HIPPOCAMPUS; WOMEN; NEUROGENESIS; COMPENDIUM; BIRTH AB Background In rodents, physical activity during pregnancy has been associated with improved learning and memory in the offspring. We used data from the Avon Longitudinal Study of Parents and Children (born in 199192) to investigate maternal physical activity during pregnancy and offspring language development. Methods At 18 weeks of gestation, women reported the hours per week they participated in 11 leisure-time physical activities and the hours per week spent in general physical activity (leisure, household and occupational). Caregivers completed a modified MacArthur Infant Communication scale at 15 months. Verbal intelligence quotient (IQ) was measured at age 8 years. Regression analysis was used to examine the associations of physical activity with MacArthur score (more than 75th percentile) and verbal IQ. The number of participants available for analyses ranged from 4529 to 7162. Results Children of women in the two highest quintiles of leisure activity (compared with no leisure activity) were more likely to have high 15-month MacArthur scores (adjusted odds ratio 1.2 [95% confidence interval 0.9, 1.4] and adjusted odds ratio 1.4 [95% CI 1.1, 1.7], respectively). Leisure activity was not associated with IQ, while general physical activity was linked with lower verbal IQ (1 and 3 points lower for the two highest quintiles). Conclusions The most robust finding was a transient increase in offspring vocabulary score at young ages with maternal leisure activity. Differences in the associations with leisure-time physical activity compared with general physical activity need further exploration. C1 [Jukic, Anne Marie Z.; Wilcox, Allen J.; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, Durham, NC 27709 USA. [Lewis, Barbara] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Liu, Jihong] Univ S Carolina, Columbia, SC 29208 USA. [Lawlor, Debbie A.] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Juhl, Mette] Univ Copenhagen, Copenhagen, Denmark. [Owe, Katrine M.] Norwegian Sch Sport Sci, Oslo, Norway. RP Jukic, AMZ (reprint author), NIEHS, POB 12233,MD A3-05, Durham, NC 27709 USA. EM jukica@niehs.nih.gov RI Liu, Jihong/Q-1364-2015; OI Liu, Jihong/0000-0001-8685-3036; Wilcox, Allen/0000-0002-3376-1311; Lawlor, Debbie A/0000-0002-6793-2262; Juhl, Mette/0000-0002-0423-3333; Juhl, Mette/0000-0003-3156-9518; Longnecker, Matthew/0000-0001-6073-5322 FU National Institute of Environmental Health Sciences, National Institute of Health; UK Medical Research Council FX We are extremely grateful to all of the families who took part in the study, midwives for their help in recruiting them, and the whole ALSPAC team who include interviewers, computer and laboratory technicians, clerical workers, research scientist, volunteers, managers and nurses. This work was supported in part by the intramural research program of the National Institute of Environmental Health Sciences, National Institute of Health. The UK Medical Research Council, Wellcome Trust and University of Bristol provide core support for ALSPAC. DA Lawlor works in a Centre that receives support from the UK Medical Research Council. The opinions in this paper are those of the authors and not necessarily any funding body. No funding body influenced data collection, analysis or interpretation. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The authors thank Drs. Todd Jusko, Freya Kamel and Jean Harry for their constructive feedback on the manuscript. NR 24 TC 8 Z9 8 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2013 VL 27 IS 3 BP 283 EP 293 DI 10.1111/ppe.12046 PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 123XG UT WOS:000317424600010 PM 23574417 ER PT J AU Andersen, DK Smith, JP Serrano, J James, SP AF Andersen, Dana K. Smith, Jill P. Serrano, Jose James, Stephen P. TI Gaps and Opportunities in Pancreatic Disease Research SO PANCREAS LA English DT Editorial Material C1 [Andersen, Dana K.; Smith, Jill P.; Serrano, Jose; James, Stephen P.] NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Andersen, DK (reprint author), NIDDKD, Clin Studies Program, Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd,Room 659,MSC 5450, Bethesda, MD 20892 USA. EM andersendk@niddk.nih.gov RI sebastianovitsch, stepan/G-8507-2013 NR 3 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAY PY 2013 VL 42 IS 4 BP 555 EP 556 DI 10.1097/MPA.0b013e31828db1ce PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 126XF UT WOS:000317655200001 PM 23591431 ER PT J AU Kunz, PL Reidy-Lagunes, D Anthony, LB Bertino, EM Brendtro, K Chan, JA Chen, H Jensen, RT Kim, MK Klimstra, DS Kulke, MH Liu, EH Metz, DC Phan, AT Sippel, RS Strosberg, JR Yao, JC AF Kunz, Pamela L. Reidy-Lagunes, Diane Anthony, Lowell B. Bertino, Erin M. Brendtro, Kari Chan, Jennifer A. Chen, Herbert Jensen, Robert T. Kim, Michelle Kang Klimstra, David S. Kulke, Matthew H. Liu, Eric H. Metz, David C. Phan, Alexandria T. Sippel, Rebecca S. Strosberg, Jonathan R. Yao, James C. TI Consensus Guidelines for the Management and Treatment of Neuroendocrine Tumors SO PANCREAS LA English DT Article DE neuroendocrine tumors; carcinoid; neuroendocrine/diagnosis; neuroendocrine/treatment; neuroendocrine/pathology; pheochromocytoma ID HEPATIC METASTASES; DIAGNOSIS; SURVIVAL; EVEROLIMUS; CARCINOMAS AB Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician. C1 [Kunz, Pamela L.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Reidy-Lagunes, Diane] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Anthony, Lowell B.] Univ Kentucky, Med Ctr, Dept Med, Lexington, KY 40536 USA. [Bertino, Erin M.] Ohio State Med Ctr, Dept Med, Columbus, OH USA. [Brendtro, Kari] NANETS & NET Patient Advocate, Vancouver, WA USA. [Chan, Jennifer A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chen, Herbert; Sippel, Rebecca S.] Univ Wisconsin, Dept Surg, Madison, WI USA. [Jensen, Robert T.] NIDDK, Digest Dis Branch, Bethesda, MD USA. [Kim, Michelle Kang] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Liu, Eric H.] Vanderbilt Univ, Dept Surg, Nashville, TN 37240 USA. [Metz, David C.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Phan, Alexandria T.; Yao, James C.] Univ Texas MD Anderson Canc Ctr, Dept Med, Houston, TX 77030 USA. [Strosberg, Jonathan R.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Med, Tampa, FL 33682 USA. RP Kunz, PL (reprint author), Stanford Univ, Sch Med, Dept Med, 875 Blake Wilbur Dr, Stanford, CA 94305 USA. EM pkunz@stanford.edu FU Genentech; Merck; Sanofi; Novartis; Onyx/Bayer; Ipsen FX Pamela L. Kunz receives grant funding from Genentech, Merck, and Sanofi, is a consultant for OncoMed and Guardant Health, and has stock options from Guardant Health. Diane Reidy-Lagunes receives grant funding from Novartis and Merck, is a consultant for Novartis and Pfizer, and receives honorarium from Novartis. Jennifer A. Chan receives grant funding from Novartis, Onyx/Bayer, and Merck and has stock options from Merck. Eric H. Liu is a consultant for Novartis. Lowell B. Anthony receives grant funding from Novartis. David C. Metz is a consultant for Novartis and receives grant funding from Ipsen. Alexandria T. Phan is a consultant for Ipsen. Jonathan R. Strosberg is a consultant for Novartis and Pfizer, receives grant funding from Genentech and Novartis, and receives honorarium from Genentech, Pfizer and Sanofi. Matthew H. Kulke is a consultant for Novartis, Ipsen, Pfizer, and Lexicon and receives grant funding from Novartis. James C. Yao serves as a consultant for Novartis, Ipsen, and Pfizer and receives grant funding from Novartis. The remaining authors declare no conflicts of interest. NR 22 TC 87 Z9 91 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAY PY 2013 VL 42 IS 4 BP 557 EP 577 DI 10.1097/MPA.0b013e31828e34a4 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 126XF UT WOS:000317655200002 PM 23591432 ER PT J AU Chaudhary, SC Singh, T Kapur, P Weng, ZP Arumugam, A Elmets, CA Kopelovich, L Athar, M AF Chaudhary, Sandeep C. Singh, Tripti Kapur, Puneet Weng, Zhiping Arumugam, Aadithya Elmets, Craig A. Kopelovich, Levy Athar, Mohammad TI Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE NSAIDs; NO-sulindac; Cell cycle; Photocarcinogenesis; Skin; UVB ID SKH-1 HAIRLESS MICE; NF-KAPPA-B; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; EPITHELIAL-MESENCHYMAL TRANSITIONS; SIGNALING PATHWAY; EXPRESSION; PREVENTION; MURINE; NOTCH; CYCLOOXYGENASES AB Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p<0.05) and volume (p<0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NF kappa B by enhancing I kappa B alpha as evidenced by the reduced expression of iNOS and COX-2, the direct NF kappa B transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial-mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. (C) 2012 Published by Elsevier Inc. C1 [Chaudhary, Sandeep C.; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A.; Athar, Mohammad] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Univ Alabama Birmingham, Dept Dermatol, 1530 3rd Ave South,VH 509, Birmingham, AL 35294 USA. EM mathar@uab.edu FU NIH/NCI [N01-CN-43300 274, R01 CA138998] FX This work has been supported by NIH/NCI N01-CN-43300 274 and R01 CA138998 grants to M.A. NR 32 TC 10 Z9 11 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 1 PY 2013 VL 268 IS 3 BP 249 EP 255 DI 10.1016/j.taap.2012.12.009 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 128UN UT WOS:000317795300001 PM 23274568 ER PT J AU Koh, C Heller, T Haynes-Williams, V Hara, K Zhao, X Feld, JJ Kleiner, DE Rotman, Y Ghany, MG Liang, TJ Hoofnagle, JH AF Koh, C. Heller, T. Haynes-Williams, V. Hara, K. Zhao, X. Feld, J. J. Kleiner, D. E. Rotman, Y. Ghany, M. G. Liang, T. J. Hoofnagle, J. H. TI Long-term outcome of chronic hepatitis C after sustained virological response to interferon-based therapy SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID QUALITY-OF-LIFE; RIBAVIRIN COMBINATION THERAPY; ALPHA-2A PLUS RIBAVIRIN; GENOTYPE 1 INFECTION; FOLLOW-UP; PEGINTERFERON ALPHA-2A; VIRUS-INFECTION; ANTIVIRAL THERAPY; HCV INFECTION; UNITED-STATES AB Background Although the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear. Aim To assess changes in markers of disease activity and fibrosis in patients followed up to 23years post-SVR. Methods The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE). Results Of 103 patients, three subsequently relapsed 0.7, 6.3 and 6.5years post therapy. The remaining 100 patients (56 men, mean age 56years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12years post SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (15227U/L), AST (8724U/L), alkaline phosphatase (7869U/L), IgG (14631113mg/dL), platelet count (209000239000/L) and AST to platelet count ratio index (APRI: 1.310.33). TE was performed in 69 patients and was normal (<7.0kPA) in 60%, moderately elevated (7.113.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (P<0.001). Conclusions In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma. C1 NIDDK, Liver Dis Branch, Div Intramural Res, Bethesda, MD USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Koh, C (reprint author), NIH, CRC 5-2740,10 Ctr Dr, Bethesda, MD 20892 USA. EM kohchris@mail.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute FX Declaration of funding interests: This study was funded by the Intramural Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. The authors are employees of the US Government and have no financial conflicts of interest to report. NR 39 TC 25 Z9 28 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAY PY 2013 VL 37 IS 9 BP 887 EP 894 DI 10.1111/apt.12273 PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 118ZH UT WOS:000317065600004 PM 23461575 ER PT J AU Gliwa, C Berkman, BE AF Gliwa, Catherine Berkman, Benjamin E. TI Response to Open Peer Commentaries on "Do Researchers Have an Obligation to Actively Look for Genetic Incidental Findings?" SO AMERICAN JOURNAL OF BIOETHICS LA English DT Letter C1 [Berkman, Benjamin E.] NHGRI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Gliwa, Catherine] NIH, Bethesda, MD 20892 USA. RP Berkman, BE (reprint author), NHGRI, Natl Inst Hlth, Bldg 10-Room 1C118,10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM berkmanbe@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999] NR 8 TC 1 Z9 1 U1 0 U2 5 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD MAY 1 PY 2013 VL 13 IS 5 BP W10 EP W11 DI 10.1080/15265161.2013.781470 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 120NI UT WOS:000317176900004 PM 23557061 ER PT J AU Defago, MD Gu, DF Hixson, JE Shimmin, LC Rice, TK Gu, CC Jaquish, CE Liu, DP He, J Kelly, TN AF Daniela Defago, Maria Gu, Dongfeng Hixson, James E. Shimmin, Lawrence C. Rice, Treva K. Gu, Charles C. Jaquish, Cashell E. Liu, De-Pei He, Jiang Kelly, Tanika N. TI Common Genetic Variants in the Endothelial System Predict Blood Pressure Response to Sodium Intake: The GenSalt Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; endothelial system; genes; hypertension; salt sensitivity ID NITRIC-OXIDE SYNTHASE; SALT-SENSITIVE HYPERTENSION; DIETARY-SODIUM; ASYMMETRICAL DIMETHYLARGININE; CARDIOVASCULAR-DISEASE; POLYMORPHISMS; ASSOCIATION; RISK; INDIVIDUALS; ENDOSTATIN AB BACKGROUND We examined the association between 14 endothelial system genes and salt-sensitivity of blood pressure (BP). METHODS After a 3-day baseline examination, during which time the usual diet was consumed, 1,906 Chinese participants received a 7-day low-sodium diet (51.3 mmol of sodium/day) followed by a 7-day high-sodium diet (307.8 mmol of sodium/day). BP measurements were obtained at baseline and at the end of each intervention using a random-zero sphygmomanometer. RESULTS The DDAH1 rs11161637 variant was associated with reduced BP salt sensitivity, conferring attenuated systolic BP (SBP) and mean arterial pressure (MAP) decreases from baseline to the low-sodium intervention (both P = 2 x 10(-4)). Examination of genotype-sex interactions revealed that this relation was driven by the strong associations observed in men (P for interactions = 1.10 x 10(-4) and 0.008, respectively). When switching from the low- to high-sodium intervention, increases in diastolic BP (DBP) and MAP were attenuated by the COL18A1 rs2838944 minor A allele (P = 1.41 x10(-4) and 1.55 x 10(-4), respectively). Conversely, the VWF rs2239153 C variant was associated with increased salt sensitivity, conferring larger DBP and MAP reductions during low-sodium intervention (P = 1.22 x 10(-4) and 4.44 x 10(-5), respectively). Ten variants from 3 independent SELE loci displayed significant genotype-sex interactions on DBP and MAP responses to low-sodium (P for interaction = 1.56 x 10(-3) to 1.00 x 10(-4)). Among men, minor alleles of 4 correlated markers attenuated BP responses to low-sodium intake, whereas minor alleles of another 4 correlated markers increased BP responses. No associations were observed in women for these variants. Further, qualitative interactions were shown for 2 correlated SELE markers. CONCLUSIONS These data support a role for the endothelial system genes in salt sensitivity. C1 [Daniela Defago, Maria] Inst Efectividad Clin & Sanitaria, Ctr Excelencia Salud Cardiovasc Cono Sur, Buenos Aires, DF, Argentina. [Daniela Defago, Maria] Univ Nacl Cordoba, Fac Ciencias Med, Escuela Nutr, RA-5000 Cordoba, Argentina. [Gu, Dongfeng] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100730, Peoples R China. [Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100730, Peoples R China. [Gu, Dongfeng; Liu, De-Pei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Rice, Treva K.; Gu, Charles C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Lung, MD USA. [Liu, De-Pei] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100730, Peoples R China. [He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [He, Jiang; Kelly, Tanika N.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. RP Kelly, TN (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. EM tkelly@tulane.edu RI Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD [U01HL072507, R01HL087263, R01 HL090682]; American Heart Association [11SDG5130026] FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by a cooperative agreement project grant (U01HL072507, R01HL087263, and R01 HL090682) from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. Dr. Kelly was supported by American Heart Association award number 11SDG5130026. NR 39 TC 9 Z9 9 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2013 VL 26 IS 5 BP 643 EP 656 DI 10.1093/ajh/hps099 PG 14 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 122LT UT WOS:000317320300009 PM 23443727 ER PT J AU Morens, DM AF Morens, David M. TI Pandemic H5N1: Receding Risk or Coming Catastrophe? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material DE epidemiology; influenza; influenza virus; pandemic; H5N1 ID AVIAN INFLUENZA; VIRUS; TRANSMISSION; INFECTIONS; ADAPTATION; FERRETS; CHINA C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, Bldg 31,Rm 7A-03,31 Ctr Dr, Bethesda, MD 20892 USA. EM dm270q@nih.gov NR 19 TC 8 Z9 9 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2013 VL 56 IS 9 BP 1213 EP 1215 DI 10.1093/cid/cit051 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123QC UT WOS:000317404300004 PM 23386632 ER PT J AU Bulterys, PL Le, T Quang, VM Nelson, KE Lloyd-Smith, JO AF Bulterys, Philip L. Thuy Le Vo Minh Quang Nelson, Kenrad E. Lloyd-Smith, James O. TI Environmental Predictors and Incubation Period of AIDS-Associated Penicillium marneffei Infection in Ho Chi Minh City, Vietnam SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE Penicillium marneffei; penicilliosis; seasonality; humidity; HIV/AIDS ID ANTIRETROVIRAL TREATMENT; NORTHERN THAILAND; OUTCOMES; PROGRAM AB Background. Penicillium marneffei is an emerging dimorphic mycosis endemic in Southeast Asia, and a leading cause of mortality among human immunodeficiency virus (HIV)-infected people in the region. Factors governing the seasonal incidence of P. marneffei infection are unknown, and may yield critical insights into possible reservoirs or modes of acquisition. Methods. This study included HIV-infected patients presenting with P. marneffei (n = 719) and Cryptococcus neoformans (n = 1598) infection to the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, from 2004 to 2010, and temperature, humidity, wind, precipitation, and HIV-related admissions data for the corresponding period. We used multivariate regression modeling to identify factors associated with P. marneffei and C. neoformans admissions. We estimated the P. marneffei incubation period by considering profile likelihoods for different exposure-to-admission delays. Results. We found that P. marneffei admissions were strongly associated with humidity (P <.001), and that precipitation, temperature, and wind did not add explanatory power. Cryptococcus neoformans admissions were not seasonal, and P. marneffei admissions were more common relative to C. neoformans admissions during months of high (>= 85%) humidity (odds ratio, 1.49; 95% confidence interval [CI], 1.10-2.01). Maximum likelihood estimation suggested a P. marneffei incubation period of 1 week (95% CI, 0-3 weeks). Conclusions. Our findings suggest that humidity is the most important environmental predictor of P. marneffei admissions, and may drive exposure by facilitating fungal growth or spore release in the environment. In addition, it appears that a high proportion of penicilliosis patients present to the hospital with primary disseminated infection within 3 weeks of exposure. C1 Univ Calif Los Angeles, David Geffen Sch Med, CALTECH, Med Scientist Training Program, Los Angeles, CA 90095 USA. [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Thuy Le] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Program, Ho Chi Minh City, Vietnam. [Vo Minh Quang] Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Thuy Le] Univ Hawaii Manoa, Hawaii Ctr AIDS, Honolulu, HI 96822 USA. [Nelson, Kenrad E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lloyd-Smith, James O.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Bulterys, PL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Med Scientist Training Program, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM bulterys@ucla.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU UCLA-Caltech Medical Scientist Training Program; Paul and Daisy Soros Fellowships for New Americans; Fogarty International Clinical Research Fellowship; Hawaii Center for AIDS; Wellcome Trust Major Overseas Program; De Logi Chair in Biological Sciences; RAPIDD program of the Science and Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health FX P. L. B. is supported by the UCLA-Caltech Medical Scientist Training Program and the Paul and Daisy Soros Fellowships for New Americans. T. L. is supported by the Fogarty International Clinical Research Fellowship, Hawaii Center for AIDS, and Wellcome Trust Major Overseas Program. J. O. L.-S. is supported by the De Logi Chair in Biological Sciences, and the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health. NR 20 TC 9 Z9 13 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2013 VL 56 IS 9 BP 1273 EP 1279 DI 10.1093/cid/cit058 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123QC UT WOS:000317404300013 PM 23386634 ER PT J AU Silver, D Karnik, G Osinusi, A Silk, R Stabinski, L Doonquah, L Henn, S Teferi, G Masur, H Kottilil, S Fishbein, D AF Silver, D. Karnik, G. Osinusi, A. Silk, R. Stabinski, L. Doonquah, L. Henn, S. Teferi, G. Masur, H. Kottilil, S. Fishbein, D. TI Effect of HIV on Liver Fibrosis Among HCV-Infected African Americans SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE liver fibrosis; HIV; HCV; African Americans ID HEPATITIS-C VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; COINFECTED PATIENTS; PROGRESSION; EPIDEMIOLOGY AB Degree of liver fibrosis largely determines treatment urgency for hepatitis C virus (HCV). This retrospective study examined fibrosis stages and predictive factors in African Americans with HCV monoinfection and human immunodeficiency virus (HIV)/HCV coinfection. Nearly 50% of patients had early-stage fibrosis in the study, despite the long duration of infection in many patients. HIV was associated with the early fibrosis group. These results indicate that a large proportion of patients with HCV infection, including those with HIV, could possibly await more-effective and better-tolerated treatment. C1 [Silver, D.; Masur, H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Karnik, G.; Osinusi, A.; Silk, R.; Stabinski, L.; Fishbein, D.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Clin Res Directorate, Bethesda, MD USA. [Stabinski, L.; Kottilil, S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Doonquah, L.] Family & Med Counseling Serv, Washington, DC USA. [Henn, S.] Whitman Walker Hlth, Washington, DC USA. [Teferi, G.] Unity Healthcare Inc, Washington, DC USA. [Fishbein, D.] MedStar Washington Hosp Ctr, Washington, DC USA. RP Silver, D (reprint author), NIH, Dept Crit Care Med, 1101 Highland Dr, Silver Spring, MD 20910 USA. EM dana.r.silver@gmail.com FU National Cancer Institute at the National Institutes of Health (NIH) [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases (NIAID); Intramural Research Program of the NIH (NIAID and the NIH Clinical Center) FX This project was supported in whole or in part with federal funds from the National Cancer Institute at the National Institutes of Health (NIH; contract number HHSN261200800001E).; This research was supported by the National Institute of Allergy and Infectious Diseases (NIAID). This project has been funded in whole or in part with federal funds from the Intramural Research Program of the NIH (NIAID and the NIH Clinical Center). NR 14 TC 3 Z9 3 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2013 VL 56 IS 9 BP 1280 EP 1283 DI 10.1093/cid/cit037 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123QC UT WOS:000317404300014 PM 23378283 ER PT J AU Shiels, MS Landgren, O Goedert, JJ Engels, EA AF Shiels, Meredith S. Landgren, Ola Goedert, James J. Engels, Eric A. TI Free Light Chains and the Risk of Nonmalignant AIDS Events in HIV-Infected Patients Treated With Combination Antiretroviral Therapy Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID DISEASE; SERUM C1 [Shiels, Meredith S.; Goedert, James J.; Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Landgren, Ola] NCI, Multiple Myeloma Sect, Ctr Canc Res, Rockville, MD 20892 USA. RP Shiels, MS (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7059, Rockville, MD 20892 USA. EM shielsms@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2013 VL 56 IS 9 BP 1350 EP 1350 DI 10.1093/cid/cit015 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123QC UT WOS:000317404300026 PM 23325426 ER PT J AU Martin, DN Starks, AM Ambs, S AF Martin, Damali N. Starks, Adrienne M. Ambs, Stefan TI Biological determinants of health disparities in prostate cancer SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE genetics; health disparity; outcome; prostate cancer; tumor marker ID AFRICAN-AMERICAN MEN; GENE FUSIONS; CLINICAL CHARACTERISTICS; ERG ONCOPROTEIN; WHITE MEN; EXPRESSION; POPULATIONS; HYPERMETHYLATION; RESISTANCE; SIGNATURE AB Purpose of review Prostate cancer mortality rates are highest among men of African ancestry in the United States and globally. Environmental exposures and ancestry-related factors may influence tumor biology and induce a more aggressive disease in this population. Here, we summarize the most recent advances in our understanding of race/ethnic differences in the tumor biology of prostate cancer with an emphasis on the excess disease burden among African-Americans. Recent findings Results from several DNA methylation studies showed an increased prevalence in DNA hypermethylation at disease-related loci in tumors from African-American patients compared with tumors from European-American patients. Analyses of genome-wide gene expression in prostate tumors revealed frequent alterations in the expression of genes related to immunobiology among the African-American patients, consistent with immune response differences between them and their European-American counterparts. Lastly, population differences in the frequency of oncogenic erythroblast transformation-specific family of transcription factors (ETS)-related gene rearrangements were evaluated in three studies that showed that these alterations manifest themselves most commonly in tumors from men of European ancestry, but are significantly less frequent in men of African ancestry, whereas least common in men of Asian ancestry. Summary Analysis of tumor markers indicates that tumor biological differences may exist between prostate cancer patients of African ancestry and those of European or Asian ancestry. These differences could affect disease aggressiveness and response to therapy. C1 [Martin, Damali N.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Starks, Adrienne M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Bldg 37 Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research, USA FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA. NR 45 TC 23 Z9 23 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2013 VL 25 IS 3 BP 235 EP 241 DI 10.1097/CCO.0b013e32835eb5d1 PG 7 WC Oncology SC Oncology GA 119RE UT WOS:000317114300005 PM 23399519 ER PT J AU Parnes, HL House, MG Tangrea, JA AF Parnes, Howard L. House, Margaret G. Tangrea, Joseph A. TI Prostate cancer prevention: strategies for agent development SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE biomarker; carcinogenesis; chemoprevention; prostate cancer ID RANDOMIZED CONTROLLED-TRIAL; SELENIUM SUPPLEMENTATION; ACTIVE SURVEILLANCE; INTRAEPITHELIAL NEOPLASIA; CLINICAL-TRIAL; VITAMIN-E; HIGH-RISK; MEN; FINASTERIDE; CHEMOPREVENTION AB Purpose of review This article provides an update of clinical research supported by the National Cancer Institute's Phase I/II prostate cancer chemoprevention agent development program. Recent findings Numerous clinical trials of pharmacologic interventions to delay, prevent or reverse carcinogenesis ('chemoprevention') with the ultimate goal of reducing cancer incidence have been conducted over the past decade. These trials range from relatively small, short-duration studies with biomarker endpoints to very large, long-term, general population trials with definitive cancer endpoints. Two large, population-based, Phase III prostate cancer prevention trials have shown a significant benefit for 5-alpha-reductase inhibitors. However, this class of agents was also associated with increased detection of high-grade prostate cancer. Another large, Phase III prostate cancer prevention trial showed no benefit for either selenium or vitamin E, given individually or in combination; in fact, a significant increase in prostate cancer was observed among men randomized to the vitamin E alone arm. Summary A number of early phase trials and three definitive Phase III trials have been conducted in the field of prostate cancer prevention over the past decade. Although a great deal has been learned from these studies, significant work remains to be done to fully realize the potential of chemoprevention in this disease. C1 [Parnes, Howard L.; House, Margaret G.; Tangrea, Joseph A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Parnes, HL (reprint author), 6130 Execut Blvd, Bethesda, MD 20892 USA. EM parnesh@mail.nih.gov NR 44 TC 12 Z9 12 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2013 VL 25 IS 3 BP 242 EP 251 DI 10.1097/CCO.0b013e32835fc8d4 PG 10 WC Oncology SC Oncology GA 119RE UT WOS:000317114300006 PM 23518594 ER PT J AU Singer, EA Gupta, GN Marchalik, D Srinivasan, R AF Singer, Eric A. Gupta, Gopal N. Marchalik, Daniel Srinivasan, Ramaprasad TI Evolving therapeutic targets in renal cell carcinoma SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE clear cell; familial renal cancer; nonclear cell; renal cell carcinoma; targeted therapy ID HOGG-DUBE-SYNDROME; FUMARATE-HYDRATASE; HEREDITARY LEIOMYOMATOSIS; KIDNEY CANCER; PROGNOSTIC-FACTORS; INTERFERON-ALPHA; PHASE-3 TRIAL; PAPILLARY; MUTATIONS; GENE AB Purpose of review Recent developments in the treatment of advanced renal cell carcinoma (RCC) will be discussed, with emphasis on data published over the past year. The genetics and molecular biology of the various histologic subtypes of kidney cancer will be reviewed, as these subtle yet important genomic and metabolic alterations provide the opportunity for rational drug development and personalized treatment regimens. Recent findings Additional targeted agents continue to be added to the uro-oncologist's armamentarium in the fight against metastatic kidney cancer. Targeting the vascular endothelial growth factor and its receptor, or the mammalian target of rapamycin complex, remains the foundation of systemic treatment. In clear cell RCC, increased emphasis is being placed on target selectivity and affinity in a bid to diminish off-target toxicity without compromising efficacy. Combination strategies targeting multiple pathways simultaneously continue to be explored. Histology-specific protocols testing later generation and novel agents in nonclear cell RCC should be made a priority, as there is still not a single drug approved specifically for a nonclear cell indication. Summary The number of approved treatments for advanced RCC continues to grow, but additional work is needed to further delineate the optimal drug, combination of agents, or sequence best suited to each subtype of RCC. C1 [Singer, Eric A.] Canc Inst New Jersey, Sect Urol Oncol, New Brunswick, NJ USA. [Singer, Eric A.] UMDNJ Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Gupta, Gopal N.] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. [Marchalik, Daniel; Srinivasan, Ramaprasad] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Srinivasan, R (reprint author), NCI, Mol Canc Sect, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr,CRC2-5950, Bethesda, MD 20892 USA. EM ramasrin@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland, USA FX This research was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, Maryland, USA. NR 75 TC 31 Z9 32 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2013 VL 25 IS 3 BP 273 EP 280 DI 10.1097/CCO.0b013e32835fc857 PG 8 WC Oncology SC Oncology GA 119RE UT WOS:000317114300010 PM 23455028 ER PT J AU Walker, DM O'Neill, JP Tyson, FL Walker, VE AF Walker, Dale M. O'Neill, J. Patrick Tyson, Frederick L. Walker, Vernon E. TI The stress response resolution assay. I. Quantitative assessment of environmental agent/condition effects on cellular stress resolution outcomes in epithelium SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE gene environment interaction; damage avoidance; damage tolerance; HPRT mutation; cell fate decisions; cellular stress response ID ETHYL-N-NITROSOUREA; DNA MISMATCH REPAIR; INDUCED PREMATURE SENESCENCE; REVERSE-TRANSCRIPTASE INHIBITORS; HUMAN LYMPHOBLASTOID-CELLS; GENE-EXPRESSION PROFILES; LESCH-NYHAN SYNDROME; EXPOSED IN-VIVO; HPRT GENE; 6-THIOGUANINE-RESISTANT LYMPHOCYTES AB The events or factors that lead from normal cell function to conditions and diseases such as aging or cancer reflect complex interactions between cells and their environment. Cellular stress responses, a group of processes involved in homeostasis and adaptation to environmental change, contribute to cell survival under stress and can be resolved with damage avoidance or damage tolerance outcomes. To investigate the impact of environmental agents/conditions upon cellular stress response outcomes in epithelium, a novel quantitative assay, the stress response resolution (SRR) assay, was developed. The SRR assay consists of pretreatment with a test agent or vehicle followed later by a calibrated stress conditions exposure step (here, using 6-thioguanine). Pilot studies conducted with a spontaneously-immortalized murine mammary epithelial cell line pretreated with vehicle or 20 mu g N-ethyl-N-nitrososurea/ml medium for 1 hr, or two hTERT-immortalized human bronchial epithelial cell lines pretreated with vehicle or 100 mu M zidovudine/lamivudine for 12 days, found minimal alterations in cell morphology, survival, or cell function through 2 weeks post-exposure. However, when these pretreatments were followed 2 weeks later by exposure to calibrated stress conditions of limited duration (for 4 days), significant alterations in stress resolution were observed in pretreated cells compared with vehicle-treated control cells, with decreased damage avoidance survival outcomes in all cell lines and increased damage tolerance outcomes in two of three cell lines. These pilot study results suggest that sub-cytotoxic pretreatments with chemical mutagens have long-term adverse impact upon the ability of cells to resolve subsequent exposure to environmental stressors. Environ. Mol. Mutagen. 54:268280, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Walker, Dale M.] Expt Pathol Labs Inc, Herndon, VA USA. [Walker, Dale M.; Walker, Vernon E.] Burlington HC Res Grp, Jericho, VT 05465 USA. [O'Neill, J. Patrick; Walker, Vernon E.] Univ Vermont, Burlington, VT USA. [Tyson, Frederick L.] NIEHS, Cellular Organs & Syst Pathobiol Branch, DERT, Res Triangle Pk, NC 27709 USA. [Walker, Vernon E.] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. RP Walker, VE (reprint author), Burlington HC Res Grp, 10 Marion Way, Jericho, VT 05465 USA. EM bhcrg@ymail.com FU Brain Tumor Society; Health Effects Institute FX Grant sponsor: The Brain Tumor Society.; Grant sponsor: The Health Effects Institute. NR 119 TC 1 Z9 1 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD MAY PY 2013 VL 54 IS 4 BP 268 EP 280 DI 10.1002/em.21772 PG 13 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 122EA UT WOS:000317298300005 PM 23554083 ER PT J AU de Miguel-Yanes, JM Porneala, B Pencina, MJ Fox, CS Florez, JC Siscovick, DS Dupuis, J Meigs, JB AF de Miguel-Yanes, Jose M. Porneala, Bianca Pencina, Michael J. Fox, Caroline S. Florez, Jose C. Siscovick, David S. Dupuis, Josee Meigs, James B. TI Lack of interaction of beta-cell-function-associated variants with hypertension on change in fasting glucose and diabetes risk: the Framingham Offspring Study SO JOURNAL OF HYPERTENSION LA English DT Article DE fasting glucose; Framingham; genes; genetic risk scores; hypertension; hypertension treatment; interaction test; single nucleotide polymorphisms; type 2 diabetes mellitus ID GENOME-WIDE ASSOCIATION; BLOOD-PRESSURE; CARDIOVASCULAR EVENTS; SUSCEPTIBILITY LOCI; THIAZIDE DIURETICS; GENETIC-VARIATION; HEART-DISEASE; FOLLOW-UP; MELLITUS; METAANALYSIS AB Objective: To test whether pancreatic beta-cell genetic frailty and hypertension (HTN) interact in their associations with change over time in fasting glucose (Delta FG) or type 2 diabetes mellitus (T2D) risk. Methods and results: We pooled data from 3471 Framingham Offspring Study participants into six similar to 4-year periods (15 852 person-examinations; mean age 52; 54% women). We defined two genetic exposures reflecting beta-cell genetic risk burden: single nucleotide polymorphism (SNP) score counts of fasting glucose-associated and T2D-associated risk alleles at 16 and 33 putative beta-cell loci, respectively; and three HTN exposures: HTN versus no-HTN; treated versus untreated HTN; and five mutually exclusive antihypertensive categories (beta-blockers, thiazides, renin-angiotensin system agents, combinations, others) versus untreated HTN. We tested similar to 4-year mean Delta FG or odds of T2D by per-risk allele score change and HTN category, seeking genetic score-by-HTN interaction. Genetic scores increased similar to 4-year Delta FG (0.6 mg/dl per-risk allele; P = 8.9 x 10(-16)) and T2D-risk (similar to 17% per-risk allele; P = 2.1 x 10(-7)). As compared to no-HTN, HTN conferred higher Delta FG (2.6 versus 1.7 mg/dl; P < 0.0001) and T2D-risk [odds ratio (OR) - 2.9, 95% confidence interval (CI) 2.8-3.0; P < 0.0001]. As compared to untreated HTN, treated HTN conferred higher Delta FG (3.4 versus 3.0 mg/dl; P < 0.0001) and T2D-risk (OR = 1.4, 95% CI 1.3-1.5; P = 0.02). Beta-blockers (OR = 1.6, 95% CI 1.1-2.4), combinations (OR = 1.6, 95% CI 1.1-2.5), and others (OR = 2.0, 95% CI 1.4-2.9) increased T2D-risk (all P < 0.02). In joint models including interaction terms, all genetic score-by-HTN interaction terms were P value greater than 0.05. In joint models without interaction, fasting glucose-SNP or T2D-SNP genetic scores (both P < 0.001) and HTN (P < 0.0001) independently increased Delta FG or T2D-risk. Conclusion: HTN, HTN treatment, and common fasting glucose-SNP genetic score/T2D-SNP genetic score independently predicted Delta FG and T2D incidence, but did not modify each other's association with Delta FG or T2D risk. C1 [de Miguel-Yanes, Jose M.] Univ Complutense Madrid, Hosp Gregorio Maranon, Madrid, Spain. [de Miguel-Yanes, Jose M.] Hosp Sureste, Madrid, Spain. [Porneala, Bianca; Meigs, James B.] Boston Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Div Gen Med, Boston, MA USA. [Pencina, Michael J.; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, Caroline S.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP de Miguel-Yanes, JM (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Dupuis, Josee/0000-0003-2871-3603 FU National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616, K24 DK080140]; Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health; Boston University School of Medicine; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affimetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This study was supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 and K24 DK080140 and the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SHARe Project, itself supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract from Affimetrix, Inc. for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analyses (LinGA - II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NR 48 TC 0 Z9 0 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD MAY PY 2013 VL 31 IS 5 BP 1001 EP 1009 DI 10.1097/HJH.0b013e32835f5a83 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 119RL UT WOS:000317115000023 PM 23425704 ER PT J AU Taha, AY Cheon, Y Ma, KZ Rapoport, SI Rao, JS AF Taha, Ameer Y. Cheon, Yewon Ma, Kaizong Rapoport, Stanley I. Rao, Jagadeesh S. TI Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Fatty acids; Lipids; Phospholipids; Brain; Prefrontal cortex; Postmortem; Schizophrenia; Composition; Concentrations ID MAGNETIC-RESONANCE-SPECTROSCOPY; MEMBRANE PHOSPHOLIPID-METABOLISM; PLACEBO-CONTROLLED-TRIAL; P-31 NMR-SPECTROSCOPY; ARACHIDONIC-ACID; DOCOSAHEXAENOIC ACID; RAT-BRAIN; UNANESTHETIZED RATS; POSTMORTEM; ABNORMALITIES AB Background: Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in patients with schizophrenia (SCZ), often as an incomplete lipid profile or a percent of total lipid concentration. In this study, we quantified absolute concentrations (nmol/g wet weight) and fractional concentrations (i.e. percent of total fatty acids) of several lipid classes and their constituent fatty acids in postmortem prefrontal cortex of SCZ patients (n = 10) and age-matched controls (n = 10). Methods: Lipids were extracted, fractionated with thin layer chromatography and assayed. Results: Mean total lipid, phospholipid, individual phospholipids, plasmalogen, triglyceride and cholesteryl ester concentrations did not differ significantly between the groups. Compared to controls, SCZ brains showed significant increases in several monounsaturated and polyunsaturated fatty acid absolute concentrations in cholesteryl ester. Significant increases or decreases occurred in palmitoleic, linoleic, gamma-linolenic and n-3 docosapentaenoic acid absolute concentrations in total lipids, triglycerides or phospholipids. Changes in fractional concentrations did not consistently reflect absolute concentration changes. Conclusion: These findings suggest disturbed prefrontal cortex fatty acid absolute concentrations, particularly within cholesteryl esters, as a pathological aspect of schizophrenia. Published by Elsevier Ltd. C1 [Taha, Ameer Y.; Cheon, Yewon; Ma, Kaizong; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Taha, AY (reprint author), NIA, BPMS, NIH, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM ameer.taha@nih.gov FU National Institute on Aging Intramural Research Program of the National Institutes of Health; PHS [R24MH068855] FX This study was entirely supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health.; This study was supported by the National Institute on Aging Intramural Research Program of the National Institutes of Health. We thank the Harvard Brain Bank, Boston, MA, for providing the postmortem brain samples under PHS grant number R24MH068855. NR 72 TC 22 Z9 22 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD MAY PY 2013 VL 47 IS 5 BP 636 EP 643 DI 10.1016/j.jpsychires.2013.01.016 PG 8 WC Psychiatry SC Psychiatry GA 124EU UT WOS:000317447400012 PM 23428160 ER PT J AU Song, BJ Rockey, DC AF Song, Byoung-Joon Rockey, Don C. TI Status of research on vitamin D supplementation in treating or preventing liver fibrosis SO LIVER INTERNATIONAL LA English DT Editorial Material ID THERAPEUTIC TARGETS; DISEASE; EXPRESSION; CIRRHOSIS; D-3 C1 [Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem, Bethesda, MD USA. [Rockey, Don C.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem, Bethesda, MD USA. FU Intramural NIH HHS [Z99 AA999999, ZIA AA000036-26] NR 20 TC 13 Z9 14 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1478-3223 J9 LIVER INT JI Liver Int. PD MAY PY 2013 VL 33 IS 5 BP 653 EP 655 DI 10.1111/liv.12147 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 122HT UT WOS:000317309900001 PM 23560728 ER PT J AU Ramamoorthy, S Cidlowski, JA AF Ramamoorthy, Sivapriya Cidlowski, John A. TI Ligand-Induced Repression of the Glucocorticoid Receptor Gene Is Mediated by an NCoR1 Repression Complex Formed by Long-Range Chromatin Interactions with Intragenic Glucocorticoid Response Elements SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DOWN-REGULATION; MESSENGER-RNA; MOLECULAR-MECHANISMS; T-CELLS; PHOSPHORYLATION; EXPRESSION; SEQUENCES; HORMONES AB Glucocorticoids are among the most potent and effective agents for treating inflammatory diseases and hematological cancers. However, subpopulations of patients are often resistant to steroid therapy, and determining the molecular mechanisms that contribute to glucocorticoid resistance is thus critical to addressing this clinical problem affecting patients with chronic inflammatory disorders. Since the cellular level of the glucocorticoid receptor (GR) is a critical determinant of glucocorticoid sensitivity and resistance, we investigated the molecular mechanisms mediating repression of glucocorticoid receptor gene expression. We show here that glucocorticoid-induced repression of GR gene expression is mediated by inhibition of transcription initiation. This process is orchestrated by the recruitment of agonist-bound GR to exon 6, followed by the assembly of a GR-NCoR1-histone deacetylase 3-containing repression complex at the transcriptional start site of the GR gene. A functional negative glucocorticoid response element (nGRE) in exon 6 of the GR gene and a long-range interaction occurring between this intragenic response element and the transcription start site appear to be instrumental in this repression. This autoregulatory mechanism of repression implies that the GR concentration can coordinate repression with excess ligand, regardless of the combinatorial associations of tissue-specific transcription factors. Consequently, the chronic nature of inflammatory conditions involving long-term glucocorticoid administration may lead to constitutive repression of GR gene transcription and thus to glucocorticoid resistance. C1 [Ramamoorthy, Sivapriya; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 42 TC 31 Z9 32 U1 0 U2 17 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2013 VL 33 IS 9 BP 1711 EP 1722 DI 10.1128/MCB.01151-12 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121VS UT WOS:000317273300003 PM 23428870 ER PT J AU Lee, BS Dekker, JD Lee, BK Iyer, VR Sleckman, BP Arthur, LS Ippolito, GC Tucker, PW AF Lee, Baeck-seung Dekker, Joseph D. Lee, Bum-kyu Iyer, Vishwanath R. Sleckman, Barry P. Shaffer, Arthur L., III Ippolito, Gregory C. Tucker, Philip W. TI The BCL11A Transcription Factor Directly Activates RAG Gene Expression and V(D)J Recombination SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID B-CELL DEVELOPMENT; ZINC-FINGER PROTEIN; CHRONIC LYMPHOCYTIC-LEUKEMIA; PRE-B; LYMPHOID DEVELOPMENT; T-LYMPHOCYTES; DIFFERENTIATION; PROMOTER; MICE; CANCER AB Recombination-activating gene 1 protein (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining (VDJ) segment recombination, an essential process for antigen receptor expression and lymphocyte development. The transcription factor BCL11A is required for B cell development, but its molecular function(s) in B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds the RAG1 promoter and Erag enhancer to activate RAG1 and RAG2 transcription in pre-B cells. We employed BCL11A overexpression with recombination substrates in a cultured pre-B cell line as well as Cre recombinase-mediated Bcl11a(lox/lox) deletion in explanted murine pre-B cells to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination. C1 [Lee, Baeck-seung; Dekker, Joseph D.; Lee, Bum-kyu; Iyer, Vishwanath R.; Ippolito, Gregory C.; Tucker, Philip W.] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Shaffer, Arthur L., III] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Tucker, PW (reprint author), Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. EM philtucker@mail.utexas.edu RI Dekker, Joseph/G-4924-2013 OI Dekker, Joseph/0000-0002-2068-3529 FU NIH [F32-CA110624, RO1-CA31534]; Cancer Prevention Research Institute [CPRIT RP100612]; Marie Betzner Morrow Endowment FX G.C.I. acknowledges support from NIH grant F32-CA110624, and P.W.T. acknowledges support from NIH grant RO1-CA31534, the Cancer Prevention Research Institute (grant CPRIT RP100612), and the Marie Betzner Morrow Endowment. NR 65 TC 7 Z9 8 U1 0 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAY PY 2013 VL 33 IS 9 BP 1768 EP 1781 DI 10.1128/MCB.00987-12 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121VS UT WOS:000317273300008 PM 23438597 ER PT J AU Stott-Miller, M Karyadi, DM Smith, T Kwon, EM Kolb, S Stanford, JL Ostrander, EA AF Stott-Miller, Marni Karyadi, Danielle M. Smith, Tiffany Kwon, Erika M. Kolb, Suzanne Stanford, Janet L. Ostrander, Elaine A. TI HOXB13 mutations in a population-based, case-control study of prostate cancer SO PROSTATE LA English DT Article DE prostate cancer; genetics; population genetics; polymorphism; prostate neoplasm; genetic susceptibility ID GENOME-WIDE SCAN; SUSCEPTIBILITY GENES; RISK; LINKAGE; ASSOCIATION; VARIANTS; FAMILIES; GENETICS; REGION AB BACKGROUND Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population. MATERIALS AND METHODS We determined the distribution and frequency of the G84E HOXB13 variant in 1,310 incipient PC cases and 1,259 age-mated controls from a population-based, casecontrol study of PC. RESULTS The G84E mutation was more frequent in cases than controls (1.3% vs. 0.4%, respectively), and men with the HOXB13 G84E variant had a 3.3-fold higher relative risk of PC compared with noncarriers (95% CI, 1.218.96). There was a stronger association between the G84E variant and PC among men with no first-degree relative with PC (OR, 4.04; 95% CI, 1.1214.51) compared to men with a family history of PC (OR, 1.49; 95% CI, 0.307.50; P=0.36 for interaction). We observed some evidence of higher risk estimates associated with the variant for men with higher versus lower Gleason score (OR, 4.13; 95% CI, 1.3812.38 vs. OR, 2.71; 95% CI, 0.888.30), and advanced versus local stage (OR, 4.47; 95% CI, 1.2815.57 vs. OR, 2.98; 95% CI, 1.048.49), however these differences were not statistically different. CONCLUSIONS These results confirm the association of a rare HOXB13 mutation with PC in the general population and suggest that this variant may be associated with features of more aggressive disease. Prostate 73: 634641, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Stott-Miller, Marni; Kolb, Suzanne; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Karyadi, Danielle M.; Smith, Tiffany; Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Ostrander, EA (reprint author), 50 South Dr,Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov RI sebastianovitsch, stepan/G-8507-2013; OI Ostrander, Elaine/0000-0001-6075-9738 FU NIH [R01 CA0566787, R01 CA092579, R01 CA082664, P50 CA097186] FX Grant sponsor: NIH; Grant numbers: R01 CA0566787, R01 CA092579, R01 CA082664, P50 CA097186. NR 28 TC 18 Z9 19 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY PY 2013 VL 73 IS 6 BP 634 EP 641 DI 10.1002/pros.22604 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 120RM UT WOS:000317189500009 PM 23129385 ER PT J AU Taioli, E Sears, V Watson, A Flores-Obando, RE Jackson, MD Ukoli, FA Colus, IMD Fernandez, P McFarlane-Anderson, N Ostrander, EA Rodrigues, IS Stanford, JL Taylor, JA Tulloch-Reid, M Ragin, CCR AF Taioli, Emanuela Sears, Vestra Watson, Alexis Flores-Obando, Rafael E. Jackson, Maria D. Ukoli, Flora A. de Syllos Colus, Ilce M. Fernandez, Pedro McFarlane-Anderson, Norma Ostrander, Elaine A. Rodrigues, Iara S. Stanford, Janet L. Taylor, Jack A. Tulloch-Reid, Marshall Ragin, Camille C. R. TI Polymorphisms in CYP17 and CYP3A4 and prostate cancer in men of African descent SO PROSTATE LA English DT Article DE prostate cancer; genetics; African ancestry ID CLINICAL PRESENTATION; STEROID-METABOLISM; GENETIC VARIANT; AMERICAN MEN; RISK; ASSOCIATION; METAANALYSIS; FINASTERIDE; SRD5A2 AB BACKGROUND A meta and pooled analysis of published and unpublished casecontrol studies was performed to evaluate the association of CYP17 (rs743572) and CYP3A4 (rs2740574) polymorphisms and prostate cancer (PCa) in men from the USA, Caribbean, and Africa. METHODS Eight publications (seven studies) and two unpublished studies for CYP17 included 1,580 subjects (559 cases and 1,021 controls) and eleven publications and three unpublished studies for CYP3A4 included 3,400 subjects (1,429 cases and 1,971 controls). RESULTS Overall, the CYP17 heterozygous and homozygous variants were not associated with PCa, but they confer a 60% increased risk of PCa in a sub-group analysis restricted to African-American men (T/C+C/C, OR: 1.6, 95% CI: 1.12.4). No associations were observed for CYP3A4, overall and in stratified analyses for African-Americans and Africans. The pooled analysis suggests that after adjusting for study, age, PSA, and family history of PCa, CYP17 was associated with PCa for men of African ancestry (Adjusted OR: 3.5, 95% CI: 1.210.0). CONCLUSIONS Our findings suggest that genetic factors involved in the androgen pathway play a role in PCa risk among men of African ancestry. Prostate 73: 668676, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Taioli, Emanuela] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Sears, Vestra] Philander Smith Coll, Dept Biol, Little Rock, AR USA. [Watson, Alexis] Harvard Univ, Dept Biol, Washington, DC USA. [Flores-Obando, Rafael E.] Suny Downstate Med Ctr, Dept Cell Biol, Brooklyn, NY 11203 USA. [Jackson, Maria D.] Univ W Indies, Dept Community Hlth & Psychiat, Kingston 7, Jamaica. [Ukoli, Flora A.] Meharry Med Coll, Dept Surg, Nashville, TN 37208 USA. [de Syllos Colus, Ilce M.; Rodrigues, Iara S.] Univ Estadual Londrina, CCB, Dept Biol Geral, Londrina, Brazil. [Fernandez, Pedro] Univ Stellenbosch, Dept Urol, ZA-7505 Tygerberg, W Cape, South Africa. [McFarlane-Anderson, Norma] Univ W Indies, Dept Basic Med Sci, Kingston 7, Jamaica. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Taylor, Jack A.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Tulloch-Reid, Marshall] Univ W Indies, TMRI, Epidemiol Res Unit, Kingston 7, Jamaica. [Ragin, Camille C. R.] Fox Chase Canc Ctr, Canc Prevent & Control Program, Philadelphia, PA 19111 USA. RP Taioli, E (reprint author), North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA. EM taiolema@gmail.com OI taylor, jack/0000-0001-5303-6398; Ostrander, Elaine/0000-0001-6075-9738 FU National Cancer Institute; National Institutes of Health [R13CA130596A, P20CA132385-01, CA006927]; Fox Chase Cancer Center Genomics Facility; National Cancer Institute, National Institutes of Health [R13CA130596A, P20CA132385-01, CA006927]; Intramural Research Program of the NIH, National Human Genome Research Institute; National Institute of Environmental Health Sciences FX Grant sponsor: National Cancer Institute; Grant sponsor: National Institutes of Health; Grant numbers: R13CA130596A, P20CA132385-01, CA006927.; We thank Ms. Denise Gibbs and the Fox Chase Cancer Center Genomics Facility for their support of this study. The authors also acknowledge Ms. Helina Tadesse, who managed the various datasets included in the pooled analysis, a significant contribution to this published work. This study was supported in part by the National Cancer Institute, National Institutes of Health [R13CA130596A, P20CA132385-01, and CA006927], by the Intramural Research Program of the NIH, National Human Genome Research Institute and National Institute of Environmental Health Sciences, and by an appropriation from the Commonwealth of Pennsylvania. NR 41 TC 14 Z9 14 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY PY 2013 VL 73 IS 6 BP 668 EP 676 DI 10.1002/pros.22612 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 120RM UT WOS:000317189500013 PM 23129512 ER PT J AU Sakamuri, RM Price, DN Lee, M Cho, SN Barry, CE Via, LE Swanson, BI Mukundan, H AF Sakamuri, Rama Murthy Price, Dominique N. Lee, Myungsun Cho, Sang Nae Barry, Clifton E., III Via, Laura E. Swanson, Basil I. Mukundan, Harshini TI Association of lipoarabinomannan with high density lipoprotein in blood: Implications for diagnostics SO TUBERCULOSIS LA English DT Article DE Lipoarabinomannan (LAM); Amphiphiles; Pathogen-associated molecular patterns; High-density lipoprotein; Apolipoprotein A1 ID PATHOGEN DETECTION; LAM-ELISA; TUBERCULOSIS; URINE; BIOSENSOR AB Understanding the pathophysiology of tuberculosis, and the bio-distribution of pathogen-associated molecules in the host is essential for the development of efficient methods of intervention. One of the key virulence factors in the pathology of tuberculosis infection is Lipoarabinomannan (LAM). Previously, we have demonstrated the reliable detection of LAM in urine from tuberculosis patients in a sandwich immunoassay format. We have also applied an ultra-sensitive detection strategy developed for amphiphilic biomarkers, membrane insertion, to the detection of LAM with a limit of detection of 10 fM. Herein, we evaluate the application of membrane insertion to the detection of LAM in patient serum, and demonstrate that the circulating concentrations of 'monomeric' LAM in serum are very low, despite significantly higher concentrations in the urine. Using spiked samples, we demonstrate that this discrepancy is due to the association of LAM with high-density lipoprotein (HDL) nanodiscs in human serum. Indeed, pull-down of HDL nanodiscs from human serum allows for the recovery of HDL-associated LAM. These studies suggest that LAM is likely associated with carrier molecules such as HDL in the blood of patients infected with tuberculosis. This phenomenon may not be limited to LAM in that many pathogen-associated molecular patterns like LAM are amphiphilic in nature and may also be associated with host lipid carriers. Such interactions are likely to affect hostepathogen interactions, pathogen bio-distribution and clearance in the host, and must be thoroughly understood for the effective design of vaccines and diagnostics. Published by Elsevier Ltd. C1 [Sakamuri, Rama Murthy; Price, Dominique N.; Mukundan, Harshini] Los Alamos Natl Lab, Div Chem, C PCS, Los Alamos, NM 87545 USA. [Lee, Myungsun; Cho, Sang Nae] Int TB Res Ctr, Chang Won, South Korea. [Barry, Clifton E., III; Via, Laura E.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. [Swanson, Basil I.] Los Alamos Natl Lab, Biosci Div, Los Alamos, NM 87545 USA. RP Mukundan, H (reprint author), Los Alamos Natl Lab, Div Chem, C PCS, MS J567, Los Alamos, NM 87545 USA. EM basil@lanl.gov; Harshini@lanl.gov RI Barry, III, Clifton/H-3839-2012; Sakamuri, Rama Murthy/D-8919-2012; OI Sakamuri, Rama Murthy/0000-0002-1640-0709; Via, Laura/0000-0001-6074-9521 FU Department of Energy; Los Alamos National Laboratory LDRD Directed Research Award; Intramural Research Program of the NIAID, NIH FX We thank Mr. K. W. Grace for help in waveguide instrumentation and Mr. A. S. Anderson for SAM chemistry and technical help. We thank the Colorado State University (BEI Resources, operated by the NIAID) for purified LAM and antibodies used in this study. The work was supported by a Department of Energy and Los Alamos National Laboratory LDRD Directed Research Award to Drs. B. T. Korber and B. I. Swanson, and (in part) by the Intramural Research Program of the NIAID, NIH. NR 21 TC 10 Z9 10 U1 0 U2 18 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD MAY PY 2013 VL 93 IS 3 BP 301 EP 307 DI 10.1016/j.tube.2013.02.015 PG 7 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 120PK UT WOS:000317183000007 PM 23507184 ER PT J AU Dean, J AF Dean, Jurrien TI HUMAN GAMETE RECOGNITION IN TRANSGENIC MICE SO ANDROLOGY LA English DT Meeting Abstract C1 [Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 J9 ANDROLOGY-US JI Andrology PD MAY PY 2013 VL 1 SU 2 SI SI BP 31 EP 31 PG 1 WC Andrology SC Endocrinology & Metabolism GA 116WD UT WOS:000316912900009 ER PT J AU Schrader, S Sundaram, R Schisterman, E Sweeney, A Chen, Z Kim, S Maisog, J Turner, T Breitenstein, M Louis, GB AF Schrader, Steven Sundaram, Rajeswhari Schisterman, Enrique Sweeney, Anne Chen, Zhen Kim, Sungduk Maisog, Jose Turner, Terry Breitenstein, Michael Louis, Germaine Buck TI PRECONCEPTION SEMEN QUALITY AND TIME-TO-PREGNANCY, LIFE STUDY SO ANDROLOGY LA English DT Meeting Abstract C1 [Sundaram, Rajeswhari; Schisterman, Enrique; Chen, Zhen; Kim, Sungduk; Maisog, Jose; Louis, Germaine Buck] NICHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 J9 ANDROLOGY-US JI Andrology PD MAY PY 2013 VL 1 SU 2 SI SI BP 103 EP 103 PG 1 WC Andrology SC Endocrinology & Metabolism GA 116WD UT WOS:000316912900127 ER PT J AU Lazarevic, D Pistorio, A Palmisani, E Miettunen, P Ravelli, A Pilkington, C Wulffraat, NM Malattia, C Garay, SM Hofer, M Quartier, P Dolezalova, P Penades, IC Ferriani, VPL Ganser, G Kasapcopur, O Melo-Gomes, JA Reed, AM Wierzbowska, M Rider, LG Martini, A Ruperto, N AF Lazarevic, Dragana Pistorio, Angela Palmisani, Elena Miettunen, Paivi Ravelli, Angelo Pilkington, Clarissa Wulffraat, Nico M. Malattia, Clara Garay, Stella Maris Hofer, Michael Quartier, Pierre Dolezalova, Pavla Penades, Inmaculada Calvo Ferriani, Virginia P. L. Ganser, Gerd Kasapcopur, Ozgur Melo-Gomes, Jose Antonio Reed, Ann M. Wierzbowska, Malgorzata Rider, Lisa G. Martini, Alberto Ruperto, Nicolino CA PRINTO TI The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; MYOSITIS ASSESSMENT SCALE; ACTIVITY CORE SET; INTERNATIONAL CONSENSUS; PROGNOSTIC-FACTORS; DAMAGE INDEXES; PROSPECTIVE VALIDATION; PROVISIONAL CRITERIA; SELECT CATEGORIES; MUSCLE FUNCTION AB Objectives To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). Methods The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen's kappa agreement. Results The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's kappa >0.8) were manual muscle testing (MMT) >= 78, physician global assessment of muscle activity = 0, physician global assessment of overall disease activity (PhyGloVAS) <= 0.2, Childhood Myositis Assessment Scale (CMAS) >= 48, Disease Activity Score <= 3 and Myositis Disease Activity Assessment Visual Analogue Scale <= 0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase <= 150, CMAS >= 48, MMT >= 78 and PhyGloVAS <= 0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. Conclusion: PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice. C1 [Lazarevic, Dragana; Palmisani, Elena; Miettunen, Paivi; Ravelli, Angelo; Martini, Alberto; Ruperto, Nicolino] PRINTO, Ist Giannina Gaslini, I-16147 Genoa, Italy. [Pistorio, Angela] PRINTO, Serv Epidemiol Biostat, I-16147 Genoa, Italy. [Ravelli, Angelo; Malattia, Clara; Martini, Alberto] Univ Genoa, Dept Pediat, Genoa, Italy. [Pilkington, Clarissa] Great Ormond St Hosp Sick Children, Ctr Paediat & Adolescent Rheumatol, London, England. [Garay, Stella Maris] Wilhelmina Childrens Hosp, Dept Pediat Immunol & Rheumatol, Utrecht, Netherlands. [Garay, Stella Maris] Hosp Sor Maria Ludov, Unidad Reumatol, La Plata, Argentina. [Hofer, Michael] Western Switzerland Lausanne Univ Hosp,Lausanne, Lausanne, Switzerland. [Hofer, Michael] Univ Hosp Geneva, Lausanne, Switzerland. [Quartier, Pierre] Univ Paris 05, Ctr Reference Natl Arthrites Juveniles, Unite Immunol Hematol & Rhumatol, Paris, France. [Quartier, Pierre] Hop Necker Enfants Malad, Paris, France. [Dolezalova, Pavla] Charles Univ Prague, Dept Pediat & Adolescent Med, Prague 2, Czech Republic. [Dolezalova, Pavla] Gen Univ Hosp, Prague 2, Czech Republic. [Penades, Inmaculada Calvo] Hosp Univ Le Fe, Unidad Reumatol Pediat, Valencia, Spain. [Ferriani, Virginia P. L.] Univ Sao Paulo, Dept Pediat, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, Brazil. [Ganser, Gerd] St Josef Stift Sendenhorst, Ctr Rheumatol North West Germany, Clin Pediat Rheumatol, Westtor, Germany. [Kasapcopur, Ozgur] Istanbul Univ, Cerrahpasa Med Fac, Istanbul, Turkey. [Melo-Gomes, Jose Antonio] Inst Portugues Reumatol, Childhood Adolescent & Young Adult Outpatients, Clin Rheumatol, Lisbon, Portugal. [Reed, Ann M.] Mayo Clin, Sch Med, Rochester, MN USA. [Reed, Ann M.] Mayo Fdn, Rochester, MN USA. [Wierzbowska, Malgorzata] Inst Rheumatol, Paediat Clin, Warsaw, Poland. [Rider, Lisa G.] NIEHS, NIH, HHS, Environm Autoimmun Grp, Bethesda, MD USA. RP Ruperto, N (reprint author), PRINTO, Ist Giannina Gaslini, Largo Gaslini 5, I-16147 Genoa, Italy. EM nicolaruperto@ospedale-gaslini.ge.it RI Ferriani, Virginia/E-2209-2012; RAVELLI, ANGELO/J-8161-2016; OI RAVELLI, ANGELO/0000-0001-9658-0385; Rider, Lisa/0000-0002-6912-2458; Kasapcopur, Ozgur/0000-0002-1125-7720 FU European Union [QLG1-CT-2000-00514]; IRCCS G. Gaslini, Genoa, Italy; European League Against Rheumatism (EULAR) Scientific Training Bursaries; National Institute of Environmental Health Sciences, National Institutes of Health FX Supported by grants from the European Union (contract no. QLG1-CT-2000-00514) and IRCCS G. Gaslini, Genoa, Italy. DL was the recipient of the European League Against Rheumatism (EULAR) Scientific Training Bursaries. PMM attended the PRINTO headquarter at Gaslini Hospital in Genoa (Italy) as part of her visiting professorship sabbatical. LGR was supported by the intramural research program of the National Institute of Environmental Health Sciences, National Institutes of Health. NR 48 TC 20 Z9 21 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAY PY 2013 VL 72 IS 5 BP 686 EP 693 DI 10.1136/annrheumdis-2012-201483 PG 8 WC Rheumatology SC Rheumatology GA 118UD UT WOS:000317050400019 PM 22736096 ER PT J AU Giovinazzi, S Morozov, VM Summers, MK Reinhold, WC Ishov, AM AF Giovinazzi, S. Morozov, V. M. Summers, M. K. Reinhold, W. C. Ishov, A. M. TI USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE Daxx; USP7; mitosis; taxanes; Aurora-A; CHFR ID SPINDLE-ASSEMBLY CHECKPOINT; TRANSCRIPTION REPRESSOR DAXX; MITOTIC STRESS CHECKPOINT; HUMAN CANCER-CELLS; BREAST-CANCER; EPIGENETIC INACTIVATION; PROTEIN; CHFR; P53; RESISTANCE AB A large number of patients are resistant to taxane-based chemotherapy. Functional mitotic checkpoints are essential for taxane sensitivity. Thus, mitotic regulators are potential markers for therapy response and could be targeted for anticancer therapy. In this study, we identified a novel function of ubiquitin (Ub)-specific processing protease-7 (USP7) that interacts and cooperates with protein death domain-associated protein (Daxx) in the regulation of mitosis and taxane resistance. Depletion of USP7 impairs mitotic progression, stabilizes cyclin B and reduces stability of the mitotic E3 Ub ligase, checkpoint with forkhead and Ring-finger (CHFR). Consequently, cells with depleted USP7 accumulate Aurora-A kinase, a CHFR substrate, thus elevating multipolar mitoses. We further show that these effects are independent of the USP7 substrate p53. Thus, USP7 and Daxx are necessary to regulate proper execution of mitosis, partially via regulation of CHFR and Aurora-A kinase stability. Results from colony formation assay, in silico analysis across the NCI60 platform and in breast cancer patients suggest that USP7 levels inversely correlate with response to taxanes, pointing at the USP7 protein as a potential predictive factor for taxane response in cancer patients. In addition, we demonstrated that inhibition of Aurora-A attenuates USP7-mediated taxane resistance, suggesting that combinatorial drug regimens of Taxol and Aurora-A inhibitors may improve the outcome of chemotherapy response in cancer patients resistant to taxane treatment. Finally, our study offers novel insights on USP7 inhibition as cancer therapy. Cell Death and Differentiation (2013) 20, 721-731; doi:10.1038/cdd.2012.169; published online 25 January 2013 C1 [Giovinazzi, S.; Morozov, V. M.; Ishov, A. M.] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Giovinazzi, S.; Morozov, V. M.; Ishov, A. M.] Univ Florida Shands Canc Ctr, Gainesville, FL USA. [Summers, M. K.] Lerner Res Inst, Dept Canc Biol, Cleveland, OH USA. [Reinhold, W. C.] NIH, Genom & Bioinformat Grp, Mol Pharmacol Lab, NCI, Bethesda, MD 20892 USA. RP Ishov, AM (reprint author), Univ Florida, Dept Anat & Cell Biol, 2033 Mowry Rd, Gainesville, FL 32610 USA. EM ishov@ufl.edu FU NIH/NCI [R01 CA127378-01A1]; Shula Foundation; Cleveland Clinic; Center for Cancer Research; NCI; DTP, Division of Cancer Treatment and Diagnosis (DCTD), NCI FX We thank Bert Vogelstein for the generous gift of HCT116 p53 WT and -/- cells. This work was supported by NIH/NCI R01 CA127378-01A1 for SG, VMM and AMI and Shula Foundation for SG, by seed funding from the Cleveland Clinic for MKS and by the Center for Cancer Research, the intramural program of NCI and the DTP, Division of Cancer Treatment and Diagnosis (DCTD), NCI for WCR. NR 60 TC 9 Z9 9 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2013 VL 20 IS 5 BP 721 EP 731 DI 10.1038/cdd.2012.169 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121SP UT WOS:000317264800006 PM 23348568 ER PT J AU Troisi, R Hyer, M Hatch, EE Titus-Ernstoff, L Palmer, JR Strohsnitter, WC Herbst, AL Adam, E Hoover, RN AF Troisi, Rebecca Hyer, Marianne Hatch, Elizabeth E. Titus-Ernstoff, Linda Palmer, Julie R. Strohsnitter, William C. Herbst, Arthur L. Adam, Ervin Hoover, Robert N. TI Medical Conditions Among Adult Offspring Prenatally Exposed to Diethylstilbestrol SO EPIDEMIOLOGY LA English DT Article ID PERSISTENT ORGANIC POLLUTANTS; SERUM CONCENTRATIONS; UNITED-STATES; IN-UTERO; ENDOCRINE DISRUPTORS; NONDIABETIC ADULTS; NATIONAL-HEALTH; BREAST-CANCER; FOLLOW-UP; WOMEN AB Background: Diethylstilbestrol (DES), a synthetic estrogen that was used in pregnancy, is a prototype endocrine-disrupting chemical. Although prenatal exposure to DES is known to increase risks of vaginal/cervical adenocarcinoma and adverse reproductive outcomes in women, and urogenital anomalies in men, data on nonreproductive medical conditions are lacking. Methods: We estimated hazard ratios and their associated 95% confidence intervals for the associations between prenatal DES exposure and the occurrence of cardiovascular disease, diabetes, osteoporosis, and related conditions among 5590 female and 2657 male offspring followed from 1994 through 2006, adjusted for birth year, cohort, sex, body mass index, smoking status, alcohol use, education, and number of general physical examinations in the past 5 years. Results: Comparing persons exposed prenatally to DES with those who were not exposed, the hazard ratios were 1.21 (95% confidence interval = 0.96-1.54) for diabetes, 1.27 (1.00-1.62) for all cardiovascular disease, 1.18 (0.88-1.59) for coronary artery disease, 1.28 (0.88-1.86) for myocardial infarction, 1.12 (1.02-1.22) for high cholesterol, 1.14 (1.02-1.28) for hypertension, 1.24 (0.99-1.54) for osteoporosis, and 1.30 (0.95-1.79) for fractures. The associations did not differ by dose and timing of DES exposure, nor, in the women, by the presence or absence of vaginal epithelial changes (a marker of DES host susceptibility). Conclusions: These data raise the possibility that prenatal exposure to DES is associated with several common medical conditions in adulthood, although differential reporting by DES status and residual confounding cannot be ruled out. Further follow-up should assess these findings with validated outcomes and seek to understand the biological mechanisms. (Epidemiology 2013; 24: 430-438) C1 [Troisi, Rebecca; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hyer, Marianne] Informat Management Serv Inc, Rockville, MD USA. [Hatch, Elizabeth E.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Titus-Ernstoff, Linda] Dartmouth Med Sch, Dept Pediat, Lebanon, NH USA. [Titus-Ernstoff, Linda] Norris Cotton Canc Ctr, Lebanon, NH USA. [Titus-Ernstoff, Linda] Hood Ctr Children & Families, Lebanon, NH USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Unit, Boston, MA 02215 USA. [Strohsnitter, William C.] Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. [Herbst, Arthur L.] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. [Adam, Ervin] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Troisi, R (reprint author), Dartmouth Hitchcock Med Ctr, Room 854,7297 Rubin Bldg,1 Med Ctr Dr, Lebanon, NH 03756 USA. EM troisir@mail.nih.gov OI Hatch, Elizabeth/0000-0001-7901-3928; Palmer, Julie/0000-0002-6534-335X FU National Cancer Institute, National Institutes of Health, US Department of Health and Human Services FX Supported by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services. NR 30 TC 8 Z9 8 U1 6 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2013 VL 24 IS 3 BP 430 EP 438 DI 10.1097/EDE.0b013e318289bdf7 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 118CA UT WOS:000316998800015 PM 23474687 ER PT J AU Baird, DD Hill, MC Schectman, JM Hollis, BW AF Baird, Donna Day Hill, Michael C. Schectman, Joel M. Hollis, Bruce W. TI Vitamin D and the Risk of Uterine Fibroids SO EPIDEMIOLOGY LA English DT Article ID SERUM 25-HYDROXYVITAMIN D; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; WHITE WOMEN; D SYSTEM; LEIOMYOMA; MECHANISMS; EXPRESSION; PROLIFERATION; POPULATION AB Background: Uterine leiomyomata (also known as fibroids) are benign tumors of uterine smooth muscle that are characterized by overproduction of extracellular matrix. Fibroids are the leading indication for hysterectomy in the United States. The active metabolite of vitamin D has been shown to inhibit cell proliferation and extracellular matrix production in fibroid tissue culture and to reduce fibroid volume in the Eker rat. No previous study has examined whether vitamin D is related to fibroid status in women. Methods: The National Institute of Environmental Health Sciences Uterine Fibroid Study enrolled randomly selected 35- to 49-year-old women who were members of an urban health plan during 1996-1999. Fibroid status was determined by ultrasound screening of premenopausal women (620 blacks, 416 whites). Vitamin D status was assessed in stored plasma by radioimmunoassay of 25-hydroxyvitamin D (25(OH) D) and questionnaire data on sun exposure. Associations were evaluated with logistic regression, controlling for potential confounders. Results: Only 10% of blacks and 50% of whites had levels of 25(OH) D regarded as sufficient (>20 ng/ml). Women with sufficient vitamin D had an estimated 32% lower odds of fibroids compared with those with vitamin D insufficiency (adjusted odds ratio [aOR] = 0.68, 95% confidence interval [CI] = 0.48-0.96). The association was similar for blacks and whites. Self-reported sun exposure >= 1 hour per day (weather permitting) was also associated with reduced odds of fibroids (aOR = 06. [0.4-0.9]), with no evidence of heterogeneity by ethnicity. Conclusions: The consistency of findings for questionnaire and biomarker data, the similar patterns seen in blacks and whites, and the biological plausibility provide evidence that sufficient vitamin D is associated with a reduced risk of uterine fibroids. (Epidemiology 2013; 24: 447-453) C1 [Baird, Donna Day] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Hill, Michael C.] George Washington Univ, Med Ctr, Dept Radiol, Washington, DC 20037 USA. [Schectman, Joel M.] George Washington Univ, Med Ctr, Dept Hlth Care Sci, Washington, DC 20037 USA. [Hollis, Bruce W.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. RP Baird, DD (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU National Institute of Environmental Health Sciences, NIH; Office of Research on Minority Health, National Institutes of Health, HHS FX Supported by the intramural program at the National Institute of Environmental Health Sciences, NIH, with support from the Office of Research on Minority Health, National Institutes of Health, HHS. NR 45 TC 37 Z9 38 U1 1 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2013 VL 24 IS 3 BP 447 EP 453 DI 10.1097/EDE.0b013e31828acca0 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 118CA UT WOS:000316998800017 PM 23493030 ER PT J AU Lin, YS Fu, R Grant, E Chen, Y Lee, JE Gupta, PC Ramadas, K Inoue, M Tsugane, S Gao, YT Tamakoshi, A Shun, XO Ozasa, K Tsuji, I Kakizaki, M Tanaka, H Chen, CJ Yoo, KY Ahn, YO Ahsan, H Pednekar, MS Sauvaget, C Sasazuki, S Yang, G Xiang, YB Ohishi, W Watanabe, T Nishino, Y Matsuo, K You, SL Park, SK Kim, DH Parvez, F Rolland, B McLerran, D Sinha, R Boffetta, P Zheng, W Thornquist, M Feng, ZD Kang, D Potter, JD AF Lin, Yingsong Fu, Rong Grant, Eric Chen, Yu Lee, Jung Eun Gupta, Prakash C. Ramadas, Kunnambath Inoue, Manami Tsugane, Shoichiro Gao, Yu-Tang Tamakoshi, Akiko Shun, Xiao-Ou Ozasa, Kotaro Tsuji, Ichiro Kakizaki, Masako Tanaka, Hideo Chen, Chien-Jen Yoo, Keun-Young Ahn, Yoon-Ok Ahsan, Habibul Pednekar, Mangesh S. Sauvaget, Catherine Sasazuki, Shizuka Yang, Gong Xiang, Yong-Bing Ohishi, Waka Watanabe, Takashi Nishino, Yoshikazu Matsuo, Keitaro You, San-Lin Park, Sue K. Kim, Dong-Hyun Parvez, Faruque Rolland, Betsy McLerran, Dale Sinha, Rashmi Boffetta, Paolo Zheng, Wei Thornquist, Mark Feng, Ziding Kang, Daehee Potter, John D. TI Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE body mass index; insulin resistance; obesity; overweight; pancreas cancer ID PHYSICAL-ACTIVITY; POOLED-ANALYSIS; KOREAN MEN; OBESITY; METAANALYSIS; MORTALITY; GLUCOSE; ADULTS; WOMEN; MECHANISMS AB We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium. The data for this pooled analysis included 883 529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios and 95% confidence intervals for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (< 18.5, 18.5-19.9, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, >= 30) were used in the analysis, with BMI of 22.5-24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and a history of diabetes. We found no statistically significant overall association between each BMI category and the risk of death from pancreas cancer in all Asians, and obesity was unrelated to the risk of mortality in both East Asians and South Asians. Age, smoking, and a history of diabetes did not modify the association between BMI and the risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI less than 18.5 was observed for individuals with a history of diabetes; hazard ratio = 2.01 (95% confidence interval: 1.01-4.00) (P for interaction = 0.07). The data do not support an association between BMI and the risk of death from pancreas cancer in these Asian populations. European Journal of Cancer Prevention 22:244-250 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Lin, Yingsong] Aichi Med Univ, Sch Med, Dept Publ Hlth, Nagakute, Aichi 4801195, Japan. [Grant, Eric; Ozasa, Kotaro] Radiat Effects Res Fdn, Dept Epidemiol, Hiroshima, Japan. [Ohishi, Waka] Radiat Effects Res Fdn, Dept Clin Studies, Hiroshima, Japan. [Inoue, Manami; Tsugane, Shoichiro; Sasazuki, Shizuka] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Epidemiol & Prevent Div, Tokyo 104, Japan. [Tamakoshi, Akiko] Hokkaido Univ, Dept Publ Hlth, Grad Sch Med, Sapporo, Hokkaido, Japan. [Tsuji, Ichiro; Kakizaki, Masako; Watanabe, Takashi] Tohoku Univ, Grad Sch Med, Dept Publ Hlth & Forens Med, Div Epidemiol, Sendai, Miyagi 980, Japan. [Nishino, Yoshikazu] Miyagi Canc Ctr, Res Inst, Div Canc Epidemiol & Prevent, Sendai, Miyagi, Japan. [Tanaka, Hideo; Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Fu, Rong; Rolland, Betsy; McLerran, Dale; Thornquist, Mark; Feng, Ziding; Potter, John D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Chen, Yu] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Parvez, Faruque] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shun, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr,Dept Med,Div Epidemiol, Nashville, TN 37212 USA. [Ahsan, Habibul] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Lee, Jung Eun] Sookmyung Womens Univ, Dept Food & Nutr, Seoul, South Korea. [Yoo, Keun-Young; Ahn, Yoon-Ok; Park, Sue K.; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Park, Sue K.] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea. [Park, Sue K.] Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul, South Korea. [Kim, Dong-Hyun] Hallym Univ, Coll Med, Dept Social & Prevent Med, Chunchon, South Korea. [Gupta, Prakash C.; Pednekar, Mangesh S.] Healis Sekhsaria Inst Publ Hlth, Navi Mumbai, India. [Ramadas, Kunnambath] Reg Canc Ctr, Div Radiat Oncol, Trivandrum 695011, Kerala, India. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chen, Chien-Jen; You, San-Lin] Acad Sinica, Genom Res Ctr, Taipei 115, Taiwan. [Chen, Chien-Jen] Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. [You, San-Lin] Natl Def Med Ctr, Sch Publ Hlth, Taipei, Taiwan. [Sauvaget, Catherine] Int Agcy Res Canc, Int Prevent Res Inst, Screening Grp, F-69372 Lyon, France. [Boffetta, Paolo; Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. RP Lin, YS (reprint author), Aichi Med Univ, Sch Med, Dept Publ Hlth, 1-1 Yazokokarimata, Nagakute, Aichi 4801195, Japan. EM linys@aichi-med-u.ac.jp RI Chen, Chien-Jen/C-6976-2008; Tsugane, Shocichiro/A-2424-2015; Sinha, Rashmi/G-7446-2015; Tanaka, Hideo/A-8145-2016; OI Sinha, Rashmi/0000-0002-2466-7462; Potter, John/0000-0001-5439-1500; Kakizaki, Masako/0000-0001-6030-8953; Sauvaget, Catherine/0000-0002-8053-4963; Matsuo, Keitaro/0000-0003-1761-6314 FU National Cancer Institute at the National Institutes of Health [R03CA150038]; Fred Hutchinson Cancer Research Center; Japan Public Health Center; Government to the National Cancer Center; Ministry of Health, Labour and Welfare, Japan; Japan Collaborative Cohort Study (JACC); Ministry of Education, Culture, Sports, Science & Technology, Japan; Ministry of Health, Labour, and Welfare, and the Ministry of Education, Culture, Sports, Science & Technology, Japan; Ministry of Health, Labour, and Welfare, Japan; Ohsaki National Health Insurance Cohort Study (Ohsaki); Radiation Effects Research Foundation (RERF); Hiroshima and Nagasaki, Japan; Japanese Ministry of Health, Labour and Welfare (MHLW); US Department of Energy (DOE); National Academy of Sciences [DE-HS0000031]; RERF [A3-10]; United States Public Health Service [R37 CA070867]; Shanghai Men's Health Study (SMHS): United States Public Health Service [R01 CA082729]; Community-Based Cancer Screening Project (CBCSP); National Science Council and Department of Health, Taiwan; Korea Multi-center Cancer Cohort (KMCC); Ministry of Education, Science and Technology, Korea; National Research Foundation of Korea [2009-0087452]; Seoul Male Cohort: the National R& D Program for Cancer Control, Ministry of Health& Welfare, Republic of Korea [0520160-1]; Mumbai Cohort Study (MCS): International Agency for Research on Cancer, Clinical Trials Service Unit/Oxford University; World Health Organization; Health Effects of Arsenic Longitudinal Study (HEALS): National Institutes for Health [P42ES010349, R01CA102484, R01CA107431]; Trivandrum Oral Cancer Screening Trial (TOCS): Associations for International Cancer Research, St Andrews, UK; Cancer Research UK FX This work was supported by the National Cancer Institute at the National Institutes of Health (R03CA150038) and by the Fred Hutchinson Cancer Research Center. The original cohorts were supported by Japan Public Health Center-based Study I & II (JPHC I & II): (a) Management Expenses Grants from the Government to the National Cancer Center; (b) Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan; (c) Grant-in-Aid for the Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labour and Welfare, Japan; Japan Collaborative Cohort Study (JACC): Grant-in-Aid for the Scientific Research from the Ministry of Education, Culture, Sports, Science & Technology, Japan; the Three Prefecture Cohort Study Aichi (3-Pref Aichi) and the three Prefecture Cohort Study Miyagi (3-Pref Miyagi): Research grant from the Ministry of Health, Labour, and Welfare, and the Ministry of Education, Culture, Sports, Science & Technology, Japan; The Miyagi Cohort Study (Miyagi); Research grant from the Ministry of Health, Labour, and Welfare, Japan; The Ohsaki National Health Insurance Cohort Study (Ohsaki): Research grant from Ministry of Health, Labour, and Welfare, Japan; Radiation Effects Research Foundation (RERF): The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan, is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labour and Welfare (MHLW) and the US Department of Energy (DOE), the latter in part through DOE Award DE-HS0000031 to the National Academy of Sciences. This publication was supported by RERF Research Protocol RP A3-10. The views of the authors do not necessarily reflect those of the two governments; Shanghai Women's Health Study (SWHS): United States Public Health Service grant (R37 CA070867); Shanghai Men's Health Study (SMHS): United States Public Health Service grant (R01 CA082729); the Community-Based Cancer Screening Project (CBCSP): National Science Council and Department of Health, Taiwan; the Korea Multi-center Cancer Cohort (KMCC): Ministry of Education, Science and Technology, Korea (2009-0087452),National Research Foundation of Korea (2009-0087452); Seoul Male Cohort: the National R&D Program for Cancer Control, Ministry of Health&Welfare, Republic of Korea (0520160-1); the Mumbai Cohort Study (MCS): International Agency for Research on Cancer, Clinical Trials Service Unit/Oxford University, World Health Organization; the Health Effects of Arsenic Longitudinal Study (HEALS): National Institutes for Health (P42ES010349, R01CA102484, R01CA107431); the Trivandrum Oral Cancer Screening Trial (TOCS): Associations for International Cancer Research, St Andrews, UK, and Cancer Research UK. NR 38 TC 9 Z9 9 U1 0 U2 16 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 MAY PY 2013 VL 22 IS 3 BP 244 EP 250 DI 10.1097/CEJ.0b013e3283592cef PG 7 WC Oncology SC Oncology GA 114IF UT WOS:000316733600006 PM 23044748 ER PT J AU Yuan, J Muljo, SA AF Yuan, Joan Muljo, Stefan A. TI Exploring the RNA world in hematopoietic cells through the lens of RNA-binding proteins SO IMMUNOLOGICAL REVIEWS LA English DT Review DE systems biology; genomics; posttranscriptional regulation; hematopoiesis; microRNA; RNA-Binding Proteins; Lin28; let-7 ID GENOME-WIDE ASSOCIATION; EMBRYONIC STEM-CELLS; LYMPHOCYTIC-LEUKEMIA CELLS; MICRORNA TARGET SITES; DOUBLE-STRANDED-RNA; NF-KAPPA-B; MESSENGER-RNA; IN-VIVO; CAENORHABDITIS-ELEGANS; GENE-EXPRESSION AB The discovery of microRNAs has renewed interest in posttranscriptional modes of regulation, fueling an emerging view of a rich RNA world within our cells that deserves further exploration. Much work has gone into elucidating genetic regulatory networks that orchestrate gene expression programs and direct cell fate decisions in the hematopoietic system. However, the focus has been to elucidate signaling pathways and transcriptional programs. To bring us one step closer to reverse engineering the molecular logic of cellular differentiation, it will be necessary to map posttranscriptional circuits as well and integrate them in the context of existing network models. In this regard, RNA-binding proteins (RBPs) may rival transcription factors as important regulators of cell fates and represent a tractable opportunity to connect the RNA world to the proteome. ChIP-seq has greatly facilitated genome-wide localization of DNA-binding proteins, helping us to understand genomic regulation at a systems level. Similarly, technological advances such as CLIP-seq allow transcriptome-wide mapping of RBP binding sites, aiding us to unravel posttranscriptional networks. Here, we review RBP-mediated posttranscriptional regulation, paying special attention to findings relevant to the immune system. As a prime example, we highlight the RBP Lin28B, which acts as a heterochronic switch between fetal and adult lymphopoiesis. C1 [Yuan, Joan; Muljo, Stefan A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, NIH, Immunol Lab, 10 Ctr Dr, Bethesda, MD 20892 USA. EM Stefan.Muljo@nih.gov RI yuan, joan/A-8185-2013; Muljo, Stefan/F-5671-2015 OI yuan, joan/0000-0001-9129-8356; Muljo, Stefan/0000-0003-1013-446X FU Intramural Research Program of the NIAID, NIH FX We acknowledge Rami Zahr and Elizabeth Liu for contribution of unpublished results and Drs. Brenna Brady, Jeremy Daniel, and Chryssa Kanellopoulou for critical reading of the manuscript. The Integrative Immunobiology Unit is supported by the Intramural Research Program of the NIAID, NIH. The authors have no conflicts of interest to declare. NR 215 TC 7 Z9 7 U1 1 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD MAY PY 2013 VL 253 SI SI BP 290 EP 303 DI 10.1111/imr.12048 PG 14 WC Immunology SC Immunology GA 119DX UT WOS:000317078800020 PM 23550653 ER PT J AU Cannon, DM Klaver, JM Klug, SA Carlson, PJ Luckenbaugh, DA Ichise, M Drevets, WC AF Cannon, Dara M. Klaver, Jacqueline M. Klug, Summer A. Carlson, Paul J. Luckenbaugh, David A. Ichise, Masanori Drevets, Wayne C. TI Gender-specific abnormalities in the serotonin transporter system in panic disorder SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Cingulate cortex; [C-11]DASB; insula; positron emission tomography; 5-HTT ID POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; HEALTHY-VOLUNTEERS; RECEPTOR-BINDING; HUMAN BRAIN; REUPTAKE INHIBITORS; ANXIETY SENSITIVITY; BIPOLAR DISORDER; SEX-DIFFERENCES; ATTACKS AB The central serotonergic system has been implicated in the pathophysiology of panic disorder (PD) by evidence of abnormally elevated serotonin-turnover, reduced pre- and post-synaptic 5-HT(1A-)receptor sensitivity and binding and clinical improvement during administration of agents that enhance serotonergic transmission. Polymorphisms in genes that putatively influence serotonergic neurotransmission increase the vulnerability for developing PD specifically in males. We tested the hypotheses that serotonin transporter (5-HTT) binding is elevated in PD subjects vs. healthy controls in regions where in vivo evidence exists for both elevated 5-HTT and 5-HT1A receptor levels in PD and investigated whether the extent of this difference depends upon gender. Volunteers were out-patients with current PD (n=24) and healthy controls (n=24). The non-displaceable component of 5-HTT binding-potential (BPND) was measured using positron emission tomography and the 5-HTT selective radioligand, [C-11]DASB. PD severity was assessed using the PD Severity Scale. The 5-HTT-BPND was increased in males with PD relative to male controls in the anterior cingulate cortex (F=8.96, p(FDR)=0.01) and midbrain (F=5.09, p(FDR)=0.03). In contrast, BPND did not differ between females with PD and female controls in any region examined. The finding that 5-HTT-binding is elevated in males but not in females with PD converges with other evidence suggesting that dysfunction within the central serotonergic system exists in PD, and also indicates that such abnormalities are influenced by gender. These findings conceivably may reflect a sexual dimorphism that underlies the greater efficacy of serotonin reuptake inhibitor treatment in females vs. males with PD. C1 [Cannon, Dara M.] Natl Univ Ireland Galway, Inst Clin Sci, Clin Neuroimaging Lab, Dept Anat, Galway, Ireland. [Cannon, Dara M.] Natl Univ Ireland Galway, Inst Clin Sci, Dept Psychiat, Galway, Ireland. [Cannon, Dara M.; Klaver, Jacqueline M.; Klug, Summer A.; Luckenbaugh, David A.; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Carlson, Paul J.] Univ Utah, Inst Brain, Salt Lake City, UT 84112 USA. [Ichise, Masanori] Columbia Univ, Dept Radiol, New York, NY USA. [Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. RP Cannon, DM (reprint author), Natl Univ Ireland Galway, Clin Neuroimaging Lab, Anat Block B, Galway, Ireland. EM dara.cannon@nuigalway.ie RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 FU NIH/NIMH-DIRP FX We thank Peter Herscovitch, MD and the Clinical Center PET Department for assistance with image acquisition, Michele Drevets RN, Joan Williams RN, Marilla Geraci RN, Denise Rallis-Voak RN and Ashish Khanna for evaluation and recruitment of research subjects, Steven J. Fromm, PhD, Allison C. Nugent, PhD and Dave Luckenbaugh, PhD for statistical and data analytic support, the NIH Clinical Center staff. This study was supported by the NIH/NIMH-DIRP. NR 68 TC 12 Z9 12 U1 4 U2 19 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2013 VL 16 IS 4 BP 733 EP 743 DI 10.1017/S1461145712000776 PG 11 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 117ZJ UT WOS:000316991800003 PM 22953744 ER PT J AU Kiselycznyk, C Zhang, XQ Huganir, RL Holmes, A Svenningsson, P AF Kiselycznyk, Carly Zhang, Xiaoqun Huganir, Richard L. Holmes, Andrew Svenningsson, Per TI Reduced phosphorylation of GluA1 subunits relates to anxiety-like behaviours in mice SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE AMPA; glutamate; hippocampus; mutant mice ID RECEPTOR GLUR1 SUBUNIT; SYNAPTIC PLASTICITY; STRESS; INVOLVEMENT; ANTAGONISM; MODULATION; FLUOXETINE; DIAZEPAM; SUBTYPE; MEMORY AB Anxiety and depression are highly prevalent and frequently co-morbid conditions. The ionotropic glutamate receptors N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA) mediate actions of monoaminergic antidepressants and have been directly targeted by novel fast-acting antidepressants. Less is known about the role of these receptors in anxiety-like states. Here we investigate how two distinct anxiolytic agents, buspirone, a partial 5-HT1A agonist, and diazepam, a benzodiazepine, influence phosphorylation of GluA1 subunits of AMPA receptors at the potentiating residue Ser(845) and Ser(831) in corticolimbic regions. To test the functional relevance of these changes, phosphomutant GluA1 mice lacking phosphorylatable Ser(845) and Ser(831) were examined in relevant behavioural paradigms. These mutant mice exhibited a reduced anxiety-like phenotype in the light/dark exploration task and elevated plus maze, but not in the novelty induced hypophagia paradigm. These data indicate that reduced potentiation of the AMPA receptor signalling, via decreased GluA1 phoshorylation, is specifically involved in approach-avoidance based paradigms relevant for anxiety-like behaviours. C1 [Kiselycznyk, Carly; Zhang, Xiaoqun; Svenningsson, Per] Karolinska Inst, Dept Clin Neurosci, Lab Translat Neuropharmacol, Stockholm, Sweden. [Huganir, Richard L.] Johns Hopkins Univ, Soloman H Snyder Dept Neurosci, Baltimore, MD USA. [Kiselycznyk, Carly; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, Bethesda, MD USA. RP Kiselycznyk, C (reprint author), 300 George St,Suite 901, New Haven, CT 06511 USA. EM carly.kiselycznyk@yale.edu FU Hjarnfonden; Soderberg's stiftelse; Vetenskapsradet; Intramural Research Program of the NIH, National Institute on Alcohol Abuse and Alcoholism FX This study was supported by grants from Hjarnfonden, Soderberg's stiftelse and Vetenskapsradet and in part by the Intramural Research Program of the NIH, National Institute on Alcohol Abuse and Alcoholism. NR 27 TC 4 Z9 4 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2013 VL 16 IS 4 BP 919 EP 924 DI 10.1017/S1461145712001174 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 117ZJ UT WOS:000316991800020 PM 23360771 ER PT J AU Yakel, JL AF Yakel, J. L. TI Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Yakel, J. L.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 53 EP 53 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700100 ER PT J AU Roche, KW AF Roche, K. W. TI Regulation of NMDA receptors by MAGUK proteins SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Roche, K. W.] NINDS, NIH, Receptor Biol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 71 EP 71 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700136 ER PT J AU Bohr, VA AF Bohr, V. A. TI Mitochondrial genome integrity and neurodegeneration SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Bohr, V. A.] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 92 EP 92 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700181 ER PT J AU Moon, KH Tajuddin, N Neafsey, EJ Marshall, SA Nixon, K Kim, HY Collins, MA AF Moon, K. H. Tajuddin, N. Neafsey, E. J. Marshall, S. A. Nixon, K. Kim, H. Y. Collins, M. A. TI Evidence for aquaporin-4 and phospholipase A2 neuroinflammatory/oxidative stress pathways in ethanol-induced neurodegeneration SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Moon, K. H.; Tajuddin, N.; Neafsey, E. J.; Collins, M. A.] Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. [Marshall, S. A.; Nixon, K.] Univ Kentucky, Lexington, KY 40506 USA. [Kim, H. Y.] NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 131 EP 132 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700276 ER PT J AU Harry, GJ McPherson, CA AF Harry, G. J. McPherson, C. A. TI Dissecting the differential profiles of resident microglia with hippocampus damage SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Harry, G. J.; McPherson, C. A.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 133 EP 133 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700281 ER PT J AU Taha, AY Blanchard, HC Cheon, Y Keleshian, V Ramadan, E Chen, M Chang, L Rapoport, SI Rao, JS AF Taha, A. Y. Blanchard, H. C. Cheon, Y. Keleshian, V. Ramadan, E. Chen, M. Chang, L. Rapoport, S. I. Rao, J. S. TI Dietary omega-6 fatty acid deprivation reduces lipopolysaccharide-induced increase in brain arachidonic acid metabolism SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Taha, A. Y.; Blanchard, H. C.; Cheon, Y.; Keleshian, V.; Ramadan, E.; Chen, M.; Chang, L.; Rapoport, S. I.; Rao, J. S.] NIA, NIH, Lab Neurosci, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 163 EP 164 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700353 ER PT J AU McPherson, CA Harry, GJ AF McPherson, C. A. Harry, G. J. TI M1 and M2 related genes are differentially expressed during chemical injury-induced neurogenesis SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [McPherson, C. A.; Harry, G. J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 169 EP 169 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700369 ER PT J AU Orihuela, R McPherson, CA Harry, GJ AF Orihuela, R. McPherson, C. A. Harry, G. J. TI Mitochondrial bioenergetics profiles in M1/M2 microglial polarization SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Orihuela, R.; McPherson, C. A.; Harry, G. J.] NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 182 EP 182 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700405 ER PT J AU Keck, TM Banala, AK Okunola, OM Kumar, V Zou, MF Burzynski, CM Bonifazi, A Newman, AH AF Keck, T. M. Banala, A. K. Okunola, O. M. Kumar, V. Zou, M. F. Burzynski, C. M. Bonifazi, A. Newman, A. H. TI Novel dopamine D3 receptor antagonists as tools for in vivo investigation in psychostimulant addiction SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 24th Biennial Meeting of the International-Society-for-Neurochemistry and the American-Society-for-Neurochemistry CY APR 20-24, 2013 CL Cancun, MEXICO SP Int Soc Neurochemistry, Amer Soc Neurochemistry C1 [Keck, T. M.; Banala, A. K.; Okunola, O. M.; Kumar, V.; Zou, M. F.; Burzynski, C. M.; Bonifazi, A.; Newman, A. H.] NIDA, Intramural Res Program, Med Chem Sect, Baltimore, MD USA. RI Keck, Thomas/G-9798-2012 OI Keck, Thomas/0000-0003-1845-9373 NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2013 VL 125 SU 1 SI SI BP 261 EP 262 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 117OB UT WOS:000316961700611 ER PT J AU Kirlic, N Newman, E LaGasse, LL Derauf, C Shah, R Smith, LM Arria, AM Huestis, MA Haning, W Strauss, A Dellagrotta, S Dansereau, LM Abar, B Neal, CR Lester, BM AF Kirlic, Namik Newman, Elana LaGasse, Linda L. Derauf, Chris Shah, Rizwan Smith, Lynne M. Arria, Amelia M. Huestis, Marilyn A. Haning, William Strauss, Arthur Dellagrotta, Sheri Dansereau, Lynne M. Abar, Beau Neal, Charles R. Lester, Barry M. TI Cortisol Reactivity in Two-Year-Old Children Prenatally Exposed to Methamphetamine SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID COCAINE EXPOSURE; LIFE-STYLE; INFANT DEVELOPMENT; SUBSTANCE EXPOSURE; STRESS; ENVIRONMENT; PREGNANCY; ALCOHOL; MOTHERS; DISORDERS AB Objective: Until now, the functioning of the hypothalamic-pituitary-adrenal (HPA) axis in children with prenatal methamphetamine exposure (PME) had been unexamined. Previous research indicates that prenatal exposure to stimulant drugs is associated with dose-response alterations in neural growth and connectivity and consequent neurobehavioral deficits. In addition, children of drug-using parents are at an increased risk for exposure to chronic postnatal stress. In this preliminary study, we examined the associations of PME and postnatal environmental stress with cortisol stress reactivity in children with PME. Method: Participants were 2-year-old children (N = 123; 55.3% male) with PME from a multicenter longitudinal Infant, Development, Environment, and Lifestyle Study. Saliva samples were obtained before and after a stress-inducing separation task. Hierarchical multiple regression analyses examined prenatal drug exposure, methodological and postnatal stress covariates, and interactions between levels of PME and postnatal stress. Results: Mild to moderate potential for child physical abuse moderated increased cortisol reactivity in high exposed children with PME. Blunted cortisol reactivity was associated with caregiver's postnatal alcohol use, child's behavioral dysregulation, and the interaction between higher levels of PME and caregiver's psychopathology. Conclusions: Consistent with the known effects of stimulant drugs and chronically stressful environments on the HPA axis and, thus, the toxic stress and allostatic load phenomena, our results imply that elevated PME may be associated with alterations in the programming of the HPA axis reflecting hyperactivity, which under significant and chronic environmental stress then may become hypoactive. (J. Stud. Alcohol Drugs, 74, 447-451, 2013) C1 [Kirlic, Namik; Newman, Elana] Univ Tulsa, Dept Psychol, Tulsa, OK 74104 USA. [LaGasse, Linda L.; Dellagrotta, Sheri; Dansereau, Lynne M.; Abar, Beau; Lester, Barry M.] Brown Univ, Warren Alpert Med Sch, Brown Ctr Study Children Risk, Providence, RI 02912 USA. [LaGasse, Linda L.; Dellagrotta, Sheri; Dansereau, Lynne M.; Abar, Beau; Lester, Barry M.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Derauf, Chris] Mayo Clin, Div Community Pediat & Adolescent Med, Rochester, MN USA. [Shah, Rizwan] Blank Hosp, Reg Child Protect Ctr Iowa Hlth, Des Moines, IA USA. [Smith, Lynne M.] Harbor UCLA Med Ctr, Dept Pediat, LABioMed Inst, Los Angeles, CA USA. [Smith, Lynne M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Arria, Amelia M.] Univ Maryland, Sch Publ Hlth, Family Sci Dept, Ctr Young Adult Hlth & Dev, College Pk, MD 20742 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Haning, William; Neal, Charles R.] Univ Hawaii, John A Burns Sch Med, Dept Pediat, Honolulu, HI 96822 USA. [Strauss, Arthur] Miller Childrens Hosp Long Beach, Long Beach, CA USA. RP Kirlic, N (reprint author), Univ Tulsa, Dept Psychol, 800 S Tucker Dr, Tulsa, OK 74104 USA. EM namik-kirlic@utulsa.edu RI sebastianovitsch, stepan/G-8507-2013; OI Arria, Amelia/0000-0002-6360-9265 FU National Institute on Drug Abuse [R01DA014948] FX This research was supported by National Institute on Drug Abuse Grant R01DA014948. NR 34 TC 4 Z9 4 U1 2 U2 22 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAY PY 2013 VL 74 IS 3 BP 447 EP 451 PG 5 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 113CR UT WOS:000316644300011 PM 23490574 ER PT J AU Fiellin, DA McGinnis, KA Maisto, SA Justice, AC Bryant, K AF Fiellin, David A. McGinnis, Kathleen A. Maisto, Stephen A. Justice, Amy C. Bryant, Kendall TI Measuring Alcohol Consumption Using Timeline Followback in Non-Treatment-Seeking Medical Clinic Patients With and Without HIV Infection: 7-, 14-, or 30-day Recall SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID QUICK DRINKING SCREEN; VETERANS; INTOXICATION; INDIVIDUALS; ADHERENCE; INTERVIEW; DRINKERS; CARE AB Objective: The measurement of alcohol consumption is an essential component of research in patients at risk for or infected with HIV. Daily estimation measures such as the Timeline Followback (TLFB) have been validated, yet the optimal time window and its performance in non-treatment-seeking medical clinic subjects and among those with HIV are not known. Method: In 1,519 HIV-infected and 1,612 uninfected men receiving medical care in general medical or infectious disease clinics, we compared the association between 7-, 14-, and 30-day TLFB reports, obtained via telephone, of alcohol consumption using Spearman's correlation coefficients. To evaluate agreement between 7-, 14-, and 30-day reports of heavy episodic drinking, we evaluated percent agreement, sensitivity, and kappa statistics, considering 30-day report as the gold standard. Results: The estimated prevalence of heavy episodic drinking was progressively higher for longer TLFB intervals (7 days: 6.3%; 14 days: 8.0%; 30 days: 9.5%). Correlation coefficients with 30-day TLFB were higher for 14 days (.94) than for 7 days (.86) overall (p < .001) and among HIV-infected (.94 vs. .86, p < .001) and uninfected (.95 vs. .87, p < 001). Correlations were similar by HIV status. When considered overall and by HIV status, the sensitivity, percent agreement, and kappa statistics are better for heavy episodic drinking based on 14 days compared with 7 days. Conclusions: A TLFB for alcohol consumption of 14 days is preferable to 7 days for non-treatment-seeking patients in medical clinics with and without HIV infection when compared with 30 days. (J Stud. Alcohol Drugs, 74, 500-504, 2013) C1 [Fiellin, David A.; Justice, Amy C.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Fiellin, David A.; Justice, Amy C.] Yale Univ, Sch Publ Hlth, Ctr Interdisciplinary Res AIDS, New Haven, CT 06520 USA. [McGinnis, Kathleen A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Maisto, Stephen A.] Syracuse Univ, Dept Psychol, Syracuse, NY USA. [Justice, Amy C.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. [Bryant, Kendall] NIAAA, Bethesda, MD 90034 USA. RP Fiellin, DA (reprint author), Yale Univ, Sch Med, 367 Cedar St,POB 208093, New Haven, CT 06520 USA. EM david.fiellin@yale.edu OI Fiellin, David/0000-0002-4006-010X FU National Institute on Alcohol Abuse and Alcoholism [U10AA013566, U01AA020795, U01AA020790, U24AA020794] FX This research was supported by National Institute on Alcohol Abuse and Alcoholism Grants U10AA013566, U01AA020795, U01AA020790, and U24AA020794. The views are not those of the Department of Veterans Affairs or of the United States Government. NR 25 TC 4 Z9 4 U1 4 U2 11 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD MAY PY 2013 VL 74 IS 3 BP 500 EP 504 PG 5 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 113CR UT WOS:000316644300018 PM 23490581 ER PT J AU Fenton, MC Geier, T Keyes, K Skodol, AE Grant, BF Hasin, DS AF Fenton, M. C. Geier, T. Keyes, K. Skodol, A. E. Grant, B. F. Hasin, D. S. TI Combined role of childhood maltreatment, family history, and gender in the risk for alcohol dependence SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Alcohol dependence; alcohol use disorder; childhood adverse events; childhood maltreatment; epidemiology ID NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; SUBSTANCE USE DISORDERS; PSYCHIATRIC DIAGNOSTIC MODULES; COGNITIVE-BEHAVIORAL THERAPY; INTERVIEW SCHEDULE AUDADIS; DSM-IV; DRUG-USE; UNITED-STATES; PERSONALITY-DISORDERS AB Background. Studies of the relationship between childhood maltreatment and alcohol dependence have not controlled comprehensively for potential confounding by co-occurring maltreatments and other childhood trauma, or determined whether parental history of alcohol disorders operates synergistically with gender and maltreatment to produce alcohol dependence. We addressed these issues using national data. Method. Face-to-face surveys of 27 712 adult participants in a national survey. Results. Childhood physical, emotional and sexual abuse, and physical neglect were associated with alcohol dependence (p < 0.001), controlling for demographics, co-occurring maltreatments and other childhood trauma. Attributable proportions (APs) due to interaction between each maltreatment and parental history revealed significant synergistic relationships for physical abuse in the entire sample, and for sexual abuse and emotional neglect in women (APs, 0.21, 0.31, 0.26 respectively), indicating that the odds of alcohol dependence given both parental history and these maltreatments were significantly higher than the additive effect of each alone (p < 0.05). Conclusions. Childhood maltreatments independently increased the risk of alcohol dependence. Importantly, results suggest a synergistic role of parental alcoholism : the effect of physical abuse on alcohol dependence may depend on parental history, while the effects of sexual abuse and emotional neglect may depend on parental history among women. Findings underscore the importance of early identification and prevention, particularly among those with a family history, and could guide genetic research and intervention development, e.g. programs to reduce the burden of childhood maltreatment may benefit from addressing the negative long-term effects of maltreatments, including potential alcohol problems, across a broad range of childhood environments. C1 [Fenton, M. C.; Keyes, K.; Hasin, D. S.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Geier, T.] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Geier, T.; Keyes, K.; Skodol, A. E.; Hasin, D. S.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Skodol, A. E.; Hasin, D. S.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Skodol, A. E.] Univ Arizona, Coll Med, Tucson, AZ USA. [Grant, B. F.] Natl Inst Alcohol Abuse & Alcoholism, Intramural Lab Epidemiol & Biometry, Rockville, MD USA. RP Hasin, DS (reprint author), Columbia Univ, Coll Phys & Surg, 1051 Riverside Dr 123, New York, NY 10032 USA. EM dsh2@columbia.edu FU National Institute of Drug Abuse [R01DA018652, F31DA026689]; National Institute on Alcohol Abuse and Alcoholism [U01AA018111, K05AA014223]; New York State Psychiatric Institute; Columbia University Department of Epidemiology; National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX This research was supported in part by the National Institute of Drug Abuse (R01DA018652, D. Hasin; F31DA026689, K. Keyes), the National Institute on Alcohol Abuse and Alcoholism (U01AA018111, K05AA014223, D. Hasin) the New York State Psychiatric Institute (D. Hasin) and Columbia University Department of Epidemiology (M. Fenton). The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support from the National Institute on Drug Abuse (NIDA). NR 68 TC 23 Z9 25 U1 3 U2 36 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD MAY PY 2013 VL 43 IS 5 BP 1045 EP 1057 DI 10.1017/S0033291712001729 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 119AC UT WOS:000317067800014 PM 22883538 ER PT J AU Czaja, W Ehler, M AF Czaja, Wojciech Ehler, Martin TI Schroedinger Eigenmaps for the Analysis of Biomedical Data SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE Schroedinger Eigenmaps; Laplacian Eigenmaps; Schroedinger operator on a graph; barrier potential; dimension reduction; manifold learning ID NONLINEAR DIMENSIONALITY REDUCTION; MACULAR DEGENERATION; GEOMETRIC FRAMEWORK; BRUCHS MEMBRANE; EYE DISEASE; DRUSEN; REGULARIZATION; SEGMENTATION; DIAGNOSIS; TOOL AB We introduce Schroedinger Eigenmaps (SE), a new semi-supervised manifold learning and recovery technique. This method is based on an implementation of graph Schroedinger operators with appropriately constructed barrier potentials as carriers of labeled information. We use our approach for the analysis of standard biomedical datasets and new multispectral retinal images. C1 [Czaja, Wojciech] Univ Maryland, Dept Math, College Pk, MD 20742 USA. [Ehler, Martin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Biomath & Biometry, D-85764 Neuherberg, Germany. [Ehler, Martin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Sect Med Biophys, Bethesda, MD 20892 USA. RP Czaja, W (reprint author), Univ Maryland, Dept Math, College Pk, MD 20742 USA. EM wojtek@math.umd.edu; ehlermar@mail.nih.gov FU NICHD/NIH; US National Science Foundation [CBET0854233]; NGA [HM15820810009]; ONR [N000140910144]; NIH/DFG [EH 405/1-1/575910] FX This work was supported by the Intramural Research Program of NICHD/NIH, by the US National Science Foundation (CBET0854233), by NGA (HM15820810009), by ONR (N000140910144), and by NIH/DFG (EH 405/1-1/575910). The authors also express their gratitude to Drs. R.F. Bonner, B. Brooks, E.Y. Chew, and S.M. Meyers for their assistance with acquiring and analyzing the included datasets. They also acknowledge V.N. Rajapakse and the anonymous referees for their valuable comments and suggestions that led to the improvement of this paper. The authors are grateful to the UCI Machine Learning Repository for providing the Wisconsin Breast Cancer, Cleveland Heart Disease, and Mammographic Mass datasets. NR 49 TC 23 Z9 23 U1 0 U2 23 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD MAY PY 2013 VL 35 IS 5 BP 1274 EP 1280 DI 10.1109/TPAMI.2012.270 PG 7 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 106EZ UT WOS:000316126800019 PM 23520264 ER PT J AU Wiener, L Zadeh, S Wexler, LH Pao, M AF Wiener, Lori Zadeh, Sima Wexler, Leonard H. Pao, Maryland TI When silence is not golden: Engaging adolescents and young adults in discussions around end-of-life care choices SO PEDIATRIC BLOOD & CANCER LA English DT Article C1 [Wiener, Lori; Zadeh, Sima] NCI, Bethesda, MD 20892 USA. [Wexler, Leonard H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Pao, Maryland] NIMH, Bethesda, MD 20892 USA. RP Wiener, L (reprint author), NCI, Psychosocial Support & Res Program, Staff Scientist, Pediat Oncol Branch,Ctr Canc Res, 10 Ctr Dr,Room 1-6466, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Institute of Mental Health FX Grant sponsor: Intramural Research Programs of the NIH; Grant sponsor: National Cancer Institute; Center for Cancer Research; National Institute of Mental Health. NR 10 TC 8 Z9 8 U1 0 U2 10 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 MAY PY 2013 VL 60 IS 5 BP 715 EP 718 DI 10.1002/pbc.24490 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 108KL UT WOS:000316291700002 PM 23483724 ER PT J AU Keir, ST Maris, JM Reynolds, CP Kang, MH Kolb, EA Gorlick, R Lock, R Carol, H Morton, CL Wu, JR Kurmasheva, RT Houghton, PJ Smith, MA AF Keir, Stephen T. Maris, John M. Reynolds, C. Patrick Kang, Min H. Kolb, E. Anders Gorlick, Richard Lock, Richard Carol, Hernan Morton, Christopher L. Wu, Jianrong Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; temodar ID CHILDRENS ONCOLOGY GROUP; PHASE-II TRIAL; ACUTE LYMPHOBLASTIC-LEUKEMIA; ADVANCED SOLID MALIGNANCIES; MISMATCH REPAIR DEFICIENCY; HIGH-RISK NEUROBLASTOMA; NERVOUS-SYSTEM TUMORS; ANTITUMOR IMIDAZOTETRAZINES; ALKYLATING-AGENTS; XENOGRAFT MODELS AB Background The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models. Procedures Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000 mu M and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380 mu M against the PPTP cell lines (range 1 to >1,000 mu M). The three lines with rIC50 values lesser than 10 mu M had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression. Pediatr Blood Cancer 2013; 60: 783790. (c) 2013 Wiley Periodicals, Inc. C1 [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Morton, Christopher L.; Wu, Jianrong] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Keir, ST (reprint author), Duke Univ, Dept Surg, Med Ctr, DUMC3624, Durham, NC 27710 USA. EM keir0001@mc.duke.edu RI Carol, Hernan/F-5750-2013; sebastianovitsch, stepan/G-8507-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 68 TC 5 Z9 5 U1 0 U2 8 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 MAY PY 2013 VL 60 IS 5 BP 783 EP 790 DI 10.1002/pbc.24368 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 108KL UT WOS:000316291700013 PM 23335050 ER PT J AU Reynolds, CP Kang, MH Carol, H Lock, R Gorlick, R Kolb, EA Kurmasheva, RT Keir, ST Maris, JM Billups, CA Houghton, PJ Smith, MA AF Reynolds, C. Patrick Kang, Min H. Carol, Hernan Lock, Richard Gorlick, Richard Kolb, E. Anders Kurmasheva, Raushan T. Keir, Stephen T. Maris, John M. Billups, Catherine A. Houghton, Peter J. Smith, Malcolm A. TI Initial testing (stage 1) of the phosphatidylinositol 3 kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; PI3K inhibitor; preclinical testing ID HUMAN CANCER; NEUROBLASTOMA-CELLS; PI3K-AKT PATHWAY; IN-VITRO; RAPAMYCIN; GROWTH; ISOFORM; TARGET; AKT; CHEMORESISTANCE AB Background Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts. Procedures SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 mu M and against the PPTP in vivo xenograft panels at a dose of 100mg/kg administered orally dailyx14. Results In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 mu M (range 2.724.5 mu M). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C>2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts. Conclusions Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered. Pediatr Blood Cancer 2013; 60: 791798. (c) 2012 Wiley Periodicals, Inc. C1 [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Reynolds, CP (reprint author), Texas Tech Univ, Hlth Sci Ctr, Sch Med, Ctr Canc, 3601 4th St STOP 9445, Lubbock, TX 79430 USA. EM Patrick.Reynolds@TTUHSC.edu RI Carol, Hernan/F-5750-2013; sebastianovitsch, stepan/G-8507-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX This work was supported by NO1-CM-42216, CA21765, and CA108786 from the National Cancer Institute and used SAR245408 supplied by Exelixis Inc., San Francisco, CA. In addition to the authors this paper represents work contributed by the following: Sherry Ansher, Ingrid Boehm, Joshua Courtright, Kathryn Evans, Edward Favours, Henry S. Friedman, Danuta Gasinski, Melissa Sammons, Chandra Tucker, Joe Zeidner, Jianrong Wu, Ellen Zhang, and Jian Zhang. Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and the Sydney Children's Hospitals Network. NR 43 TC 10 Z9 10 U1 0 U2 10 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 MAY PY 2013 VL 60 IS 5 BP 791 EP 798 DI 10.1002/pbc.24301 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 108KL UT WOS:000316291700014 PM 23002019 ER PT J AU Masuda, M Braun-Sommargren, M Crooks, D Smith, DR AF Masuda, Melisa Braun-Sommargren, Michelle Crooks, Dan Smith, Donald R. TI Golgi phosphoprotein 4 (GPP130) is a sensitive and selective cellular target of manganese exposure SO SYNAPSE LA English DT Article DE neurotoxicity; GABAergic; manganese; rodents; AF5 cells; homeostasis ID IRON REGULATION; BASAL GANGLIA; PROTEIN; CELLS; NEUROTOXICITY; METABOLISM; BRAIN; ACCUMULATION; TRANSPORTER; HOMEOSTASIS AB Chronic elevated exposure to manganese (Mn) is associated with neurocognitive and fine motor deficits in children. However, relatively little is understood about cellular responses to Mn spanning the transition between physiologic to toxic levels of exposure. Here, we investigated the specificity, sensitivity, and time course of the Golgi Phosphoprotein 4 (GPP130) response to Mn exposure in AF5 GABAergic neuronal cells, and we determined the extent to which GPP130 degradation occurs in brain cells in vivo in rats subchronically exposed to Mn. Our results show that GPP130 degradation in AF5 cells was specific to Mn, and did not occur following exposure to cobalt, copper, iron, nickel, or zinc. GPP130 degradation occurred without measurable increases in intracellular Mn levels and at Mn exposures as low as 0.54 mu M. GPP130 protein was detectable by immunofluorescence in only approximate to 1530% of cells in striatal and cortical rat brain slices, and Mn-exposed animals exhibited a significant reduction in both the number of GPP130-positive cells, and the overall levels of GPP130 protein, demonstrating the in vivo relevance of this Mn-specific response within the primary target organ of Mn toxicity. These results provide insight into specific mechanism(s) of cellular Mn regulation and toxicity within the brain, including the selective susceptibility of cells to Mn cytotoxicity. Synapse 67:205215, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Masuda, Melisa; Smith, Donald R.] Univ Calif Santa Cruz, Dept Microbiol & Environm Toxicol, Santa Cruz, CA 95064 USA. [Braun-Sommargren, Michelle] Locus Dev Inc, San Francisco, CA 94107 USA. [Crooks, Dan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, Bethesda, MD 20892 USA. RP Smith, DR (reprint author), Univ Calif Santa Cruz, Dept Microbiol & Environm Toxicol, 1156 High St, Santa Cruz, CA 95064 USA. EM drsmith@ucsc.edu RI sebastianovitsch, stepan/G-8507-2013 FU National Institutes of Health [R01ES018990, R01ES019222] FX Contract grant sponsor: National Institutes of Health; Contract grant number: R01ES018990, R01ES019222. NR 42 TC 6 Z9 6 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAY PY 2013 VL 67 IS 5 BP 205 EP 215 DI 10.1002/syn.21632 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 112UJ UT WOS:000316619000001 PM 23280773 ER PT J AU Taplin, SH Foster, MK Shortell, SM AF Taplin, Stephen H. Foster, Mary K. Shortell, Stephen M. TI Organizational Leadership For Building Effective Health Care Teams SO ANNALS OF FAMILY MEDICINE LA English DT Article DE health care delivery; collaboration; health services research; quality of health care; health care teams; health care organizations ID MORTALITY AB The movement toward accountable care organizations and patient-centered medical homes will increase with implementation of the Affordable Care Act (ACA). The ACA will therefore give further impetus to the growing importance of teams in health care. Teams typically involve 2 or more people embedded in a larger social system who differentiate their roles, share common goals, interact with each other, and perform tasks affecting others. Multiple team types fit within this definition, and they all need support from leadership to succeed. Teams have been invoked as a necessary tool to address the needs of patients with multiple chronic conditions and to address medical workforce shortages. Invoking teams, however, is much easier than making them function effectively, so we need to consider the implications of the growing emphasis on teams. Although the ACA will spur team development, organizational leadership must use what we know now to train, support, and incentivize team function. Meanwhile, we must also advance research regarding teams in health care to give those leaders more evidence to guide their work. C1 [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Behav Res Program, Proc Care Res Branch, Bethesda, MD 20892 USA. [Foster, Mary K.] Morgan State Univ, Earl G Graves Sch Business & Management, Baltimore, MD 21239 USA. [Shortell, Stephen M.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. RP Taplin, SH (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, Proc Care Res Branch, MSC 9761,3E522, Bethesda, MD 20892 USA. EM taplins@mail.nih.gov RI Foster, Mary/A-7160-2011 OI Foster, Mary/0000-0003-2257-4825 NR 17 TC 14 Z9 14 U1 1 U2 24 PU ANNALS FAMILY MEDICINE PI LEAWOOD PA 11400 TOMAHAWK CREEK PARKWAY, LEAWOOD, KS 66211-2672 USA SN 1544-1709 EI 1544-1717 J9 ANN FAM MED JI Ann. Fam. Med. PD MAY-JUN PY 2013 VL 11 IS 3 BP 279 EP 281 DI 10.1370/afm.1506 PG 3 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AI3WS UT WOS:000336796600015 PM 23690329 ER PT J AU Micale, RT La Maestra, S Di Pietro, A Visalli, G Baluce, B Balansky, R Steele, VE De Flora, S AF Micale, Rosanna T. La Maestra, Sebastiano Di Pietro, Angela Visalli, Giuseppa Baluce, Barbara Balansky, Roumen Steele, Vernon E. De Flora, Silvio TI Oxidative stress in the lung of mice exposed to cigarette smoke either early in life or in adulthood (vol 87, pg 915, 2013) SO ARCHIVES OF TOXICOLOGY LA English DT Correction C1 [Micale, Rosanna T.; La Maestra, Sebastiano; Balansky, Roumen; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. [Di Pietro, Angela; Visalli, Giuseppa; Baluce, Barbara] Univ Messina, Dept Hyg Publ Hlth & Prevent Med, I-98125 Messina, Italy. [Baluce, Barbara] Fdn IRCCS Ca Granda, Osped Maggiore Policlin, Cell Factory, Dept Regenerat Med, I-20122 Milan, Italy. [Balansky, Roumen] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD 20852 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM rosannamicale@yahoo.it; lamaestra78@yahoo.it; adipietr@unime.it; giusyvisally@yahoo.it; barbarabaluce@yahoo.it; rubalansky@sbaloncology.bg; steelev@mail.nih.gov; sdf@unige.it NR 1 TC 1 Z9 1 U1 0 U2 0 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 MAY PY 2013 VL 87 IS 5 AR 919 DI 10.1007/s00204-013-1036-2 PG 1 WC Toxicology SC Toxicology GA V44EL UT WOS:000209732200001 ER PT J AU Chu, XK Wang, YJ Ardeljan, D Tuo, JS Chan, CC AF Chu, Xi K. Wang, Yujuan Ardeljan, Daniel Tuo, Jingsheng Chan, Chi-Chao TI Controversial view of a genetically altered mouse model of focal retinal degeneration SO BIOENGINEERED LA English DT Article DE age-related macular degeneration; TSG-6; Ccl2; Cx3cr1; rd8; animal model ID HIGH-FAT DIET; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; PIGMENT EPITHELIUM; MURINE MODEL; COMPLEMENT ACTIVATION; ANIMAL-MODEL; CRB1 GENE; MICE; INFLAMMATION AB Tuo et al. (2012) demonstrated tumor necrosis factor-inducible gene 6 recombinant protein (TSG-6) arrest of focal retinal lesions on a Ccl2 and Cx3cr1 double deficient mouse (DKO) on rd8 background (hereon referred to as DKO rd8). DKO rd8, a model of focal retinal degeneration with earlier onset and higher penetrance than Ccl2 and Cx3cr1 single knockout strains, demonstrates characteristic features of AMD such as focal photoreceptor atrophy, retinal pigmented epithelium (RPE) degeneration, elevated ocular A2E levels and complement deposition in addition to retinal dystrophy. The discovery of the accidently introduced Crb1 mutation (rd8) in the C57BL/6N strain has led to the recent opinion that DKO rd8 is not a model of AMD but solely a model of Crb1-associated retinal degeneration. Differences between DKO rd8 and Crb1(rd8) photoreceptor and RPE pathology, as well as increased A2E and immune dysfunction, show that DKO rd8 recapitulates some AMD-like features in addition to rd8 retinal dystrophy. The appearance of rd8 lesions and Ccl2/Cx3cr1 lesions and the amelioration of most Ccl2/Cx3cr1 lesions in intervention studies show DKO rd8 to be a useful and appropriate model for therapeutic compound screening, such as the case with anti-inflammatory TSG-6. C1 [Chu, Xi K.; Wang, Yujuan; Ardeljan, Daniel; Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunopathol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov RI wang, yujuan/C-8428-2016; OI Tuo, Jingsheng/0000-0002-1372-7810 FU NEI FX This work was supported by the NEI intramural fund. NR 35 TC 10 Z9 11 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2165-5979 EI 2165-5987 J9 BIOENGINEERED JI Bioengineered PD MAY-JUN PY 2013 VL 4 IS 3 BP 130 EP 135 DI 10.4161/bioe.22949 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AI5JV UT WOS:000336903200011 PM 23196746 ER PT J AU Appella, DH AF Appella, Daniel H. TI Controlling Conformation and Sidechains in Peptide Nucleic Acids for Detection and Multivalent Display SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 231 EP 231 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200023 ER PT J AU Schneider, J AF Schneider, Joel TI The Evolution of Anticancer Peptides from Self-Assembled Hydrogels SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Schneider, Joel] NCI, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 234 EP 234 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200033 ER PT J AU Sinthuvanich, C Medina, S Schneider, J AF Sinthuvanich, C. Medina, S. Schneider, J. TI Cancer-cell Localization and Anticancer Activity of the SVS-1 Peptide SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Sinthuvanich, C.; Medina, S.; Schneider, J.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 255 EP 255 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200112 ER PT J AU Zhao, XZ Metifiot, M Maddali, K Smith, SJ Marchand, C Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Metifiot, Mathieu Maddali, Kasthuraiah Smith, Steven J. Marchand, Christophe Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI HIV Viral Protein R (Vpr)-derived Peptides Designed as HIV-1 Integrase Photoaffinity Ligands SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. [Metifiot, Mathieu; Maddali, Kasthuraiah; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RI Zhao, Xue Zhi/N-9594-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364 NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 262 EP 263 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200140 ER PT J AU Nagy, KJ Schneider, JP AF Nagy, Katelyn J. Schneider, Joel P. TI Enantiomeric Peptide Co-Assembly Leads to Hydrogels with Enhanced Material Rigidity SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Nagy, Katelyn J.] Univ Delaware, Dept Chem & Biochem, Newark, DE 19716 USA. [Nagy, Katelyn J.; Schneider, Joel P.] NIH, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 291 EP 291 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200245 ER PT J AU Gaidamakova, E Myles, I McDaniel, D Gayen, M Gupta, P Sharma, A Glass, P Maheshwari, R Datta, S Daly, MJ AF Gaidamakova, Elena Myles, Ian McDaniel, Dennis Gayen, Manoshi Gupta, Paridhi Sharma, Anuj Glass, Pamela Maheshwari, Radha Datta, Sandip Daly, Michael J. TI Applying a Radioprotective Mn(II)-peptide-Pi Complex to the Preparation of Irradiated Vaccines SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Gaidamakova, Elena; McDaniel, Dennis; Gayen, Manoshi; Gupta, Paridhi; Sharma, Anuj; Maheshwari, Radha; Daly, Michael J.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Myles, Ian; Datta, Sandip] NIAID, Bethesda, MD 20892 USA. [Glass, Pamela] US Army Med Res Inst Infect Dis, Ft Detrick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 297 EP 297 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200269 ER PT J AU Cheong, C Murugan, RN Lee, KS Bang, JK AF Cheong, Chaejoon Murugan, Ravichandran N. Lee, Kyung S. Bang, Jeong Kyu TI Molecular Basis of Ligand Orientation in determining Plk1 PBD Binding Activity and Specificity SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Cheong, Chaejoon; Murugan, Ravichandran N.; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM cheong@kbsi.re.kr NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 301 EP 301 PG 1 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200282 ER PT J AU Murugan, RN Ahn, M Park, JE Nam, KY Kim, HY Lee, WC Lee, KS Bang, JK AF Murugan, Ravichandran N. Ahn, Mija Park, Jung-Eun Nam, Ky-Youb Kim, Hye-Yeon Lee, Woo Cheol Lee, Kyung S. Bang, Jeong Kyu TI Identification of High Affinity Thioether-bridged Cyclic Peptomers as Selective Polo-like Kinase 1 Inhibitors SO BIOPOLYMERS LA English DT Meeting Abstract CT 23rd American Peptide Symposium CY JUN 22-27, 2013 CL Waikoloa, HI C1 [Murugan, Ravichandran N.; Ahn, Mija; Kim, Hye-Yeon; Lee, Woo Cheol; Bang, Jeong Kyu] Korea Basic Sci Inst, Div Magnet Resonance, Ochang 363883, Chung Buk, South Korea. [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nam, Ky-Youb] B128A Yonsei Univ, Bioinformat & Mol Design Res Ctr, Seoul 120749, South Korea. EM ravi@kbsi.re.kr NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3525 EI 1097-0282 J9 BIOPOLYMERS JI Biopolymers PD MAY PY 2013 VL 100 IS 3 SI SI BP 306 EP 307 PG 2 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AI0IL UT WOS:000336530200301 ER PT J AU Chen, HX Sharon, E AF Chen, Helen X. Sharon, Elad TI IGF-1R as an anti-cancer target-trials and tribulations SO CHINESE JOURNAL OF CANCER LA English DT Review DE IGF-1R; insulin receptor ID GROWTH-FACTOR-I; BREAST-CANCER CELLS; RECEPTOR MONOCLONAL-ANTIBODY; REFRACTORY SOLID TUMORS; PHASE-II; COLORECTAL-CANCER; MULTIPLE-MYELOMA; INSULIN-RECEPTOR; PROSTATE-CANCER; DOSE-ESCALATION AB Type I insulin-like e growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development. C1 [Chen, Helen X.; Sharon, Elad] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Chen, HX (reprint author), 9609 Med Ctr Dr,Room 5W-456, Bethesda, MD 20892 USA. EM helen.chen@nih.gov NR 94 TC 47 Z9 50 U1 1 U2 9 PU SUN YAT SEN UNIV MED SCI WHO PI GUANGZHOU PA 651 DONGFENG RD E, GUANGZHOU, GUANGDONG 510060, PEOPLES R CHINA SN 1000-467X EI 1944-446X J9 CHIN J CANCER JI Chin. J. Cancer PD MAY PY 2013 VL 32 IS 5 BP 242 EP 252 DI 10.5732/cjc.012.10263 PG 11 WC Oncology SC Oncology GA AM2AE UT WOS:000339649700003 PM 23601239 ER PT J AU Fujita, M Hines, C Zoghbi, S Mallinger, A Zhang, Y Pike, V Drevets, W Zarate, C Innis, R AF Fujita, Masahiro Hines, Christina Zoghbi, Sami Mallinger, Alan Zhang, Yi Pike, Victor Drevets, Wayne Zarate, Carlos Innis, Robert TI cAMP cascade in major depressive disorder - Downregulation in unmedicated patients and response to antidepressant SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 [Fujita, Masahiro; Hines, Christina; Zoghbi, Sami; Mallinger, Alan; Zhang, Yi; Pike, Victor; Zarate, Carlos; Innis, Robert] NIMH, Bethesda, MD 20892 USA. [Drevets, Wayne] Univ Oklahoma, Tulsa, OK USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2013 VL 54 SU 2 MA 33 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V40KY UT WOS:000209478700027 ER PT J AU Tonietto, M Rizzo, G Veronese, M Zanotti-Fregonara, P Lohith, T Fujita, M Zoghbi, S Innis, R Bertoldo, A AF Tonietto, Matteo Rizzo, Gaia Veronese, Mattia Zanotti-Fregonara, Paolo Lohith, Talakad Fujita, Masahiro Zoghbi, Sami Innis, Robert Bertoldo, Alessandra TI Plasma metabolite correction: Improvements of current parent plasma models SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 [Tonietto, Matteo; Rizzo, Gaia; Veronese, Mattia; Bertoldo, Alessandra] Univ Padua, Dept Informat Engn, Padua, Italy. [Zanotti-Fregonara, Paolo; Lohith, Talakad; Fujita, Masahiro; Zoghbi, Sami; Innis, Robert] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2013 VL 54 SU 2 MA 43 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V40KY UT WOS:000209478700037 ER PT J AU Wang, GJ Dardo, T Convit, A Volkow, N Logan, J Wong, C Shumay, E Fowler, J AF Wang, Gene-Jack Dardo, Tomasi Convit, Antonio Volkow, Nora Logan, Jean Wong, Christopher Shumay, Elena Fowler, Joanna TI Peripheral insulin resistance affects brain dopaminergic signaling after glucose ingestion SO JOURNAL OF NUCLEAR MEDICINE LA English DT Meeting Abstract C1 [Wang, Gene-Jack] SUNY Stony Brook, Radiol, Upton, NY USA. [Logan, Jean; Shumay, Elena; Fowler, Joanna] Brookhaven Natl Lab, Biosci, Upton, NY 11973 USA. [Convit, Antonio] NYU, Psychiat, New York, NY USA. [Dardo, Tomasi; Wong, Christopher] NIAAA, Neuroimaging, Upton, NY USA. [Volkow, Nora] NIDA, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD MAY PY 2013 VL 54 SU 2 MA 29 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V40KY UT WOS:000209478700023 ER PT J AU Lusvarghi, S Sztuba-Solinska, J Purzycka, KJ Rausch, JW Le Grice, SFJ AF Lusvarghi, Sabrina Sztuba-Solinska, Joanna Purzycka, Katarzyna J. Rausch, Jason W. Le Grice, Stuart F. J. TI RNA Secondary Structure Prediction Using High-throughput SHAPE SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Genetics; Issue 75; Molecular Biology; Biochemistry; Virology; Cancer Biology; Medicine; Genomics; Nucleic Acid Probes; RNA Probes; RNA; High-throughput SHAPE; Capillary electrophoresis; RNA structure; RNA probing; RNA folding; secondary structure; DNA; nucleic acids; electropherogram; synthesis; transcription; high throughput; sequencing AB Understanding the function of RNA involved in biological processes requires a thorough knowledge of RNA structure. Toward this end, the methodology dubbed "high-throughput selective 2' hydroxyl acylation analyzed by primer extension", or SHAPE, allows prediction of RNA secondary structure with single nucleotide resolution. This approach utilizes chemical probing agents that preferentially acylate single stranded or flexible regions of RNA in aqueous solution. Sites of chemical modification are detected by reverse transcription of the modified RNA, and the products of this reaction are fractionated by automated capillary electrophoresis (CE). Since reverse transcriptase pauses at those RNA nucleotides modified by the SHAPE reagents, the resulting cDNA library indirectly maps those ribonucleotides that are single stranded in the context of the folded RNA. Using ShapeFinder software, the electropherograms produced by automated CE are processed and converted into nucleotide reactivity tables that are themselves converted into pseudo-energy constraints used in the RNAStructure (v5.3) prediction algorithm. The two-dimensional RNA structures obtained by combining SHAPE probing with in silico RNA secondary structure prediction have been found to be far more accurate than structures obtained using either method alone. C1 [Lusvarghi, Sabrina; Sztuba-Solinska, Joanna; Purzycka, Katarzyna J.; Rausch, Jason W.; Le Grice, Stuart F. J.] Frederick Natl Lab Canc Res, HIV Drug Resistance Program, RT Biochem Sect, Frederick, MD 21701 USA. RP Le Grice, SFJ (reprint author), Frederick Natl Lab Canc Res, HIV Drug Resistance Program, RT Biochem Sect, Frederick, MD 21701 USA. EM legrices@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA FX S. Lusvarghi, J. Sztuba-Solinska, K.J. Purzycka, J.W. Rausch and S.F.J. Le Grice are supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA. NR 30 TC 0 Z9 0 U1 1 U2 7 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD MAY PY 2013 IS 75 AR UNSP e50243 DI 10.3791/50243 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RE UT WOS:000209227700025 PM 23748604 ER PT J AU Tong, H Hu, C Li, KF Mei, C Zhuang, ZP Ye, L Lu, DM Jin, J AF Tong, H. Hu, C. Li, K. F. Mei, C. Zhuang, Z. P. Ye, L. Lu, D. M. Jin, J. TI LB1, targeting inhibiting protein phosphatase 2A (PP2A), enhances daunorubicin suppression of MDS cell line (SKM-1) in vitro and in vivo SO LEUKEMIA RESEARCH LA English DT Meeting Abstract C1 [Tong, H.; Hu, C.; Ye, L.; Lu, D. M.; Jin, J.] Zhejiang Univ Coll, Affiliated Hosp 1, Inst Hematol, Dept Hematol, Hangzhou, Zhejiang, Peoples R China. [Li, K. F.] Yin Zhou People Hosp, Dept Hematol, Ningbo, Zhejiang, Peoples R China. [Mei, C.] Zhejiang Univ Coll, Sir Run Run Shaw Hosp, Dept Hematol, Hangzhou, Zhejiang, Peoples R China. [Zhuang, Z. P.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD MAY PY 2013 VL 37 SU 1 MA P-285 BP S150 EP S151 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA V40RR UT WOS:000209496200331 ER PT J AU Vlachos, A Farrar, JE Atsidaftos, E Muir, E Narla, A Markello, TC Singh, S Blanc, L Landowski, M Gazda, HT Liu, JM Ellis, SR Arceci, RJ Ebert, BL Bodine, DM Lipton, JM AF Vlachos, A. Farrar, J. E. Atsidaftos, E. Muir, E. Narla, A. Markello, T. C. Singh, S. Blanc, L. Landowski, M. Gazda, H. T. Liu, J. M. Ellis, S. R. Arceci, R. J. Ebert, B. L. Bodine, D. M. Lipton, J. M. TI 5q-syndrome or diamond blackfan anemia: The perplexing diagnostic puzzle of red cell aplasia SO LEUKEMIA RESEARCH LA English DT Meeting Abstract C1 [Vlachos, A.; Singh, S.; Blanc, L.; Liu, J. M.; Lipton, J. M.] Cohen Childrens Med Ctr, Feinstein Inst Med Res, Hematol Oncol & Stem Cell Transplantat, Manhasset, NY USA. [Farrar, J. E.] Winthrop P Rockefeller Canc Inst, Pediat Hematol Oncol, Little Rock, AR USA. [Atsidaftos, E.; Muir, E.] Feinstein Inst Med Res, Pediat Hematol Oncol, Manhasset, NY USA. [Narla, A.] Boston Childrens Hosp, Hematol Oncol, Boston, MA USA. [Markello, T. C.] NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. [Landowski, M.] Boston Childrens Hosp, Genet, Boston, MA USA. [Landowski, M.] Boston Childrens Hosp, Program Genom, Boston, MA USA. [Gazda, H. T.] Harvard Univ, Sch Med, Genet, Boston, MA USA. [Gazda, H. T.] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Genom, Boston, MA USA. [Ellis, S. R.] Univ Louisville, Biochem & Mol Biol, Louisville, KY 40292 USA. [Arceci, R. J.] Johns Hopkins Univ, Sidney Kimmel CCC, Pediat Oncol, Baltimore, MD USA. [Ebert, B. L.] Harvard Univ, Brigham & Womens Hosp, Hematol, Sch Med, Boston, MA 02115 USA. [Bodine, D. M.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD MAY PY 2013 VL 37 SU 1 MA P-083 BP S59 EP S59 PG 1 WC Oncology; Hematology SC Oncology; Hematology GA V40RR UT WOS:000209496200131 ER PT J AU Van Calster, B Vickers, AJ Pencina, MJ Baker, SG Timmerman, D Steyerberg, EW AF Van Calster, Ben Vickers, Andrew J. Pencina, Michael J. Baker, Stuart G. Timmerman, Dirk Steyerberg, Ewout W. TI Evaluation of Markers and Risk Prediction Models: Overview of Relationships between NRI and Decision-Analytic Measures SO MEDICAL DECISION MAKING LA English DT Article DE clinical prediction rules; decision rules; decision analysis ID RELATIVE UTILITY CURVES; ROC CURVE; DIAGNOSTIC-TESTS; RECLASSIFICATION; PERFORMANCE; CANCER; AREA; FRAMEWORK; ABILITY AB Background. For the evaluation and comparison of markers and risk prediction models, various novel measures have recently been introduced as alternatives to the commonly used difference in the area under the receiver operating characteristic (ROC) curve (DAUC). The net reclassification improvement (NRI) is increasingly popular to compare predictions with 1 or more risk thresholds, but decision-analytic approaches have also been proposed. Objective. We aimed to identify the mathematical relationships between novel performance measures for the situation that a single risk threshold T is used to classify patients as having the outcome or not. Methods. We considered the NRI and 3 utility-based measures that take misclassification costs into account: difference in net benefit (Delta NB), difference in relative utility (Delta RU), and weighted NRI (wNRI). We illustrate the behavior of these measures in 1938 women suspect of having ovarian cancer (prevalence 28%). Results. The 3 utility-based measures appear to be transformations of each other and hence always lead to consistent conclusions. On the other hand, conclusions may differ when using the standard NRI, depending on the adopted risk threshold T, prevalence P, and the obtained differences in sensitivity and specificity of the 2 models that are compared. In the case study, adding the CA-125 tumor marker to a baseline set of covariates yielded a negative NRI yet a positive value for the utility-based measures. Conclusions. The decision-analytic measures are each appropriate to indicate the clinical usefulness of an added marker or compare prediction models since these measures each reflect misclassification costs. This is of practical importance as these measures may thus adjust conclusions based on purely statistical measures. A range of risk thresholds should be considered in applying these measures. C1 [Van Calster, Ben; Timmerman, Dirk] Univ Louvain, KU Leuven, Dept Dev & Regenerat, B-3000 Louvain, Belgium. [Van Calster, Ben; Steyerberg, Ewout W.] Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Vickers, Andrew J.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Pencina, Michael J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Pencina, Michael J.] Harvard Clin Res Inst, Boston, MA USA. [Baker, Stuart G.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Van Calster, B (reprint author), Univ Louvain, KU Leuven, Dept Dev & Regenerat, Herestr 49 Box 7003, B-3000 Louvain, Belgium. EM ben.vancalster@med.kuleuven.be OI Vickers, Andrew/0000-0003-1525-6503; Steyerberg, Ewout/0000-0002-7787-0122; Van Calster, Ben/0000-0003-1613-7450 FU Research Foundation-Flanders (FWO) [1251609N, 1251612N, G049312N]; Agency for Innovation by Science and Technology (IWT-Vlaanderen) [TBM070706-IOTA3]; Center for Translational Molecular Medicine (PCMM project); Prostate Cancer Foundation; Sidney Kimmel Center for Prostate and Urologic Cancers; National Cancer Institute [P50-CA92629 SPORE]; National Institutes of Health FX Financial support for this study was provided in part by Research Foundation-Flanders (FWO) (1251609N, 1251612N, G049312N), Agency for Innovation by Science and Technology (IWT-Vlaanderen) (grant TBM070706-IOTA3), Center for Translational Molecular Medicine (PCMM project), Prostate Cancer Foundation (funds from David H. Koch), the Sidney Kimmel Center for Prostate and Urologic Cancers, National Cancer Institute (P50-CA92629 SPORE grant to Dr. P. T. Scardino), National Institutes of Health (SGB). The funding agreement ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report. BVC is a postdoctoral fellow of the Research Foundation-Flanders (FWO). Revision accepted for publication 16 October 2012. NR 34 TC 22 Z9 22 U1 3 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD MAY PY 2013 VL 33 IS 4 BP 490 EP 501 DI 10.1177/0272989X12470757 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AI8QF UT WOS:000337185400005 PM 23313931 ER PT J AU Yoon, JS Lee, JH Tweedie, D Mughal, MR Chigurupati, S Greig, NH Mattson, MP AF Yoon, Jeong Seon Lee, Jong-Hwan Tweedie, David Mughal, Mohamed R. Chigurupati, Srinivasulu Greig, Nigel H. Mattson, Mark P. TI 3,6 '-dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE ICAM-1; inflammation; ischemia; microglia; neuroprotection; occlusion; stroke; thalidomide; TNF ID TUMOR-NECROSIS-FACTOR; BLOOD-BRAIN-BARRIER; FOCAL CEREBRAL-ISCHEMIA; ALPHA SYNTHESIS INHIBITOR; INFLAMMATORY RESPONSE; COGNITIVE DEFICITS; ALZHEIMERS-DISEASE; IN-VITRO; TNF; THALIDOMIDE AB Tumor necrosis factor- (TNF) plays a prominent role in the brain damage and functional deficits that result from ischemic stroke. It was recently reported that the thalidomide analog 3,6-dithiothalidomide (3,6-DT) can selectively inhibit the synthesis of TNF in cultured cells. We therefore tested the therapeutic potential of 3,6-DT in a mouse model of focal ischemic stroke. Administration of 3,6-DT immediately prior to a stroke or within 3 hr after the stroke reduced infarct volume, neuronal death, and neurological deficits, whereas thalidomide was effective only when administered prior to stroke. Neuroprotection was accompanied by decreased inflammation; 3,6-DT-treated mice exhibited reduced expression of TNF, interleukin-1, and inducible nitric oxide synthase; reduced numbers of activated microglia/macrophages, astrocytes, and neutrophils; and reduced expression of intercellular adhesion molecule-1 in the ischemic brain tissue. 3,6-DT treatment attenuated stroke-induced disruption of the bloodbrain barrier by a mechanism that appears to involve suppression of matrix metalloproteinase-9 and preservation of occludin. Treatment with 3,6-DT did not reduce ischemic brain damage in mice lacking TNF receptors, consistent with a critical role for suppression of TNF production and TNF signaling in the therapeutic action of 3,6-DT. These findings suggest that anti-inflammatory mechanisms underlie the therapeutic actions of 3,6-DT in an animal model of stroke. (c) 2013 Wiley Periodicals, Inc. C1 [Yoon, Jeong Seon; Tweedie, David; Mughal, Mohamed R.; Chigurupati, Srinivasulu; Greig, Nigel H.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Lee, Jong-Hwan] Konkuk Univ, Coll Vet Med, Dept Anat, Seoul, South Korea. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov FU National Institute on Aging Intramural Research Program FX Contract grant sponsor: National Institute on Aging Intramural Research Program. NR 55 TC 16 Z9 16 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY PY 2013 VL 91 IS 5 BP 671 EP 680 DI 10.1002/jnr.23190 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 104CY UT WOS:000315968700006 PM 23404341 ER PT J AU Lu, WH Wang, CY Chen, PS Wang, JW Chuang, DM Yang, CS Tzeng, SF AF Lu, Wen-Hsin Wang, Chih-Yen Chen, Po-See Wang, Jing-Wen Chuang, De-Maw Yang, Chung-Shi Tzeng, Shun-Fen TI Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE microglia; spinal cord injury; valproic acid; purinergic P2X4R ID HISTONE DEACETYLASE INHIBITION; PROTECTS DOPAMINERGIC-NEURONS; P2X(7) RECEPTOR; NEUROTROPHIC FACTOR; NEUROPATHIC PAIN; CONTUSIVE INJURY; SODIUM-BUTYRATE; GENE-EXPRESSION; NITRIC-OXIDE; RAT AB Peripheral injection with a high dose of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, into animals with mild or moderate spinal cord injury (SCI) for 1 week can reduce spinal cord tissue loss and promote hindlimb locomotor recovery. A purinergic adenosine triphosphate (ATP) receptor subtype, P2X4 receptor (P2X4R), has been considered as a potential target to diminish SCI-associated inflammatory responses. In this study, using a minipump-based infusion system, we found that intraspinal infusion with VPA for 3 days into injured spinal cord significantly improved hindlimb locomotion of rats with severe SCI induced by a 10-g NYU impactor dropping from the height of 50 mm onto the spinal T9/10 segment. The neuronal fibers in the injured spinal cord tissues were significantly preserved in VPA-treated rats compared with those observed in vehicle-treated animals. Moreover, the accumulation of microglia/macrophages and astrocytes in the injured spinal cord was attenuated in the animal group receiving VPA infusion. VPA also significantly reduced P2X4R expression post-SCI. Furthermore, in vitro study indicated that VPA, but not the other HDAC inhibitors, sodium butyrate and trichostatin A (TSA), caused downregulation of P2X4R in microglia activated with lipopolysaccharide (LPS). Moreover, p38 mitogen-activated protein kinase (MAPK)-triggered signaling was involved in the effect of VPA on the inhibition of P2X4R gene expression. In addition to the findings from others, our results also provide important evidence to show the inhibitory effect of VPA on P2X4R expression in activated microglia, which may contribute to reduction of SCI-induced gliosis and subsequently preservation of spinal cord tissues. (c) 2013 Wiley Periodicals, Inc. C1 [Lu, Wen-Hsin; Wang, Chih-Yen; Wang, Jing-Wen; Tzeng, Shun-Fen] Natl Cheng Kung Univ, Dept Life Sci, Tainan 70101, Taiwan. [Chen, Po-See] Natl Cheng Kung Univ, Dept Psychiat, Coll Med, Tainan 70101, Taiwan. [Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Yang, Chung-Shi] Natl Hlth Res Inst, Ctr Nanomed Res, Zhunan, Taiwan. RP Tzeng, SF (reprint author), Natl Cheng Kung Univ, Dept Life Sci, Tainan 70101, Taiwan. EM cyang@nhri.org.tw; stzeng@mail.ncku.edu.tw RI Yang, Chung-Shi/E-3999-2010 FU National Science Council of Taiwan [NSC 98-2321-B-006-002, NSC 99-2321-B-006-002] FX Contract grant sponsor: National Science Council of Taiwan; Contract grant number: NSC 98-2321-B-006-002; Contract grant number: NSC 99-2321-B-006-002. NR 60 TC 19 Z9 22 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY PY 2013 VL 91 IS 5 BP 694 EP 705 DI 10.1002/jnr.23200 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 104CY UT WOS:000315968700008 PM 23404572 ER PT J AU Jamshidi, M Schmidt, MK Dork, T Garcia-Closas, M Heikkinen, T Cornelissen, S van den Broek, AJ Schurmann, P Meyer, A Park-Simon, TW Figueroa, J Sherman, M Lissowska, J Keong, GTH Irwanto, A Laakso, M Hautaniemi, S Aittomaki, K Blomqvist, C Liu, JJ Nevanlinna, H AF Jamshidi, Maral Schmidt, Marjanka K. Doerk, Thilo Garcia-Closas, Montserrat Heikkinen, Tuomas Cornelissen, Sten van den Broek, Alexandra J. Schuermann, Peter Meyer, Andreas Park-Simon, Tjoung-Won Figueroa, Jonine Sherman, Mark Lissowska, Jolanta Keong, Garrett Teoh Hor Irwanto, Astrid Laakso, Marko Hautaniemi, Sampsa Aittomaki, Kristiina Blomqvist, Carl Liu, Jianjun Nevanlinna, Heli TI Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE TP53; MDM2; PRKAG2; PPP2R2B; breast cancer; hormonal therapy ID ACTIVATED PROTEIN-KINASE; GENOME-WIDE ASSOCIATION; TUMOR-SUPPRESSOR; MDM2 SNP309; TYROSINE PHOSPHORYLATION; PHOSPHATASE 2A; P53; PP2A; CELL; SUSCEPTIBILITY AB Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.30.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.70.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.20.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.60.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.50.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients. C1 [Jamshidi, Maral; Heikkinen, Tuomas; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Biomedicum Helsinki, Helsinki 00029, Finland. [Jamshidi, Maral; Heikkinen, Tuomas; Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Helsinki 00029, Finland. [Schmidt, Marjanka K.; Cornelissen, Sten] Netherlands Canc Inst, Dept Mol Pathol, NL-1066 CX Amsterdam, Netherlands. [Schmidt, Marjanka K.; van den Broek, Alexandra J.] Netherlands Canc Inst, Dept Psychosocial Res & Epidemiol, NL-1066 CX Amsterdam, Netherlands. [Doerk, Thilo; Schuermann, Peter; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Gynecol, Hannover, Germany. [Doerk, Thilo; Schuermann, Peter; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Garcia-Closas, Montserrat] Breakthrough Breast Canc Res Ctr, London, England. [Meyer, Andreas] Hannover Med Sch, Clin Radiat Oncol, Hannover, Germany. [Figueroa, Jonine] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Sherman, Mark] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Keong, Garrett Teoh Hor; Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Laakso, Marko; Hautaniemi, Sampsa] Univ Helsinki, Computat Syst Biol Lab, Genome Scale Biol Res Program, Inst Biomed, Helsinki 00029, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki 00029, Finland. RP Nevanlinna, H (reprint author), Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, Biomedicum Helsinki, POB 700, Helsinki 00029, Finland. EM heli.nevanlinna@hus.fi RI Hautaniemi, Sampsa/A-3122-2009; Dork, Thilo/J-8620-2012; Garcia-Closas, Montserrat /F-3871-2015 OI Hautaniemi, Sampsa/0000-0002-7749-2694; Lissowska, Jolanta/0000-0003-2695-5799; Nevanlinna, Heli/0000-0002-0916-2976; Garcia-Closas, Montserrat /0000-0003-1033-2650 FU European Community [223175, HEALTH-F2-2009-223175]; Dutch Cancer Society [NKI2009-4363, NKI2007-3839]; Helsinki University Central Hospital Research Fund; Sigrid Juselius Foundation; Finnish Cancer Society; Nordic Cancer Union; Academy of Finland [132473]; Agency for Science, Technology and Research (A*STAR) of Singapore; Intramural Research Program of the U.S. National Cancer Institute, Department of Health and Human Services, USA FX Grant sponsor: European Community's Seventh Framework Programme under grant agreement 223175; Grant number: HEALTH-F2-2009-223175; Grant sponsor: Dutch Cancer Society; Grant numbers: NKI2009-4363, NKI2007-3839; Grant sponsors: Helsinki University Central Hospital Research Fund, the Sigrid Juselius Foundation, the Finnish Cancer Society, the Nordic Cancer Union; Grant sponsor: Academy of Finland; Grant number: 132473; Grant sponsor: Agency for Science, Technology and Research (A*STAR) of Singapore; Grant sponsors: Intramural Research Program of the U.S. National Cancer Institute, Department of Health and Human Services, USA NR 52 TC 5 Z9 5 U1 0 U2 43 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2013 VL 132 IS 9 BP 2044 EP 2055 DI 10.1002/ijc.27884 PG 12 WC Oncology SC Oncology GA 092KV UT WOS:000315121100008 PM 23034890 ER PT J AU Pinsky, PF Zhu, C Skates, SJ Black, A Partridge, E Buys, SS Berg, CD AF Pinsky, Paul F. Zhu, Claire Skates, Steve J. Black, Amanda Partridge, Edward Buys, Saundra S. Berg, Christine D. TI Potential effect of the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ovarian cancer; Prostate; Lung; Colorectal and Ovarian (PLCO) cancer trial; risk of ovarian cancer algorithm (ROCA); screening; mortality AB Recently, the Prostate, Lung, Colorectal and Ovarian (PLCO) Trial reported no mortality benefit for annual screening with CA-125 and transvaginal ultrasound (TVU). Currently ongoing is the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), which utilizes the risk of ovarian cancer algorithm (ROCA), a statistical tool that considers current and past CA125 values to determine ovarian cancer risk. In contrast, PLCO used a single cutoff for CA125, based on current levels alone. We investigated whether having had used ROCA in PLCO could have, under optimal assumptions, resulted in a significant mortality benefit by applying ROCA to PLCO CA125 screening values. A best-case scenario assumed that all cancers showing a positive screen result earlier with ROCA than under the PLCO protocol would have avoided mortality; under a stage-shift scenario, such women were assigned survival equivalent to Stage I/II screen-detected cases. Updated PLCO data show 132 intervention arm ovarian cancer deaths versus 119 in usual care (relative risk, RR = 1.11). Forty-three ovarian cancer cases, 25 fatal, would have been detected earlier with ROCA, with a median (minimum) advance time for fatal cases of 344 (147) days. Best-case and stage-shift scenarios gave 25 and 19 deaths prevented with ROCA, for RRs of 0.90 (95% CI: 0.691.17) and 0.95 (95% CI: 0.741.23), respectively. Having utilized ROCA in PLCO would not have led to a significant mortality benefit of screening. However, ROCA could still show a significant effect in other screening trials, including UKCTOCS. C1 [Pinsky, Paul F.; Zhu, Claire; Berg, Christine D.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Skates, Steve J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Black, Amanda] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Partridge, Edward] Univ Alabama Birmingham, Birmingham, AL USA. [Buys, Saundra S.] Univ Utah, Salt Lake City, UT USA. RP Pinsky, PF (reprint author), 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. EM pp4f@nih.gov RI Berg , Christine/K-1047-2014 NR 9 TC 16 Z9 16 U1 0 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 1 PY 2013 VL 132 IS 9 BP 2127 EP 2133 DI 10.1002/ijc.27909 PG 7 WC Oncology SC Oncology GA 092KV UT WOS:000315121100016 PM 23065684 ER PT J AU Cantrell, CL Zheljazkov, VD Osbrink, WLA Castro, A Maddox, V Craker, LE Astatkie, T AF Cantrell, Charles L. Zheljazkov, Valcho D. Osbrink, Weste L. A. Castro, Amaya Maddox, Victor Craker, Lyle E. Astatkie, Tess TI Podophyllotoxin and essential oil profile of Juniperus and related species SO INDUSTRIAL CROPS AND PRODUCTS LA English DT Article DE Eastern red cedar; Medicinal plant; Anti-cancer; Antimicrobial; Antileishmania; Anti-termite ID EASTERN RED CEDAR; PELTATUM; LIGNANS; VIRGINIANA; ETOPOSIDE; ISOPTERA; LEAVES; PLANT; L. AB Podophyllotoxin is currently in high demand as the lead chemical precursor for the anti-cancer drugs etoposide and teniposide. We conducted a two-phase study: (i) screening of Juniperus and other related species and identified Juniperus virginiana as the species with the highest podophyllotoxin concentration and (ii) established the limits of variations of podophyllotoxin and essential oil content and composition in J. virginiana in the United States. In the second phase of the study. J. virginiana trees at 49 locations in Mississippi. Alabama, Tennessee, and North Dakota were sampled and analyzed for both podophyllotoxin and essential oil. Both the essential oil and podophyllotoxin had similar concentration ranges as percent of dry J. virginiana leaves. Hence the following qualitative grouping with respect to concentration of natural products in the leaves was assigned: very high (>0.3%), high (0.2-0.3%), medium (0.1-0.2%), and low (<0.1%). Based on the above qualitative grouping, the J. virginiana accession were divided into 10 different groups (chemotypes). The J. virginiana accessions also differed in essential oil composition, with wide variation of individual constituents. Based on the essential oil composition, the J. virginiana accessions were divided into the following groups (chemotypes): (1) safrole-limonene-linalool; (2) safrole-beta-pinene-limonene-linalool; (3) beta-pinene-limonene; (4) limonene; (5) limonene-linalool; (6) limonene-safrole; (7) limonene-safrole-beta-pinene; (8) beta-pinene-limonene-bornyl acetate; (9) beta-pinene-limonene-linalool-bornyl acetate; and (10) myrcene-limonene chemotype. The essential oil of two of the J. virginiana chemotypes showed differential antioxidant activity. J. virginiana leaves, a by-product from the timber industry could be used as a sustainable source for both podophyllotoxin and essential oil. The availability of various chemotypes offers an opportunity for the development of cultivars for commercial production of podophyllotoxin and essential oil with specific compositional profile to meet the market requirements. (C) 2012 Elsevier B.V. All rights reserved. C1 [Zheljazkov, Valcho D.] Univ Wyoming, Sheridan Res & Extens Ctr, Sheridan, WY 82801 USA. [Cantrell, Charles L.] ARS, Nat Prod Utilizat Res Unit, USDA, University, MS 38677 USA. [Osbrink, Weste L. A.] ARS, Formosan Subterranean Termite Res Unit, USDA, New Orleans, LA 70124 USA. [Castro, Amaya] Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Maddox, Victor] Mississippi State Univ, Geosyst Res Inst, Mississippi State, MS 39762 USA. [Craker, Lyle E.] Univ Massachusetts, Dept Plant Soil & Insect Sci, Amherst, MA 01003 USA. [Astatkie, Tess] Dalhousie Univ, Fac Agr, Truro, NS, Canada. RP Zheljazkov, VD (reprint author), Univ Wyoming, Sheridan Res & Extens Ctr, 663 Wyarno Rd, Sheridan, WY 82801 USA. EM vjeliazk@uwyo.edu RI Astatkie, Tess/J-7231-2012 OI Astatkie, Tess/0000-0002-9779-8789 FU Mississippi State University project 'Bioprospecting for production of the anti-cancer drug podophyllotoxin' FX The authors thank Solomon Green III and Amber Reichley for technical assistance at the National Center for Natural Products Research in Oxford, MS, and USDA-ARS. Financial support was provided in part from the Mississippi State University project 'Bioprospecting for production of the anti-cancer drug podophyllotoxin' and a contribution of the Mississippi Agricultural and Forestry Exp. Sta. journal article No. J-11588. The authors also thank Thomas Horgan and Ekaterina Jeliazkova of Mississippi State for their help with the sampling and Dr. Pamela Collins for providing access to the Mississippi State arboretum. Shabana Khan, Babu Tekwani and Melissa Jacob are acknowledged for biological screening at NCNPR, University of Mississippi. NR 34 TC 9 Z9 9 U1 2 U2 87 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0926-6690 J9 IND CROP PROD JI Ind. Crop. Prod. PD MAY PY 2013 VL 43 BP 668 EP 676 DI 10.1016/j.indcrop.2012.07.075 PG 9 WC Agricultural Engineering; Agronomy SC Agriculture GA 047TS UT WOS:000311865000100 ER PT J AU Abend, R Karni, A Sadeh, A Fox, NA Pine, DS Bar-Haim, Y AF Abend, Rany Karni, Avi Sadeh, Avi Fox, Nathan A. Pine, Daniel S. Bar-Haim, Yair TI Learning to Attend to Threat Accelerates and Enhances Memory Consolidation SO PLOS ONE LA English DT Article ID MOTOR SEQUENCE; FACIAL EXPRESSIONS; ATTENTIONAL BIAS; SELECTIVE ATTENTION; SKILLED PERFORMANCE; ANGRY FACES; TERM-MEMORY; TIME-COURSE; SLEEP; ACQUISITION AB Practice on a procedural task involves within-session learning and between-session consolidation of learning, with the latter requiring a minimum of about four hours to evolve due to involvement of slower cellular processes. Learning to attend to threats is vital for survival and thus may involve faster memory consolidation than simple procedural learning. Here, we tested whether attention to threat modulates the time-course and magnitude of learning and memory consolidation effects associated with skill practice. All participants (N = 90) practiced in two sessions on a dot-probe task featuring pairs of neutral and angry faces followed by target probes which were to be discriminated as rapidly as possible. In the attend-threat training condition, targets always appeared at the angry face location, forming an association between threat and target location; target location was unrelated to valence in a control training condition. Within each attention training condition, duration of the between-session rest interval was varied to establish the time-course for emergence of consolidation effects. During the first practice session, we observed robust improvement in task performance (online, within-session gains), followed by saturation of learning. Both training conditions exhibited similar overall learning capacities, but performance in the attend-threat condition was characterized by a faster learning rate relative to control. Consistent with the memory consolidation hypothesis, between-session performance gains (delayed gains) were observed only following a rest interval. However, rest intervals of 1 and 24 hours yielded similar delayed gains, suggesting accelerated consolidation processes. Moreover, attend-threat training resulted in greater delayed gains compared to the control condition. Auxiliary analyses revealed that enhanced performance was retained over several months, and that training to attend to neutral faces resulted in effects similar to control. These results provide a novel demonstration of how attention to threat can accelerate and enhance memory consolidation effects associated with skill acquisition. C1 [Abend, Rany; Sadeh, Avi; Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Karni, Avi] Univ Haifa, Sagol Dept Neurobiol, IL-31999 Haifa, Israel. [Karni, Avi] Univ Haifa, Study Learning Disabil, Edmond J Safra Brain Res Ctr, IL-31999 Haifa, Israel. [Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Pine, Daniel S.] NIMH, Sect Dev Affect Neurosci, Bethesda, MD 20892 USA. RP Abend, R (reprint author), Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. EM abend@tau.ac.il RI Sadeh, Avi/K-5392-2012 FU Bi-National Science Foundation (BSF) [2009340] FX Bi-National Science Foundation (BSF) grant 2009340 (http://www.bsf.org.il/BSFPublic/Default.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 6 Z9 6 U1 1 U2 14 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 APR 30 PY 2013 VL 8 IS 4 AR e62501 DI 10.1371/journal.pone.0062501 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146GG UT WOS:000319077300070 PM 23638100 ER PT J AU Anderson, MJ Naiche, LA Wilson, CP Elder, C Swing, DA Lewandoski, M AF Anderson, Matthew J. Naiche, L. A. Wilson, Catherine P. Elder, Cindy Swing, Deborah A. Lewandoski, Mark TI TCreERT2, a Transgenic Mouse Line for Temporal Control of Cre-Mediated Recombination in Lineages Emerging from the Primitive Streak or Tail Bud SO PLOS ONE LA English DT Article ID SEGMENTATION CLOCK; NERVOUS-SYSTEM; GENE; MESODERM; MICE; FGF8; INACTIVATION; EXPRESSION; BRACHYURY; KIDNEY AB The study of axis extension and somitogenesis has been greatly advanced through the use of genetic tools such as the TCre mouse line. In this line, Cre is controlled by a fragment of the T (Brachyury) promoter that is active in progenitor cells that reside within the primitive streak and tail bud and which give rise to lineages emerging from these tissues as the embryonic axis extends. However, because TCre-mediated recombination occurs early in development, gene inactivation can result in an axis truncation that precludes the study of gene function in later or more posterior tissues. To address this limitation, we have generated an inducible TCre transgenic mouse line, called TCreERT2, that provides temporal control, through tamoxifen administration, in all cells emerging from the primitive streak or tail bud throughout development. TCreERT2 activity is mostly silent in the absence of tamoxifen and, in its presence, results in near complete recombination of emerging mesoderm from E7.5 through E13.5. We demonstrate the utility of the TCreERT2 line for determining rate of posterior axis extension and somite formation, thus providing the first in vivo tool for such measurements. To test the usefulness of TCreERT2 for genetic manipulation, we demonstrate that an early deletion of beta-Catenin via TCreERT2 induction phenocopies the TCre-mediated deletion of beta-Catenin defect, whereas a later induction bypasses this early phenotype and produces a similar defect in more caudal tissues. TCreERT2 provides a useful and novel tool for the control of gene expression of emerging embryonic lineages throughout development. C1 [Anderson, Matthew J.; Naiche, L. A.; Wilson, Catherine P.; Elder, Cindy; Lewandoski, Mark] NCI, Inst Canc & Dev Biol, Frederick, MD 21701 USA. [Swing, Deborah A.] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Lewandoski, M (reprint author), NCI, Inst Canc & Dev Biol, Frederick, MD 21701 USA. EM Lewandom@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 7 Z9 7 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 30 PY 2013 VL 8 IS 4 AR e62479 DI 10.1371/journal.pone.0062479 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146GG UT WOS:000319077300064 PM 23638095 ER PT J AU Chen, HY Martin, B Daimon, CM Siddiqui, S Luttrell, LM Maudsley, S AF Chen, Hongyu Martin, Bronwen Daimon, Caitlin M. Siddiqui, Sana Luttrell, Louis M. Maudsley, Stuart TI Textrous!: Extracting Semantic Textual Meaning from Gene Sets SO PLOS ONE LA English DT Article ID SYNAPTIC PLASTICITY; KNOCKOUT MICE; HIPPOCAMPUS; ONTOLOGY; BDNF; TOOL AB The un-biased and reproducible interpretation of high-content gene sets from large-scale genomic experiments is crucial to the understanding of biological themes, validation of experimental data, and the eventual development of plans for future experimentation. To derive biomedically-relevant information from simple gene lists, a mathematical association to scientific language and meaningful words or sentences is crucial. Unfortunately, existing software for deriving meaningful and easily-appreciable scientific textual 'tokens' from large gene sets either rely on controlled vocabularies (Medical Subject Headings, Gene Ontology, BioCarta) or employ Boolean text searching and co-occurrence models that are incapable of detecting indirect links in the literature. As an improvement to existing web-based informatic tools, we have developed Textrous!, a web-based framework for the extraction of biomedical semantic meaning from a given input gene set of arbitrary length. Textrous! employs natural language processing techniques, including latent semantic indexing (LSI), sentence splitting, word tokenization, parts-of-speech tagging, and noun-phrase chunking, to mine MEDLINE abstracts, PubMed Central articles, articles from the Online Mendelian Inheritance in Man (OMIM), and Mammalian Phenotype annotation obtained from Jackson Laboratories. Textrous! has the ability to generate meaningful output data with even very small input datasets, using two different text extraction methodologies (collective and individual) for the selecting, ranking, clustering, and visualization of English words obtained from the user data. Textrous!, therefore, is able to facilitate the output of quantitatively significant and easily appreciable semantic words and phrases linked to both individual gene and batch genomic data. C1 [Chen, Hongyu; Siddiqui, Sana; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Martin, Bronwen; Daimon, Caitlin M.] NIA, Metab Unit, Lab Clin Invest, NIH, Baltimore, MD 21224 USA. [Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, Lab Neurosci, NIH, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This research was funded and supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 6 Z9 6 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 30 PY 2013 VL 8 IS 4 AR e62665 DI 10.1371/journal.pone.0062665 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146GG UT WOS:000319077300087 PM 23646135 ER PT J AU Osmundson, TW Robert, VA Schoch, CL Baker, LJ Smith, A Robich, G Mizzan, L Garbelotto, MM AF Osmundson, Todd W. Robert, Vincent A. Schoch, Conrad L. Baker, Lydia J. Smith, Amy Robich, Giovanni Mizzan, Luca Garbelotto, Matteo M. TI Filling Gaps in Biodiversity Knowledge for Macrofungi: Contributions and Assessment of an Herbarium Collection DNA Barcode Sequencing Project SO PLOS ONE LA English DT Article ID INTERNAL TRANSCRIBED SPACER; MOLECULAR-IDENTIFICATION; SPECIES IDENTIFICATION; MYCORRHIZAL FUNGI; TAXONOMY; DIVERSITY; DATABASES; ECOLOGY; NUCLEAR; FUTURE AB Despite recent advances spearheaded by molecular approaches and novel technologies, species description and DNA sequence information are significantly lagging for fungi compared to many other groups of organisms. Large scale sequencing of vouchered herbarium material can aid in closing this gap. Here, we describe an effort to obtain broad ITS sequence coverage of the approximately 6000 macrofungal-species-rich herbarium of the Museum of Natural History in Venice, Italy. Our goals were to investigate issues related to large sequencing projects, develop heuristic methods for assessing the overall performance of such a project, and evaluate the prospects of such efforts to reduce the current gap in fungal biodiversity knowledge. The effort generated 1107 sequences submitted to GenBank, including 416 previously unrepresented taxa and 398 sequences exhibiting a best BLAST match to an unidentified environmental sequence. Specimen age and taxon affected sequencing success, and subsequent work on failed specimens showed that an ITS1 mini-barcode greatly increased sequencing success without greatly reducing the discriminating power of the barcode. Similarity comparisons and nonmetric multidimensional scaling ordinations based on pairwise distance matrices proved to be useful heuristic tools for validating the overall accuracy of specimen identifications, flagging potential misidentifications, and identifying taxa in need of additional species-level revision. Comparison of within- and among-species nucleotide variation showed a strong increase in species discriminating power at 1-2% dissimilarity, and identified potential barcoding issues (same sequence for different species and vice-versa). All sequences are linked to a vouchered specimen, and results from this study have already prompted revisions of species-sequence assignments in several taxa. C1 [Osmundson, Todd W.; Baker, Lydia J.; Smith, Amy; Garbelotto, Matteo M.] Univ Calif Berkeley, Dept Environm Sci Policy & Management, Forest Pathol & Mycol Lab, Berkeley, CA 94720 USA. [Robert, Vincent A.] CBS KNAW Fungal Biodivers Ctr, Cent Bur Schimmelcultures, Utrecht, Netherlands. [Schoch, Conrad L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Robich, Giovanni; Mizzan, Luca] Venice Museum Nat Hist, Venice, Italy. RP Garbelotto, MM (reprint author), Univ Calif Berkeley, Dept Environm Sci Policy & Management, Forest Pathol & Mycol Lab, Berkeley, CA 94720 USA. EM matteog@berkeley.edu FU Intramural Research Program of the NIH, National Library of Medicine; Gordon and Betty Moore Foundation FX CLS was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Funding by the Gordon and Betty Moore Foundation to MG for the Moorea BIOCODE project generated much-needed synergy with the Venice herbarium project. Sequencing was performed in house thanks to equipment purchased through a grant by the Gordon and Betty Moore Foundation to MG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 35 Z9 36 U1 4 U2 45 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 APR 30 PY 2013 VL 8 IS 4 AR UNSP e62419 DI 10.1371/journal.pone.0062419 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146GG UT WOS:000319077300055 PM 23638077 ER PT J AU Koonin, EV Landweber, LF Lipman, DJ AF Koonin, Eugene V. Landweber, Laura F. Lipman, David J. TI Biology direct: celebrating 7 years of open, published peer review SO BIOLOGY DIRECT LA English DT Editorial Material C1 [Koonin, Eugene V.; Lipman, David J.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Landweber, Laura F.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD APR 30 PY 2013 VL 8 AR 11 DI 10.1186/1745-6150-8-11 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 144AF UT WOS:000318910700001 PM 23631729 ER PT J AU Yepes, AJ Prieur-Gaston, E Neveol, A AF Yepes, Antonio Jimeno Prieur-Gaston, Elise Neveol, Aurelie TI Combining MEDLINE and publisher data to create parallel corpora for the automatic translation of biomedical text SO BMC BIOINFORMATICS LA English DT Article DE Multilingual corpus generation; Statistical machine translation; Biomedical domain ID HEALTH INFORMATION; RETRIEVAL AB Background: Most of the institutional and research information in the biomedical domain is available in the form of English text. Even in countries where English is an official language, such as the United States, language can be a barrier for accessing biomedical information for non-native speakers. Recent progress in machine translation suggests that this technique could help make English texts accessible to speakers of other languages. However, the lack of adequate specialized corpora needed to train statistical models currently limits the quality of automatic translations in the biomedical domain. Results: We show how a large-sized parallel corpus can automatically be obtained for the biomedical domain, using the MEDLINE database. The corpus generated in this work comprises article titles obtained from MEDLINE and abstract text automatically retrieved from journal websites, which substantially extends the corpora used in previous work. After assessing the quality of the corpus for two language pairs (English/French and English/Spanish) we use the Moses package to train a statistical machine translation model that outperforms previous models for automatic translation of biomedical text. Conclusions: We have built translation data sets in the biomedical domain that can easily be extended to other languages available in MEDLINE. These sets can successfully be applied to train statistical machine translation models. While further progress should be made by incorporating out-of-domain corpora and domain-specific lexicons, we believe that this work improves the automatic translation of biomedical texts. C1 [Yepes, Antonio Jimeno] US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. [Yepes, Antonio Jimeno] NICTA Victoria Res Lab, Melbourne, Vic 3010, Australia. [Prieur-Gaston, Elise] Univ Rouen, LITIS EA 4108, F-76821 Mont St Aignan, France. [Neveol, Aurelie] US Natl Lib Med, Natl Ctr Biotechnol Commun, Bethesda, MD USA. [Neveol, Aurelie] LIMSI CNRS, F-91400 Orsay, France. RP Yepes, AJ (reprint author), US Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, 8600 Rockville Pike, Bethesda, MD USA. EM antonio.jimeno@gmail.com; neveol@limsi.fr OI Jimeno Yepes, Antonio Jose/0000-0002-6581-094X FU Intramural Research Program of the National Institutes of Health; National Library of Medicine; Australian Government; Australian Research Council through the ICT Centre of Excellence program FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine and by an appointment of A. Jimeno-Yepes to the NLM Research Participation Program sponsored by the National Library of Medicine and administered by the Oak Ridge Institute for Science and Education. The authors thank Dr. Michael Filhol for his editorial assistance.; NICTA is funded by the Australian Government as represented by the Department of Broadband, Communications and the Digital Economy and the Australian Research Council through the ICT Centre of Excellence program. The authors thank Dr. Darmoni for helpful discussions on the study. NR 24 TC 1 Z9 1 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD APR 30 PY 2013 VL 14 AR 146 DI 10.1186/1471-2105-14-146 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 140RV UT WOS:000318673600001 PM 23631733 ER PT J AU Fu, D Mitra, K Sengupta, P Jarnik, M Lippincott-Schwartz, J Arias, IM AF Fu, Dong Mitra, Kasturi Sengupta, Prabuddha Jarnik, Michal Lippincott-Schwartz, Jennifer Arias, Irwin M. TI Coordinated elevation of mitochondrial oxidative phosphorylation and autophagy help drive hepatocyte polarization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE energy metabolism; AMPK; mitochondrial fusion ID ACTIVATED PROTEIN-KINASE; NETWORK FORMATION; CELL-MIGRATION; ENERGY SENSOR; AMPK; METABOLISM; FUSION; DEATH; MORPHOGENESIS; TRAFFICKING AB Cell polarization requires increased cellular energy and metabolic output, but how these energetic demands are met by polarizing cells is unclear. To address these issues, we investigated the roles of mitochondrial bioenergetics and autophagy during cell polarization of hepatocytes cultured in a collagen sandwich system. We found that as the hepatocytes begin to polarize, they use oxidative phosphorylation to raise their ATP levels, and this energy production is required for polarization. After the cells are polarized, the hepatocytes shift to become more dependent on glycolysis to produce ATP. Along with this central reliance on oxidative phosphorylation as the main source of ATP production in polarizing cultures, several other metabolic processes are reprogrammed during the time course of polarization. As the cells polarize, mitochondria elongate and mitochondrial membrane potential increases. In addition, lipid droplet abundance decreases over time. These findings suggest that polarizing cells are reliant on fatty acid oxidation, which is supported by pharmacologic inhibition of beta-oxidation by etomoxir. Finally, autophagy is up-regulated during cell polarization, with inhibition of autophagy retarding cell polarization. Taken together, our results describe a metabolic shift involving a number of coordinated metabolic pathways that ultimately serve to increase energy production during cell polarization. C1 [Fu, Dong; Mitra, Kasturi; Sengupta, Prabuddha; Jarnik, Michal; Lippincott-Schwartz, Jennifer; Arias, Irwin M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Fu, Dong] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia. [Mitra, Kasturi] Univ Alabama Birmingham, Sch Med, Dept Genet, Birmingham, AL 35294 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov; ariasi@mail.nih.gov NR 42 TC 14 Z9 14 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 30 PY 2013 VL 110 IS 18 BP 7288 EP 7293 DI 10.1073/pnas.1304285110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140UV UT WOS:000318682300045 PM 23589864 ER PT J AU Sungur, CM Tang-Feldman, YJ Ames, E Alvarez, M Chen, MY Longo, DL Pomeroy, C Murphy, WJ AF Sungur, Can M. Tang-Feldman, Yajarayma J. Ames, Erik Alvarez, Maite Chen, Mingyi Longo, Dan L. Pomeroy, Claire Murphy, William J. TI Murine natural killer cell licensing and regulation by T regulatory cells in viral responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunity; innate immune system; virology; education; arming ID MHC CLASS-I; NK CELLS; CYTOMEGALOVIRUS-INFECTION; INHIBITORY RECEPTORS; CUTTING EDGE; SELF-TOLERANCE; TRANSPLANTATION; RESPONSIVENESS; MICE; MOLECULES AB Natural killer (NK) cells show differential functionality based on their capability of binding to self-MHC consistent with licensing. Here we show in vivo confirmation of the physiologic effects of licensing with differential effects of NK subsets on anti-murine cytomegalovirus (anti-MCMV) responses after syngeneic hematopoietic stem cell transplantation (HSCT) or regulatory T-cell (Treg) depletion. After HSCT, depletion of licensed NK cells led to far greater viral loads in target organs early after infection compared with nondepleted and unlicensed depleted mice. There was a preferential expansion of licensed, C-type lectin-like activating receptor Ly49H+ NK cells with increased IFN gamma production after infection in nondepleted mice post-HSCT and after Treg depletion. Adoptive transfer of licensed NK subsets into immunodeficient hosts provided significantly greater MCMV resistance compared with transfer of total NK populations or unlicensed subsets. In non-HSCT mice, only concurrent depletion of Tregs or TGF-beta neutralization resulted in detection of NK licensing effects. This suggests that licensed NK cells are the initial and rapidly responding population of NK cells to MCMV infection, but are highly regulated by Tregs and TGF-beta. C1 [Sungur, Can M.; Ames, Erik; Alvarez, Maite; Murphy, William J.] Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. [Tang-Feldman, Yajarayma J.; Pomeroy, Claire; Murphy, William J.] Univ Calif Davis, Sch Med, Dept Internal Med, Sacramento, CA 95817 USA. [Chen, Mingyi] Univ Calif Davis, Sch Med, Dept Pathol, Sacramento, CA 95817 USA. [Longo, Dan L.] NIA, NIH, Baltimore, MD 21224 USA. RP Murphy, WJ (reprint author), Univ Calif Davis, Sch Med, Dept Dermatol, Sacramento, CA 95817 USA. EM wmjmurphy@ucdavis.edu FU National Institutes of Health [R01 HL089905] FX We thank Raymond Lochhead and Weihong Ma for their technical expertise, Dr. Athena Soulika for providing GKO mice, and Dr. Lewis Lanier and Dr. Joseph Tuscano for helpful comments. This work was funded by National Institutes of Health Grant R01 HL089905. NR 42 TC 16 Z9 17 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 30 PY 2013 VL 110 IS 18 BP 7401 EP 7406 DI 10.1073/pnas.1218767110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140UV UT WOS:000318682300063 PM 23589894 ER PT J AU Deng, L Zhong, LL Struble, E Duan, HY Ma, L Harman, C Yan, HL Virata-Theimer, ML Zhao, Z Feinstone, S Alter, H Zhang, P AF Deng, Lu Zhong, Lilin Struble, Evi Duan, Hongying Ma, Li Harman, Christine Yan, Hailing Virata-Theimer, Maria Luisa Zhao, Zhong Feinstone, Stephen Alter, Harvey Zhang, Pei TI Structural evidence for a bifurcated mode of action in the antibody-mediated neutralization of hepatitis C virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MONOCLONAL-ANTIBODIES; E2 PROTEIN; INFECTION; CHIMPANZEES; EPITOPES; VACCINE AB Hepatitis C virus (HCV) envelope glycoprotein E2 has been considered as a major target for vaccine design. Epitope II, mapped between residues 427-446 within the E2 protein, elicits antibodies that are either neutralizing or nonneutralizing. The fundamental mechanism of antibody-mediated neutralization at epitope II remains to be defined at the atomic level. Here we report the crystal structure of the epitope II peptide in complex with a monoclonal antibody (mAb#8) capable of neutralizing HCV. The complex structure revealed that this neutralizing antibody engages epitope II via interactions with both the C-terminal a-helix and the N-terminal loop using a bifurcated mode of action. Our structural insights into the key determinants for the antibody-mediated neutralization may contribute to the immune prophylaxis of HCV infection and the development of an effective HCV vaccine. C1 [Deng, Lu; Zhong, Lilin; Struble, Evi; Ma, Li; Harman, Christine; Yan, Hailing; Virata-Theimer, Maria Luisa; Zhao, Zhong; Zhang, Pei] US FDA, Div Hematol, Off Blood Res & Review, Bethesda, MD 20892 USA. [Duan, Hongying; Feinstone, Stephen] US FDA, Div Viral Prod, Off Vaccine Res & Review, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Alter, Harvey] NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Alter, H (reprint author), NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. EM halter@dtm.cc.nih.gov; pei.zhang@fda.hhs.gov FU Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences; National Center for Research Resources of the National Institutes of Health; Modernizing Science grant from the Center for Biologics Evaluation and Research, Food and Drug Administration FX We thank Drs. John Finlayson and Shan-Lu Liu for their comments on the manuscript and Drs. Tsan Xiao and Tengchuan Jin (National Institute of Allergy and Infectious Diseases) for providing the instrument for crystallization screening. We thank Howard Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Beamline X29 is supported by the Department of Energy Offices of Biological and Environmental Research and Basic Energy Sciences and by the National Center for Research Resources of the National Institutes of Health. This study was funded by a Modernizing Science grant from the Center for Biologics Evaluation and Research, Food and Drug Administration. NR 26 TC 19 Z9 19 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 30 PY 2013 VL 110 IS 18 BP 7418 EP 7422 DI 10.1073/pnas.1305306110 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140UV UT WOS:000318682300066 PM 23589879 ER PT J AU Topanurak, S Ferraris, JD Li, JX Izumi, Y Williams, CK Gucek, M Wang, GH Zhou, XM Burg, MB AF Topanurak, Supachai Ferraris, Joan D. Li, Jinxi Izumi, Yuichiro Williams, Chester K. Gucek, Marjan Wang, Guanghui Zhou, Xiaoming Burg, Maurice B. TI High NaCl- and urea-induced posttranslational modifications that increase glycerophosphocholine by inhibiting GDPD5 phosphodiesterase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE peroxiredoxin; Phos-tag ID NEURONAL DIFFERENTIATION; ORGANIC OSMOLYTES; PROTEIN GDE2; MDCK CELLS; IN-VIVO; ACTIVATION; GRADIENT; SYSTEMS; STRESS; ENZYME AB Glycerophosphocholine (GPC) is high in cells of the renal inner medulla where high interstitial NaCl and urea power concentration of the urine. GPC protects inner medullary cells against the perturbing effects of high NaCl and urea by stabilizing intracellular macromolecules. Degradation of GPC is catalyzed by the glycerophosphocholine phosphodiesterase activity of glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5). We previously found that inhibitory posttranslational modification (PTM) of GDPD5 contributes to high NaCl-and urea-induced increase of GPC. The purpose of the present studies was to identify the PTM(s). We find at least three such PTMs in HEK293 cells: (i) Formation of a disulfide bond between C25 and C571. High NaCl and high urea increase reactive oxygen species (ROS). The ROS increase disulfide bonding between GDPD5-C25 and -C571, which inhibits GDPD5 activity, as supported by the findings that the antioxidant N-acetylcysteine prevents high NaCl-and urea-induced inhibition of GDPD5; GDPD5-C25S/C571S mutation or over expression of peroxiredoxin increases GDPD5 activity; H2O2 inhibits activity of wild type GDPD5, but not of GDPD5-C25S/C571S; and peroxiredoxin is relatively low in the renal inner medulla where GPC is high. (ii) Dephosphorylation of GDPD5-T587. GDPD5 threonine 587 is constitutively phosphorylated. High NaCl and high urea dephosphorylate GDPD5-T587. Mutation of GDPD5-T587 to alanine, which cannot be phosphorylated, decreases GPC-PDE activity of GDPD5. (iii) Alteration at an unknown site mediated by CDK1. Inhibition of CDK1 protein kinase reduces GDE-PDE activity of GDPD5 without altering phosphorylation at T587, and CDK1/5 inhibitor reduces activity of GDPD5-C25S/C571S-T587A. C1 [Topanurak, Supachai; Ferraris, Joan D.; Li, Jinxi; Izumi, Yuichiro; Williams, Chester K.; Gucek, Marjan; Wang, Guanghui; Zhou, Xiaoming; Burg, Maurice B.] NHLBI, Syst Biol Ctr, Bethesda, MD 20892 USA. [Zhou, Xiaoming] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NHLBI, Syst Biol Ctr, Bldg 10, Bethesda, MD 20892 USA. EM maurice_burg@nih.gov NR 24 TC 4 Z9 5 U1 3 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 30 PY 2013 VL 110 IS 18 BP 7482 EP 7487 DI 10.1073/pnas.1305220110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140UV UT WOS:000318682300077 PM 23589856 ER PT J AU DeRouchey, J Hoover, B Rau, DC AF DeRouchey, Jason Hoover, Brandon Rau, Donald C. TI A Comparison of DNA Compaction by Arginine and Lysine Peptides: A Physical Basis for Arginine Rich Protarnines SO BIOCHEMISTRY LA English DT Article ID HERRING SPERM DNA; L-AMINO ACIDS; INTERMOLECULAR FORCES; DOUBLE HELICES; HUMAN SPERMATOZOA; HYDRATION FORCES; CHAIN LENGTHS; X-RAY; PROTAMINE; AGGREGATION AB Protamines are small, highly positively charged peptides used to package DNA at very high densities in sperm nuclei. Tight DNA packing is considered essential for the minimization of DNA damage by mutagens and reactive oxidizing species. A striking and general feature of protamines is the almost exclusive use of arginine over lysine for the positive charge to neutralize DNA. We have investigated whether this preference for arginine, might arise from a difference in DNA condensation by arginine and lysine peptides. The forces underlying DNA compaction by arginine, lysine, and ornithine peptides are measured using the osmotic stress technique coupled with X-ray scattering. The equilibrium spacings between DNA helices condensed by lysine and ornithine peptides are significantly larger than the interhelical distances with comparable arginine peptides. The DNA surface-to-surface separation, for example, is some 50% larger with polylysine than with polyarginine. DNA packing by lysine rich peptides in sperm nuclei would allow much greater accessibility to small molecules that could damage DNA. The larger spacing with lysine peptides is caused by both a weaker attraction and a stronger short-range repulsion relative to that of the arginine peptides. A previously proposed model for binding of polyarginine and protamine to DNA provides a convenient framework for understanding the differences between the ability of lysine and arginine peptides to assemble DNA. C1 [DeRouchey, Jason] Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. [Hoover, Brandon; Rau, Donald C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Rau, DC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM raud@mail.nih.gov RI DeRouchey, Jason/C-5907-2011 OI DeRouchey, Jason/0000-0002-3624-4432 FU Intramural Research Program of the National Institutes of Health, NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) FX This work was supported by the Intramural Research Program of the National Institutes of Health, NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development). NR 49 TC 29 Z9 31 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD APR 30 PY 2013 VL 52 IS 17 BP 3000 EP 3009 DI 10.1021/bi4001408 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 136AZ UT WOS:000318333100015 PM 23540557 ER PT J AU Jain, A Liu, K Ferrucci, L Criqui, MH Tian, L Guralnik, JM Tao, HM McDermott, MM AF Jain, Atul Liu, Kiang Ferrucci, Luigi Criqui, Michael H. Tian, Lu Guralnik, Jack M. Tao, Huimin McDermott, Mary M. TI Declining Walking Impairment Questionnaire Scores Are Associated With Subsequent Increased Mortality in Peripheral Artery Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE functional limitation; intermittent claudication; mortality; peripheral artery disease ID ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; PHYSICAL-ACTIVITY; PREVALENCE; EXERCISE; RISK AB Objectives This study determined whether greater 2-year declines in Walking Impairment Questionnaire (WIQ) stair climbing, distance, or speed scores were associated with higher all-cause and cardiovascular disease (CVD) mortality among men and women with lower extremity peripheral artery disease (PAD). Background Associations of decline in the WIQ with mortality among people with PAD are unknown. Methods Participants were 442 men and women with PAD identified from Chicago area medical centers. The WIQ was completed at baseline and at 2-year follow-up. Cox proportional hazard models were used to assess associations across categories of 2-year changes in WIQ stair climbing, WIQ distance, and WIQ speed scores with subsequent all-cause and CVD mortality, adjusting for age, sex, race, ankle-brachial index, body mass index, smoking, comorbidities, and other covariates. Results One hundred twenty-three participants (27.8%) died during a median follow-up of 4.7 years after the 2-year change in WIQ score measurements. Forty-five participants died from CVD. Adjusting for covariates, participants with WIQ score declines >= 20.0 points had higher all-cause mortality (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.01 to 3.68 for WIQ stair climbing; HR: 2.34, 95% CI: 1.15 to 4.75 for WIQ distance; and HR: 3.55, 95% CI: 1.57 to 8.04 for WIQ speed, respectively) compared with participants with >= 20.0 point improvement in each of the corresponding WIQ categories. Participants with >= 20.0 point declines in the WIQ distance score had higher CVD mortality (HR: 4.56, 95% CI: 1.30 to 16.01) compared with those with >= 20.0 point improvement in the WIQ distance score. Conclusions Patients with PAD who experienced >= 20.0 point declines in the WIQ stair climbing, distance, and speed scores had a higher rate of all-cause mortality compared with those with less declines in each WIQ score. (J Am Coll Cardiol 2013;61:1820-9) (C) 2013 by the American College of Cardiology Foundation C1 [Jain, Atul] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Liu, Kiang; Tao, Huimin; McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Ferrucci, Luigi] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Prevent Med, La Jolla, CA 92093 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy Biostat, Palo Alto, CA 94304 USA. [Guralnik, Jack M.] Univ Maryland, Dept Epidemiol & Publ Hlth, Bethesda, MD USA. [Guralnik, Jack M.] Uniformed Serv Univ Hlth Sci, Sch Med, Bethesda, MD 20814 USA. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Div Gen Internal Med, 750 North Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute [K12-HL083790, R01-HL083064, R01-HL64739, R01-HL71223]; National Center for Research Resources, National Institutes of Health [RR-00048]; National Institute on Aging FX This study was supported by grants from the National Heart, Lung, and Blood Institute (K12-HL083790, R01-HL083064, R01-HL64739, and R01-HL71223) and by a grant from the National Center for Research Resources, National Institutes of Health (RR-00048). This study was also supported by the National Institute on Aging. The authors have no relationships relevant to the contents of this paper to disclose. William Hiatt, MD, acted as Guest Editor for this paper. NR 16 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 30 PY 2013 VL 61 IS 17 BP 1820 EP 1829 DI 10.1016/j.jacc.2013.01.060 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 129LT UT WOS:000317842200011 PM 23500321 ER PT J AU Lopez, KC Lalonde, F Mattai, A Wade, B Clasen, L Rapoport, J Giedd, JN AF Lopez, Katherine C. Lalonde, Francois Mattai, Anand Wade, Benjamin Clasen, Liv Rapoport, Judith Giedd, Jay N. TI Quantitative morphology of the corpus callosum in obsessive-compulsive disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Obsessive-compulsive disorder; Corpus callosum; Morphometry; Magnetic resonance imaging ID WHITE-MATTER MICROSTRUCTURE; GLUCOSE METABOLIC RATES; MEDIAL FRONTAL-CORTEX; DIFFUSION-TENSOR; OCD PATIENTS; ABNORMALITIES; CONNECTIVITY; TRACTOGRAPHY; CHILDREN; VOLUME AB Neuroimaging studies have implicated the corpus callosum (CC) in the pathophysiology of obsessive-compulsive disorder (OCD). Putative dysfunctions in prefrontal cortical regions suggest anomalies in anterior segments of the CC. However, recent studies have also implicated the middle and posterior CC. The present study soughts to examine the CC using parcellation scheme informed by diffusion tensor imaging. Anatomic brain magnetic resonance scans were obtained from 21 OCD subjects (mean age=26.9 +/- 9.93) and 42 healthy age- and sex-matched controls (mean age=26.6 +/- 9.46) between the ages of 14 and 49. Area and volume measures of five subregions of the CC were obtained via manual tracings. A multivariate analysis of variance (after correcting for multiple comparisons) identified smaller area and volume in the mid-anterior region of the CC in OCD patients relative to controls. These findings implicate media-frontal regions of the cortex in the pathophysiology of OCD. (C) 2013 Published by Elsevier Ireland Ltd. C1 [Lopez, Katherine C.; Lalonde, Francois; Mattai, Anand; Wade, Benjamin; Clasen, Liv; Rapoport, Judith; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Giedd, JN (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 4C110,10 Ctr Dr,MSC 1367, Bethesda, MD 20892 USA. EM jg@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z99 MH999999] NR 35 TC 5 Z9 5 U1 1 U2 12 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD APR 30 PY 2013 VL 212 IS 1 BP 1 EP 6 DI 10.1016/j.pscychresns.2012.10.012 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 127MD UT WOS:000317702200001 PM 23453697 ER PT J AU Bozdag, S Li, AG Riddick, G Kotliarov, Y Baysan, M Iwamoto, FM Cam, MC Kotliarova, S Fine, HA AF Bozdag, Serdar Li, Aiguo Riddick, Gregory Kotliarov, Yuri Baysan, Mehmet Iwamoto, Fabio M. Cam, Margaret C. Kotliarova, Svetlana Fine, Howard A. TI Age-Specific Signatures of Glioblastoma at the Genomic, Genetic, and Epigenetic Levels SO PLOS ONE LA English DT Article ID COPY-NUMBER ALTERATION; HIGH-GRADE GLIOMA; DNA METHYLATION; RECURRENT GLIOBLASTOMA; MOLECULAR SUBTYPES; RADIATION-THERAPY; MALIGNANT GLIOMAS; TUMOR PROGRESSION; EXPRESSION; CANCER AB Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs. C1 [Bozdag, Serdar; Li, Aiguo; Riddick, Gregory; Kotliarov, Yuri; Baysan, Mehmet; Iwamoto, Fabio M.; Cam, Margaret C.; Kotliarova, Svetlana; Fine, Howard A.] NINDS, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. [Bozdag, Serdar] Marquette Univ, Dept Math Stat & Comp Sci, Milwaukee, WI 53233 USA. [Kotliarov, Yuri] NHLBI, Ctr Human Immunol Autoimmun & Inflammat, NIH, Bethesda, MD 20892 USA. [Iwamoto, Fabio M.] Columbia Univ, Coll Phys & Surg, Neurol Inst New York, New York, NY USA. [Fine, Howard A.] NYU, Inst Canc, Langone Med Ctr, New York, NY USA. RP Bozdag, S (reprint author), NINDS, Neurooncol Branch, NCI, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM serdar.bozdag@marquette.edu RI Kotliarov, Yuri/B-6938-2017 FU National Institutes of Health (NIH), National Cancer Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 18 Z9 18 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 29 PY 2013 VL 8 IS 4 AR e62982 DI 10.1371/journal.pone.0062982 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 181JC UT WOS:000321662800071 PM 23658659 ER PT J AU Alvheim, AR Torstensen, BE Lin, YH Lillefosse, HH Lock, EJ Madsen, L Hibbeln, JR Malde, MK AF Alvheim, Anita R. Torstensen, Bente E. Lin, Yu Hong Lillefosse, Haldis H. Lock, Erik-Jan Madsen, Lise Hibbeln, Joseph R. Malde, Marian K. TI Dietary linoleic acid elevates endogenous 2-arachidonoylglycerol and anandamide in Atlantic salmon (Salmo salar L.) and mice, and induces weight gain and inflammation in mice SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Linoleic acid; 2-Arachidonoylglycerol; Anandamide; Obesity; Inflammation; Atlantic salmon ID POLYUNSATURATED FATTY-ACIDS; ADIPOSE-TISSUE DEVELOPMENT; CORONARY-HEART-DISEASE; FISH-OIL REPLACEMENT; OBESE-DIABETIC MICE; VEGETABLE-OIL; ENDOCANNABINOID LEVELS; N-ACYLETHANOLAMINES; GENE-EXPRESSION; SOYBEAN OIL AB Dietary intake of linoleic acid (LA) has increased dramatically during the twentieth century and is associated with a greater prevalence of obesity. Vegetable oils are recognised as suitable alternatives to fish oil (FO) in feed for Atlantic salmon (Salmo salar L.) but introduce high amounts of LA in the salmon fillet. The effect on fish consumers of such a replacement remains to be elucidated. Here, we investigate the effect of excessive dietary LA from soyabean oil (SO) on endocannabinoid levels in Atlantic salmon and mice, and study the metabolic effects in mice when SO replaces FO in feed for Atlantic salmon. Atlantic salmon were fed FO and SO for 6 months, and the salmon fillet was used to produce feed for mice. Male C57BL/6J mice were fed diets of 35% of energy as fat based on FO- and SO-enriched salmon for 16 weeks. We found that replacing FO with SO in feed for Atlantic salmon increased LA, arachidonic acid (AA), decreased EPA and DHA, elevated the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), and increased TAG accumulation in the salmon liver. In mice, the SO salmon diet increased LA and AA and decreased EPA and DHA in the liver and erythrocyte phospholipids, and elevated 2-AG and AEA associated with increased feed efficiency, weight gain and adipose tissue inflammation compared with mice fed the FO salmon diet. In conclusion, excessive dietary LA elevates endocannabinoids in the liver of salmon and mice, and increases weight gain and counteracts the anti-inflammatory properties of EPA and DHA in mice. C1 [Alvheim, Anita R.; Torstensen, Bente E.; Lillefosse, Haldis H.; Lock, Erik-Jan; Madsen, Lise; Malde, Marian K.] Natl Inst Nutr & Seafood Res NIFES, N-5817 Bergen, Norway. [Alvheim, Anita R.] Univ Bergen, Dept Biomed, Bergen, Norway. [Lin, Yu Hong; Hibbeln, Joseph R.] NIAAA, Rockville, MD 20852 USA. [Lillefosse, Haldis H.; Madsen, Lise] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. RP Malde, MK (reprint author), Natl Inst Nutr & Seafood Res NIFES, POB 2029, N-5817 Bergen, Norway. EM mma@nifes.no RI Lock, Erik-Jan/F-3115-2012; Madsen, Lise/C-6246-2012; Kjellevold, Marian/C-2973-2012 OI Madsen, Lise/0000-0003-4468-1947; Kjellevold, Marian/0000-0001-7070-5784 FU National Institute of Nutrition and Seafood Research, Bergen, Norway; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA; Research Council of Norway [186908/l10] FX The present study was supported by the National Institute of Nutrition and Seafood Research, Bergen, Norway, the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, USA, and the Research Council of Norway 186908/l10. The authors' responsibilities were as follows: A. R. A. and M. K. M. designed the study and conducted the mouse trial. A. R. A., Y. H. L., E.-J. L. and H. H. L. analysed the data. A. R. A. performed the statistical analysis and had primary responsibility for the final content; B. E. T. designed the study and conducted the fish trial. A. R. A., L. M. and B. E. T. wrote the paper; J. R. H. contributed to the design and provided the essential equipment. The authors declare that they have no conflict of interest. NR 69 TC 18 Z9 18 U1 2 U2 22 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD APR 28 PY 2013 VL 109 IS 8 BP 1508 EP 1517 DI 10.1017/S0007114512003364 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 124AG UT WOS:000317434200017 PM 22883314 ER PT J AU Ho, Y Tsao, SW Zeng, MS Lui, VWY AF Ho, Yeung Tsao, Sai-Wah Zeng, Musheng Lui, Vivian Wai Yan TI STAT3 as a therapeutic target for Epstein-Barr virus (EBV) - associated nasopharyngeal carcinoma SO CANCER LETTERS LA English DT Review DE STAT3; Nasopharyngeal cancer; EBV; Molecular targeting; Head and neck cancers ID EPIDERMAL-GROWTH-FACTOR; G-QUARTET OLIGONUCLEOTIDES; SIGNALING INDUCES APOPTOSIS; SMALL-MOLECULE INHIBITOR; SQUAMOUS-CELL CARCINOMA; JSI-124 CUCURBITACIN-I; PROSTATE-CANCER CELLS; DNA-BINDING ACTIVITY; EPITHELIAL-CELLS; FACTOR-RECEPTOR AB Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer found in Southeast Asia, is etiologically associated with the infection of an oncogenic virus, the Epstein-Barr virus (EBV). Here, we review literature findings on the potential/putative role of STAT3 signaling in its pathogenesis and discuss anti-STAT3 targeting as a therapeutic and possibly prevention strategy for NPC. Lastly, the potential involvement of STAT3 in other oncovirus-associated (e.g. the human papillomavirus) head and neck cancers have not been investigated and we hope that findings in EBV-associated NPC can prompt future investigations in these cancers, which are of increasing impact in the Western countries. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Ho, Yeung] NCI, Gene Regulat Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Tsao, Sai-Wah] Univ Hong Kong, Dept Anat, Hong Kong, Hong Kong, Peoples R China. [Zeng, Musheng] Sun Yat Sen Univ, State Key Lab Oncol South China, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Lui, Vivian Wai Yan] Univ Pittsburgh, Dept Otolaryngol, Sch Med, Pittsburgh, PA 15213 USA. RP Lui, VWY (reprint author), 200 Lothrop St,W912 BST, Pittsburgh, PA 15213 USA. EM luivw@upmc.edu RI Lui, Vivian/I-5458-2016 FU Pittsburgh Foundation, USA; Career Development Program of the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer [5P50 CA097190-05]; Head and Neck Cancer SPORE Developmental Research Award [5P50 CA097007]; Hong Kong General Research Fund [HKU 770809M, HKU776608M, HKU779810M, HKI780911M]; AoE NPC grant [AoE/M-06/08]; RCG Grant from University of Hong Kong; National Natural Science Foundation of China [81025014, 81161120408] FX VWYL is supported by the Patricia L. Knebel Fund of the Pittsburgh Foundation, USA, the Career Development Program of the Specialized Program of Research Excellence (SPORE) in Head and Neck Cancer (5P50 CA097190-05), the Head and Neck Cancer SPORE Developmental Research Award (5P50 CA097007). SWT received funding support from the Hong Kong General Research Fund (HKU 770809M, HKU776608M, HKU779810M and HKI780911M), the AoE NPC grant (AoE/M-06/08), and RCG Grant from University of Hong Kong. MZ is supported by National Natural Science Foundation of China (81025014 and 81161120408). NR 144 TC 10 Z9 11 U1 1 U2 34 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD APR 28 PY 2013 VL 330 IS 2 BP 141 EP 149 DI 10.1016/j.canlet.2012.11.052 PG 9 WC Oncology SC Oncology GA 095AX UT WOS:000315308000003 PM 23220625 ER PT J AU Salmon, DA Proschan, M Forshee, R Gargiullo, P Bleser, W Burwen, DR Cunningham, F Garman, P Greene, SK Lee, GM Vellozzi, C Yih, WK Gellin, B Lurie, N AF Salmon, Daniel A. Proschan, Michael Forshee, Richard Gargiullo, Paul Bleser, William Burwen, Dale R. Cunningham, Francesca Garman, Patrick Greene, Sharon K. Lee, Grace M. Vellozzi, Claudia Yih, W. Katherine Gellin, Bruce Lurie, Nicole CA H1N1 GBS Meta-Anal Working Grp TI Association between Guillain-Barre syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis SO LANCET LA English DT Article ID SAFETY DATALINK PROJECT; PRACTICE RESEARCH DATABASE; UNITED-STATES; IMMUNIZATION-SAFETY; VACCINATION; SURVEILLANCE; RECEIPT; PROGRAM; KINGDOM; COHORT AB Background The influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barre syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barre syndrome is a rare but serious health disorder in which a person's own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barre syndrome. Methods Data were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barre syndrome per million vaccinations. We used a self-controlled risk-interval design. Findings Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barre syndrome (incidence rate ratio 2.35, 95% CI 1.42-4.01, p=0.0003). This finding translated to about 1.6 excess cases of Guillain-Barre syndrome per million people vaccinated. Interpretation The modest risk of Guillain-Barre syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks. C1 [Salmon, Daniel A.; Bleser, William; Gellin, Bruce] Dept Hlth & Human Serv, Natl Vaccine Program Off, Off Assistant Secretary Hlth, Washington, DC USA. [Lurie, Nicole] Dept Hlth & Human Serv, Washington, DC USA. [Salmon, Daniel A.] Johns Hopkins Bloomberg Sch Publ Hlth, Inst Vaccine Safety, Baltimore, MD 21205 USA. [Proschan, Michael] NIH, Bethesda, MD 20892 USA. [Forshee, Richard; Burwen, Dale R.] US FDA, Rockville, MD 20857 USA. [Gargiullo, Paul; Vellozzi, Claudia] Ctr Dis Control & Prevent, Atlanta, GA USA. [Cunningham, Francesca] US Dept Vet Affairs, Hines, IL USA. [Garman, Patrick] US Dept Def, Washington, DC 20305 USA. [Greene, Sharon K.; Lee, Grace M.; Yih, W. Katherine] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Greene, Sharon K.; Lee, Grace M.; Yih, W. Katherine] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Salmon, DA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Inst Vaccine Safety, Baltimore, MD 21205 USA. EM dsalmon@jhsph.edu OI Jacobsen, Steven/0000-0002-8174-8533; Bleser, William/0000-0002-4640-8680 FU US Federal Government FX US Federal Government. NR 40 TC 55 Z9 55 U1 0 U2 74 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD APR 27 PY 2013 VL 381 IS 9876 BP 1461 EP 1468 DI 10.1016/S0140-6736(12)62189-8 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 139TK UT WOS:000318607300035 PM 23498095 ER PT J AU Fricke, T Valle-Casuso, JC White, TE Brandariz-Nunez, A Bosche, WJ Reszka, N Gorelick, R Diaz-Griffero, F AF Fricke, Thomas Valle-Casuso, Jose Carlos White, Tommy E. Brandariz-Nunez, Alberto Bosche, William J. Reszka, Natalia Gorelick, Robert Diaz-Griffero, Felipe TI The ability of TNPO3-depleted cells to inhibit HIV-1 infection requires CPSF6 SO RETROVIROLOGY LA English DT Article ID NUCLEAR IMPORT; REVERSE TRANSCRIPTION; TRANSPORTIN 3; RING DOMAIN; VIRUS; REPLICATION; TRIM5-ALPHA; PROTEINS; RESTRICTION; INTEGRATION AB Background: Expression of the cellular karyopherin TNPO3/transportin-SR2/Tnp3 is necessary for HIV-1 infection. Depletion of TNPO3 expression in mammalian cells inhibits HIV-1 infection after reverse transcription but prior to integration. Results: This work explores the role of cleavage and polyadenylation specificity factor subunit 6 (CPSF6) in the ability of TNPO3-depleted cells to inhibit HIV-1 infection. Our findings showed that depletion of TNPO3 expression inhibits HIV-1 infection, while the simultaneous depletion of TNPO3 and CPSF6 expression rescues HIV-1 infection. Several experiments to understand the rescue of infectivity by CPSF6 were performed. Our experiments revealed that the HIV-1 capsid binding ability of the endogenously expressed CPSF6 from TNPO3-depleted cells does not change when compared to CPSF6 from wild type cells. In agreement with our previous results, depletion of TNPO3 did not change the nuclear localization of CPSF6. Studies on the formation of 2-LRT circles during HIV-1 infection revealed that TNPO3-depleted cells are impaired in the integration process or exhibit a defect in the formation of 2-LTR circles. To understand whether the cytosolic fraction of CPSF6 is responsible for the inhibition of HIV-1 in TNPO3-depleted cells, we tested the ability of a cytosolic full-length CPSF6 to block HIV-1 infection. These results demonstrated that overexpression of a cytosolic full-length CPSF6 blocks HIV-1 infection at the nuclear import step. Fate of the capsid assays revealed that cytosolic expression of CPSF6 enhances stability of the HIV-1 core during infection. Conclusions: These results suggested that inhibition of HIV-1 by TNPO3-depleted cells requires CPSF6. C1 [Fricke, Thomas; Valle-Casuso, Jose Carlos; White, Tommy E.; Brandariz-Nunez, Alberto; Reszka, Natalia; Diaz-Griffero, Felipe] Albert Einstein Coll Med Bronx, Dept Microbiol & Immunol, New York, NY 10461 USA. [Bosche, William J.; Gorelick, Robert] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Diaz-Griffero, F (reprint author), Albert Einstein Coll Med Bronx, Dept Microbiol & Immunol, 1301 Morris Pk Price Ctr 501, New York, NY 10461 USA. EM Felipe.Diaz-Griffero@einstein.yu.edu OI Brandariz-Nunez, Alberto/0000-0002-0640-1599 FU NIH [R01 AI087390]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc. FX We would like to thank Chris Aiken and Greg Towers for providing reagents. This work was funded by an NIH R01 AI087390 to F.D.-G. This project has been also funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E with SAIC-Frederick, Inc. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 27 TC 36 Z9 36 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD APR 26 PY 2013 VL 10 AR 46 DI 10.1186/1742-4690-10-46 PG 14 WC Virology SC Virology GA 172PP UT WOS:000321016900001 PM 23622145 ER PT J AU Francischetti, IMB Assumpcao, TCF Ma, DY Li, Y Vicente, EC Uieda, W Ribeiro, JMC AF Francischetti, Ivo M. B. Assumpcao, Teresa C. F. Ma, Dongying Li, Yuan Vicente, Eliane C. Uieda, Wilson Ribeiro, Jose M. C. TI The "Vampirome": Transcriptome and proteome analysis of the principal and accessory submaxillary glands of the vampire bat Desmodus rotundus, a vector of human rabies SO JOURNAL OF PROTEOMICS LA English DT Article DE Vampire bat; Desmodus rotundus; Hematophagy; Bat ecology; Proteome; Illumina ID PLATELET-AGGREGATION INHIBITORS; VASOACTIVE-INTESTINAL-PEPTIDE; TISSUE FACTOR COMPLEX; SALIVARY-GLAND; PLASMINOGEN-ACTIVATOR; SNAKE-VENOM; IXODES-SCAPULARIS; RHODNIUS-PROLIXUS; ANTIMICROBIAL PEPTIDES; EXTRACELLULAR-MATRIX AB Vampire bats are notorious for being the sole mammals that strictly feed on fresh blood for their survival. While their saliva has been historically associated with anticoagulants, only one antihemostatic (plasminogen activator) has been molecularly and functionally characterized. Here, RNAs from both principal and accessory submaxillary (submandibular) salivary glands of Desmodus rotundus were extracted, and similar to 200 million reads were sequenced by Illumina. The principal gland was enriched with plasminogen activators with fibrinolytic properties, members of lipocalin and secretoglobin families, which bind prohemostatic prostaglandins, and endonucleases, which cleave neutrophil-derived procoagulant NETs. Anticoagulant (tissue factor pathway inhibitor, TFPI), vasodilators (PACAP and C-natriuretic peptide), and metalloproteases (ADAMTS-1) were also abundantly expressed. Members of the TSG-6 (anti-inflammatory), antigen 5/CRISP, and CCL28-like (antimicrobial) protein families were also sequenced. Apyrases (which remove platelet agonist ADP), phosphatases (which degrade procoagulant polyphosphates), and sphingomyelinase were found at lower transcriptional levels. Accessory glands were enriched with antimicrobials (lysozyme, defensin, lactotransferrin) and protease inhibitors (TIL-domain, cystatin, Kazal). Mucins, heme-oxygenase, and IgG chains were present in both glands. Proteome analysis by nano LC-MS/MS confirmed that several transcripts are expressed in the glands. The database presented herein is accessible online at http://exon.niaid.nih.gov/transcriptome/D_rotundus/Supplemental-web.xlsx. These results reveal that bat saliva emerges as a novel source of modulators of vascular biology. Biological significance Vampire bat saliva emerges as a novel source of antihemostatics which modulate several aspects of vascular biology. Published by Elsevier B.V. C1 [Francischetti, Ivo M. B.; Assumpcao, Teresa C. F.; Ma, Dongying; Li, Yuan; Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [Vicente, Eliane C.] Projeto Morcegos Brasileiros & Unorp Unipos, EcoRefugius, BR-15080080 Sao Jose Do Rio Preto, SP, Brazil. [Uieda, Wilson] Univ Estadual Paulista UNESP, Inst Biociencias, Dept Zool, BR-18618970 Botucatu, SP, Brazil. RP Francischetti, IMB (reprint author), NIAID, Lab Malaria & Vector Res, Sect Vector Biol, NIH, 12735 Twinbrook Pkwy,Room 2E-32C, Rockville, MD 20892 USA. EM ifrancischetti@niaid.nih.gov; jribeiro@niaid.nih.gov RI ma, dongying/D-8623-2012; Ribeiro, Jose/J-7011-2015; OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA) FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (USA). We thank Drs. Glenn Nardone, Renee Olano, Carl Hammer, and Ming Zhao (Research Technology Branch, NIAID, NIH) for the support and continuous assistance with the proteome study. We are thankful to Brenda Rae Marshall (DPSS, NIAID) for the editorial assistance. NR 145 TC 13 Z9 13 U1 1 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD APR 26 PY 2013 VL 82 BP 288 EP 319 DI 10.1016/j.jprot.2013.01.009 PG 32 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 154AG UT WOS:000319643300020 PM 23411029 ER PT J AU Boulanger, CA Bruno, RD Mack, DL Gonzales, M Castro, NP Salomon, DS Smith, GH AF Boulanger, Corinne A. Bruno, Robert D. Mack, David L. Gonzales, Monica Castro, Nadia P. Salomon, David S. Smith, Gilbert H. TI Embryonic Stem Cells Are Redirected to Non-Tumorigenic Epithelial Cell Fate by Interaction with the Mammary Microenvironment SO PLOS ONE LA English DT Article ID IN-VIVO; MOUSE; EXPRESSION; GLAND; DIFFERENTIATION; MORPHOGENESIS; PHENOTYPE; STRAIN; CANCER; GENES AB Experiments were conducted to redirect mouse Embryonic Stem (ES) cells from a tumorigenic phenotype to a normal mammary epithelial phenotype in vivo. Mixing LacZ-labeled ES cells with normal mouse mammary epithelial cells at ratios of 1:5 and 1:50 in phosphate buffered saline and immediately inoculating them into epithelium-divested mammary fat pads of immune-compromised mice accomplished this. Our results indicate that tumorigenesis occurs only when normal mammary ductal growth is not achieved in the inoculated fat pads. When normal mammary gland growth occurs, we find ES cells (LacZ+) progeny interspersed with normal mammary cell progeny in the mammary epithelial structures. We demonstrate that these progeny, marked by LacZ expression, differentiate into multiple epithelial subtypes including steroid receptor positive luminal cells and myoepithelial cells indicating that the ES cells are capable of epithelial multipotency in this context but do not form teratomas. In addition, in secondary transplants, ES cell progeny proliferate, contribute apparently normal mammary progeny, maintain their multipotency and do not produce teratomas. C1 [Boulanger, Corinne A.; Bruno, Robert D.; Mack, David L.; Smith, Gilbert H.] NCI, Mammary Stem Cell Biol Sect, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Gonzales, Monica; Castro, Nadia P.; Salomon, David S.] NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Stem Cell Biol Sect, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. EM gs4d@nih.gov RI sebastianovitsch, stepan/G-8507-2013; OI Bruno, Robert/0000-0003-3329-9478 NR 27 TC 7 Z9 7 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 26 PY 2013 VL 8 IS 4 AR e62019 DI 10.1371/journal.pone.0062019 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136EF UT WOS:000318343700028 PM 23637952 ER PT J AU Galis, ZS Black, JB Skarlatos, SI AF Galis, Zorina S. Black, Jodi B. Skarlatos, Sonia I. TI National Heart, Lung, and Blood Institute and the Translation of Cardiovascular Discoveries Into Therapeutic Approaches SO CIRCULATION RESEARCH LA English DT Article DE cardiovascular; National Heart, Lung, and Blood Institute; National Institutes of Health; programs resources; translational ID ACID ALPHA-GLUCOSIDASE; POMPE-DISEASE; GENE-THERAPY; INFANTILE AB The molecular causes of approximate to 4000 medical conditions have been described, yet only 5% have associated therapies. For decades, the average time for drug development through approval has taken 10 to 20 years. In recent years, the serious challenges that confront the private sector have made it difficult to capitalize on new opportunities presented by advances in genomics and cellular therapies. Current trends are disturbing. Pharmaceutical companies are reducing their investments in research, and biotechnology companies are struggling to obtain venture funds. To support early-stage translation of the discoveries in basic science, the National Institutes of Health and the National Heart, Lung, and Blood Institute have developed new approaches to facilitating the translation of basic discoveries into clinical applications and will continue to develop a variety of programs that create teams of academic investigators and industry partners. The goal of these programs is to maximize the public benefit of investment of taxpayer dollars in biomedical research and to lessen the risk required for industry partners to make substantial investments. This article highlights several examples of National Heart, Lung, and Blood Institute-initiated translational programs and National Institutes of Health translational resources designed to catalyze and enable the earliest stages of the biomedical product development process. The translation of latest discoveries into therapeutic approaches depends on continued federal funding to enhance the early stages of the product development process and to stimulate and catalyze partnerships between academia, industry, and other sources of capital. (Circ Res. 2013;112:1212-1218.) C1 [Galis, Zorina S.; Skarlatos, Sonia I.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Black, Jodi B.] NHLBI, Div Extramural Res Activ, Bethesda, MD 20892 USA. RP Skarlatos, SI (reprint author), NHLBI, Div Cardiovasc Sci, Rockledge 2,Rm 8124,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM skarlats@nhlbi.nih.gov NR 24 TC 3 Z9 3 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD APR 26 PY 2013 VL 112 IS 9 BP 1212 EP 1218 DI 10.1161/CIRCRESAHA.113.301100 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 132KA UT WOS:000318065200006 PM 23620235 ER PT J AU Trivedi, DB Loftin, CD Clark, J Myers, P DeGraff, LM Cheng, J Zeldin, DC Langenbach, R AF Trivedi, Darshini B. Loftin, Charles D. Clark, James Myers, Page DeGraff, Laura M. Cheng, Jennifer Zeldin, Darryl C. Langenbach, Robert TI beta-Arrestin-2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation in Mice SO CIRCULATION RESEARCH LA English DT Article DE aneurysm; angiotensin; beta-arrestin-2; cyclooxygenase-2 ID SMOOTH-MUSCLE-CELLS; II-INDUCED ATHEROSCLEROSIS; PROSTAGLANDIN E-2 SYNTHESIS; ANGIOTENSIN-II; BETA-ARRESTINS; BLOOD-PRESSURE; SIGNALING PATHWAYS; RECEPTOR; EXPRESSION; CYCLOOXYGENASE-2 AB Rationale: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. beta-arrestin (beta arr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for beta arr2 in AngII-induced AAA formation is currently unknown. Objective: To determine whether beta arr2 played a role in AngII-induced AAA formation in mice. Methods and Results: Treatment of beta arr2(+/+) and beta arr(2-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that beta arr2 deficiency significantly attenuated AAA formation. beta arr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1 alpha, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/beta arr2(+/+) aortas, whereas beta arr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/beta arr2(+/+) mice to the level observed in apoE(-/-)/beta arr2(-/-)mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/beta arr2(+/+) aortas, and beta arr2 deficiency reduced these effects. Conclusions: beta arr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, beta arr2-dependent signaling plays a major role in AngII-induced AAA formation. (Circ Res. 2013;112:1219-1229.) C1 [Trivedi, Darshini B.; Langenbach, Robert] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Clark, James; Myers, Page] NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. [DeGraff, Laura M.; Cheng, Jennifer; Zeldin, Darryl C.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Loftin, Charles D.] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40506 USA. RP Langenbach, R (reprint author), NIEHS, Lab Toxicol & Pharmacol, 111 TW Alexander Dr,MD C4-09, Durham, NC 27709 USA. EM langenb1@niehs.nih.gov FU National Institute of Health [HL083122]; Division of Intramural Research of the National Institute of Environmental Health Sciences at the National Institutes of Health FX This work was supported by the Division of Intramural Research of the National Institute of Environmental Health Sciences at the National Institutes of Health. C.D.L. is supported by the National Institute of Health (HL083122). NR 58 TC 12 Z9 12 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD APR 26 PY 2013 VL 112 IS 9 BP 1219 EP U64 DI 10.1161/CIRCRESAHA.112.280399 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 132KA UT WOS:000318065200007 PM 23524589 ER PT J AU Maldonado, EN Sheldon, KL DeHart, DN Patnaik, J Manevich, Y Townsend, DM Bezrukov, SM Rostovtseva, TK Lemasters, JJ AF Maldonado, Eduardo N. Sheldon, Kely L. DeHart, David N. Patnaik, Jyoti Manevich, Yefim Townsend, Danyelle M. Bezrukov, Sergey M. Rostovtseva, Tatiana K. Lemasters, John J. TI Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells REGULATION BY FREE TUBULIN AND ERASTIN SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN NEUROBLASTOMA-CELLS; OUTER-MEMBRANE; VDAC CHANNELS; WARBURG; PERMEABILITY; RESPIRATION; ADP; ACTIVATION; GLYCOLYSIS; APOPTOSIS AB Respiratory substrates and adenine nucleotides cross the mitochondrial outer membrane through the voltage-dependent anion channel (VDAC), comprising three isoforms - VDAC1, 2, and 3. We characterized the role of individual isoforms in mitochondrial metabolism by HepG2 human hepatoma cells using siRNA. With VDAC3 to the greatest extent, all VDAC isoforms contributed to the maintenance of mitochondrial membrane potential, but only VDAC3 knockdown decreased ATP, ADP, NAD(P)H, and mitochondrial redox state. Cells expressing predominantly VDAC3 were least sensitive to depolarization induced by increased free tubulin. In planar lipid bilayers, free tubulin inhibited VDAC1 and VDAC2 but not VDAC3. Erastin, a compound that interacts with VDAC, blocked and reversed mitochondrial depolarization after microtubule destabilizers in intact cells and antagonized tubulin-induced VDAC blockage in planar bilayers. In conclusion, free tubulin inhibits VDAC1/2 and limits mitochondrial metabolism in HepG2 cells, contributing to the Warburg phenomenon. Reversal of tubulin-VDAC interaction by erastin antagonizes Warburg metabolism and restores oxidative mitochondrial metabolism. C1 [Lemasters, John J.] Med Univ S Carolina, Ctr Cell Death Injury & Regenerat, Charleston, SC 29425 USA. [Maldonado, Eduardo N.; DeHart, David N.; Patnaik, Jyoti; Townsend, Danyelle M.; Lemasters, John J.] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Lemasters, John J.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Cell & Mol Pharmacol & Expt Therapeut, Charleston, SC 29425 USA. [Maldonado, Eduardo N.; Townsend, Danyelle M.; Lemasters, John J.] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Sheldon, Kely L.; Bezrukov, Sergey M.; Rostovtseva, Tatiana K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Sheldon, Kely L.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, W Harry Feinstein Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. RP Lemasters, JJ (reprint author), Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Ctr Cell Death Injury & Regenerat, DD504 Drug Discovery Bldg,70 President St,MSC 140, Charleston, SC 29425 USA. EM JJLemasters@musc.edu FU National Institutes of Health [DK37034, DK073336]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Specialized Program of Research Excellence Career Development Award [P50 CA058187] FX This work was supported, in part, by Grants DK37034 and DK073336 from the National Institutes of Health. This work was also supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (to K. L. S., S. M. B., and T. K. R).; Recipient of a Specialized Program of Research Excellence Career Development Award (Grant P50 CA058187). NR 50 TC 43 Z9 43 U1 5 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2013 VL 288 IS 17 BP 11920 EP 11929 DI 10.1074/jbc.M112.433847 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133RP UT WOS:000318157600027 PM 23471966 ER PT J AU Mikelis, CM Palmby, TR Simaan, M Li, WL Szabo, R Lyons, R Martin, D Yagi, H Fukuhara, S Chikumi, H Galisteo, R Mukouyama, YS Bugge, TH Gutkind, JS AF Mikelis, Constantinos M. Palmby, Todd R. Simaan, May Li, Wenling Szabo, Roman Lyons, Ruth Martin, Daniel Yagi, Hiroshi Fukuhara, Shigetomo Chikumi, Hiroki Galisteo, Rebeca Mukouyama, Yoh-suke Bugge, Thomas H. Gutkind, J. Silvio TI PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTORS; LEUKEMIA-ASSOCIATED RHO; HETEROTRIMERIC G-PROTEINS; VASCULAR SMOOTH-MUSCLE; ANGIOTENSIN-II; PLEXIN-B; IN-VIVO; CELLS; G-ALPHA(13); GTPASES AB G protein-coupled receptors (GPCRs) linked to both members of the G alpha(12) family of heterotrimeric G proteins alpha subunits, G alpha(12) and G alpha(13), regulate the activation of Rho GTPases, thereby contributing to many key biological processes. Multiple Rho GEFs have been proposed to link G alpha(12/13) GPCRs to Rho activation, including PDZ-RhoGEF (PRG), leukemia-associated Rho GEF (LARG), p115-RhoGEF (p115), lymphoid blast crisis (Lbc), and Dbl. PRG, LARG, and p115 share the presence of a regulator of G protein signaling homology (RGS) domain. There is limited information on the biological roles of this RGS-containing family of RhoGEFs in vivo. p115-deficient mice are viable with some defects in the immune system and gastrointestinal motor dysfunctions, whereas in an initial study we showed that mice deficient for Larg are viable and resistant to salt-induced hypertension. Here, we generated knock-out mice for Prg and observed that these mice do not display any overt phenotype. However, deficiency in Prg and Larg leads to complex developmental defects and early embryonic lethality. Signaling from G alpha(11/q)-linked GPCRs to Rho was not impaired in mouse embryonic fibroblasts defective in all three RGS-containing RhoGEFs. However, a combined lack of Prg, Larg, and p115 expression C1 [Mikelis, Constantinos M.; Palmby, Todd R.; Simaan, May; Szabo, Roman; Lyons, Ruth; Martin, Daniel; Yagi, Hiroshi; Fukuhara, Shigetomo; Chikumi, Hiroki; Galisteo, Rebeca; Bugge, Thomas H.; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Li, Wenling; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDCR, NIH, 30 Convent Dr,Bldg 30,Rm 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov FU National Institutes of Health Grant [Z01DE00551]; Intramural Research Program of the NIDCR, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grant Z01DE00551 and the Intramural Research Program of the NIDCR, National Institutes of Health. NR 43 TC 21 Z9 21 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2013 VL 288 IS 17 BP 12232 EP 12243 DI 10.1074/jbc.M112.428599 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133RP UT WOS:000318157600055 PM 23467409 ER PT J AU Wu, CJ Mannan, P Lu, M Udey, MC AF Wu, Chuan-Jin Mannan, Poonam Lu, Michael Udey, Mark C. TI Epithelial Cell Adhesion Molecule (EpCAM) Regulates Claudin Dynamics and Tight Junctions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EP-CAM; BARRIER FUNCTION; COLORECTAL-CARCINOMA; TUMOR PROGRESSION; CANCER; ANTIGEN; PROTEINS; GENE; PERMEABILITY; METASTASIS AB Epithelial cell adhesion molecule (EpCAM) (CD326) is a surface glycoprotein expressed by invasive carcinomas and some epithelia. Herein, we report that EpCAM regulates the composition and function of tight junctions (TJ). EpCAM accumulated on the lateral interfaces of human colon carcinoma and normal intestinal epithelial cells but did not co-localize with TJ. Knockdown of EpCAM in T84 and Caco-2 cells using shRNAs led to changes in morphology and adhesiveness. TJ formed readily after EpCAM knockdown; the acquisition of trans-epithelial electroresistance was enhanced, and TJ showed increased resistance to disruption by calcium chelation. Preparative immunoprecipitation demonstrated that EpCAM bound tightly to claudin-7. Co-immunoprecipitation documented associations of EpCAM with claudin-7 and claudin-1 but not claudin-2 or claudin-4. Claudin-1 associated with claudin-7 in co-transfection experiments, and claudin-7 was required for association of claudin-1 with EpCAM. EpCAM knockdown resulted in decreases in claudin-7 and claudin-1 proteins that were reversed with lysosome inhibitors. Immunofluorescence microscopy revealed that claudin-7 and claudin-1 continually trafficked into lysosomes. Although EpCAM knockdown decreased claudin-1 and claudin-7 protein levels overall, accumulations of claudin-1 and claudin-7 in TJ increased. Physical interactions between EpCAM and claudins were required for claudin stabilization. These findings suggest that EpCAM modulates adhesion and TJ function by regulating intracellular localization and degradation of selected claudins. C1 [Wu, Chuan-Jin; Lu, Michael; Udey, Mark C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Mannan, Poonam] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM udeym@mail.nih.gov FU National Institutes of Health grant from the Intramural Research Program, Center for Cancer Research; National Institutes of Health grant from NCI FX This work was supported, in whole or in part, by National Institutes of Health grants from the Intramural Research Program, Center for Cancer Research, and NCI. NR 48 TC 28 Z9 30 U1 1 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2013 VL 288 IS 17 BP 12253 EP 12268 DI 10.1074/jbc.M113.457499 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133RP UT WOS:000318157600057 PM 23486470 ER PT J AU Wei, H Bera, TK Wayne, AS Xiang, LM Colantonio, S Chertov, O Pastan, I AF Wei, Hui Bera, Tapan K. Wayne, Alan S. Xiang, Laiman Colantonio, Simona Chertov, Oleg Pastan, Ira TI A Modified Form of Diphthamide Causes Immunotoxin Resistance in a Lymphoma Cell Line with a Deletion of the WDR85 Gene SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ZINC-FINGER PROTEIN; HEMATOLOGIC MALIGNANCIES; OVARIAN-CANCER; RECOMBINANT IMMUNOTOXIN; PSEUDOMONAS EXOTOXIN; CYTOTOXIC ACTIVITY; TUMOR-SUPPRESSOR; BIOSYNTHESIS; LEUKEMIA; OVCA1 AB HA22 is a recombinant immunotoxin that kills CD22-expressing cells by ADP-ribosylating and inactivating elongation factor-2 (EF2). HA22 is composed of an Fv that binds to CD22 fused to a portion of Pseudomonas exotoxin A. HA22 is very active in drug-resistant hairy cell leukemia but is less active in children with acute lymphoblastic leukemia. To understand why some patients do not respond to HA22, we isolated an HA22-resistant lymphoma cell line and showed that resistance was due to the inability of HA22 to ADP-ribosylate and inactivate EF2. We analyzed the diphthamide synthesis genes and found that the WDR85 gene was deleted. We show that WDR85 knockdown conferred HA22 resistance to sensitive cells and that sensitivity was restored by introduction of a WDR85 cDNA into resistant cells. Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5. Inactivation of the WDR85 gene could be a mechanism of immunotoxin resistance in patients undergoing immunotoxin therapy. C1 [Wei, Hui; Bera, Tapan K.; Wayne, Alan S.; Xiang, Laiman; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Colantonio, Simona; Chertov, Oleg] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Adv Technol Program, Prot Chem Lab, Frederick, MD 21702 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Rm 5106,37 Convent Dr, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Center for Cancer Research, NCI, National Institutes of Health; NCI, National Institutes of Health [HHSN261200800001E]; MedImmune, LLC. FX This work was supported, in whole or in part, by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health, in part with federal funds from NCI, National Institutes of Health, under Contract HHSN261200800001E and under a Cooperative Research and Development Agreement with MedImmune, LLC. Dr. Pastan is an inventor of patents on immunotoxins that have all been assigned to the National Institutes of Health. NR 34 TC 16 Z9 17 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 26 PY 2013 VL 288 IS 17 BP 12305 EP 12312 DI 10.1074/jbc.M113.461343 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133RP UT WOS:000318157600061 PM 23486472 ER PT J AU Zeng, MY Pham, D Bagaitkar, J Liu, JY Otero, K Shan, M Wynn, TA Brombacher, F Brutkiewicz, RR Kaplan, MH Dinauer, MC AF Zeng, Melody Yue Pham, Duy Bagaitkar, Juhi Liu, Jianyun Otero, Karel Shan, Ming Wynn, Thomas A. Brombacher, Frank Brutkiewicz, Randy R. Kaplan, Mark H. Dinauer, Mary C. TI An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD SO BLOOD LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; V(ALPHA)14 NKT CELLS; DENDRITIC CELLS; APOPTOTIC CELLS; T-CELLS; ALTERNATIVE ACTIVATION; NADPH OXIDASE; IMMUNOREGULATORY AXIS; IMMUNE-RESPONSES; TUMOR-IMMUNITY AB Efferocytosis of apoptotic neutrophils by macrophages following tissue injury is fundamental to the resolution of inflammation and initiation of tissue repair. Using a sterile peritonitis model in mice, we identified interleukin (IL)-4-producing efferocytosing macrophages in the peritoneum that activate invariant natural killer T (iNKT) cells to produce cytokines including IL-4, IL-13, and interferon-gamma. Importantly, IL-4 from macrophages contributes to alternative activation of peritoneal exudate macrophages and augments type 2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4R alpha expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The reduced NAD phosphate oxidase is also critical for this model, because in mice with X-linked chronic granulomatous disease (X-CGD) that lack oxidase subunits, activation of iNKT cells by X-CGD peritoneal exudate macrophages was impaired during sterile peritonitis, resulting in enhanced and prolonged inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of IL-4-producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair. C1 [Zeng, Melody Yue; Pham, Duy; Kaplan, Mark H.] Indiana Univ Sch Med, Riley Hosp Children, Herman B Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN 46202 USA. [Zeng, Melody Yue; Pham, Duy; Liu, Jianyun; Brutkiewicz, Randy R.; Kaplan, Mark H.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Bagaitkar, Juhi; Otero, Karel; Shan, Ming; Dinauer, Mary C.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Brombacher, Frank] Int Ctr Genet Engn & Biotechnol, Cape Town Component, South Africa. [Brombacher, Frank] Univ Cape Town, ZA-7700 Rondebosch, South Africa. [Dinauer, Mary C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Dinauer, MC (reprint author), Washington Univ, Sch Med, Dept Pediat, 660 South Euclid Ave, St Louis, MO 63110 USA. EM dinauer_m@kids.wustl.edu FU NIH [R01 AI045515, R01 AI057459, R01 HL45635, R01 AI46455, T32 AI060519, T32 HL07910]; Children's Discovery Institute at Washington University; St. Louis Children's Hospital FX This work was supported by NIH grants (R01 AI045515, R01 AI057459 to M. H. K., R01 HL45635 (to M. C. D.), and R01 AI46455 (to R. R. B.), and from the Children's Discovery Institute at Washington University and St. Louis Children's Hospital (M. C. D.). M.Y.Z was supported by NIH grant T32 AI060519. D. P. was supported by NIH grant T32 HL07910 to Indiana University School of Medicine. NR 50 TC 16 Z9 17 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 25 PY 2013 VL 121 IS 17 BP 3473 EP 3483 DI 10.1182/blood-2012-10-461913 PG 11 WC Hematology SC Hematology GA 183QG UT WOS:000321831600024 PM 23426944 ER PT J AU Harbison, ST McCoy, LJ Mackay, TFC AF Harbison, Susan T. McCoy, Lenovia J. Mackay, Trudy F. C. TI Genome-wide association study of sleep in Drosophila melanogaster SO BMC GENOMICS LA English DT Article DE Sleep; Drosophila melanogaster; Genome-wide association; Genetic variance of environmental variation ID GENE DISRUPTION PROJECT; RESTLESS-LEGS-SYNDROME; ENVIRONMENTAL VARIANCE; QUANTITATIVE TRAITS; COMMON VARIANTS; HUMAN-DISEASE; NARCOLEPSY; HUMANS; DISORDERS; TRIBBLES AB Background: Sleep is a highly conserved behavior, yet its duration and pattern vary extensively among species and between individuals within species. The genetic basis of natural variation in sleep remains unknown. Results: We used the Drosophila Genetic Reference Panel (DGRP) to perform a genome-wide association (GWA) study of sleep in D. melanogaster. We identified candidate single nucleotide polymorphisms (SNPs) associated with differences in the mean as well as the environmental sensitivity of sleep traits; these SNPs typically had sex-specific or sex-biased effects, and were generally located in non-coding regions. The majority of SNPs (80.3%) affecting sleep were at low frequency and had moderately large effects. Additive models incorporating multiple SNPs explained as much as 55% of the genetic variance for sleep in males and females. Many of these loci are known to interact physically and/or genetically, enabling us to place them in candidate genetic networks. We confirmed the role of seven novel loci on sleep using insertional mutagenesis and RNA interference. Conclusions: We identified many SNPs in novel loci that are potentially associated with natural variation in sleep, as well as SNPs within genes previously known to affect Drosophila sleep. Several of the candidate genes have human homologues that were identified in studies of human sleep, suggesting that genes affecting variation in sleep are conserved across species. Our discovery of genetic variants that influence environmental sensitivity to sleep may have a wider application to all GWA studies, because individuals with highly plastic genotypes will not have consistent phenotypes. C1 [Harbison, Susan T.; McCoy, Lenovia J.; Mackay, Trudy F. C.] N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. RP Harbison, ST (reprint author), NHLBI, Lab Syst Genet, NIH, 10 Ctr Dr MSC 1654,Bldg 10,Room 7D13, Bethesda, MD 20892 USA. EM susan.harbison@nih.gov RI Harbison, Susan/P-2577-2016 OI Harbison, Susan/0000-0001-7233-0947 FU National Institutes of Health (NIH) [R01 GM45146]; Intramural Research Program of the NIH, National Heart Lung and Blood Institute FX This work was supported by National Institutes of Health (NIH) grant R01 GM45146 to T. F. C. M. and by the Intramural Research Program of the NIH, National Heart Lung and Blood Institute. The authors would like to thank M. M. Magwire for technical assistance, W. Huang for assistance with the analysis of population structure, and M. I. Harbison for computer equipment. NR 75 TC 28 Z9 30 U1 5 U2 55 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD APR 25 PY 2013 VL 14 AR 281 DI 10.1186/1471-2164-14-281 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 138RE UT WOS:000318525300001 PM 23617951 ER PT J AU O'Shea, JJ Jones, RG AF O'Shea, John J. Jones, Russell G. TI AUTOIMMUNITY Rubbing salt in the wound SO NATURE LA English DT Editorial Material ID T-CELLS; INFLAMMATION; INNATE C1 [O'Shea, John J.] NIAMSD, Intramural Res Program, Bethesda, MD 20892 USA. [Jones, Russell G.] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Dept Physiol, Montreal, PQ H3G 1Y6, Canada. RP O'Shea, JJ (reprint author), NIAMSD, Intramural Res Program, Bethesda, MD 20892 USA. EM osheaj@arb.niams.nih.gov; russell.jones@mcgill.ca NR 13 TC 13 Z9 14 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 25 PY 2013 VL 496 IS 7446 BP 437 EP 439 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131HU UT WOS:000317984400026 PM 23467087 ER PT J AU Wynn, TA Chawla, A Pollard, JW AF Wynn, Thomas A. Chawla, Ajay Pollard, Jeffrey W. TI Macrophage biology in development, homeostasis and disease SO NATURE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; ALTERNATIVELY ACTIVATED MACROPHAGES; TUMOR-ASSOCIATED MACROPHAGES; COLONY-STIMULATING FACTOR; HEMATOPOIETIC STEM-CELLS; INSULIN-RESISTANCE; MYELOID CELLS; ADIPOSE-TISSUE; DENDRITIC CELLS; MOUSE MODEL AB Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases. C1 [Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Program Tissue Immun & Repair, NIH, Gaithersburg, MD 20877 USA. [Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Gaithersburg, MD 20877 USA. [Chawla, Ajay] Univ Calif San Francisco, Dept Physiol & Med, Cardiovasc Res Inst, San Francisco, CA 94158 USA. [Pollard, Jeffrey W.] Univ Edinburgh, Queens Med Res Inst, Med Res Council Ctr Reprod Hlth, Edinburgh EH16 4TJ, Midlothian, Scotland. [Pollard, Jeffrey W.] Albert Einstein Coll Med, Dept Dev & Mol Biol, Ctr Study Reprod Biol & Womens Hlth, New York, NY 10461 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Program Tissue Immun & Repair, NIH, Gaithersburg, MD 20877 USA. EM twynn@niaid.nih.gov; ajay.chawla@ucsf.edu; jeff.pollard@ed.ac.uk FU National Institutes of Allergy and Infectious Diseases (National Institutes of Health (NIH)); National Cancer Institute of the NIH [R01CA131270S, U54HD058155, PO1CA100324, HL076746, DK094641]; Diabetes Family Fund; American Heart Association (AHA) [12PILT11840038]; NIH [DP1AR064158] FX The authors apologize to colleagues whose papers they were unable to cite on this occasion. T. A. W. is supported by the intramural research program of the National Institutes of Allergy and Infectious Diseases (National Institutes of Health (NIH)). This work was supported by the National Cancer Institute of the NIH (award numbers R01CA131270S, U54HD058155 and PO1CA100324 (to J.W.P.), and HL076746, DK094641 and DK094641 (to A. C.)); the Diabetes Family Fund (to the University of California, San Francisco), an American Heart Association (AHA) Innovative Award (12PILT11840038) and a NIH Director's Pioneer Award (DP1AR064158 to A.C.). NR 125 TC 706 Z9 736 U1 40 U2 326 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 25 PY 2013 VL 496 IS 7446 BP 445 EP 455 DI 10.1038/nature12034 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131HU UT WOS:000317984400031 PM 23619691 ER PT J AU Liao, HX Lynch, R Zhou, TQ Gao, F Alam, SM Boyd, SD Fire, AZ Roskin, KM Schramm, CA Zhang, ZH Zhu, J Shapiro, L Mullikin, JC Gnanakaran, S Hraber, P Wiehe, K Kelsoe, G Yang, G Xia, SM Montefiori, DC Parks, R Lloyd, KE Scearce, RM Soderberg, KA Cohen, M Kamanga, G Louder, MK Tran, LM Chen, Y Cai, FP Chen, SR Moquin, S Du, XL Joyce, MG Srivatsan, S Zhang, BS Zheng, AQ Shaw, GM Hahn, BH Kepler, TB Korber, BTM Kwong, PD Mascola, JR Haynes, BF AF Liao, Hua-Xin Lynch, Rebecca Zhou, Tongqing Gao, Feng Alam, S. Munir Boyd, Scott D. Fire, Andrew Z. Roskin, Krishna M. Schramm, Chaim A. Zhang, Zhenhai Zhu, Jiang Shapiro, Lawrence Mullikin, James C. Gnanakaran, S. Hraber, Peter Wiehe, Kevin Kelsoe, Garnett Yang, Guang Xia, Shi-Mao Montefiori, David C. Parks, Robert Lloyd, Krissey E. Scearce, Richard M. Soderberg, Kelly A. Cohen, Myron Kamanga, Gift Louder, Mark K. Tran, Lillian M. Chen, Yue Cai, Fangping Chen, Sheri Moquin, Stephanie Du, Xiulian Joyce, M. Gordon Srivatsan, Sanjay Zhang, Baoshan Zheng, Anqi Shaw, George M. Hahn, Beatrice H. Kepler, Thomas B. Korber, Bette T. M. Kwong, Peter D. Mascola, John R. Haynes, Barton F. CA NISC Comparative Sequencing Progra TI Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus SO NATURE LA English DT Article ID B-CELL RESPONSES; HUMAN MONOCLONAL-ANTIBODIES; IN-SITU PROTEOLYSIS; CD4 BINDING-SITE; HIV-1-INFECTED INDIVIDUALS; CONFORMATIONAL EPITOPE; POTENT NEUTRALIZATION; ENVELOPE GLYCOPROTEIN; VACCINE DESIGN; SUBTYPE-B AB Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination. C1 [Liao, Hua-Xin; Gao, Feng; Alam, S. Munir; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C.; Parks, Robert; Lloyd, Krissey E.; Scearce, Richard M.; Soderberg, Kelly A.; Chen, Yue; Cai, Fangping; Chen, Sheri; Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Human Vaccine Inst, Durham, NC 27710 USA. [Liao, Hua-Xin; Gao, Feng; Alam, S. Munir; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C.; Parks, Robert; Lloyd, Krissey E.; Scearce, Richard M.; Soderberg, Kelly A.; Chen, Yue; Cai, Fangping; Chen, Sheri; Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Human Vaccine Inst, Durham, NC 27710 USA. [Liao, Hua-Xin; Gao, Feng; Alam, S. Munir; Wiehe, Kevin; Kelsoe, Garnett; Yang, Guang; Xia, Shi-Mao; Montefiori, David C.; Parks, Robert; Lloyd, Krissey E.; Scearce, Richard M.; Soderberg, Kelly A.; Chen, Yue; Cai, Fangping; Chen, Sheri; Haynes, Barton F.] Duke Ctr HIV AIDS Vaccine Immunol & Immunogen Dis, Durham, NC 27710 USA. [Lynch, Rebecca; Zhou, Tongqing; Zhu, Jiang; Shapiro, Lawrence; Louder, Mark K.; Tran, Lillian M.; Moquin, Stephanie; Du, Xiulian; Joyce, M. Gordon; Srivatsan, Sanjay; Zhang, Baoshan; Zheng, Anqi; Kwong, Peter D.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Boyd, Scott D.; Fire, Andrew Z.; Roskin, Krishna M.] Stanford Univ, Dept Pathol, Palo Alto, CA 94305 USA. [Schramm, Chaim A.; Zhang, Zhenhai; Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Mullikin, James C.] NIH, NISC Comparat Sequencing Program, Bethesda, MD 20892 USA. [Mullikin, James C.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. [Gnanakaran, S.; Hraber, Peter; Korber, Bette T. M.] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87544 USA. [Cohen, Myron] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Cohen, Myron] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Cohen, Myron] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Kamanga, Gift] Univ North Carolina Project, Kamuzu Cent Hosp, Lilongwe, Malawi. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. [Kepler, Thomas B.] Boston Univ, Dept Microbiol, Boston, MA 02215 USA. RP Liao, HX (reprint author), Duke Univ, Sch Med, Dept Med, Human Vaccine Inst, Durham, NC 27710 USA. EM hliao@duke.edu; barton.haynes@duke.edu RI Zhou, Tongqing/A-6880-2010; OI Zhou, Tongqing/0000-0002-3935-4637; Kepler, Thomas/0000-0002-1383-6865; Gnanakaran, S/0000-0002-9368-3044; Korber, Bette/0000-0002-2026-5757; Hraber, Peter/0000-0002-2920-4897 FU National Institutes of Allergy and Infectious Diseases (NIAID); intramural National Institutes of Health (NIH); NIH, NIAID [AI067854, AI100645]; US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX This study was supported by the National Institutes of Allergy and Infectious Diseases (NIAID) and by intramural National Institutes of Health (NIH) support for the NIAID Vaccine Research Center, by grants from the NIH, NIAID, AI067854 (the Center for HIV/AIDS Vaccine Immunology) and AI100645 (the Center for Vaccine Immunology-Immunogen Discovery). The authors thank J. Pritchett, H. Chen, D. Pause, M. Cooper, E. Solomon, J. Blinn, K. Yarborough, E. Friberg, M. Smith, A. Hogan, C. Peckels, A. Foulger and T. Jeffries for technical assistance, and J. Kircherr and C. Andrews for project management. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract number W-31-109-Eng-38. The opinions herein are those of the authors and should not be construed as official or representing the views of the US Department of Health and Human Services, National Institute for Allergy and Infectious Diseases. NR 71 TC 350 Z9 357 U1 10 U2 133 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 25 PY 2013 VL 496 IS 7446 BP 469 EP + DI 10.1038/nature12053 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131HU UT WOS:000317984400034 PM 23552890 ER PT J AU Bhatt, S Gething, PW Brady, OJ Messina, JP Farlow, AW Moyes, CL Drake, JM Brownstein, JS Hoen, AG Sankoh, O Myers, MF George, DB Jaenisch, T Wint, GRW Simmons, CP Scott, TW Farrar, JJ Hay, SI AF Bhatt, Samir Gething, Peter W. Brady, Oliver J. Messina, Jane P. Farlow, Andrew W. Moyes, Catherine L. Drake, John M. Brownstein, John S. Hoen, Anne G. Sankoh, Osman Myers, Monica F. George, Dylan B. Jaenisch, Thomas Wint, G. R. William Simmons, Cameron P. Scott, Thomas W. Farrar, Jeremy J. Hay, Simon I. TI The global distribution and burden of dengue SO NATURE LA English DT Article ID PLASMODIUM-FALCIPARUM; HEMORRHAGIC-FEVER; YELLOW-FEVER; DISEASE; TRANSMISSION; ENDEMICITY; VACCINE; VECTOR; VIRUS; INDIA AB Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes(1). For some patients, dengue is a life-threatening illness(2). There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread(3). The contemporary worldwide distribution of the risk of dengue virus infection(4) and its public health burden are poorly known(2,5). Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284-528) dengue infections per year, of which 96 million (67-136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization(2). Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation. C1 [Bhatt, Samir; Gething, Peter W.; Brady, Oliver J.; Messina, Jane P.; Farlow, Andrew W.; Moyes, Catherine L.; Drake, John M.; Myers, Monica F.; Wint, G. R. William; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Brady, Oliver J.] Oxitec Ltd, Abingdon OX14 4RX, Oxon, England. [Drake, John M.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Brownstein, John S.] Harvard Univ, Sch Med, Dept Phys, Boston, MA 02115 USA. [Brownstein, John S.] Boston Childrens Hosp, Childrens Hosp Informat Program, Boston, MA 02115 USA. [Hoen, Anne G.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Hanover, NH 03755 USA. [Sankoh, Osman] INDEPTH Network Secretariat, East Legon, Accra, Ghana. [Sankoh, Osman] Univ Witwatersrand, Sch Publ Hlth, ZA-2000 Johannesburg, South Africa. [Sankoh, Osman] Heidelberg Univ, Inst Publ Hlth, D-69120 Heidelberg, Germany. [George, Dylan B.; Scott, Thomas W.; Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Jaenisch, Thomas] Univ Heidelberg Hosp, Dept Infect Dis, Sect Clin Trop Med, INF 324, D-69120 Heidelberg, Germany. [Wint, G. R. William] Univ Oxford, Dept Zool, ERGO, Oxford OX1 3PS, England. [Simmons, Cameron P.; Farrar, Jeremy J.] Oxford Univ Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Simmons, Cameron P.; Farrar, Jeremy J.] Univ Oxford, Churchill Hosp, Ctr Trop Med, Oxford OX3 7LJ, England. [Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Farrar, Jeremy J.] Natl Univ Singapore, Dept Med, Singapore 119228, Singapore. RP Hay, SI (reprint author), Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Tinbergen Bldg,South Parks Rd, Oxford OX1 3PS, England. EM simon.hay@zoo.ox.ac.uk RI Vale, Pedro/C-5518-2009; Hay, Simon/F-8967-2015; OI Vale, Pedro/0000-0003-4558-9202; Hay, Simon/0000-0002-0611-7272; Simmons, Cameron P./0000-0002-9039-7392; Drake, John/0000-0003-4646-1235; Gething, Peter/0000-0001-6759-5449; Brady, Oliver/0000-0002-3235-2129; Farrar, Jeremy/0000-0002-2700-623X; Moyes, Catherine/0000-0002-8028-4079 FU Wellcome Trust [095066, 084368]; BBSRC Industrial CASE studentship; International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS) [21803]; EU [2011-261504 EDENEXT]; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust (095066) which also supports S. B. and P. W. G. C. P. S. is also funded by a Senior Research Fellowship from the Wellcome Trust (084368). O.J.B. is funded by a BBSRC Industrial CASE studentship. J.P.M., A. W. F., T.J., G. R. W. W., C. P. S., T. W. S. and S. I. H. received funding from, and with S. B., P. W. G., O.J.B. and J.J.F. acknowledge the contribution of, the International Research Consortium on Dengue Risk Assessment Management and Surveillance (IDAMS, 21803, http://www.idams.eu). This work was funded in part by EU grant 2011-261504 EDENEXT and the paper is catalogued by the EDENEXT Steering Committee as EDENEXT. S. I. H. and T. W. S. also acknowledge funding support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 30 TC 1561 Z9 1619 U1 89 U2 541 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD APR 25 PY 2013 VL 496 IS 7446 BP 504 EP 507 DI 10.1038/nature12060 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131HU UT WOS:000317984400041 PM 23563266 ER PT J AU Li, F Mao, GG Tong, D Huang, J Gu, LY Yang, W Li, GM AF Li, Feng Mao, Guogen Tong, Dan Huang, Jian Gu, Liya Yang, Wei Li, Guo-Min TI The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through Its Interaction with MutS alpha SO CELL LA English DT Article ID IDENTIFIES FREQUENT MUTATION; CELL NUCLEAR ANTIGEN; PWWP DOMAIN; MICROSATELLITE INSTABILITY; RECOGNITION COMPLEX; RENAL-CARCINOMA; HUMAN CANCER; TUMOR-CELLS; REPLICATION; METHYLATION AB DNA mismatch repair (MMR) ensures replication fidelity by correcting mismatches generated during DNA replication. Although human MMR has been reconstituted in vitro, how MMR occurs in vivo is unknown. Here, we show that an epigenetic histone mark, H3K36me3, is required in vivo to recruit the mismatch recognition protein hMutS alpha (hMSH2-hMSH6) onto chromatin through direct interactions with the hMSH6 PWWP domain. The abundance of H3K36me3 in G1 and early S phases ensures that hMutS alpha is enriched on chromatin before mispairs are introduced during DNA replication. Cells lacking the H3K36 trimethyltransferase SETD2 display microsatellite instability (MSI) and an elevated spontaneous mutation frequency, characteristic of MMR-deficient cells. This work reveals that a histone mark regulates MMR in human cells and explains the long-standing puzzle of MSI-positive cancer cells that lack detectable mutations in known MMR genes. C1 [Li, Feng; Mao, Guogen; Gu, Liya; Li, Guo-Min] Univ Kentucky, Coll Med, Markey Canc Ctr, Grad Ctr Toxicol, Lexington, KY 40506 USA. [Tong, Dan; Huang, Jian] Wuhan Univ, Coll Life Sci, Wuhan 430072, Peoples R China. [Tong, Dan; Li, Guo-Min] Tsinghua Univ, Sch Med, Beijing 10084, Peoples R China. [Yang, Wei] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gu, LY (reprint author), Univ Kentucky, Coll Med, Markey Canc Ctr, Grad Ctr Toxicol, Lexington, KY 40506 USA. EM lgu0@uky.edu; gmli@uky.edu RI Yang, Wei/D-4926-2011; Li, Guo-Min/I-5016-2014; OI Yang, Wei/0000-0002-3591-2195; Li, Guo-Min/0000-0002-9842-4578 FU National Institutes of Health [CA167181, CA115942, GM089684, CA104333]; National Institute of Diabetes and Digestive and Kidney Diseases intramural research fund; Kentucky Lung Cancer Research Program FX We thank Richard Kolodner, Tom Misteli, Jeffrey Parvin, Youfeng Yang, and Akira Yasui for reagents and Yang Shi, Dangsheng Li, Charles Ensor, and Nathan Vanderford for stimulating discussions and helpful comments. This work was supported in part by grants from the National Institutes of Health (CA167181, CA115942, and GM089684 to G.-M.L.) (CA104333 to L.G.), the National Institute of Diabetes and Digestive and Kidney Diseases intramural research fund (to W.Y.), and a grant from the Kentucky Lung Cancer Research Program. G.-M.L. holds the James-Gardner Chair in Cancer Research. NR 59 TC 147 Z9 156 U1 6 U2 83 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD APR 25 PY 2013 VL 153 IS 3 BP 590 EP 600 DI 10.1016/j.cell.2013.03.025 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 132JK UT WOS:000318063500012 PM 23622243 ER PT J AU Henriques, T Adelman, K AF Henriques, Telmo Adelman, Karen TI Catching the Waves: Following the Leading Edge of Elongating RNA Polymerase II SO MOLECULAR CELL LA English DT Editorial Material ID IN-VIVO; TRANSCRIPTION; ROLES; RATES C1 [Henriques, Telmo; Adelman, Karen] NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Adelman, K (reprint author), NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. EM adelmank@niehs.nih.gov FU Intramural NIH HHS [ZIA ES101987-07] NR 10 TC 1 Z9 1 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 25 PY 2013 VL 50 IS 2 BP 159 EP 160 DI 10.1016/j.molcel.2013.04.009 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 134KH UT WOS:000318208600002 PM 23622514 ER PT J AU Snyder, EL Watanabe, H Magendantz, M Hoersch, S Chen, TA Wang, DG Crowley, D Whittaker, CA Meyerson, M Kimura, S Jacks, T AF Snyder, Eric L. Watanabe, Hideo Magendantz, Margaret Hoersch, Sebastian Chen, Tiffany A. Wang, Diana G. Crowley, Denise Whittaker, Charles A. Meyerson, Matthew Kimura, Shioko Jacks, Tyler TI Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma SO MOLECULAR CELL LA English DT Article ID NUCLEAR FACTOR 4-ALPHA; THYROID TRANSCRIPTION FACTOR-1; K-RAS; BRONCHIOLOALVEOLAR CARCINOMA; PULMONARY ADENOCARCINOMA; EPIGENETIC SIGNATURES; EPITHELIAL-CELLS; GENE-EXPRESSION; IN-VIVO; CANCER AB Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to determine how the identity of lung epithelial cells changes upon loss of their master cell-fate regulator. Nkx2-1 deletion in normal and neoplastic lungs causes not only loss of pulmonary identity but also conversion to a gastric lineage. Nkx2-1 is likely to maintain pulmonary identity by recruiting transcription factors Foxa1 and Foxa2 to lung-specific loci, thus preventing them from binding gastrointestinal targets. Nkx2-1-negative murine lung tumors mimic mucinous human lung adenocarcinomas, which express gastric markers. Loss of the gastrointestinal transcription factor Hnf4 alpha leads to derepression of the embryonal proto-oncogene Hmga2 in Nkx2-1-negative tumors. These observations suggest that loss of both active and latent differentiation programs is required for tumors to reach a primitive, poorly differentiated state. C1 [Snyder, Eric L.; Magendantz, Margaret; Hoersch, Sebastian; Chen, Tiffany A.; Wang, Diana G.; Crowley, Denise; Whittaker, Charles A.; Jacks, Tyler] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Crowley, Denise; Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Snyder, Eric L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Watanabe, Hideo; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Watanabe, Hideo; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Watanabe, Hideo; Meyerson, Matthew] Broad Inst Harvard, Canc Program, Cambridge, MA 02142 USA. [Watanabe, Hideo; Meyerson, Matthew] MIT, Cambridge, MA 02142 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Jacks, T (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. EM tjacks@mit.edu FU Burroughs Wellcome Fund; National Institutes of Health [U01-CA84306, K08-CA154784-01]; Howard Hughes Medical Institute; Ludwig Center for Molecular Oncology at MIT; National Cancer Institute [P30-CA14051] FX We thank N. Dimitrova, D. Feldser, and M. Mendoza for critical reading of the manuscript; the Swanson Biotechnology Center for histology, Illumina sequencing, and bioinformatic support; the BioMicro Center for library preparation and Illumina sequencing; L. Sholl and L. Chirieac for assistance with human lung adenocarcinoma collection; and M. Winslow and the entire Jacks Lab for helpful discussions. E.L.S. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. This work was supported by National Institutes of Health grants U01-CA84306 (to T.J.) and K08-CA154784-01 (to E.L.S.), the Howard Hughes Medical Institute, the Ludwig Center for Molecular Oncology at MIT, and in part by the Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. NR 65 TC 48 Z9 48 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 25 PY 2013 VL 50 IS 2 BP 185 EP 199 DI 10.1016/j.molcel.2013.02.018 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 134KH UT WOS:000318208600005 PM 23523371 ER PT J AU Vitolo, MI Boggs, AE Whipple, RA Yoon, JR Thompson, K Matrone, MA Cho, EH Balzer, EM Martin, SS AF Vitolo, M. I. Boggs, A. E. Whipple, R. A. Yoon, J. R. Thompson, K. Matrone, M. A. Cho, E. H. Balzer, E. M. Martin, S. S. TI Loss of PTEN induces microtentacles through PI3K-independent activation of cofilin SO ONCOGENE LA English DT Article DE PTEN; microtentacle; actin; contractility; cofilin; metastasis ID CIRCULATING TUMOR-CELLS; NONMUSCLE MYOSIN-II; LIGHT-CHAIN KINASE; BREAST-CANCER; LIM-KINASE; F-ACTIN; PHOSPHOINOSITIDE-BINDING; PHOSPHATASE SLINGSHOT; INHIBITION; EXPRESSION AB Loss of PTEN tumor suppressor enhances metastatic risk in breast cancer, although the underlying mechanisms are poorly defined. We report that homozygous deletion of PTEN in mammary epithelial cells induces tubulin-based microtentacles (McTNs) that facilitate cell reattachment and homotypic aggregation. Treatment with contractility-modulating drugs showed that McTNs in PTEN-/- cells are suppressible by controlling the actin cytoskeleton. Because outward microtubule extension is counteracted by actin cortical contraction, increased activity of actin-severing proteins could release constraints on McTN formation in PTEN-/- cells. One such actin-severing protein, cofilin, is activated in detached PTEN-/- cells that could weaken the actin cortex to promote McTNs. Expression of wild-type cofilin, an activated mutant (S3A), and an inactive mutant (S3E) demonstrated that altering cofilin phosphorylation directly affects McTNs formation. Chemical inhibition of PI3K did not reduce McTNs or inactivate cofilin in PTEN-/- cells. Additionally, knock-in expression of the two most common PI3K-activating mutations observed in human cancer patients did not increase McTNs or activate cofilin. PTEN loss and PI3K activation also caused differential activation of the cofilin regulators, LIM-kinase1 (LIMK) and Slingshot-1L (SSH). Furthermore, McTNs were suppressed and cofilin was inactivated by restoration of PTEN in the PTEN-/- cells, indicating that both the elevation of McTNs and the activation of cofilin are specific results arising from PTEN loss. These data identify a novel mechanism by which PTEN loss could remodel the cortical actin network to facilitate McTNs that promote tumor cell reattachment and aggregation. Using isogenic MCF-10A PTEN-/- and PIK3CA mutants, we have further demonstrated that there are clear differences in activation of cofilin, LIMK and SSH between PTEN loss and PI3K activation, providing a new evidence that these mutations yield distinct cytoskeletal phenotypes, which could have an impact on tumor biology. Oncogene (2013) 32, 2200-2210; doi:10.1038/onc.2012.234; published online 11 June 2012 C1 [Vitolo, M. I.; Boggs, A. E.; Whipple, R. A.; Yoon, J. R.; Thompson, K.; Martin, S. S.] Univ Maryland, Marlene & Stewart Greenebaum NCI Canc Ctr, Baltimore, MD 21201 USA. [Boggs, A. E.; Yoon, J. R.; Martin, S. S.] Univ Maryland, Grad Program Life Sci, Program Mol Med, Baltimore, MD 21201 USA. [Matrone, M. A.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Cho, E. H.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Balzer, E. M.] Johns Hopkins Univ, Johns Hopkins Inst NanoBioTechnol, Baltimore, MD USA. [Martin, S. S.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. RP Martin, SS (reprint author), Univ Maryland, Sch Med, Dept Physiol, Room 10-29,Bressler Bldg,655 West Baltimore St, Baltimore, MD 21201 USA. EM ssmartin@som.umaryland.edu FU Ruth L Kirschstein-National Service Research Award [T32-HL07698]; National Cancer Institute [R01-CA124704]; Susan G Komen Foundation [KG100240]; Era of Hope Scholar award from the Department of Defense [BC100675] FX This work was supported by grants from the Ruth L Kirschstein-National Service Research Award, T32-HL07698 (MIV), National Cancer Institute, R01-CA124704 (SSM), Susan G Komen Foundation, KG100240 (SSM) and an Era of Hope Scholar award from the Department of Defense, BC100675 (SSM). NR 58 TC 13 Z9 14 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD APR 25 PY 2013 VL 32 IS 17 BP 2200 EP 2210 DI 10.1038/onc.2012.234 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 132JD UT WOS:000318062800009 PM 22689060 ER PT J AU Ali, MK Bullard, KM Saaddine, JB Cowie, CC Imperatore, G Gregg, EW AF Ali, Mohammed K. Bullard, Kai McKeever Saaddine, Jinan B. Cowie, Catherine C. Imperatore, Giuseppina Gregg, Edward W. TI Achievement of Goals in U.S. Diabetes Care, 1999-2010 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BLOOD-GLUCOSE CONTROL; CARDIOVASCULAR-DISEASE; PERFORMANCE-MEASURES; GLYCEMIC TARGETS; US ADULTS; FOLLOW-UP; TYPE-2; HEALTH; RISK; COMPLICATIONS AB Background Tracking national progress in diabetes care may aid in the evaluation of past efforts and identify residual gaps in care. Methods We analyzed data for adults with self-reported diabetes from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to examine risk-factor control, preventive practices, and risk scores for coronary heart disease over the 1999-2010 period. Results From 1999 through 2010, the weighted proportion of survey participants who met recommended goals for diabetes care increased, by 7.9 percentage points (95% confidence interval [CI], 0.8 to 15.0) for glycemic control (glycated hemoglobin level <7.0%), 9.4 percentage points (95% CI, 3.0 to 15.8) for individualized glycemic targets, 11.7 percentage points (95% CI, 5.7 to 17.7) for blood pressure (target, <130/80 mm Hg), and 20.8 percentage points (95% CI, 11.6 to 30.0) for lipid levels (target level of low-density lipoprotein [LDL] cholesterol, <100 mg per deciliter [2.6 mmol per liter]). Tobacco use did not change significantly, but the 10-year probability of coronary heart disease decreased by 2.8 to 3.7 percentage points. However, 33.4 to 48.7% of persons with diabetes still did not meet the targets for glycemic control, blood pressure, or LDL cholesterol level. Only 14.3% met the targets for all three of these measures and for tobacco use. Adherence to the recommendations for annual eye and dental examinations was unchanged, but annual lipid-level measurement and foot examination increased by 5.5 percentage points (95% CI, 1.6 to 9.4) and 6.8 percentage points (95% CI, 4.8 to 8.8), respectively. Annual vaccination for influenza and receipt of pneumococcal vaccination for participants 65 years of age or older rose by 4.5 percentage points (95% CI, 0.8 to 8.2) and 6.9 percentage points (95% CI, 3.4 to 10.4), respectively, and daily glucose monitoring increased by 12.7 percentage points (95% CI, 10.3 to 15.1). Conclusions Although there were improvements in risk-factor control and adherence to preventive practices from 1999 to 2010, tobacco use remained high, and almost half of U.S. adults with diabetes did not meet the recommended goals for diabetes care. C1 [Ali, Mohammed K.; Bullard, Kai McKeever; Saaddine, Jinan B.; Imperatore, Giuseppina; Gregg, Edward W.] Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Ali, Mohammed K.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Cowie, Catherine C.] NIDDK, NIH, Bethesda, MD USA. RP Ali, MK (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Mailstop K10,4770 Buford Hwy NE, Atlanta, GA 30341 USA. EM ise1@cdc.gov NR 41 TC 254 Z9 260 U1 5 U2 38 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 25 PY 2013 VL 368 IS 17 BP 1613 EP 1624 DI 10.1056/NEJMsa1213829 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 130YK UT WOS:000317956300010 PM 23614587 ER PT J AU Kaneko, H Ishijima, M Futami, I Tomikawa-Ichikawa, N Kosaki, K Sadatsuki, R Yamada, Y Kurosawa, H Kaneko, K Arikawa-Hirasawa, E AF Kaneko, Haruka Ishijima, Muneaki Futami, Ippei Tomikawa-Ichikawa, Naoki Kosaki, Keisuke Sadatsuki, Ryo Yamada, Yoshihiko Kurosawa, Hisashi Kaneko, Kazuo Arikawa-Hirasawa, Eri TI Synovial perlecan is required for osteophyte formation in knee osteoarthritis SO MATRIX BIOLOGY LA English DT Article DE Synovial perlecan; Osteophyte; Osteoarthritis; TGF-beta; Synovium ID GROWTH-FACTOR-I; HEPARAN-SULFATE PROTEOGLYCAN; PERIOSTEUM-DERIVED CELLS; MESENCHYMAL STEM-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; LINING MACROPHAGES; FACTOR-BETA; CARTILAGE; JOINT; EXPRESSION AB The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2(-/-)-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2(-/-)-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-beta-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2(-/-)-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2(-/-)-Tg mice. The reduced osteophyte formation in Hspg2(-/-)-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-beta model, the osteophyte size and maturation were also significantly reduced in Hspg2(-/-)-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy. (C) 2013 Elsevier B.V. All rights reserved. C1 [Kaneko, Haruka; Ishijima, Muneaki; Futami, Ippei; Sadatsuki, Ryo; Kaneko, Kazuo] Juntendo Univ, Grad Sch Med, Dept Med Orthopaed & Motor Organ, Tokyo 1138421, Japan. [Kaneko, Haruka; Ishijima, Muneaki; Futami, Ippei; Sadatsuki, Ryo; Kurosawa, Hisashi; Kaneko, Kazuo] Juntendo Univ, Sch Med, Dept Orthopaed, Tokyo 1138421, Japan. [Tomikawa-Ichikawa, Naoki; Arikawa-Hirasawa, Eri] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo 1138421, Japan. [Kosaki, Keisuke; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Ishijima, M (reprint author), Juntendo Univ, Sch Med, Dept Orthopaed, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan. EM harukago@juntendo.ac.jp; ishijima@juntendo.ac.jp; ippei@juntendo.ac.jp; naoichi@fmu.ac.jp; kkosaki@t3.rim.or.jp; rsadatsu@juntendo.ac.jp; yyamada@dir.nidcr.nih.gov; kuro@juntendo.ac.jp; k-kaneko@juntendo.ac.jp; ehirasaw@juntendo.ac.jp FU Ministry of Education, Culture, Sport, Science and Technology, Japan [19791047, 21791418, 22300223]; Intramural Program of National Institute of Dental and Craniofacial Research, the National Institutes of Health FX We would like to thank Dr. T. Sasaki and Dr. G. Lunstrum for providing the antibodies, Dr. Z. Xu, Dr. S. de Vega and Dr. R. Nonaka for mouse management and technical assistance, and T. Sueyoshi, Y. Kojima, J. Furuhata, Y. Toui, K. Miyahara, and H. Sakai for technical assistance. This study was funded in part by a High Technology Research Center Grant from the Ministry of Education, Culture, Sport, Science and Technology, Japan (19791047 and 21791418 for M.I. and 22300223 for EA-E.) and the Intramural Program of National Institute of Dental and Craniofacial Research, the National Institutes of Health (to Y.Y.). NR 50 TC 22 Z9 23 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD APR 24 PY 2013 VL 32 IS 3-4 BP 178 EP 187 DI 10.1016/j.matbio.2013.01.004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152LS UT WOS:000319533800005 PM 23339896 ER PT J AU Kar, AN MacGibeny, MA Gervasi, NM Gioio, AE Kaplan, BB AF Kar, Amar N. MacGibeny, Margaret A. Gervasi, Noreen M. Gioio, Anthony E. Kaplan, Barry B. TI Intra-axonal Synthesis of Eukaryotic Translation Initiation Factors Regulates Local Protein Synthesis and Axon Growth in Rat Sympathetic Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ACTIN MESSENGER-RNA; BETA-ACTIN; CONE COLLAPSE; DISTAL AXONS; LOCALIZATION; DISTINCT; APLYSIA; PHOSPHORYLATION; IDENTIFICATION; FACILITATION AB Axonal protein synthesis is a complex process involving selective mRNA localization and translational regulation. In this study, using in situ hybridization and metabolic labeling, we show that the mRNAs encoding eukaryotic translation initiation factors eIF2B2 and eIF4G2 are present in the axons of rat sympathetic neurons and are locally translated. We also report that a noncoding microRNA, miR16, modulates the axonal expression of eIF2B2 and eIF4G2. Transfection of axons with precursor miR16 and anti-miR16 showed that local miR16 levels modulated axonal eIF2B2 and eIF4G2 mRNA and protein levels, as well as axon outgrowth. siRNA-mediated knock-down of axonal eIF2B2 and eIF4G2 mRNA also resulted in a significant decrease in axonal eIF2B2 and eIF4G2 protein. Moreover, results of metabolic labeling studies showed that downregulation of axonal eIF2B2 and eIF4G2 expression also inhibited local protein synthesis and axon growth. Together, these data provide evidence that miR16 mediates axonal growth, at least in part, by regulating the local protein synthesis of eukaryotic translation initiation factors eIF2B2 and eIF4G2 in the axon. C1 [Kar, Amar N.; MacGibeny, Margaret A.; Gervasi, Noreen M.; Gioio, Anthony E.; Kaplan, Barry B.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kaplan, BB (reprint author), NIMH, Mol Biol Lab, Bldg 10,Room 4N-212, Bethesda, MD 20892 USA. EM Barry.Kaplan@nih.gov OI Kar, Amar/0000-0003-2380-7504 FU Division of Intramural Research Programs of the National Institute of Mental Health FX This work was supported by the Division of Intramural Research Programs of the National Institute of Mental Health. We thank Ms. Sanah Vohra for invaluable technical assistance and critical reading of the manuscript. NR 41 TC 16 Z9 16 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 24 PY 2013 VL 33 IS 17 BP 7165 EP 7174 DI 10.1523/JNEUROSCI.2040-12.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 137EW UT WOS:000318419300006 PM 23616526 ER PT J AU Subramanian, J Dye, L Morozov, A AF Subramanian, Jaichandar Dye, Louis Morozov, Alexei TI Rap1 Signaling Prevents L-Type Calcium Channel-Dependent Neurotransmitter Release SO JOURNAL OF NEUROSCIENCE LA English DT Article ID B-RAF; STRUCTURAL PLASTICITY; MAP KINASE; ACTIVATION; PATHWAY; EXPRESSION; PROTEINS; VESICLES; AMYGDALA; POOL AB The small GTPase Rap1 contributes to fear learning and cortico-amygdala plasticity by inhibiting glutamate release from cortical neurons, but mechanisms of this inhibition remain unknown. Conversely, L-type calcium channels (LTCCs) become involved in glutamate release after fear learning and LTP induction. Here, we show that Rap1 deletion in mouse primary cortical neurons increases synaptic vesicle exocytosis without altering endocytosis or vesicle pool size in an LTCC-dependent manner. We identify Erk1/2 as the downstream effector of Rap1 and show that its inhibition increases plasma membrane expression of LTCCs near presynaptic terminals. We propose that the Rap1 signaling enables plasticity and fear learning by regulating LTCCs at cortico-amygdala synapses. C1 [Subramanian, Jaichandar; Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Dye, Louis] NICHHD, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 USA. [Morozov, Alexei] Virginia Tech Caril Res Inst, Roanoke, VA 24016 USA. [Morozov, Alexei] Virginia Polytech Inst & State Univ, Sch Biomed Engn & Sci, Blacksburg, VA 24061 USA. RP Morozov, A (reprint author), Virginia Tech Caril Res Inst, 2 Riverside Circle, Roanoke, VA 24016 USA. EM jaichandar@gmail.com; alexeim@vtc.vt.edu FU National Institute of Mental Health (NIMH) Intramural Research Program FX This work was supported by National Institute of Mental Health (NIMH) Intramural Research Program. We thank Dr. Vincent Schram, Lynne Holtzclaw, and Dr. James T. Russell [Microscopy and Imaging Core, National Institute of Child Health and Human Development, National Institutes of Health (NIH)] and Dr. Carolyn Smith at the Light Imaging Facility (National Institute of Neurological Disorders and Stroke, NIH). We also thank Tsegaye Lemma (NIMH, NIH) for help with animal maintenance. NR 25 TC 6 Z9 6 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 24 PY 2013 VL 33 IS 17 BP 7245 EP 7252 DI 10.1523/JNEUROSCI.5963-11.2013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 137EW UT WOS:000318419300013 PM 23616533 ER PT J AU Jhou, TC Good, CH Rowley, CS Xu, SP Wang, HK Burnham, NW Hoffman, AF Lupica, CR Ikemoto, S AF Jhou, Thomas C. Good, Cameron H. Rowley, Courtney S. Xu, Sheng-ping Wang, Huikun Burnham, Nathan W. Hoffman, Alexander F. Lupica, Carl R. Ikemoto, Satoshi TI Cocaine Drives Aversive Conditioning via Delayed Activation of Dopamine-Responsive Habenular and Midbrain Pathways SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; OPPONENT-PROCESS ACTIONS; SELF-ADMINISTERED COCAINE; NEGATIVE REWARD SIGNALS; LATERAL HABENULA; INTRAVENOUS COCAINE; NUCLEUS-ACCUMBENS; SUBSTANTIA-NIGRA; NEURONS; RATS AB Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons. C1 [Jhou, Thomas C.; Xu, Sheng-ping; Ikemoto, Satoshi] NIDA, Behav Neurosci Res Branch, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Good, Cameron H.; Wang, Huikun; Hoffman, Alexander F.; Lupica, Carl R.] NIDA, Electrophysiol Res Sect, NIH, US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Jhou, Thomas C.; Rowley, Courtney S.; Burnham, Nathan W.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. RP Jhou, TC (reprint author), Med Univ S Carolina, Dept Neurosci, 173 Ashley Ave, Charleston, SC 29425 USA. EM jhou@musc.edu RI Hoffman, Alexander/H-3035-2012; OI Hoffman, Alexander/0000-0002-2676-0628; Ikemoto, Satoshi/0000-0002-0732-7386 FU NIH [DA032898, MH094489]; National Institute on Drug Abuse Intramural Research Program FX This work was funded by NIH Grants DA032898 and MH094489 (to T.C.J.) and by the National Institute on Drug Abuse Intramural Research Program. We thank Dr. P.J. Vento for helpful comments on the manuscript and Dr. A. Ettenberg for advice establishing the runway technique. NR 59 TC 63 Z9 64 U1 2 U2 16 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD APR 24 PY 2013 VL 33 IS 17 BP 7501 EP 7512 DI 10.1523/JNEUROSCI.3634-12.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 137EW UT WOS:000318419300035 PM 23616555 ER PT J AU Barron, L Smith, AM El Kasmi, KC Qualls, JE Huang, XZ Cheever, A Borthwick, LA Wilson, MS Murray, PJ Wynn, TA AF Barron, Luke Smith, Amber M. El Kasmi, Karim C. Qualls, Joseph E. Huang, Xiaozhu Cheever, Allen Borthwick, Lee A. Wilson, Mark S. Murray, Peter J. Wynn, Thomas A. TI Role of Arginase 1 from Myeloid Cells in Th2-Dominated Lung Inflammation SO PLOS ONE LA English DT Article ID MANSONI ANTIGENS MODULATE; NITRIC-OXIDE SYNTHASE; L-ARGININE METABOLISM; ALLERGIC-ASTHMA; SCHISTOSOMA-MANSONI; AIRWAY HYPERRESPONSIVENESS; IMMUNE-RESPONSE; MURINE MODEL; MOUSE MODEL; T-CELLS AB Th2-driven lung inflammation increases Arginase 1 (Arg1) expression in alternatively-activated macrophages (AAMs). AAMs modulate T cell and wound healing responses and Arg1 might contribute to asthma pathogenesis by inhibiting nitric oxide production, regulating fibrosis, modulating arginine metabolism and restricting T cell proliferation. We used mice lacking Arg1 in myeloid cells to investigate the contribution of Arg1 to lung inflammation and pathophysiology. In six model systems encompassing acute and chronic Th2-mediated lung inflammation we observed neither a pathogenic nor protective role for myeloid-expressed Arg1. The number and composition of inflammatory cells in the airways and lungs, mucus secretion, collagen deposition, airway hyper-responsiveness, and T cell cytokine production were not altered if AAMs were deficient in Arg1 or simultaneously in both Arg1 and NOS2. Our results argue that Arg1 is a general feature of alternative activation but only selectively regulates Th2 responses. Therefore, attempts to experimentally or therapeutically inhibit arginase activity in the lung should be examined with caution. C1 [Barron, Luke; Wynn, Thomas A.] NIAID, Program Barrier Immun & Repair, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Smith, Amber M.; El Kasmi, Karim C.; Qualls, Joseph E.; Murray, Peter J.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [Smith, Amber M.; El Kasmi, Karim C.; Qualls, Joseph E.; Murray, Peter J.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Huang, Xiaozhu] Univ Calif San Francisco, Dept Med, Lung Biol Ctr, San Francisco, CA USA. [Cheever, Allen] Biomed Res Inst, Rockville, MD 20852 USA. [Borthwick, Lee A.] Newcastle Univ, Sch Med, Inst Cellular Med, Tissue Fibrosis & Repair Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wilson, Mark S.] Natl Inst Med Res, MRC, Div Mol Immunol, London NW7 1AA, England. RP Barron, L (reprint author), NIAID, Program Barrier Immun & Repair, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM BarronL@niaid.nih.gov RI sebastianovitsch, stepan/G-8507-2013; OI Borthwick, Lee/0000-0003-2885-3382 FU Sandler Program for Asthma Research; NIH [AI062921]; CORE [P30 CA21765]; American Lebanese Syrian Associated Charities; NIAID intramural research program FX This work was supported by the Sandler Program for Asthma Research (PJM), NIH grant AI062921 (PJM), CORE grant P30 CA21765, the American Lebanese Syrian Associated Charities, and the NIAID intramural research program (TAW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 27 Z9 28 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 24 PY 2013 VL 8 IS 4 AR e61961 DI 10.1371/journal.pone.0061961 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136DE UT WOS:000318340400061 PM 23637937 ER PT J AU Valle, BL D'Souza, T Becker, KG Wood, WH Zhang, YQ Wersto, RP Morin, PJ AF Valle, Blanca L. D'Souza, Theresa Becker, Kevin G. Wood, William H., III Zhang, Yongqing Wersto, Robert P. Morin, Patrice J. TI Non-Steroidal Anti-inflammatory Drugs Decrease E2F1 Expression and Inhibit Cell Growth in Ovarian Cancer Cells SO PLOS ONE LA English DT Article ID TRANSCRIPTION FACTOR E2F-1; CYCLE ARREST; GENE-EXPRESSION; CARCINOMA-CELLS; DOWN-REGULATION; NUDE-MICE; INDOMETHACIN; APOPTOSIS; ASPIRIN; TUMORS AB Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and experiments in mouse models have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. However, there are limited preclinical studies investigating the effects of NSAIDs in ovarian cancer. Here, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in ovarian cancer cell lines and in a xenograft mouse model. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and apoptosis. In addition, diclofenac and indomethacin reduced tumor volume in a xenograft model of ovarian cancer. To identify possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, we performed microarray analysis of ovarian cancer cells treated with indomethacin or diclofenac. Interestingly, several of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1. E2F1 was downregulated at the mRNA and protein level upon treatment with diclofenac and indomethacin, and overexpression of E2F1 rescued cells from the growth inhibitory effects of diclofenac and indomethacin. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1. C1 [Valle, Blanca L.; D'Souza, Theresa; Morin, Patrice J.] NIA, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA. [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing; Wersto, Robert P.] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Morin, Patrice J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), Amer Assoc Canc Res, Philadelphia, PA USA. EM pat.morin@aacr.org OI Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 11 Z9 12 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 24 PY 2013 VL 8 IS 4 AR e61836 DI 10.1371/journal.pone.0061836 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136DE UT WOS:000318340400054 PM 23637916 ER PT J AU Singleton, AB AF Singleton, Andrew B. TI Finding Risk in All the Right Places SO NEURON LA English DT Editorial Material ID ONSET ALZHEIMERS-DISEASE; COMMON VARIANTS; ASSOCIATION; CD2AP; EPHA1; CD33 AB In this issue of Neuron, Cruchaga et al. (2013) identify genetic variability linked to altered levels of tau protein in cerebrospinal fluid. They show that the same genetic variants can also confer risk for Alzheimer's disease. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 FU Intramural NIH HHS [ZIA AG000950-11] NR 12 TC 0 Z9 0 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD APR 24 PY 2013 VL 78 IS 2 BP 207 EP 208 DI 10.1016/j.neuron.2013.04.011 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 134HY UT WOS:000318202200001 PM 23622057 ER PT J AU Selby, JV Krumholz, HM Kuntz, RE Collins, FS AF Selby, Joseph V. Krumholz, Harlan M. Kuntz, Richard E. Collins, Francis S. TI Network News: Powering Clinical Research SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material C1 [Selby, Joseph V.] Patient Ctr Outcomes Res Inst PCORI, Washington, DC 20036 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Kuntz, Richard E.] Medtronic, Minneapolis, MN 55432 USA. [Collins, Francis S.] NIH, Bethesda, MD 20892 USA. EM francis.collins@nih.gov NR 5 TC 9 Z9 9 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD APR 24 PY 2013 VL 5 IS 182 AR 182fs13 DI 10.1126/scitranslmed.3006298 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 131TF UT WOS:000318018300002 PM 23612587 ER PT J AU Liang, F Bond, E Sandgren, KJ Smed-Sorensen, A Rangaka, MX Lange, C Koup, RA McComsey, GA Lederman, MM Wilkinson, RJ Andersson, J Lore, K AF Liang, Frank Bond, Emily Sandgren, Kerrie J. Smed-Sorensen, Anna Rangaka, Molebogeng X. Lange, Christoph Koup, Richard A. McComsey, Grace A. Lederman, Michael M. Wilkinson, Robert J. Andersson, Jan Lore, Karin TI Dendritic cell recruitment in response to skin antigen tests in HIV-1-infected individuals correlates with the level of T-cell infiltration SO AIDS LA English DT Article DE delayed-type hypersensitivity reaction; dendritic cells; HIV-1; Ki67; plasmacytoid; skin; skin test ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; DELAYED-TYPE HYPERSENSITIVITY; EPIDERMAL LANGERHANS CELLS; CANDIDA-ALBICANS; TYPE-1 INFECTION; LYMPHOID-TISSUE; IN-VITRO; SUBSETS; SUSCEPTIBILITY AB Objectives: To study whether in-vivo recruitment of dendritic cells in response to antigen administration in the skin is altered during HIV-1 infection. Design: Skin punch biopsies were collected from HIV-1-positive as well as seronegative individuals at 48 h after intradermal injection of inactivated antigens of mumps virus, Candida albicans, or purified protein derivate (PPD) from Mycobacterium tuberculosis. Methods: Cryosections were analyzed by in-situ staining and computerized imaging. Results: Control skin biopsies showed that there was no difference in the number of skin-resident dendritic cells between seronegative and HIV-1-positive individuals. Antigen injection resulted in substantial infiltration of dendritic cells compared to the frequencies found in donor-matched control skin. In HIV-1-positive individuals, CD123(+)/CD303(+) plasmacytoid dendritic cells and CD11c(+) myeloid dendritic cells, including the CD141(+) cross-presenting subset, were recruited at lower levels compared to healthy controls in response to PPD and mumps but not C. albicans. The level of dendritic cell recruitment correlated with the frequencies of T cells infiltrating the respective antigen sites. Ki67(+) cycling T cells at the injection sites were much more frequent in response to each of the antigens in the HIV-1-positive individuals, including those with AIDS, compared to healthy controls. Conclusion: Multiple dendritic cell subsets infiltrate the dermis in response to antigen exposure. There was no obvious depletion or deficiency in mobilization of dendritic cells in response to antigen skin tests during chronic HIV-1 infection. Instead, the levels of antigen-specific memory T cells that accumulate at the antigen site may determine the level of dendritic cell infiltration. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:1071-1080 C1 [Liang, Frank; Bond, Emily; Sandgren, Kerrie J.; Andersson, Jan; Lore, Karin] Karolinska Inst, Ctr Infect Med, Dept Med, Stockholm, Sweden. [Smed-Sorensen, Anna] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Rangaka, Molebogeng X.; Wilkinson, Robert J.] Univ Cape Town, Inst Infect Dis & Mol Med, Clin Infect Dis Res Initiat, ZA-7925 Cape Town, South Africa. [Lange, Christoph] TB Ctr Borstel, Med Clin, Clin Infect Dis, Borstel, Germany. [Liang, Frank; Koup, Richard A.; Lore, Karin] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [McComsey, Grace A.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Lederman, Michael M.; Wilkinson, Robert J.] Natl Inst Med Res, MRC, Mill Hill, England. [Wilkinson, Robert J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. RP Lore, K (reprint author), Karolinska Univ, Huddinge Hosp, Ctr Infect Med, Karolinska Inst F59, S-14186 Stockholm, Sweden. EM Karin.Lore@ki.se RI Lange, Christoph/J-6289-2012; Rangaka, Molebogeng/E-4116-2015; OI Bond, Emily/0000-0001-5374-7085; Wilkinson, Robert/0000-0002-2753-1800 FU Vetenskapsradet; Swedish International Development Agency (Sida); Swedish Physicians Against AIDS Foundation; Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Society of Medicine; Fernstrom Foundation; Swedish Society for Medical Research; Wellcome Trust; Medical Research Council (UK); H.W. and J. Hector Foundation FX K.L. is supported by grants from Vetenskapsradet, the Swedish International Development Agency (Sida), the Swedish Physicians Against AIDS Foundation, and the Swedish Governmental Agency for Innovation Systems (Vinnova). F. L. and K.J.S. are recipients of scholarships from the Swedish Society of Medicine, the Fernstrom Foundation, and the Swedish Society for Medical Research. R.J.W. and M. X. R. are supported by the Wellcome Trust and the Medical Research Council (UK), and C. L. by the H.W. and J. Hector Foundation for logistic and shipping costs. NR 49 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD APR 24 PY 2013 VL 27 IS 7 BP 1071 EP 1080 DI 10.1097/QAD.0b013e32835ecaca PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 124QE UT WOS:000317479500003 PM 23324660 ER PT J AU Wilkinson, JD Williams, PL Leister, E Zeldow, B Shearer, WT Colan, SD Siberry, GK Dooley, LB Scott, GB Rich, KC Lipshultz, SE AF Wilkinson, James D. Williams, Paige L. Leister, Erin Zeldow, Bret Shearer, William T. Colan, Steven D. Siberry, George K. Dooley, Laurie B. Scott, Gwendolyn B. Rich, Kenneth C. Lipshultz, Steven E. CA Pediat HIV AIDS Cohort Study PHACS TI Cardiac biomarkers in HIV-exposed uninfected children SO AIDS LA English DT Article DE antiretroviral drugs; cardiac biomarkers; echocardiography; HIV; pediatric ID C-REACTIVE PROTEIN; ACUTE LYMPHOBLASTIC-LEUKEMIA; TROPONIN-T; MYOCARDIAL INJURY; DOXORUBICIN THERAPY; ANTIRETROVIRAL THERAPY; INDUCED CARDIOTOXICITY; NATRIURETIC PEPTIDE; PEDIATRIC-PATIENTS; INFECTED PATIENTS AB Objectives: To evaluate associations of cardiac biomarkers with in-utero antiretroviral drug exposures and cardiac function/structure measured by echocardiograms in HIV-exposed but uninfected (HEU) children. Design and methods: We analyzed the association of three cardiac biomarkers (cardiac troponin T, cTnT; high sensitivity C-reactive protein, hsCRP; and N-terminal pro-brain natriuretic peptide, NT-proBNP) with prenatal antiretroviral drug exposures, maternal-child characteristics, and echocardiographic parameters. Results: Among 338 HEU children (mean age 4.3 years), 51% had at least one elevated cardiac biomarker. Maternal tobacco use was associated with elevated NT-proBNP [adjusted odds ratio (aOR) 2.28, P = 0.02]. Maternal alcohol and abacavir use were associated with elevated cTnT levels (aOR 3.56, P = 0.01 and aOR 2.33, P = 0.04, respectively). Among 94 children with paired echocardiogram-biomarker measurements, cTnT measurements were correlated with increased left-ventricular thickness-to-dimension ratio (r = 0.21, P = 0.04); and elevated cTnT was associated with higher mean left-ventricular end-diastolic (LVED) posterior wall thickness (P = 0.04). hsCRP measurements were negatively correlated with septal thickness (r = -0.22, P = 0.03) and elevated hsCRP was associated with lower mean left-ventricular contractility Z-scores (P = 0.04). NT-proBNP measurements were correlated with increased LVED dimension (r = 0.20, P = 0.05) and elevated NT-proBNP was associated with lower mean end-systolic septal thickness (P = 0.03). Conclusion: Our findings suggest that cardiac biomarkers may help identify HEU children who require further cardiac evaluation including echocardiography. Potential cardiac effects of prenatal abacavir exposure in this population need further investigation. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:1099-1108 C1 [Wilkinson, James D.; Scott, Gwendolyn B.; Lipshultz, Steven E.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33101 USA. [Williams, Paige L.; Leister, Erin; Zeldow, Bret] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Shearer, William T.] Baylor Coll Med, Dept Pediat & Pathol & Immunol, Houston, TX 77030 USA. [Shearer, William T.] Texas Childrens Hosp, Houston, TX 77030 USA. [Colan, Steven D.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Siberry, George K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Dooley, Laurie B.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. [Rich, Kenneth C.] Univ Illinois, Dept Pediat, Chicago, IL USA. RP Lipshultz, SE (reprint author), Univ Miami, Miller Sch Med, Dept Pediat D820, POB 016820, Miami, FL 33101 USA. EM slipshultz@med.miami.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute on Allergy and Infectious Diseases; Office of AIDS Research; National Institute of Mental Health; National Institute of Neurological Diseases and Stoke; National Institute of Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute; National Institute of Dental and Craniofacial Research; National Institute on Alcohol Abuse and Alcoholism FX We thank the children and families for their participation in the PHACS protocol 'Surveillance Monitoring of ART Toxicities' (SMARTT), and the individuals and institutions involved in the conduct of PHACS SMARTT. The following institutions, clinical site investigators and staff participated in conducting PHACS SMARTT in 2010, in alphabetical order: Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon; Children's Hospital of Philadelphia: Richard Rutstein, Carol Vincent, Nancy Silverman; Children's Memorial Hospital: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Helen Rozelman; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: Hermann Mendez, Ava Dennie, Susan Bewley; SUNY Stony Brook: Sharon Nachman, Margaret Oliver, Helen Rozelman; Tulane University Health Sciences Center: Russell Van Dyke, Karen Craig, Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Newana Beatty, Dan Marullo; University of California, San Diego: Stephen Spector, Jean Manning, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Robin McEvoy; University of Florida/Jacksonville: Mobeen Rathore, Kristi Stowers, Ann Usitalo; University of Illinois, Chicago: Kenneth Rich, Delmyra Turpin, Renee Smith; University of Maryland, Baltimore: Douglas Watson, LaToya Stubbs, Rose Belanger; University of Medicine and Dentistry of New Jersey: Arry Dieudonne, Linda Bettica, Susan Adubato; University of Miami: Gwendolyn Scott, Claudia Florez, ElizabethWillen; University of Southern California: Toinette Frederick, Mariam Davtyan, Maribel Mejia; University of Puerto Rico Medical Center: Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio. PHACS was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from the National Institute on Drug Abuse, the National Institute on Allergy and Infectious Diseases, the Office of AIDS Research, National Institute of Mental Health, the National Institute of Neurological Diseases and Stoke, the National Institute of Deafness and Other Communication Disorders, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with Harvard School of Public Health and Tulane School of Medicine. Data management services were provided by Frontier Science and regulatory services and logistical support by Westat. The conclusions and opinions expressed are those of the authors and do not necessarily reflect those of the NIH or DHHS. NR 57 TC 10 Z9 10 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD APR 24 PY 2013 VL 27 IS 7 BP 1099 EP 1108 DI 10.1097/QAD.0b013e32835cf21c PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 124QE UT WOS:000317479500006 PM 23211773 ER PT J AU Abhyankar, S McDonald, CJ AF Abhyankar, Swapna McDonald, Clement J. TI Overweight, Obesity, and All-Cause Mortality SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Abhyankar, Swapna; McDonald, Clement J.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. RP Abhyankar, S (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD USA. EM swapna.abhyankar@nih.gov NR 5 TC 2 Z9 2 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. 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