FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Mazzacuva, F Mills, PB Mills, K Platt, F Maekawa, M Porter, FD Clayton, PT AF Mazzacuva, Francesca Mills, Philippa B. Mills, Kevin Platt, Frances Maekawa, Masamitsu Porter, Forbes D. Clayton, Peter T. TI Identification of new biomarkers suitable for an early diagnosis of Niemann-Pick Cl SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 12th Annual WORLD Symposium CY FEB 29-MAR 04, 2016 CL San Diego, CA C1 [Mazzacuva, Francesca; Mills, Philippa B.; Mills, Kevin; Clayton, Peter T.] UCL, London, England. [Platt, Frances] Univ Oxford, London, England. [Maekawa, Masamitsu] Tohoku Univ Hosp, London, Japan. [Porter, Forbes D.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2016 VL 117 IS 2 MA 196 BP S78 EP S78 DI 10.1016/j.ymgme.2015.12.354 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE8LS UT WOS:000370888100197 ER PT J AU Vu, ML Li, R Zheng, W AF My Linh Vu Li, Rong Zheng, Wei TI Patient iPS-derived neural stem cells and neuronal cells as a cell-based model system for Tay-Sachs disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 12th Annual WORLD Symposium CY FEB 29-MAR 04, 2016 CL San Diego, CA C1 [My Linh Vu; Li, Rong; Zheng, Wei] NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 3 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2016 VL 117 IS 2 MA 321 BP S118 EP S118 DI 10.1016/j.ymgme.2015.12.479 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE8LS UT WOS:000370888100322 ER PT J AU Porter, FD Farhat, NY Ottinger, EA McKew, JC Weissfeld, L Machielse, B Berry-Kavis, EM Vite, CH Walkley, SU Ory, DS AF Porter, Forbes D. Farhat, Nicole Y. Ottinger, Elizabeth A. McKew, John C. Weissfeld, Lisa Machielse, Ben Berry-Kavis, Elizabeth M. Vite, Charles H. Walkley, Steven U. Ory, Daniel S. CA TRND Team TI Phase 1/2 evaluation of intrathecal 2-hydroxypropyl-beta-cyclodextrin for the treatment of Niemann-Pick disease type C1 SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 12th Annual WORLD Symposium CY FEB 29-MAR 04, 2016 CL San Diego, CA C1 [Porter, Forbes D.; Farhat, Nicole Y.; Ottinger, Elizabeth A.; McKew, John C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Weissfeld, Lisa] Stat Collaborat, Washington, DC USA. [Machielse, Ben] Vtesse, Gaithersburg, MD USA. [Berry-Kavis, Elizabeth M.] Rush Univ, Chicago, MD USA. [Vite, Charles H.] Univ Penn, Philadelphia, PA 19104 USA. [Walkley, Steven U.] Albert Einstein Coll Med, New York, NY USA. [Ory, Daniel S.] Washington Univ, Sch Med, St Louis, MO USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2016 VL 117 IS 2 MA 253 BP S97 EP S97 DI 10.1016/j.ymgme.2015.12.411 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE8LS UT WOS:000370888100254 ER PT J AU Raben, N AF Raben, Nina TI Pompe disease: From pathophysiology to therapy and back again SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT 12th Annual WORLD Symposium CY FEB 29-MAR 04, 2016 CL San Diego, CA C1 [Raben, Nina] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2016 VL 117 IS 2 MA 257 BP S98 EP S98 DI 10.1016/j.ymgme.2015.12.415 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA DE8LS UT WOS:000370888100258 ER PT J AU Ibrahim-Verbaas, CA Bressler, J Debette, S Schuur, M Smith, AV Bis, JC Davies, G Trompet, S Smith, JA Wolf, C Chibnik, LB Liu, Y Vitart, V Kirin, M Petrovic, K Polasek, O Zgaga, L Fawns-Ritchie, C Hoffmann, P Karjalainen, J Lahti, J Llewellyn, DJ Schmidt, CO Mather, KA Chouraki, V Sun, Q Resnick, SM Rose, LM Oldmeadow, C Stewart, M Smith, BH Gudnason, V Yang, Q Mirza, SS Jukema, JW Dejager, PL Harris, TB Liewald, DC Amin, N Coker, LH Stegle, O Lopez, OL Schmidt, R Teumer, A Ford, I Karbalai, N Becker, JT Jonsdottir, MK Au, R Fehrmann, RSN Herms, S Nalls, M Zhao, W Turner, ST Yaffe, K Lohman, K van Swieten, JC Kardia, SLR Knopman, DS Meeks, WM Heiss, G Holliday, EG Schofield, PW Tanaka, T Stott, DJ Wang, J Ridker, P Gow, AJ Pattie, A Starr, JM Hocking, LJ Armstrong, NJ McLachlan, S Shulman, JM Pilling, LC Eiriksdottir, G Scott, RJ Kochan, NA Palotie, A Hsieh, YC Eriksson, JG Penman, A Gottesman, RF Oostra, BA Yu, L DeStefano, AL Beiser, A Garcia, M Rotter, JI Nothen, MM Hofman, A Slagboom, PE Westendorp, RGJ Buckley, BM Wolf, PA Uitterlinden, AG Psaty, BM Grabe, HJ Bandinelli, S Chasman, DI Grodstein, F Roikkonen, K Lambert, JC Porteous, DJ Price, JF Sachdev, PS Ferrucci, L Attia, JR Rudan, I Hayward, C Wright, AF Wilson, JF Cichon, S Franke, L Schmidt, H Ding, J de Craen, AJM Fornage, M Bennett, DA Deary, IJ Ikram, MA Launer, LJ Fitzpatrick, AL Seshadri, S van Duijn, CM Mosley, TH AF Ibrahim-Verbaas, C. A. Bressler, J. Debette, S. Schuur, M. Smith, A. V. Bis, J. C. Davies, G. Trompet, S. Smith, J. A. Wolf, C. Chibnik, L. B. Liu, Y. Vitart, V. Kirin, M. Petrovic, K. Polasek, O. Zgaga, L. Fawns-Ritchie, C. Hoffmann, P. Karjalainen, J. Lahti, J. Llewellyn, D. J. Schmidt, C. O. Mather, K. A. Chouraki, V. Sun, Q. Resnick, S. M. Rose, L. M. Oldmeadow, C. Stewart, M. Smith, B. H. Gudnason, V. Yang, Q. Mirza, S. S. Jukema, J. W. Dejager, P. L. Harris, T. B. Liewald, D. C. Amin, N. Coker, L. H. Stegle, O. Lopez, O. L. Schmidt, R. Teumer, A. Ford, I. Karbalai, N. Becker, J. T. Jonsdottir, M. K. Au, R. Fehrmann, R. S. N. Herms, S. Nalls, M. Zhao, W. Turner, S. T. Yaffe, K. Lohman, K. van Swieten, J. C. Kardia, S. L. R. Knopman, D. S. Meeks, W. M. Heiss, G. Holliday, E. G. Schofield, P. W. Tanaka, T. Stott, D. J. Wang, J. Ridker, P. Gow, A. J. Pattie, A. Starr, J. M. Hocking, L. J. Armstrong, N. J. McLachlan, S. Shulman, J. M. Pilling, L. C. Eiriksdottir, G. Scott, R. J. Kochan, N. A. Palotie, A. Hsieh, Y-C Eriksson, J. G. Penman, A. Gottesman, R. F. Oostra, B. A. Yu, L. DeStefano, A. L. Beiser, A. Garcia, M. Rotter, J. I. Noethen, M. M. Hofman, A. Slagboom, P. E. Westendorp, R. G. J. Buckley, B. M. Wolf, P. A. Uitterlinden, A. G. Psaty, B. M. Grabe, H. J. Bandinelli, S. Chasman, D. I. Grodstein, F. Roikkonen, K. Lambert, J-C Porteous, D. J. Price, J. F. Sachdev, P. S. Ferrucci, L. Attia, J. R. Rudan, I. Hayward, C. Wright, A. F. Wilson, J. F. Cichon, S. Franke, L. Schmidt, H. Ding, J. de Craen, A. J. M. Fornage, M. Bennett, D. A. Deary, I. J. Ikram, M. A. Launer, L. J. Fitzpatrick, A. L. Seshadri, S. van Duijn, C. M. Mosley, T. H. CA Generation Scotland TI GWAS for executive function and processing speed suggests involvement of the CADM2 gene SO MOLECULAR PSYCHIATRY LA English DT Article ID ONSET ALZHEIMERS-DISEASE; GENOME-WIDE ASSOCIATION; COGNITIVE FUNCTION; LINKAGE ANALYSIS; COMMON VARIANTS; LOCI; INTELLIGENCE; EXPRESSION; DISORDER; SCHIZOPHRENIA AB To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value = 3.12 x 10(-8)) and in the joint discovery and replication meta-analysis (P-value = 3.28 x 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value= 4x10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value = 7.22 x 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value = 1.36 x 10(-11)) and neuron cell-cell adhesion (P-value = 1.48 x 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. C1 [Ibrahim-Verbaas, C. A.; Schuur, M.; Amin, N.; Oostra, B. A.; van Duijn, C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Ibrahim-Verbaas, C. A.; Schuur, M.; van Swieten, J. C.; Ikram, M. A.] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Bressler, J.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA. [Debette, S.; Au, R.; DeStefano, A. L.; Beiser, A.; Wolf, P. A.; Seshadri, S.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Debette, S.] Univ Bordeaux, Epidemiol & Biostat, U897, INSERM, Bordeaux, France. 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L.] Brigham & Womens Hosp, Div Neurol, Program Translat Neuropsychiat Gen, Boston, MA 02115 USA. [Liu, Y.; Lohman, K.] Wake Forest Sch Med, Dept Epidemiol, Winston Salem, NC USA. [Petrovic, K.; Schmidt, R.; Schmidt, H.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Kirin, M.; Stewart, M.; McLachlan, S.; Price, J. F.; Rudan, I.; Wilson, J. F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Petrovic, K.; Schmidt, R.; Schmidt, H.] Med Univ & Gen Hosp Graz, Dept Neurol, Graz, Austria. [Polasek, O.] Univ Split, Dept Publ Hlth, Split, Croatia. [Zgaga, L.] Trintiy Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland. [Hoffmann, P.; Cichon, S.] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany. [Hoffmann, P.; Herms, S.; Cichon, S.] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Hoffmann, P.; Herms, S.; Noethen, M. 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M.] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA. [Rose, L. M.; Ridker, P.; Chasman, D. I.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Oldmeadow, C.; Holliday, E. G.; Scott, R. J.; Attia, J. R.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia. [Oldmeadow, C.; Holliday, E. G.; Scott, R. J.; Attia, J. R.] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia. [Smith, B. H.] Univ Dundee, Med Res Inst, Dundee, Scotland. [Yang, Q.; Au, R.; DeStefano, A. L.; Beiser, A.; Wolf, P. A.; Seshadri, S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Yang, Q.; Wang, J.; DeStefano, A. L.; Beiser, A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mirza, S. S.; Hofman, A.; Uitterlinden, A. G.; Ikram, M. A.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Mirza, S. S.; Hofman, A.; Uitterlinden, A. G.; Ikram, M. A.; van Duijn, C. M.] Netherlands Consortium Hlth Ageing, Leiden, Netherlands. [Harris, T. 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J.] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia. [Armstrong, N. J.] Univ New S Wales, Sch Math & Stat, Sydney, NSW, Australia. [Armstrong, N. J.] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia. [Shulman, J. M.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Shulman, J. M.] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Dept Mol & Human Genet, Houston, TX 77030 USA. [Pilling, L. C.] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Kochan, N. A.; Sachdev, P. S.] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia. [Palotie, A.] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England. [Palotie, A.] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, A.] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, A.] Univ Cent Hosp, Helsinki, Finland. [Hsieh, Y-C] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan. [Eriksson, J. 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G. J.] Leiden Acad Vital & Ageing, Leiden, Netherlands. [Buckley, B. M.] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Uitterlinden, A. G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Psaty, B. M.; Fitzpatrick, A. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, B. M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, B. M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Grabe, H. J.] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, Stralsund, Germany. [Ibrahim-Verbaas, C. A.; Bressler, J.; Debette, S.; Schuur, M.; Smith, A. V.; Bis, J. C.; Davies, G.; Bandinelli, S.] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Porteous, D. J.] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland. [Ding, J.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, M.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ikram, M. A.] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. [Mosley, T. H.] Univ Mississippi, Med Ctr, Dept Med & Neurol, Jackson, MS 39216 USA. RP Mosley, TH (reprint author), Univ Mississippi, Med Ctr, Dept Med Geriatr, 2500 North State St, Jackson, MS 39216 USA. EM tmosley@umc.edu RI Smith, Albert Vernon/K-5150-2015; Lambert, jean-charles/A-9553-2014; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Slagboom, P. Eline/R-4790-2016; Fehrmann, Rudolf/E-2551-2011; Polasek, Ozren/B-6002-2011; Gudnason, Vilmundur/K-6885-2015 OI van Swieten, John /0000-0001-6278-6844; Lahti, Jari/0000-0002-4310-5297; Nothen, Markus/0000-0002-8770-2464; Sachdev, Perminder/0000-0002-9595-3220; Smith, Blair/0000-0002-5362-9430; Beiser, Alexa/0000-0001-8551-7778; Smith, Jennifer/0000-0002-3575-5468; Gow, Alan/0000-0002-3320-4531; Raikkonen, Katri/0000-0003-3124-3470; Smith, Albert Vernon/0000-0003-1942-5845; Lambert, jean-charles/0000-0003-0829-7817; Franke, Lude/0000-0002-5159-8802; Slagboom, P. Eline/0000-0002-2875-4723; Fehrmann, Rudolf/0000-0002-7516-315X; Polasek, Ozren/0000-0002-5765-1862; Stegle, Oliver/0000-0002-8818-7193; Zgaga, Lina/0000-0003-4089-9703; Hocking, Lynne J/0000-0002-2414-2826; Gudnason, Vilmundur/0000-0001-5696-0084 FU National Foundation for Alzheimer's disease and related disorders; Institut Pasteur de Lille; Centre National de Genotypage; Inserm; FRC (fondation pour la recherche sur le cerveau); Rotary; LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease); MEDIALZ Project - ERDF (European Regional Development Fund) [11001003]; Conseil Regional Nord Pas de Calais; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; Direction Generale de la Sante; MGEN; Institut de la Longevite; Agence Francaise de Securite Sanitaire des Produits de Sante; Aquitaine and Bourgogne Regional Councils; Fondation de France; joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program; Eisai; Wellcome Trust; British Heart Foundation; Chief Scientist Office of the Scottish Executive; NIA [N01-AG-12100]; National Heart, Lung and Blood Institute Contracts [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH Roadmap for Medical Research; Austrian Science Fond (FWF) [P20545-P05, P13180]; Intramural Research Program of the NIH, National Institute on Aging; NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC850863, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [R01AG023629, R01AG15928, R01AG20098, R01AG027058]; National Center for Advancing Translational Sciences; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; Medical Research Council (UK); European Commission Framework 6 project EUROSPAN [LSHG-CT-2006-018947]; Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; Netherlands Organization for Scientific Research (NWO); Internationale Stichting Alzheimer Onderzoek (ISAO); Hersenstichting Nederland (HSN); Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI); Russian Foundation for Basic Research (RFBR); National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278, U01 HL096917, R01 HL093029]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; National Institute of Neurological Disorders and Stroke [NS17950]; National Institute of Aging [U01 AG049505, AG033193, AG008122, AG16495]; Agence National de la Recherche; Leducq Foundation; National Heart, Lung and Blood Institute [HL054464, HL054457, HL054481, HL071917, HL87660, HL043851, HL080467]; National Institute of Neurological Disorders and Stroke of the National Institutes of Health [NS041558]; Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6]; Scottish Funding Council [HR03006]; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT089062]; University of Newcastle's Strategic Initiative Fund; Vincent Fairfax Family Foundation; Hunter Medical Research Institute; Italian Ministry of Health [ICS 110.1RS97.71]; US National Institute on Aging [N01[AG]916413, N01[AG]821336, 263 MD 9164 13, 263 MD 821336]; Intramural Research Program, National Institute on Aging, National Institutes of Health; BBSRC; Royal Society; Chief Scientist Office of the Scottish Government; Research Into Ageing; UK Biotechnology and Biological Sciences Research Council (BBSRC); Engineering and Physical Sciences Research Council (EPSRC); Economic and Social Research Council (ESRC); MRC; NHMRC [401184]; Australian National Health & Medical Research Council [350833, 568969]; Capacity Building Grant [568940]; NHMRC Project [525453]; National Institutes of Health [CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958, DK070756]; MRC Human Genetics Unit; Arthritis Research UK; European Union [LSHG-CT-2006-018947]; Bristol-Myers Squibb; Netherlands Heart Foundation [2001 D 032]; European commission [223004]; Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission 49 (DG XII); Municipality of Rotterdam; ZonMW Veni Grant [916.13.054]; NIA Grants [P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290, K25AG41906]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; National Cancer Institute [CA047988]; Donald W Reynolds Foundation; Fondation Leducq; Amgen FX CS: The work was made possible by the generous participation of the control subjects and their families. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille, the Centre National de Genotypage, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease). JCL was funded by the MEDIALZ Project (Grant 11001003) financed by ERDF (European Regional Development Fund) and Conseil Regional Nord Pas de Calais. The Three-City Study was performed as part of a collaboration between the Institut National de la Sante et de la Recherche Medicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program. Lille Genopole received an unconditional grant from Eisai.; AAA: We thank the cohort participants and team members who contributed to this study. Phenotype collection and DNA extraction were supported by the Wellcome Trust, the British Heart Foundation and the Chief Scientist Office of the Scottish Executive. The AAA Trial was performed and the database is maintained by members of the University of Edinburgh Molecular Epidemiology Research Group in the Centre for Population Health Sciences. We also thank staff at the Wellcome Trust Clinical Research Facility in Edinburgh where some of the research clinics and genotyping were undertaken.; AGES: Aging Gene-Environment Susceptibility-Reykjavik Study: The research has been funded by NIA Contract N01-AG-12100 with contributions from NEI, NIDCD and NHLBI, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).; ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402; and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; ASPS: We thank Ing. Johann Semmler and Irmgard Polzl for creating the DNA bank and for supervising the quality management of the biobanking and DNA analyses. The ASPS is funded by the Austrian Science Fond (FWF) Grant Number P20545-P05 and P13180.; BLSA: Baltimore Longitudinal Study of Aging (BLSA): The Baltimore Longitudinal Study of Aging is supported by the Intramural Research Program of the NIH, National Institute on Aging.; Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629, R01AG15928, R01AG20098, and R01AG027058 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHSNHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; CROATIA-Korcula: The CROATIA-Korcula study was funded by grants from the Medical Research Council (UK), European Commission Framework 6 project EUROSPAN (Contract No. LSHG-CT-2006-018947) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the people of Korcula. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum Munchen, Neuherberg, Germany.; CROATIA-Vis: The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to IR (108-1080315-0302). We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland.; ERF: This study was financially supported by the Netherlands Organization for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) and by the Russian Foundation for Basic Research (RFBR). We thank the participants from the Genetic Research in Isolated Populations, Erasmus Rucphen Family, who made this work possible. Also, we thank Petra Veraart for collecting all genealogical data.; FHS: This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and Grants (U01 HL096917 and R01 HL093029). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the National Institute of Neurological Disorders and Stroke (NS17950) and the National Institute of Aging (U01 AG049505, AG033193, AG008122, AG16495). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA, NIH or AHA. Dr. Debette is a recipient of a Chaire d'Excellence grant from the Agence National de la Recherche and a grant from the Leducq Foundation.; GENOA: Support for the Genetic Epidemiology Network of Arteriopathy (GENOA) was provided by the National Heart, Lung and Blood Institute (HL054464, HL054457, HL054481, HL071917 and HL87660) and the National Institute of Neurological Disorders and Stroke (NS041558) of the National Institutes of Health. Genotyping was performed at the Mayo Clinic (S.T.T., Mariza de Andrade, Julie Cunningham) and was made possible by the University of Texas Health Sciences Center (Eric Boerwinkle, Megan L Grove-Gaona). We would also like to thank the families that participated in the GENOA study.; GS: We are grateful to the GS Executive Committee Professors Blair H. Smith, David J. Porteous, Sandosh Padmanabhan and Dr. Lynne J. Hocking, and all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006].; HBCS: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhalsan Research Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation and Wellcome Trust (Grant Number WT089062).; Health ABC: This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.; Hunter: The authors would like to thank the men and women participating in the HCS as well as all the staff, investigators and collaborators who have supported or been involved in the project to date. The cohort was made possible with support from the University of Newcastle's Strategic Initiative Fund, the Vincent Fairfax Family Foundation and the Hunter Medical Research Institute.; InCHIANTI: The Invechhiare in Chianti (InCHIANTI) Study was supported as a targeted project (ICS 110.1RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (Contracts N01[AG]916413, N01[AG]821336, 263 MD 9164 13, and 263 MD 821336), and, in part, by the Intramural Research Program, National Institute on Aging, National Institutes of Health.; LBC1921/LBC1936: We thank the cohort participants and team members who contributed to these studies. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research Into Ageing (continues as part of Age UK The Disconnected Mind project). Genotyping of the cohorts was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, Engineering and Physical Sciences Research Council (EPSRC), Economic and Social Research Council (ESRC) and MRC is gratefully acknowledged.; MAS: We would like to acknowledge and thank the Sydney MAS participants and the Research Team for their contributions and assistance. We would like to specifically acknowledge the support and contributions of Professor Henry Brodaty (Chief Investigator), Dr Simone Reppermund (Study Co-ordinator), Professor Peter Schofield, Dr Arezoo Assareh and Dr John Kwok to this work. DNA was extracted by Genetic Repositories Australia, an Enabling Facility supported by NHMRC Grant 401184. DNA sample preparation was undertaken in the laboratory of Professor Peter Schofield and Dr John Kwok, Neuroscience Research Australia, with the assistance of Dr Arezoo Assareh. Genotyping was performed by the Ramaciotti Centre, University of New South Wales. Sydney MAS is supported by the Australian National Health & Medical Research Council Program Grants 350833 and 568969. Karen Mather is supported by the Capacity Building Grant 568940. Nicola Armstrong is supported by the NHMRC Project Grant 525453.; Hippocampal eQTL: The hippocampal gene expression study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia, under the auspices of the National Genome Research Network plus (NGFNplus)).; NHS: This study was supported by research Grants CA87969, CA49449, HL34594, U01HG004399, DK058845, CA65725, CA67262, CA50385, 5UO1CA098233, EY09611, EY015473, HG004728, HL35464, CA55075, CA134958 and DK070756 from the National Institutes of Health. The genotyping was partly supported by an unrestricted grant from Merck Research Laboratories. Dr Sun is supported by career development award K99HL098459 from the National Heart, Lung and Blood Institute. Supported in part by NIH.; ORCADES: ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (Contract No. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney.; PROSPER: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr JW Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (Grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant 050-060-810).; RS: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission 49 (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Dr Ikram was supported by a ZonMW Veni Grant: 916.13.054.; RUSH: Supported in part by NIA Grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, K08AG34290 and K25AG41906.; SHIP: SHIP is part of the Community Medicine Research net of the University Medicine of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The SHIP authors are grateful to Holger Prokisch and Thomas Meitinger (Helmholtz Zentrum Munchen) for the genotyping of the SHIP-TREND cohort.; WGHS: The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung and Blood Institute and CA047988 from the National Cancer Institute, the Donald W Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. NR 59 TC 4 Z9 4 U1 8 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2016 VL 21 IS 2 BP 189 EP 197 DI 10.1038/mp.2015.37 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DE7LI UT WOS:000370817800005 PM 25869804 ER PT J AU Qin, H Samuels, JF Wang, Y Zhu, Y Grados, MA Riddle, MA Greenberg, BD Knowles, JA Fyer, AJ McCracken, JT Murphy, DL Rasmussen, SA Cullen, BA Piacentini, J Geller, D Stewart, SE Pauls, D Bienvenu, OJ Goes, FS Maher, B Pulver, AE Valle, D Lange, C Mattheisen, M McLaughlin, NC Liang, KY Nurmi, EL Askland, KD Nestadt, G Shugart, YY AF Qin, H. Samuels, J. F. Wang, Y. Zhu, Y. Grados, M. A. Riddle, M. A. Greenberg, B. D. Knowles, J. A. Fyer, A. J. McCracken, J. T. Murphy, D. L. Rasmussen, S. A. Cullen, B. A. Piacentini, J. Geller, D. Stewart, S. E. Pauls, D. Bienvenu, O. J. Goes, F. S. Maher, B. Pulver, A. E. Valle, D. Lange, C. Mattheisen, M. McLaughlin, N. C. Liang, K-Y Nurmi, E. L. Askland, K. D. Nestadt, G. Shugart, Y. Y. TI Whole-genome association analysis of treatment response in obsessive-compulsive disorder SO MOLECULAR PSYCHIATRY LA English DT Article ID WIDE ASSOCIATION; GENETICS; LINKAGE; GRIN2B; GENES; POLYMORPHISMS; TRANSPORTER; SLC1A1; DISP1; SCAN AB Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n = 514) or 'non-response' (n = 290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P = 1.76 x 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P < 10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 x 10(-6) and 8.41 x 10(-6), respectively. The other 35 variations with signals of potential significance (P < 10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR) = 0.0097) and the serotonergic system (FDR = 0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed. C1 [Qin, H.; Shugart, Y. Y.] NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Samuels, J. F.; Wang, Y.; Grados, M. A.; Riddle, M. A.; Cullen, B. A.; Bienvenu, O. J.; Goes, F. S.; Maher, B.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Zhu, Y.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Greenberg, B. D.; Rasmussen, S. A.; Pauls, D.] Brown Univ, Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Knowles, J. A.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Fyer, A. J.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Geller, D.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Geller, D.] Harvard Univ, Sch Med, Boston, MA USA. [Stewart, S. E.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Pulver, A. E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. [Valle, D.] Johns Hopkins Univ, Sch Med, Inst Human Genet, Dept Mol Biol & Genet, Baltimore, MD USA. [Lange, C.; Mattheisen, M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lange, C.; Mattheisen, M.] Univ Bonn, Dept Genom Math, Bonn, Germany. [Mattheisen, M.] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, M.] Aarhus Univ, Ctr Integrated Sequencing ISEQ, Aarhus, Denmark. [McLaughlin, N. C.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Liang, K-Y] Johns Hopkins Univ Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Nurmi, E. L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Askland, K. D.] Brown Univ, Warren Alpert Sch Med, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. RP Shugart, YY (reprint author), NIMH, Unit Stat Genom, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. EM yin.yao@nih.gov OI Mattheisen, Manuel/0000-0002-8442-493X; Samuels, Jack/0000-0002-6715-7905 FU NIMH [MH071507, MH079489, MH079487, MH079488, MH079494]; IRP [MH002930-04] FX This project is a multiple sites collaborative project of OCD Collaborative Genetics Association Study (OCGAS), which is a collaboration among investigators at seven sites in the United States (namely Brown University, Columbia University, University of Southern California, Johns Hopkins University, Massachusetts General Hospital, University of California at Los Angeles, and the National Institute of Mental Health) funded by NIMH Grant Numbers: MH071507, MH079489, MH079487, MH079488 and MH079494. Qin and Shugart are both supported by IRP (Project number MH002930-04). The views expressed in this presentation do not necessarily represent the views of the NIMH, NIH, HHS or the United States Government. NR 39 TC 6 Z9 7 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2016 VL 21 IS 2 BP 270 EP 276 DI 10.1038/mp.2015.32 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DE7LI UT WOS:000370817800014 PM 25824302 ER PT J AU Li, JC Cai, T Jiang, Y Chen, HQ He, X Chen, C Li, XF Shao, QZ Ran, X Li, ZS Xia, K Liu, CY Sun, ZS Wu, JY AF Li, Jinchen Cai, Tao Jiang, Yi Chen, Huiqian He, Xin Chen, Chao Li, Xianfeng Shao, Qianzhi Ran, Xia Li, Zhongshan Xia, Kun Liu, Chunyu Sun, Zhong Sheng Wu, Jinyu TI Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database SO MOLECULAR PSYCHIATRY LA English DT Article ID AUTISM SPECTRUM DISORDER; INTELLECTUAL-DISABILITY; EPILEPTIC ENCEPHALOPATHIES; CODING MUTATIONS; DISEASE; BRAIN; SCHIZOPHRENIA; VARIANTS; PATTERNS; GENETICS AB Currently, many studies on neuropsychiatric disorders have utilized massive trio-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17 104 DNMs from 3555 trios across four neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, intellectual disability and schizophrenia, in addition to unaffected siblings (control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3334 exonic DNMs for evaluation of their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders compared with the one in the controls (P < 1.3 x 10(-7)). The elevated DNM frequency is dominated by loss-of-function/deleterious single-nucleotide variants and frameshift indels (that is, extreme mutations, P < 4.5 x 10(-5)). With extensive annotation of these 'extreme' mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P < 0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders. C1 [Li, Jinchen; Sun, Zhong Sheng; Wu, Jinyu] Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China. [Li, Jinchen; Jiang, Yi; Chen, Huiqian; Shao, Qianzhi; Ran, Xia; Li, Zhongshan; Sun, Zhong Sheng; Wu, Jinyu] Wenzhou Med Univ, Inst Genom Med, Wenzhou, Peoples R China. [Li, Jinchen; Chen, Chao; Li, Xianfeng; Xia, Kun; Liu, Chunyu] Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. [Cai, Tao] NIDCR, Expt Med Sect, NIH, Bethesda, MD USA. [He, Xin] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Chen, Chao; Liu, Chunyu] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. RP Sun, ZS; Wu, JY (reprint author), Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China.; Liu, CY (reprint author), Cent S Univ, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China. EM liucy@uic.edu; sunzs@mail.biols.ac.cn; wujy@mail.biols.ac.cn FU National Natural Science Foundation of China [31171236/C060503]; National Basic Research Program of China [2012CB517902, 2012CB517904]; National '12th Five-Year' scientific and technological support projects [2012BAI03B02]; Special Funds of National Health and Family Planning Commission of China [201302002] FX The project was funded by the National Natural Science Foundation of China (31171236/C060503), the National Basic Research Program of China (No. 2012CB517902 and 2012CB517904), the National '12th Five-Year' scientific and technological support projects (No. 2012BAI03B02) and the Special Funds of National Health and Family Planning Commission of China (No. 201302002). As a disclaimer, Tao Cai represented his own perspective in the article, not NIDCR/NIH. NR 72 TC 13 Z9 13 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2016 VL 21 IS 2 BP 290 EP 297 DI 10.1038/mp.2015.40 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA DE7LI UT WOS:000370817800016 PM 25849321 ER PT J AU Chandler, RJ LaFave, MC Varshney, GK Burgess, SM Venditti, CP AF Chandler, Randy J. LaFave, Matthew C. Varshney, Gaurav K. Burgess, Shawn M. Venditti, Charles P. TI Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy? SO MOLECULAR THERAPY LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; INSERTIONAL MUTAGENESIS; INTEGRATION SITES; GENOME BROWSER; LIVER; DISEASE; UCSC C1 [Chandler, Randy J.; Venditti, Charles P.] NHGRI, Mol Genom & Metab Genet Branch, NIH, 49 Convent Dr,Room 4A18, Bethesda, MD 20892 USA. [LaFave, Matthew C.; Varshney, Gaurav K.; Burgess, Shawn M.] NHGRI, Translat & Funct Genom Branch, NIH, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Mol Genom & Metab Genet Branch, NIH, 49 Convent Dr,Room 4A18, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov OI LaFave, Matthew/0000-0001-9165-041X; Varshney, Gaurav K./0000-0002-0429-1904 NR 19 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 EI 1525-0024 J9 MOL THER JI Mol. Ther. PD FEB PY 2016 VL 24 IS 2 BP 198 EP 201 DI 10.1038/mt.2016.17 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DE9MH UT WOS:000370961200002 PM 26906613 ER PT J AU Tse, L Kang, TM Yuan, J Mihora, D Becket, E Maslowska, KH Schaaper, RM Miller, JH AF Tse, Lawrence Kang, Tina Manzhu Yuan, Jessica Mihora, Danielle Becket, Elinne Maslowska, Katarzyna H. Schaaper, Roel M. Miller, Jeffrey H. TI Extreme dNTP pool changes and hypermutability in dcd ndk strains SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Hypermutability; dNTP pools; dcd ndk mutant ID ESCHERICHIA-COLI K-12; DEOXYRIBONUCLEOSIDE TRIPHOSPHATE POOLS; RIBONUCLEOTIDE REDUCTASE; DEOXYCYTIDYLATE DEAMINASE; MISMATCH-REPAIR; DIPHOSPHATE KINASE; DNA-REPLICATION; SPONTANEOUS MUTATION; BASE SUBSTITUTIONS; THYMINE STARVATION AB Cells lacking deoxycytidine deaminase (DCD) have been shown to have imbalances in the normal dNTP pools that lead to multiple phenotypes, including increased mutagenesis, increased sensitivity to oxidizing agents, and to a number of antibiotics. In particular, there is an increased dCTP pool, often accompanied by a decreased dTTP pool. In the work presented here, we show that double mutants of Escherichia coli lacking both DCD and NDK (nucleoside diphosphate kinase) have even more extreme imbalances of dNTPs than mutants lacking only one or the other of these enzymes. In particular, the dCTP pool rises to very high levels, exceeding even the cellular ATP level by several-fold. This increased level of dCTP, coupled with more modest changes in other dNTPs, results in exceptionally high mutation levels. The high mutation levels are attenuated by the addition of thymidine. The results corroborate the critical importance of controlling DNA precursor levels for promoting genome stability. We also show that the addition of certain exogenous nucleosides can influence replication errors in DCD-proficient strains that are deficient in mismatch repair. (C) 2016 Elsevier B.V. All rights reserved. C1 [Tse, Lawrence; Kang, Tina Manzhu; Yuan, Jessica; Mihora, Danielle; Becket, Elinne; Miller, Jeffrey H.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Tse, Lawrence; Kang, Tina Manzhu; Yuan, Jessica; Mihora, Danielle; Becket, Elinne; Miller, Jeffrey H.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Tse, Lawrence; Kang, Tina Manzhu; Yuan, Jessica; Mihora, Danielle; Becket, Elinne; Miller, Jeffrey H.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Maslowska, Katarzyna H.; Schaaper, Roel M.] NIEHS, Genome Integr & Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. RP Miller, JH (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. EM jhmiller@microbio.ucla.edu FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES065086] FX This work was supported, in part, by project number Z01 ES065086 of the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 57 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD FEB-MAR PY 2016 VL 784 BP 16 EP 24 DI 10.1016/j.mrfmmm.2015.12.004 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA DF2QV UT WOS:000371189800003 PM 26789486 ER PT J AU Benoit, JB Adelman, ZN Reinhardt, K Dolan, A Poelchau, M Jennings, EC Szuter, EM Hagan, RW Gujar, H Shukla, JN Zhu, F Mohan, M Nelson, DR Rosendale, AJ Derst, C Resnik, V Wernig, S Menegazzi, P Wegener, C Peschel, N Hendershot, JM Blenau, W Predel, R Johnston, PR Ioannidis, P Waterhouse, RM Nauen, R Schorn, C Ott, MC Maiwald, F Johnston, JS Gondhalekar, AD Scharf, ME Peterson, BF Raje, KR Hottel, BA Armisen, D Crumiere, AJJ Refki, PN Santos, ME Sghaier, E Viala, S Khila, A Ahn, SJ Childers, C Lee, CY Lin, H Hughes, DST Duncan, EJ Murali, SC Qu, JX Dugan, S Lee, SL Chao, H Dinh, H Han, Y Doddapaneni, H Worley, KC Muzny, DM Wheeler, D Panfilio, KA Jentzsch, IMV Vargo, EL Booth, W Friedrich, M Weirauch, MT Anderson, MAE Jones, JW Mittapalli, O Zhao, CY Zhou, JJ Evans, JD Attardo, GM Robertson, HM Zdobnov, EM Ribeiro, JMC Gibbs, RA Werren, JH Palli, SR Schal, C Richards, S AF Benoit, Joshua B. Adelman, Zach N. Reinhardt, Klaus Dolan, Amanda Poelchau, Monica Jennings, Emily C. Szuter, Elise M. Hagan, Richard W. Gujar, Hemant Shukla, Jayendra Nath Zhu, Fang Mohan, M. Nelson, David R. Rosendale, Andrew J. Derst, Christian Resnik, Valentina Wernig, Sebastian Menegazzi, Pamela Wegener, Christian Peschel, Nicolai Hendershot, Jacob M. Blenau, Wolfgang Predel, Reinhard Johnston, Paul R. Ioannidis, Panagiotis Waterhouse, Robert M. Nauen, Ralf Schorn, Corinna Ott, Mark-Christoph Maiwald, Frank Johnston, J. Spencer Gondhalekar, Ameya D. Scharf, Michael E. Peterson, Brittany F. Raje, Kapil R. Hottel, Benjamin A. Armisen, David Crumiere, Antonin Jean Johan Refki, Peter Nagui Santos, Maria Emilia Sghaier, Essia Viala, Severine Khila, Abderrahman Ahn, Seung-Joon Childers, Christopher Lee, Chien-Yueh Lin, Han Hughes, Daniel S. T. Duncan, Elizabeth J. Murali, Shwetha C. Qu, Jiaxin Dugan, Shannon Lee, Sandra L. Chao, Hsu Dinh, Huyen Han, Yi Doddapaneni, Harshavardhan Worley, Kim C. Muzny, Donna M. Wheeler, David Panfilio, Kristen A. Jentzsch, Iris M. Vargas Vargo, Edward L. Booth, Warren Friedrich, Markus Weirauch, Matthew T. Anderson, Michelle A. E. Jones, Jeffery W. Mittapalli, Omprakash Zhao, Chaoyang Zhou, Jing-Jiang Evans, Jay D. Attardo, Geoffrey M. Robertson, Hugh M. Zdobnov, Evgeny M. Ribeiro, Jose M. C. Gibbs, Richard A. Werren, John H. Palli, Subba R. Schal, Coby Richards, Stephen TI Unique features of a global human ectoparasite identified through sequencing of the bed bug genome SO NATURE COMMUNICATIONS LA English DT Article ID CIMEX-LECTULARIUS L.; INSECTICIDE RESISTANCE; TRAUMATIC INSEMINATION; HEMIPTERA-CIMICIDAE; RHODNIUS-PROLIXUS; PROTEIN GENES; R CONSENSUS; ARTHROPODS; DROSOPHILA; RECEPTORS AB The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite. C1 [Benoit, Joshua B.; Jennings, Emily C.; Szuter, Elise M.; Hagan, Richard W.; Rosendale, Andrew J.; Hendershot, Jacob M.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. [Adelman, Zach N.; Anderson, Michelle A. E.] Virginia Tech, Fralin Life Sci Inst, Blacksburg, VA 24061 USA. [Adelman, Zach N.; Anderson, Michelle A. E.] Virginia Tech, Dept Entomol, Blacksburg, VA 24061 USA. [Reinhardt, Klaus] Tech Univ Dresden, Dept Biol, Appl Zool, D-01062 Dresden, Germany. [Dolan, Amanda; Werren, John H.] Univ Rochester, Dept Biol, Rochester, NY 14627 USA. [Poelchau, Monica; Childers, Christopher; Lee, Chien-Yueh; Lin, Han] Natl Agr Lib, Beltsville, MD 20705 USA. [Gujar, Hemant; Shukla, Jayendra Nath; Zhu, Fang; Palli, Subba R.] Univ Kentucky, Dept Entomol, Lexington, KY 40546 USA. [Zhu, Fang] Washington State Univ, Dept Entomol, Pullman, WA 99164 USA. [Mohan, M.] Indian Council Agr Res, ICAR Natl Bur Agr Insect Resources, Bengaluru 560024, Karnataka, India. [Nelson, David R.] Univ Tennessee, Ctr Hlth Sci, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA. [Derst, Christian; Blenau, Wolfgang; Predel, Reinhard] Univ Cologne, Cologne Bioctr, D-50674 Cologne, Germany. [Derst, Christian; Blenau, Wolfgang; Predel, Reinhard] Univ Cologne, Inst Zool, D-50674 Cologne, Germany. [Resnik, Valentina; Wernig, Sebastian] Goethe Univ Frankfurt, Inst Bienenkunde, Polytech Gesell, D-61440 Oberursel, Germany. [Menegazzi, Pamela; Wegener, Christian; Peschel, Nicolai] Univ Wurzburg, Bioctr, Theodor Boveri Inst, Dept Neurobiol & Genet, D-97074 Wurzburg, Germany. [Johnston, Paul R.] Free Univ Berlin, Inst Biol, Dept Evolutionary Biol, D-14195 Berlin, Germany. [Johnston, J. Spencer; Vargo, Edward L.] Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA. [Ioannidis, Panagiotis; Waterhouse, Robert M.; Zdobnov, Evgeny M.] Univ Geneva, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Ioannidis, Panagiotis; Waterhouse, Robert M.; Zdobnov, Evgeny M.] Univ Geneva, Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.] Massachusetts Inst Technol & Broad Inst MIT & Har, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Nauen, Ralf; Schorn, Corinna; Ott, Mark-Christoph; Maiwald, Frank] Bayer CropSci AG, Pest Control Biol & Res Technol, D-40789 Monheim, Germany. [Gondhalekar, Ameya D.; Scharf, Michael E.; Peterson, Brittany F.; Raje, Kapil R.] Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA. [Hottel, Benjamin A.] Univ Florida, Dept Entomol & Nematol, Gainesville, FL 32611 USA. [Armisen, David; Crumiere, Antonin Jean Johan; Refki, Peter Nagui; Santos, Maria Emilia; Sghaier, Essia; Viala, Severine; Khila, Abderrahman] Ecole Normale Super Lyon, CNRS UMR5242, IGFL, F-69007 Lyon, France. [Ahn, Seung-Joon] Max Planck Inst Chem Ecol, Dept Entomol, D-07745 Jena, Germany. [Lee, Chien-Yueh; Lin, Han] Natl Taiwan Univ, Grad Inst Biomed Elect & Bioinformat, Taipei 10617, Taiwan. [Hughes, Daniel S. T.; Murali, Shwetha C.; Qu, Jiaxin; Dugan, Shannon; Lee, Sandra L.; Chao, Hsu; Dinh, Huyen; Han, Yi; Doddapaneni, Harshavardhan; Worley, Kim C.; Muzny, Donna M.; Gibbs, Richard A.; Richards, Stephen] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Human & Mol Genet, Houston, TX 77030 USA. [Duncan, Elizabeth J.] Univ Otago, Dept Biochem & Genet Otago, Dunedin 9054, New Zealand. [Wheeler, David] Massey Univ, Inst Fundamental Sci, Palmerston North 4442, New Zealand. [Panfilio, Kristen A.; Jentzsch, Iris M. Vargas] Univ Cologne, Inst Dev Biol, D-50674 Cologne, Germany. [Booth, Warren] Univ Tulsa, Dept Biol Sci, Tulsa, OK 74104 USA. [Friedrich, Markus; Jones, Jeffery W.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Weirauch, Matthew T.] Univ Cincinnati, Ctr Autoimmune Genom & Etiol, Div Biomed Informat, Cincinnati, OH 45229 USA. [Weirauch, Matthew T.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Dept Pediat,Coll Med, Cincinnati, OH 45229 USA. [Mittapalli, Omprakash; Zhao, Chaoyang] Ohio State Univ, Dept Entomol, Wooster, OH 44691 USA. [Zhou, Jing-Jiang] BBSRC, Rothamsted Res, Dept Biol Chem & Crop Protect, Harpenden AL5 2JQ, Herts, England. [Evans, Jay D.] ARS, USDA, Bee Res Lab, Beltsville, MD 20705 USA. [Attardo, Geoffrey M.] Yale Univ, Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, New Haven, CT 06520 USA. [Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Schal, Coby] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Schal, Coby] N Carolina State Univ, WM Keck Ctr Behav Biol, Raleigh, NC 27695 USA. RP Benoit, JB (reprint author), Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA.; Richards, S (reprint author), Baylor Coll Med, Human Genome Sequencing Ctr, Dept Human & Mol Genet, Houston, TX 77030 USA. EM joshua.benoit@uc.edu; stephenr@bcm.edu RI Blenau, Wolfgang/A-4304-2010; Waterhouse, Robert/A-1858-2010; Zhu, Fang/L-3411-2016; Schal, Coby/A-8717-2010; Zdobnov, Evgeny/K-1133-2012; Ioannidis, Panagiotis/I-4281-2014; OI Evans, Jay/0000-0002-0036-4651; Ribeiro, Jose/0000-0002-9107-0818; Menegazzi, Pamela/0000-0001-5232-1920; Khila, Abderrahman/0000-0003-0908-483X; Ahn, Seung-Joon/0000-0002-5980-106X; Waterhouse, Robert/0000-0003-4199-9052; Schal, Coby/0000-0001-7195-6358; Duncan, Elizabeth/0000-0002-1841-504X; Childers, Chris/0000-0002-1253-5550; Wegener, Christian/0000-0003-4481-3567; Ioannidis, Panagiotis/0000-0003-0939-6745; Adelman, Zach/0000-0001-5901-7171; Panfilio, Kristen/0000-0002-6417-251X FU NHGRI grant [U54 HG003273]; Blanton J. Whitmire endowment, Housing and Urban Development [NCHHU-00017-13]; National Science Foundation [IOS-1052238, DEB-1257053]; Alfred P. Sloan Foundation [2013-5-35 MBE]; NIH [GM070559-9]; Royal Society of New Zealand Marsden Fast Start Grant [11-UOO-124]; Fralin Life Sciences Institutes and Virginia Agriculture Experimental Station; European Research Council [ERC-CoG 616346, 260986]; Deutsche Forschungsgemeinschaft (DFG) [Pe1798/2-1, PA2044/1-1, BL469/7-1, 766/11-1]; Exzellenzinitiative of the Deutsche Forschungsgemeinschaft; Biotechnology and Biological Sciences Research Council; University of Cincinnati Faculty Development Research Grant; Ohio Supercomputer Center Research Allocation; Marie Curie International Outgoing Fellowship [PIOF-GA-2011-303312]; Swiss National Science Foundation [31003A-125350, 31003A-143936]; Deutsche Forschungsgemeinschaft (DFG): collaborative research center [SFB 1047] FX Funding for genome sequencing, assembly and automated annotation was provided by NHGRI grant U54 HG003273 to R.A.G. Funding for bed bug lines development was provided by Blanton J. Whitmire endowment, Housing and Urban Development (NCHHU-00017-13), National Science Foundation (IOS-1052238), Alfred P. Sloan Foundation (2013-5-35 MBE) to Cob. S. Funding for preparation of genomic DNA and RNA for sequencing and for manual curation of some of the genes was provided by NIH (GM070559-9) to S.R.P. Funding for manual curation and other analyses were provided by the Royal Society of New Zealand Marsden Fast Start Grant (11-UOO-124) to E.J.D., Fralin Life Sciences Institutes and Virginia Agriculture Experimental Station to Z.N.A., European Research Council (ERC-CoG 616346) to A.K., Deutsche Forschungsgemeinschaft (DFG): Pe1798/2-1 to N.P., Deutsche Forschungsgemeinschaft (DFG): PA2044/1-1 to K.A.P., Deutsche Forschungsgemeinschaft (DFG): collaborative research center SFB 1047 `Insect timing,' Project A1 to P.M., The Zukunftskonzept at TU Dresden funded by the Exzellenzinitiative of the Deutsche Forschungsgemeinschaft to K.R., Deutsche Forschungsgemeinschaft (DFG): BL469/7-1 to Wo.B., Deutsche Forschungsgemeinschaft (DFG): 766/11-1 to R.P., European Research Council grant 260986 to P. J., Biotechnology and Biological Sciences Research Council to J.-J.Z., University of Cincinnati Faculty Development Research Grant and Ohio Supercomputer Center Research Allocation to J.B.B., Marie Curie International Outgoing Fellowship PIOF-GA-2011-303312 to R.M.W., National Science Foundation (DEB-1257053) to J.H.W., and Swiss National Science Foundation awards 31003A-125350 and 31003A-143936 to E.M.Z. We thank Rick Santangelo for generating the full-sib mating line used in this project. Given the restriction in the number of citations, it was not possible include all publications associated with programs used in this study. As an alternative, we have provided links to websites for each program. i5k genome sequencing initiative assisting in the sequencing of the bed bug genome. NR 70 TC 12 Z9 13 U1 15 U2 44 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10165 DI 10.1038/ncomms10165 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0EC UT WOS:000371010800002 PM 26836814 ER PT J AU Bhutani, K Nazor, KL Williams, R Tran, H Dai, H Dzakula, Z Cho, EH Pang, AWC Rao, M Cao, H Schork, NJ Loring, JF AF Bhutani, Kunal Nazor, Kristopher L. Williams, Roy Ha Tran Dai, Heng Dzakula, Zeljko Cho, Edward H. Pang, Andy W. C. Rao, Mahendra Cao, Han Schork, Nicholas J. Loring, Jeanne F. TI Whole-genome mutational burden analysis of three pluripotency induction methods SO NATURE COMMUNICATIONS LA English DT Article ID STEM-CELLS; COPY-NUMBER; VARIANT ANNOTATION; DNA; GENERATION; FRAMEWORK AB There is concern that the stresses of inducing pluripotency may lead to deleterious DNA mutations in induced pluripotent stem cell (iPSC) lines, which would compromise their use for cell therapies. Here we report comparative genomic analysis of nine isogenic iPSC lines generated using three reprogramming methods: integrating retroviral vectors, non-integrating Sendai virus and synthetic mRNAs. We used whole-genome sequencing and de novo genome mapping to identify single-nucleotide variants, insertions and deletions, and structural variants. Our results show a moderate number of variants in the iPSCs that were not evident in the parental fibroblasts, which may result from reprogramming. There were only small differences in the total numbers and types of variants among different reprogramming methods. Most importantly, a thorough genomic analysis showed that the variants were generally benign. We conclude that the process of reprogramming is unlikely to introduce variants that would make the cells inappropriate for therapy. C1 [Bhutani, Kunal; Schork, Nicholas J.] Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Bhutani, Kunal; Schork, Nicholas J.] Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. [Nazor, Kristopher L.; Williams, Roy; Ha Tran; Loring, Jeanne F.] Scripps Res Inst, Dept Physiol Chem, Ctr Regenerat Med, La Jolla, CA 92037 USA. [Dai, Heng; Dzakula, Zeljko; Cho, Edward H.; Pang, Andy W. C.; Cao, Han] BioNano Genom, San Diego, CA 92121 USA. [Rao, Mahendra] NIH, Bldg 10, Bethesda, MD 20892 USA. [Bhutani, Kunal; Schork, Nicholas J.] J Craig Venter Inst, La Jolla, CA 92037 USA. [Dai, Heng] WuXi NextCODE Genom, Shanghai 200131, Peoples R China. [Rao, Mahendra] New York Stem Cell Fdn, New York, NY 10023 USA. RP Schork, NJ (reprint author), Scripps Translat Sci Inst, La Jolla, CA 92037 USA.; Schork, NJ (reprint author), Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA.; Loring, JF (reprint author), Scripps Res Inst, Dept Physiol Chem, Ctr Regenerat Med, La Jolla, CA 92037 USA. EM nschork@jcvi.org; jloring@scripps.edu FU National Science Foundation Graduate Research Fellowship [DGE-1144086]; Autism Speaks Fellowship; NIH [U19 AG023122, R21 AG045789, R33 MH087925]; Tanner Foundation; California Institute for Regenerative Medicine CIRM [RT1-01108, RT3-07655, TR1-01250, TR3-05603, CL1-00502]; NIHCRM; New York Stem Cell Foundation unrestricted funds; BioNano Genomics, Inc.; NIH common fund program FX K.B. was supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1144086. K.L.N. was supported by an Autism Speaks Fellowship. N.J.S. and K.B. were supported in part by NIH Grants U19 AG023122 and R21 AG045789, and the Tanner Foundation. J.F.L., K.L.N., H.T. and R.W. were supported by grants from the California Institute for Regenerative Medicine CIRM (RT1-01108, RT3-07655, TR1-01250, TR3-05603 and CL1-00502) and NIH (R33 MH087925). M.R. was supported by NIHCRM, a NIH common fund program, and New York Stem Cell Foundation unrestricted funds. H.D., Z.D., E.H.C., A.W.C.P. and H.C. were supported by BioNano Genomics, Inc. NR 26 TC 17 Z9 17 U1 6 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10536 DI 10.1038/ncomms10536 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0FC UT WOS:000371013400001 PM 26892726 ER PT J AU Cheetham, CEJ Park, U Belluscio, L AF Cheetham, Claire E. J. Park, Una Belluscio, Leonardo TI Rapid and continuous activity-dependent plasticity of olfactory sensory input SO NATURE COMMUNICATIONS LA English DT Article ID PROTEIN GAMMA-SUBUNIT; MARKER PROTEIN; IN-VIVO; DENDRITIC SPINES; NERVE-TERMINALS; FUNCTIONAL MATURATION; SUBVENTRICULAR ZONE; SYNAPSE FORMATION; TUFTED CELLS; NEURONS AB Incorporation of new neurons enables plasticity and repair of circuits in the adult brain. Adult neurogenesis is a key feature of the mammalian olfactory system, with new olfactory sensory neurons (OSNs) wiring into highly organized olfactory bulb (OB) circuits throughout life. However, neither when new postnatally generated OSNs first form synapses nor whether OSNs retain the capacity for synaptogenesis once mature, is known. Therefore, how integration of adult-born OSNs may contribute to lifelong OB plasticity is unclear. Here, we use a combination of electron microscopy, optogenetic activation and in vivo time-lapse imaging to show that newly generated OSNs form highly dynamic synapses and are capable of eliciting robust stimulus-locked firing of neurons in the mouse OB. Furthermore, we demonstrate that mature OSN axons undergo continuous activity-dependent synaptic remodelling that persists into adulthood. OSN synaptogenesis, therefore, provides a sustained potential for OB plasticity and repair that is much faster than OSN replacement alone. C1 [Cheetham, Claire E. J.; Park, Una; Belluscio, Leonardo] NINDS, Dev Neural Plast Unit, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. [Cheetham, Claire E. J.] Carnegie Mellon Univ, Dept Biol Sci, 4400 Fifth Ave, Pittsburgh, PA 15213 USA. RP Cheetham, CEJ; Belluscio, L (reprint author), NINDS, Dev Neural Plast Unit, NIH, 35 Convent Dr, Bethesda, MD 20892 USA.; Cheetham, CEJ (reprint author), Carnegie Mellon Univ, Dept Biol Sci, 4400 Fifth Ave, Pittsburgh, PA 15213 USA. EM cheetham@andrew.cmu.edu; belluscl@ninds.nih.gov RI Cheetham, Claire/A-2612-2017 OI Cheetham, Claire/0000-0002-4038-1501 FU NINDS Intramural Program [1-ZIA-NS003002]; Human Frontier Science Program Long-Term Fellowship FX This work was supported by the NINDS Intramural Program (1-ZIA-NS003002) and a Human Frontier Science Program Long-Term Fellowship to C.E.J.C. We thank Alison Barth, Jeff Diamond, Gerry Hammond, Mark Hoon and Nick Ryba for helpful comments, Roger Tsien for plasmids, Sue Cheng and Virginia Crocker in the NINDS EM Core for help with electron microscopy, Zhishang Zhou for help with electrophysiology experiments, and Bryce Grier and Li Bai for technical support. NR 71 TC 0 Z9 0 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10729 DI 10.1038/ncomms10729 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0NV UT WOS:000371036800002 PM 26898529 ER PT J AU Dutta, B Azhir, A Merino, LH Guo, YJ Revanur, S Madhamshettiwar, PB Germain, RN Smith, JA Simpson, KJ Martin, SE Beuhler, E Fraser, IDC AF Dutta, Bhaskar Azhir, Alaleh Merino, Louis-Henri Guo, Yongjian Revanur, Swetha Madhamshettiwar, Piyush B. Germain, Ronald N. Smith, Jennifer A. Simpson, Kaylene J. Martin, Scott E. Beuhler, Eugen Fraser, Iain D. C. TI An interactive web-based application for Comprehensive Analysis of RNAi-screen Data SO NATURE COMMUNICATIONS LA English DT Article ID REPLICATION; EXPRESSION; ENRICHMENT; BIOLOGY; GENES; SMCX AB RNAi screens are widely used in functional genomics. Although the screen data can be susceptible to a number of experimental biases, many of these can be corrected by computational analysis. For this purpose, here we have developed a web-based platform for integrated analysis and visualization of RNAi screen data named CARD (for Comprehensive Analysis of RNAi Data; available at https://card.niaid.nih.gov). CARD allows the user to seamlessly carry out sequential steps in a rigorous data analysis workflow, including normalization, off-target analysis, integration of gene expression data, optimal thresholds for hit selection and network/pathway analysis. To evaluate the utility of CARD, we describe analysis of three genome-scale siRNA screens and demonstrate: (i) a significant increase both in selection of subsequently validated hits and in rejection of false positives, (ii) an increased overlap of hits from independent screens of the same biology and (iii) insight to microRNA (miRNA) activity based on siRNA seed enrichment. C1 [Dutta, Bhaskar; Azhir, Alaleh; Merino, Louis-Henri; Guo, Yongjian; Revanur, Swetha; Germain, Ronald N.; Fraser, Iain D. C.] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Madhamshettiwar, Piyush B.] Peter MacCallum Canc Ctr, Victorian Ctr Funct Genom, East Melbourne, Vic 3002, Australia. [Smith, Jennifer A.] Harvard Univ, Sch Med, ICCB Longwood Screening Facil, Boston, MA 02115 USA. [Simpson, Kaylene J.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3002, Australia. [Martin, Scott E.; Beuhler, Eugen] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. RP Dutta, B (reprint author), NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bhaskar.dutta@gmail.com; fraseri@niaid.nih.gov OI Simpson, Kaylene/0000-0001-9136-1781 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences; Harvard Medical School; Australian Cancer Research Foundation (ACRF); Victorian Department of Industry, Innovation and Regional Development (DIIRD); Australian Phenomics Network (APN); Australian Government's Education Investment Fund through the Super Science Initiative; Australasian Genomics Technologies Association (AMATA); Brockhoff Foundation; Peter MacCallum Cancer Centre Foundation FX We thank colleagues in the Laboratory of Systems Biology and Rajarshi Guha at NCATS for helpful discussions during the development of this software. We are also grateful to the NIAID Office of Cyber Infrastructure and Computational Biology for hosting the CARD server and thoroughly testing the application for potential vulnerabilities. This work was generously supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (B.D., L.-H.M., A.A., Y.G., S.R., R.N.G. and I.D.C.F.), the National Center for Advancing Translational Sciences (S.E.M. and E.B.) and Harvard Medical School (J.A.S.). The Victorian Centre for Functional Genomics (P.M. and K.J.S.) was funded by the Australian Cancer Research Foundation (ACRF), the Victorian Department of Industry, Innovation and Regional Development (DIIRD), the Australian Phenomics Network (APN) and supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative, the Australasian Genomics Technologies Association (AMATA), the Brockhoff Foundation and the Peter MacCallum Cancer Centre Foundation. NR 31 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10578 DI 10.1038/ncomms10578 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0FU UT WOS:000371015300013 PM 26902267 ER PT J AU Freyberg, Z Sonders, MS Aguilar, JI Hiranita, T Karam, CS Flores, J Pizzo, AB Zhang, YC Farino, ZJ Chen, A Martin, CA Kopajtic, TA Fei, H Hu, G Lin, YY Mosharov, EV McCabe, BD Freyberg, R Wimalasena, K Hsin, LW Sames, D Krantz, DE Katz, JL Sulzer, D Javitch, JA AF Freyberg, Zachary Sonders, Mark S. Aguilar, Jenny I. Hiranita, Takato Karam, Caline S. Flores, Jorge Pizzo, Andrea B. Zhang, Yuchao Farino, Zachary J. Chen, Audrey Martin, Ciara A. Kopajtic, Theresa A. Fei, Hao Hu, Gang Lin, Yi-Ying Mosharov, Eugene V. McCabe, Brian D. Freyberg, Robin Wimalasena, Kandatege Hsin, Ling-Wei Sames, Dalibor Krantz, David E. Katz, Jonathan L. Sulzer, David Javitch, Jonathan A. TI Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain SO NATURE COMMUNICATIONS LA English DT Article ID VESICULAR MONOAMINE TRANSPORTER; CHROMAFFIN GRANULES; NEUROTRANSMITTER TRANSPORTERS; SECRETORY VESICLES; METHAMPHETAMINE; RELEASE; NEURONS; INHIBITION; EXPRESSION; SEROTONIN AB Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT's role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects. C1 [Freyberg, Zachary; Sonders, Mark S.; Aguilar, Jenny I.; Karam, Caline S.; Pizzo, Andrea B.; Zhang, Yuchao; Farino, Zachary J.; Sulzer, David; Javitch, Jonathan A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Freyberg, Zachary; Sonders, Mark S.; Aguilar, Jenny I.; Karam, Caline S.; Pizzo, Andrea B.; Zhang, Yuchao; Farino, Zachary J.; Sulzer, David; Javitch, Jonathan A.] New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA. [Sonders, Mark S.; Mosharov, Eugene V.; Sulzer, David] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Hiranita, Takato; Kopajtic, Theresa A.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, US Dept HHS,NIH, Baltimore, MD 21224 USA. [Flores, Jorge] Columbia Univ, Coll Phys & Surg, Howard Hughes Med Inst, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Chen, Audrey; Fei, Hao; Krantz, David E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Hatos Ctr Neuropharmacol, Los Angeles, CA 90095 USA. [Chen, Audrey; Fei, Hao; Krantz, David E.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Hatos Ctr Neuropharmacol, Los Angeles, CA 90095 USA. [Martin, Ciara A.] Univ Calif Los Angeles, UCLA Interdept Program Mol Toxicol, Los Angeles, CA 90095 USA. [Hu, Gang; Sames, Dalibor] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Lin, Yi-Ying; Hsin, Ling-Wei] Natl Taiwan Univ, Coll Med, Sch Pharm, Taipei 10055, Taiwan. [McCabe, Brian D.] Columbia Univ, Coll Phys & Surg, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. [McCabe, Brian D.] Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY 10032 USA. [McCabe, Brian D.] Columbia Univ, Coll Phys & Surg, Dept Neurosci, New York, NY 10032 USA. [Freyberg, Robin] Yeshiva Univ, Stern Coll Women, Dept Psychol, New York, NY 10016 USA. [Wimalasena, Kandatege] Wichita State Univ, Dept Chem, Wichita, KS 67260 USA. [Sulzer, David; Javitch, Jonathan A.] Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. RP Javitch, JA (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA.; Javitch, JA (reprint author), New York State Psychiat Inst & Hosp, Div Mol Therapeut, New York, NY 10032 USA.; Javitch, JA (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. EM Javitch@nyspi.columbia.edu OI Freyberg, Zachary/0000-0001-6460-0118; Katz, Jonathan/0000-0002-1068-1159 FU Leon Levy Foundation; NARSAD Young Investigator Award [K05 DA022413, P01 DA12408]; Lieber Center for Schizophrenia Research and Treatment award [R01 DA007418, PO1 DA0 10154]; JPB and Parkinson's Disease Foundations; G. Harold & Leila Y. Mathers Charitable Foundation [NS075572, AG08702]; Dana Foundation; Gatsby Initiative in Brain Circuitry; New York Presbyterian Seizure Disorders Fund [R01 MH076900, R01 ES015747, P01 ES016732]; Brain and behaviour Research Foundation; Brain Research Institute; UCLA Molecular Toxicology Program; Intramural Research Program of NIDA; [K08 DA031241]; [R01 MH086545]; [T32 ES015457]; [GM07185]; [R01 NS075222] FX We are grateful to Richard Axel, Arthur Cho, Lynnette Daws, Erik Floor, Martin Heisenberg, Adam Henke, N. Markiavelli, Stephen Rayport and Leslie Vosshall for helpful discussion and comments on the manuscript as well as to Maryann Carrigan and Patty Ballerstadt for administrative assistance (J.L.K.). We also gratefully acknowledge the contributions of Dawn French-Evans in conducting both catalepsy and locomotor activity studies in mice and of Eve Vagg for assistance with figures. This work was financially supported by K08 DA031241 (Z.F.), Louis V. Gerstner, Jr, Scholars Program (Z.F.), Leon Levy Foundation (Z.F.), NARSAD Young Investigator Award (C.S.K.), K05 DA022413, (J.A.J.), P01 DA12408 (J.A.J.), Lieber Center for Schizophrenia Research and Treatment award (J.A.J.), R01 DA007418 (D. Sulzer), PO1 DA0 10154 (D. Su.), JPB and Parkinson's Disease Foundations (D. Su.), R01 MH086545 (D. Sames), G. Harold & Leila Y. Mathers Charitable Foundation (D. Sa.), NS075572 (B.D.M.), AG08702 (B.D.M.), the Dana Foundation (B.D.M.), the Gatsby Initiative in Brain Circuitry (B.D.M.), New York Presbyterian Seizure Disorders Fund (B.D.M.), R01 MH076900 (D.E.K.), R01 ES015747 (D.E.K.), P01 ES016732 (D.E.K.), Brain and behaviour Research Foundation (D.E.K.), UCLA Brain Research Institute (D.E.K.), UCLA Molecular Toxicology Program, Ruth L. Kirschstein T32 ES015457 (C.A.M.), Ruth L. Kirschstein GM07185 (A.C.), R01 NS075222 (E.M.), and the Intramural Research Program of NIDA (J.L.K.). NR 74 TC 4 Z9 4 U1 3 U2 21 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10652 DI 10.1038/ncomms10652 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0HY UT WOS:000371021000004 PM 26879809 ER PT J AU Gulia-Nuss, M Nuss, AB Meyer, JM Sonenshine, DE Roe, RM Waterhouse, RM Sattelle, DB de la Fuente, J Ribeiro, JM Megy, K Thimmapuram, J Miller, JR Walenz, BP Koren, S Hostetler, JB Thiagarajan, M Joardar, VS Hannick, LI Bidwell, S Hammond, MP Young, S Zeng, QD Abrudan, JL Almeida, FC Ayllon, N Bhide, K Bissinger, BW Bonzon-Kulichenko, E Buckingham, SD Caffrey, DR Caimano, MJ Croset, V Driscoll, T Gilbert, D Gillespie, JJ Giraldo-Calderon, GI Grabowski, JM Jiang, D Khalil, SMS Kim, D Kocan, KM Koci, J Kuhn, RJ Kurtti, TJ Lees, K Lang, EG Kennedy, RC Kwon, H Perera, R Qi, YM Radolf, JD Sakamoto, JM Sanchez-Gracia, A Severo, MS Silverman, N Simo, L Tojo, M Tornador, C Van Zee, JP Vazquez, J Vieira, FG Villar, M Wespiser, AR Yang, YL Zhu, JW Arensburger, P Pietrantonio, PV Barker, SC Shao, RF Zdobnov, EM Hauser, F Grimmelikhuijzen, CJP Park, Y Rozas, J Benton, R Pedra, JHF Nelson, DR Unger, MF Tubio, JMC Tu, ZJ Robertson, HM Shumway, M Sutton, G Wortman, JR Lawson, D Wikel, SK Nene, VM Fraser, CM Collins, FH Birren, B Nelson, KE Caler, E Hill, CA AF Gulia-Nuss, Monika Nuss, Andrew B. Meyer, Jason M. Sonenshine, Daniel E. Roe, R. Michael Waterhouse, Robert M. Sattelle, David B. de la Fuente, Jose Ribeiro, Jose M. Megy, Karine Thimmapuram, Jyothi Miller, Jason R. Walenz, Brian P. Koren, Sergey Hostetler, Jessica B. Thiagarajan, Mathangi Joardar, Vinita S. Hannick, Linda I. Bidwell, Shelby Hammond, Martin P. Young, Sarah Zeng, Qiandong Abrudan, Jenica L. Almeida, Francisca C. Ayllon, Nieves Bhide, Ketaki Bissinger, Brooke W. Bonzon-Kulichenko, Elena Buckingham, Steven D. Caffrey, Daniel R. Caimano, Melissa J. Croset, Vincent Driscoll, Timothy Gilbert, Don Gillespie, Joseph J. Giraldo-Calderon, Gloria I. Grabowski, Jeffrey M. Jiang, David Khalil, Sayed M. S. Kim, Donghun Kocan, Katherine M. Koci, Juraj Kuhn, Richard J. Kurtti, Timothy J. Lees, Kristin Lang, Emma G. Kennedy, Ryan C. Kwon, Hyeogsun Perera, Rushika Qi, Yumin Radolf, Justin D. Sakamoto, Joyce M. Sanchez-Gracia, Alejandro Severo, Maiara S. Silverman, Neal Simo, Ladislav Tojo, Marta Tornador, Cristian Van Zee, Janice P. Vazquez, Jesus Vieira, Filipe G. Villar, Margarita Wespiser, Adam R. Yang, Yunlong Zhu, Jiwei Arensburger, Peter Pietrantonio, Patricia V. Barker, Stephen C. Shao, Renfu Zdobnov, Evgeny M. Hauser, Frank Grimmelikhuijzen, Cornelis J. P. Park, Yoonseong Rozas, Julio Benton, Richard Pedra, Joao H. F. Nelson, David R. Unger, Maria F. Tubio, Jose M. C. Tu, Zhijian Robertson, Hugh M. Shumway, Martin Sutton, Granger Wortman, Jennifer R. Lawson, Daniel Wikel, Stephen K. Nene, Vishvanath M. Fraser, Claire M. Collins, Frank H. Birren, Bruce Nelson, Karen E. Caler, Elisabet Hill, Catherine A. TI Genomic insights into the Ixodes scapularis tick vector of Lyme disease SO NATURE COMMUNICATIONS LA English DT Article ID ANAPLASMA-PHAGOCYTOPHILUM INFECTION; BEETLE TRIBOLIUM-CASTANEUM; BOOPHILUS-MICROPLUS; CATTLE TICK; CHEMOSENSORY RECEPTORS; EVOLUTIONARY ANALYSES; UNITED-STATES; LIFE-STYLE; DROSOPHILA; PROTEIN AB Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing similar to 57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent. C1 [Gulia-Nuss, Monika; Nuss, Andrew B.; Meyer, Jason M.; Giraldo-Calderon, Gloria I.; Grabowski, Jeffrey M.; Lang, Emma G.; Van Zee, Janice P.; Hill, Catherine A.] Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA. [Sonenshine, Daniel E.] Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. [Roe, R. Michael; Bissinger, Brooke W.; Zhu, Jiwei] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Waterhouse, Robert M.; Zdobnov, Evgeny M.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.; Zdobnov, Evgeny M.] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Waterhouse, Robert M.] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Waterhouse, Robert M.; Birren, Bruce] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Sattelle, David B.; Buckingham, Steven D.] UCL, Div Med, UCL Resp Dept, Ctr Resp Biol, Rayne Bldg,5 Univ St, London WC1E 6JF, England. [de la Fuente, Jose; Ayllon, Nieves; Villar, Margarita] UCLM, CSIC, JCCM, SaBio,Inst Invest Recursos Cineget,IREC, Ronda Toledo Sn, Ciudad Real 13005, Spain. [de la Fuente, Jose; Kocan, Katherine M.] Oklahoma State Univ, Ctr Vet Hlth Sci, Dept Vet Pathobiol, 250 McElroy Hall, Stillwater, OK 74078 USA. [Ribeiro, Jose M.] NIAID, Lab Malaria & Vector Res, Rockville, MD 20852 USA. [Megy, Karine; Hammond, Martin P.; Lawson, Daniel] VectorBase EMBL EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. [Thimmapuram, Jyothi; Bhide, Ketaki] Purdue Univ, Bioinformat Core, W Lafayette, IN 47907 USA. [Miller, Jason R.; Walenz, Brian P.; Koren, Sergey; Hostetler, Jessica B.; Thiagarajan, Mathangi; Joardar, Vinita S.; Hannick, Linda I.; Bidwell, Shelby; Shumway, Martin; Sutton, Granger; Wortman, Jennifer R.; Nene, Vishvanath M.; Nelson, Karen E.; Caler, Elisabet] J Craig Venter Inst, Rockville, MD 20850 USA. [Young, Sarah; Zeng, Qiandong] Broad Inst, Genome Sequencing & Anal Program, Cambridge, MA 02142 USA. [Abrudan, Jenica L.; Giraldo-Calderon, Gloria I.; Unger, Maria F.; Collins, Frank H.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Almeida, Francisca C.; Sanchez-Gracia, Alejandro; Vieira, Filipe G.; Rozas, Julio] Univ Barcelona, Dept Genet, E-08028 Barcelona, Spain. [Almeida, Francisca C.; Sanchez-Gracia, Alejandro; Vieira, Filipe G.; Rozas, Julio] Univ Barcelona, Inst Recerca Biodiversitat IRBio, E-08028 Barcelona, Spain. [Bonzon-Kulichenko, Elena; Vazquez, Jesus] Ctr Nacl Invest Cardiovasc, Vasc Physiopathol, Madrid 28029, Spain. [Caffrey, Daniel R.; Silverman, Neal; Wespiser, Adam R.] Univ Massachusetts, Sch Med, Div Infect Dis, Dept Med, Worcester, MA 01605 USA. [Caimano, Melissa J.; Radolf, Justin D.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT 06030 USA. [Croset, Vincent; Benton, Richard] Univ Lausanne, Fac Biol & Med, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Driscoll, Timothy; Gillespie, Joseph J.] Virginia Tech, Virginia Bioinformat Inst, Genet Bioinformat & Computat Biol Program, Blacksburg, VA 24061 USA. [Gilbert, Don] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Grabowski, Jeffrey M.; Kuhn, Richard J.; Perera, Rushika] Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA. [Jiang, David; Qi, Yumin; Tu, Zhijian] Virginia Tech, Dept Biochem, Blacksburg, VA 24061 USA. [Khalil, Sayed M. S.] Agr Genet Engn Res Inst, Dept Microbial Mol Biol, Giza 12619, Egypt. [Kim, Donghun; Kwon, Hyeogsun; Yang, Yunlong; Pietrantonio, Patricia V.] Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA. [Koci, Juraj; Simo, Ladislav; Park, Yoonseong] Kansas State Univ, Dept Entomol, Manhattan, KS 66506 USA. [Kurtti, Timothy J.] Univ Minnesota, Dept Entomol, St Paul, MN 55108 USA. [Lees, Kristin] Univ Manchester, Fac Life Sci, Dept Neurosyst, Manchester M13 9PT, Lancs, England. [Kennedy, Ryan C.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Sakamoto, Joyce M.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Severo, Maiara S.; Pedra, Joao H. F.] Univ Calif Riverside, Ctr Dis Vector Res, Dept Entomol, Riverside, CA 92506 USA. [Tojo, Marta] Univ Cambridge, Cambridge Genom Serv, Dept Pathol, Cambridge CB2 1QP, England. [Tojo, Marta] Univ Santiago de Compostela, Inst Invest Sanitarias, CIMUS, Dept Physiol,Sch Med, Santiago De Compostela 15782, Spain. [Tornador, Cristian] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona 08003, Spain. [Arensburger, Peter] Calif State Polytech Univ Pomona, Dept Biol Sci, Pomona, CA 91768 USA. [Barker, Stephen C.] Univ Queensland, Sch Chem & Mol Biosci, Parasitol Sect, Brisbane, Qld 4072, Australia. [Shao, Renfu] Univ Sunshine Coast, GeneCol Res Ctr, Fac Sci Hlth Educ & Engn, Maroochydore, Qld 4556, Australia. [Hauser, Frank; Grimmelikhuijzen, Cornelis J. P.] Univ Copenhagen, Ctr Funct & Comparat Insect Genom, Dept Biol, DK-2100 Copenhagen, Denmark. [Nelson, David R.] Univ Tennessee, Ctr Hlth Sci, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA. [Tubio, Jose M. C.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. [Tubio, Jose M. C.] Univ Vigo, Dept Biochem Genet & Immunol, Vigo 36310, Spain. [Robertson, Hugh M.] Univ Illinois, Dept Entomol, 320 Morrill Hall, Urbana, IL 61801 USA. [Wikel, Stephen K.] Quinnipiac Univ, Frank H Netter MD Sch Med, Dept Med Sci, Hamden, CT 06518 USA. [Fraser, Claire M.] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Gulia-Nuss, Monika] Univ Nevada, Dept Biochem & Mol Biol, Reno, NV 89503 USA. [Nuss, Andrew B.] Univ Nevada, Dept Agr Nutr & Vet Sci, Reno, NV 89557 USA. [Meyer, Jason M.] Monsanto Co, Dept Biotechnol, Chesterfield, MO 63017 USA. [Megy, Karine] Univ Cambridge, Dept Haematol, NHSBT Bldg,Long Rd, Cambridge CB2 0PT, England. [Walenz, Brian P.; Koren, Sergey] NHGRI, Genome Informat Sect, Computat & Stat Genom Branch, NIH, Bethesda, MD 20892 USA. [Hostetler, Jessica B.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Hannick, Linda I.; Tojo, Marta] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Joardar, Vinita S.; Bidwell, Shelby; Shumway, Martin] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Abrudan, Jenica L.] Univ Nevada, Nevada Inst Personalized Med, Las Vegas, NV 89154 USA. [Bissinger, Brooke W.] AgBiome Inc, Res Triangle Pk, NC 27709 USA. [Croset, Vincent] Univ Oxford, Ctr Neural Circuits & Behaviour, Oxford OX1 3SR, England. [Driscoll, Timothy] W Virginia Univ, Dept Biol, Morgantown, WV 26505 USA. [Gillespie, Joseph J.; Pedra, Joao H. F.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Grabowski, Jeffrey M.] NIAID, Rocky Mt Labs, Biol Vector Borne Viruses Sect, NIH, Hamilton, MT 59840 USA. [Kim, Donghun] Kansas State Univ, Dept Entomol, Manhattan, KS 66506 USA. [Koci, Juraj] Univ Maryland, Sch Med, Dept Vet Med, Baltimore, MD 21201 USA. [Lees, Kristin] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119074, Singapore. [Kwon, Hyeogsun] Iowa State Univ, Dept Entomol, Ames, IA 50011 USA. [Perera, Rushika] Colorado State Univ, Arthropod Borne & Infect Dis Lab, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Severo, Maiara S.] Max Planck Inst Infekt Biol, Dept Vector Biol, Charitepl 1, D-10117 Berlin, Germany. [Simo, Ladislav] French Natl Inst Agr Res, UMR BIPAR INRA ANSES ENVA, F-94700 Maisons Alfort, France. [Wortman, Jennifer R.] Seres Therapeut, Cambridge, MA 02142 USA. [Nene, Vishvanath M.] Int Livestock Res Inst, Nairobi 00100, Kenya. [Caler, Elisabet] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Hill, CA (reprint author), Purdue Univ, Dept Entomol, W Lafayette, IN 47907 USA. EM hillca@purdue.edu RI Waterhouse, Robert/A-1858-2010; Villar-Rayo, Marga/J-4155-2012; Rozas, Julio/A-1733-2009; Vazquez, Jesus/B-7697-2015; Zdobnov, Evgeny/K-1133-2012; Severo, Milton/I-3497-2012; Sanchez-Gracia, Alejandro/F-4686-2014; Garrett Vieira, Filipe/B-9464-2015; Perera, Rushika/E-7183-2017; OI Megy, Karyn/0000-0002-2826-3879; Pedra, Joao/0000-0001-8740-2667; Driscoll, Timothy/0000-0002-5119-0372; Ribeiro, Jose/0000-0002-9107-0818; Waterhouse, Robert/0000-0003-4199-9052; Villar-Rayo, Marga/0000-0003-4172-9079; Rozas, Julio/0000-0002-6839-9148; Lawson, Daniel/0000-0001-7765-983X; Vazquez, Jesus/0000-0003-1461-5092; Severo, Milton/0000-0002-5787-4871; Sanchez-Gracia, Alejandro/0000-0003-4543-4577; Garrett Vieira, Filipe/0000-0002-8464-7770; Perera, Rushika/0000-0001-6798-2537; Grimmelikhuijzen, Cornelis/0000-0001-6486-2046 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (NIAID, NIH, DHHS) [N01-AI30071, HHSN272200900007C, HHSN266200400001C, 5R01GM77117-5]; NIH-NIAID [HHSN266200400039C, HHSN272200900039C]; Australian Research Council [DP120100240]; Ministerio de Ciencia e Innovacion of Spain [BFU2007-6292, BFU2010-15484, BIO2009-07990, BIO2012-37926]; NIH [1R01AI090062, 1R21AI096268, HHSN272200900040C, R01AI017828, R01AI043006]; NSF [IOS-0949194]; Xunta de Galicia of Spain [10PXIB918057PR]; EU FP7 ANTIGONE [278976]; USDA-NRI/CREES [2008-35302-18820]; Texas AgriLife Research Vector Biology grant; European Research Council Starting Independent Researcher Grant [205202]; NIAID; Marie Curie International Outgoing Fellowship [PIOF-GA-2011-303312]; Swiss National Science Foundation [31003A-125350, 31003A-143936]; NIH-NCATS award [TL1 TR000162]; NSF; Fundacao para a Ciencia e a Tecnologia, Portugal fellowship [SFRH/BD/22360/2005]; Lundbeck Foundation (Denmark); Broad Genomics Platform; [BFU2011-23896] FX This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services (NIAID, NIH, DHHS) under contract numbers N01-AI30071, HHSN272200900007C, HHSN266200400001C and 5R01GM77117-5. Its contents are solely the responsibility of the authors and do not represent the official views of the NIH. Additional grants and contracts supporting work described in this manuscript were from the NIH-NIAID (HHSN266200400039C and HHSN272200900039C) to F.H.C., and a subcontract under HHSN272200900039C to C.A.H. and J.M.M., the Australian Research Council Discovery Project (DP120100240) to S.C.B. and R.S., the Ministerio de Ciencia e Innovacion of Spain (BFU2007-6292; BFU2010-15484) to J.R., BIO2009-07990 and BIO2012-37926 to J.V. NIH-1R01AI090062 to Y.P., L.S., and J.K., NIH 1R21AI096268 and NSF IOS-0949194 to R.M.R., the Xunta de Galicia of Spain (10PXIB918057PR) to J.M.C.T. and M.T., BFU2011-23896 and EU FP7 ANTIGONE (278976) to J.F., the USDA-NRI/CREES (2008-35302-18820) and Texas AgriLife Research Vector Biology grant to P.V.P. and European Research Council Starting Independent Researcher Grant (205202) to R.B., J.M.R was supported by the intramural program of the NIAID, R.M.W. by a Marie Curie International Outgoing Fellowship PIOF-GA-2011-303312, E.M.Z. by Swiss National Science Foundation awards 31003A-125350 and 31003A-143936, J.M.G. by an NIH-NCATS award TL1 TR000162 and NSF Graduate Research Fellowship (DGE 1333468), V.C. by a Boehringer Ingelheim Ph.D. Fellowship, F.G.V. by a Fundacao para a Ciencia e a Tecnologia, Portugal fellowship (SFRH/BD/22360/2005), C.J.P.G. and F.H. by The Lundbeck Foundation (Denmark), and J.J.G. by NIH awards HHSN272200900040C, R01AI017828 and R01AI043006. Support from the Broad Genomics Platform is gratefully acknowledged. NR 69 TC 30 Z9 30 U1 12 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10507 DI 10.1038/ncomms10507 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0ET UT WOS:000371012500004 PM 26856261 ER PT J AU Hatori, Y Yan, Y Schmidt, K Furukawa, E Hasan, NM Yang, N Liu, CN Sockanathan, S Lutsenko, S AF Hatori, Yuta Yan, Ye Schmidt, Katharina Furukawa, Eri Hasan, Nesrin M. Yang, Nan Liu, Chin-Nung Sockanathan, Shanthini Lutsenko, Svetlana TI Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway SO NATURE COMMUNICATIONS LA English DT Article ID ALPHA-AMIDATING MONOOXYGENASE; DOPAMINE-BETA-HYDROXYLASE; OXIDATIVE STRESS; RETINOIC ACID; SPINAL-CORD; NERVOUS-SYSTEM; MENKES ATPASE; SH-SY5Y CELLS; TRAFFICKING; ATOX1 AB Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site. Concomitantly, expression of Atox1 and its partner, a copper transporter ATP7A, is upregulated. These events produce a higher flux of copper through the secretory pathway that balances copper in the cytosol and increases supply of the cofactor to copper-dependent enzymes, expression of which is elevated in differentiated neurons. Direct link between glutathione oxidation and copper compartmentalization allows for rapid metabolic adjustments essential for normal neuronal function. C1 [Hatori, Yuta; Schmidt, Katharina; Furukawa, Eri; Hasan, Nesrin M.; Yang, Nan; Liu, Chin-Nung; Lutsenko, Svetlana] Johns Hopkins Univ, Sch Med, Dept Physiol, 725 N Wolfe St, Baltimore, MD 21205 USA. [Yan, Ye; Sockanathan, Shanthini] Johns Hopkins Univ, Sch Med, Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. [Hatori, Yuta] Yasuda Womens Univ, Dept Pharm, Fac Pharm, Asaminami Ku, 6-13-1 Yasuhigashi, Hiroshima 7310153, Japan. [Yan, Ye] NHLBI, Ctr Mol Med, NIH Bldg 10 CRC Room 5-3288,10 Ctr Dr, Bethesda, MD 20892 USA. [Furukawa, Eri] Univ Texas MD Anderson Canc Ctr, Dept Genet, Unit1010, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Liu, Chin-Nung] Natl Yang Ming Univ, Sch Med, Fac Med, 155,Sec 2,Li Nong St, Taipei 112, Taiwan. RP Lutsenko, S (reprint author), Johns Hopkins Univ, Sch Med, Dept Physiol, 725 N Wolfe St, Baltimore, MD 21205 USA. EM lutsenko@jhmi.edu FU National Institutes of Health [R01 GM101502, DK071865, NS046336] FX This work was financially supported, in whole or in part, by National Institutes of Health Grant R01 GM101502 and DK071865 (to S.L.) and NS046336 (to S.S.). We thank Dr Ann Hubbard's laboratory for pShuttle-CMV vector and HEK293A cell line; Dr Lelita Breiterman for technical help for generating adenovirus; Dr Rajini Rao's laboratory for anti-EEA1 and anti-Rab11 antibodies; Dr Betty Eipper for anti-PAM antibody; Dr Tobias Dick for pEGIW/Grx1-roGFP2. NR 48 TC 4 Z9 4 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10640 DI 10.1038/ncomms10640 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0HU UT WOS:000371020600006 PM 26879543 ER PT J AU Joubert, BR den Dekker, HT Felix, JF Bohlin, J Ligthart, S Beckett, E Tiemeier, H van Meurs, JB Uitterlinden, AG Hofman, A Haberg, SE Reese, SE Peters, MJ Andreassen, BK Steegers, EAP Nilsen, RM Vollset, SE Midttun, O Ueland, PM Franco, OH Dehghan, A de Jongste, JC Wu, MC Wang, TY Peddada, SD Jaddoe, VWV Nystad, W Duijts, L London, SJ AF Joubert, Bonnie R. den Dekker, Herman T. Felix, Janine F. Bohlin, Jon Ligthart, Symen Beckett, Emma Tiemeier, Henning van Meurs, Joyce B. Uitterlinden, Andre G. Hofman, Albert Haberg, Siri E. Reese, Sarah E. Peters, Marjolein J. Andreassen, Bettina Kulle Steegers, Eric A. P. Nilsen, Roy M. Vollset, Stein E. Midttun, Oivind Ueland, Per M. Franco, Oscar H. Dehghan, Abbas de Jongste, Johan C. Wu, Michael C. Wang, Tianyuan Peddada, Shyamal D. Jaddoe, Vincent W. V. Nystad, Wenche Duijts, Liesbeth London, Stephanie J. TI Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns SO NATURE COMMUNICATIONS LA English DT Article ID FOLIC-ACID SUPPLEMENTATION; COPY NUMBER VARIATIONS; ONE-CARBON METABOLISM; GERM-CELL TUMORS; NORWEGIAN MOTHER; BREAST-CANCER; CHILD COHORT; GENE LISTS; ASSOCIATION; SUPPRESSOR AB Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring. C1 [Joubert, Bonnie R.; Reese, Sarah E.; Wang, Tianyuan; Peddada, Shyamal D.; London, Stephanie J.] NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [den Dekker, Herman T.; Felix, Janine F.; Jaddoe, Vincent W. V.; Duijts, Liesbeth] Univ Med Ctr Rotterdam, Generat R Study Grp, Erasmus MC, NL-3000 CA Rotterdam, Netherlands. [den Dekker, Herman T.; de Jongste, Johan C.; Duijts, Liesbeth] Univ Med Ctr Rotterdam, Div Resp Med, Erasmus MC, Dept Pediat, NL-3000 CA Rotterdam, Netherlands. [den Dekker, Herman T.; Felix, Janine F.; Ligthart, Symen; Tiemeier, Henning; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Dehghan, Abbas; Jaddoe, Vincent W. V.; Duijts, Liesbeth] Univ Med Ctr Rotterdam, Dept Epidemiol, Erasmus MC, NL-3000 CA Rotterdam, Netherlands. [Felix, Janine F.; Jaddoe, Vincent W. V.] Univ Med Ctr Rotterdam, Dept Pediat, Erasmus MC, NL-3000 CA Rotterdam, Netherlands. [Bohlin, Jon; Haberg, Siri E.; Vollset, Stein E.; Nystad, Wenche] Norwegian Inst Publ Hlth, N-0403 Oslo, Norway. [Beckett, Emma] Univ Newcastle, Sch Environm & Life Sci, Dept Appl Sci, Ourimbah, NSW 2258, Australia. [Beckett, Emma] CSIRO, Food & Nutr Flagship, N Ryde, NSW 2113, Australia. [Tiemeier, Henning] Univ Med Ctr Rotterdam, Erasmus MC, Dept Psychiat, NL-3000 CA Rotterdam, Netherlands. [van Meurs, Joyce B.; Uitterlinden, Andre G.; Peters, Marjolein J.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Andreassen, Bettina Kulle] Univ Oslo, Inst Clin Med, Dept Clin Mol Biol, N-0316 Oslo, Norway. [Steegers, Eric A. P.] Univ Med Ctr Rotterdam, Erasmus MC, Dept Obstet & Gynaecol, NL-3000 CA Rotterdam, Netherlands. [Nilsen, Roy M.] Haukeland Hosp, Dept Res & Dev, Clin Res Ctr, N-5021 Bergen, Norway. [Vollset, Stein E.] Univ Bergen, Dept Global Publ Hlth & Primary Care, N-5018 Bergen, Norway. [Midttun, Oivind] Bevital AS, Laboratoriebygget, N-5018 Bergen, Norway. [Ueland, Per M.] Univ Bergen, Dept Clin Sci, N-5018 Bergen, Norway. [Ueland, Per M.] Haukeland Hosp, Lab Clin Biochem, N-5018 Bergen, Norway. [Wu, Michael C.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Program, Seattle, WA 98109 USA. RP Joubert, BR (reprint author), NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM joubertbr@niehs.nih.gov RI Ueland, Per/C-7340-2013; OI Joubert, Bonnie/0000-0001-7952-1180; Beckett, Emma/0000-0002-8888-3789; Dehghan, Abbas/0000-0001-6403-016X; London, Stephanie/0000-0003-4911-5290; Bohlin, Jon/0000-0002-0992-1311; Wu, Michael C./0000-0002-3357-6570 FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01-ES-49019]; NIH Office of Dietary Supplements; Norwegian Ministry of Health; Ministry of Education and Research, NIH/NIEHS [N01-ES-75558]; NIH/NINDS [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10]; Adam J Berry Memorial Scholarship; Foundation for the National Institutes of Health; Erasmus Medical Center, Rotterdam; Erasmus University Rotterdam; Netherlands Organization for Health Research and Development; European Union's Horizon research and innovation programme [633595]; Nestle Nutrition (Nestec Ltd); Metagenics Inc; AXA; Netherlands Organization for Health Research and Development [VENI 916.12.154, VIDI 016.136.361]; EUR Fellowship; European Research Council [ERC-2014-CoG-64916]; Lung Foundation Netherlands [3.2.12.089]; Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019). Additional funding support was provided by the NIH Office of Dietary Supplements. We acknowledge Shuangshuang Dai of Integrative Bioinformatics at the NIEHS and Jianping Jin of Westat for their expert data management and programming assistance. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. N01-ES-75558), NIH/NINDS (grant no. 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). We are grateful to all the participating families in Norway who take part in this ongoing cohort study. E.B. was supported by the Adam J Berry Memorial Scholarship administered by the Australian Academy of Science and the Foundation for the National Institutes of Health. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond, Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The study protocol was approved by the Medical Ethical Committee of the Erasmus Medical Centre, Rotterdam. We thank Mr Michael Verbiest, Ms Mila Jhamai, Ms Sarah Higgins, Mr Marijn Verkerk and Dr Lisette Stolk for their help in creating the EWAS database. The Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam and the Netherlands Organization for Health Research and Development. J.F.F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595. O.F. works in ErasmusAGE, a centre for aging research across the life course funded by Nestle Nutrition (Nestec Ltd), Metagenics Inc and AXA. Nestle Nutrition (Nestec Ltd.), Metagenics Inc. and AXA had no role in design and conduct of the study, in the collection, management, analysis and interpretation of the data, or in the preparation, review and approval of the manuscript. A.D. received an additional grant from the Netherlands Organization for Health Research and Development (VENI 916.12.154) and the EUR Fellowship. V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-64916). L.D. received an additional grant from the Lung Foundation Netherlands (no 3.2.12.089; 2012). The generation and management of the Illumina 450K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, the Netherlands. The EWAS data was funded by a grant to V.W.V.J. from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), and by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center. NR 60 TC 12 Z9 12 U1 6 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10577 DI 10.1038/ncomms10577 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0FU UT WOS:000371015300012 PM 26861414 ER PT J AU Kilpelainen, TO Carli, JFM Skowronski, AA Sun, Q Kriebel, J Feitosa, MF Hedman, AK Drong, AW Hayes, JE Zhao, JH Pers, TH Schick, U Grarup, N Kutalik, Z Trompet, S Mangino, M Kristiansson, K Beekman, M Lyytikainen, LP Eriksson, J Henneman, P Lahti, J Tanaka, T Luan, JA Del Greco, F Pasko, D Renstrom, F Willems, SM Mahajan, A Rose, LM Guo, XQ Liu, YM Kleber, ME Perusse, L Gaunt, T Ahluwalia, TS Sung, YJ Ramos, YF Amin, N Amuzu, A Barroso, I Bellis, C Blangero, J Buckley, BM Bohringer, S Chen, YDI de Craen, AJN Crosslin, DR Dale, CE Dastani, Z Day, FR Deelen, J Delgado, GE Demirkan, A Finucane, FM Ford, I Garcia, ME Gieger, C Gustafsson, S Hallmans, G Hankinson, SE Havulinna, AS Herder, C Hernandez, D Hicks, AA Hunter, DJ Illig, T Ingelsson, E Ioan-Facsinay, A Jansson, JO Jenny, NS Jorgensen, ME Jorgensen, T Karlsson, M Koenig, W Kraft, P Kwekkeboom, J Laatikainen, T Ladwig, KH LeDuc, CA Lowe, G Lu, YC Marques-Vidal, P Meisinger, C Menni, C Morris, AP Myers, RH Mannisto, S Nalls, MA Paternoster, L Peters, A Pradhan, AD Rankinen, T Rasmussen-Torvik, LJ Rathmann, W Rice, TK Richards, JB Ridker, PM Sattar, N Savage, DB Soderberg, S Timpson, NJ Vandenput, L van Heemst, D Uh, HW Vohl, MC Walker, M Wichmann, HE Widen, E Wood, AR Yao, J Zeller, T Zhang, YY Meulenbelt, I Kloppenburg, M Astrup, A Sorensen, TIA Sarzynski, MA Rao, DC Jousilahti, P Vartiainen, E Hofman, A Rivadeneira, F Uitterlinden, AG Kajantie, E Osmond, C Palotie, A Eriksson, JG Heliovaara, M Knekt, PB Koskinen, S Jula, A Perola, M Huupponen, RK Viikari, JS Kahonen, M Lehtimaki, T Raitakari, OT Mellstrom, D Lorentzon, M Casas, JP Bandinelli, S Marz, W Isaacs, A van Dijk, KW van Duijn, CM Harris, TB Bouchard, C Allison, MA Chasman, DI Ohlsson, C Lind, L Scott, RA Langenberg, C Wareham, NJ Ferrucci, L Frayling, TM Pramstaller, PP Borecki, IB Waterworth, DM Bergmann, S Waeber, G Vollenweider, P Vestergaard, H Hansen, T Pedersen, O Hu, FB Slagboom, PE Grallert, H Spector, TD Jukema, JW Klein, RJ Schadt, EE Franks, PW Lindgren, CM Leibel, RL Loos, RJF AF Kilpelainen, Tuomas O. Carli, Jayne F. Martin Skowronski, Alicja A. Sun, Qi Kriebel, Jennifer Feitosa, Mary F. Hedman, Asa K. Drong, Alexander W. Hayes, James E. Zhao, Jinghua Pers, Tune H. Schick, Ursula Grarup, Niels Kutalik, Zoltan Trompet, Stella Mangino, Massimo Kristiansson, Kati Beekman, Marian Lyytikainen, Leo-Pekka Eriksson, Joel Henneman, Peter Lahti, Jari Tanaka, Toshiko Luan, Jian'an Del Greco M, Fabiola Pasko, Dorota Renstrom, Frida Willems, Sara M. Mahajan, Anubha Rose, Lynda M. Guo, Xiuqing Liu, Yongmei Kleber, Marcus E. Perusse, Louis Gaunt, Tom Ahluwalia, Tarunveer S. Sung, Yun Ju Ramos, Yolande F. Amin, Najaf Amuzu, Antoinette Barroso, Ines Bellis, Claire Blangero, John Buckley, Brendan M. Bohringer, Stefan Chen, Yii-Der I. de Craen, Anton J. N. Crosslin, David R. Dale, Caroline E. Dastani, Zari Day, Felix R. Deelen, Joris Delgado, Graciela E. Demirkan, Ayse Finucane, Francis M. Ford, Ian Garcia, Melissa E. Gieger, Christian Gustafsson, Stefan Hallmans, Goran Hankinson, Susan E. Havulinna, Aki S. Herder, Christian Hernandez, Dena Hicks, Andrew A. Hunter, David J. Illig, Thomas Ingelsson, Erik Ioan-Facsinay, Andreea Jansson, John-Olov Jenny, Nancy S. Jorgensen, Marit E. Jorgensen, Torben Karlsson, Magnus Koenig, Wolfgang Kraft, Peter Kwekkeboom, Joanneke Laatikainen, Tiina Ladwig, Karl-Heinz LeDuc, Charles A. Lowe, Gordon Lu, Yingchang Marques-Vidal, Pedro Meisinger, Christa Menni, Cristina Morris, Andrew P. Myers, Richard H. Mannisto, Satu Nalls, Mike A. Paternoster, Lavinia Peters, Annette Pradhan, Aruna D. Rankinen, Tuomo Rasmussen-Torvik, Laura J. Rathmann, Wolfgang Rice, Treva K. Richards, J. Brent Ridker, Paul M. Sattar, Naveed Savage, David B. Soderberg, Stefan Timpson, Nicholas J. Vandenput, Liesbeth van Heemst, Diana Uh, Hae-Won Vohl, Marie-Claude Walker, Mark Wichmann, Heinz-Erich Widen, Elisabeth Wood, Andrew R. Yao, Jie Zeller, Tanja Zhang, Yiying Meulenbelt, Ingrid Kloppenburg, Margreet Astrup, Arne Sorensen, Thorkild I. A. Sarzynski, Mark A. Rao, D. C. Jousilahti, Pekka Vartiainen, Erkki Hofman, Albert Rivadeneira, Fernando Uitterlinden, Andre G. Kajantie, Eero Osmond, Clive Palotie, Aarno Eriksson, Johan G. Heliovaara, Markku Knekt, Paul B. Koskinen, Seppo Jula, Antti Perola, Markus Huupponen, Risto K. Viikari, Jorma S. Kahonen, Mika Lehtimaki, Terho Raitakari, Olli T. Mellstrom, Dan Lorentzon, Mattias Casas, Juan P. Bandinelli, Stefanie Maerz, Winfried Isaacs, Aaron van Dijk, Ko W. van Duijn, Cornelia M. Harris, Tamara B. Bouchard, Claude Allison, Matthew A. Chasman, Daniel I. Ohlsson, Claes Lind, Lars Scott, Robert A. Langenberg, Claudia Wareham, Nicholas J. Ferrucci, Luigi Frayling, Timothy M. Pramstaller, Peter P. Borecki, Ingrid B. Waterworth, Dawn M. Bergmann, Sven Waeber, Gerard Vollenweider, Peter Vestergaard, Henrik Hansen, Torben Pedersen, Oluf Hu, Frank B. Slagboom, P. Eline Grallert, Harald Spector, Tim D. Jukema, J. W. Klein, Robert J. Schadt, Erik E. Franks, Paul W. Lindgren, Cecilia M. Leibel, Rudolph L. Loos, Ruth J. F. TI Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels SO NATURE COMMUNICATIONS LA English DT Article ID EARLY-ONSET OBESITY; GENE-EXPRESSION; PLASMA LEPTIN; ADIPOSE-TISSUE; SERUM LEPTIN; RECOMBINANT LEPTIN; INSULIN-RESISTANCE; PROVIDES INSIGHTS; WEIGHT-LOSS; FAT MASS AB Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P < 10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P < 5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. C1 [Kilpelainen, Tuomas O.; Pers, Tune H.; Grarup, Niels; Ahluwalia, Tarunveer S.; Sorensen, Thorkild I. A.; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Univ Pk 1,DIKU Bldg, DK-2100 Copenhagen, Denmark. [Kilpelainen, Tuomas O.; Zhao, Jinghua; Luan, Jian'an; Day, Felix R.; Finucane, Francis M.; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; Loos, Ruth J. F.] Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Kilpelainen, Tuomas O.; Schick, Ursula; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Carli, Jayne F. Martin] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Skowronski, Alicja A.] Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. [Sun, Qi; Hankinson, Susan E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. 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[LeDuc, Charles A.; Zhang, Yiying; Leibel, Rudolph L.] Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10029 USA. [Lowe, Gordon] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Marques-Vidal, Pedro; Waeber, Gerard; Vollenweider, Peter] Univ Lausanne Hosp, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Pradhan, Aruna D.; Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Rasmussen-Torvik, Laura J.] Northwestern Feinberg Sch Med, Prevent Med, Chicago, IL 60611 USA. [Rathmann, Wolfgang] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, D-40225 Dusseldorf, Germany. [Richards, J. Brent] McGill Univ, Dept Med Human Genet & Epidemiol, Montreal, PQ H3A 0G4, Canada. [Sattar, Naveed] BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow G12 8QQ, Lanark, Scotland. [Soderberg, Stefan] Umea Univ, Cardiol & Heart Ctr, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Vohl, Marie-Claude] Univ Laval, Sch Nutr, Quebec City, PQ G1V 0A6, Canada. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wichmann, Heinz-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-80336 Munich, Germany. [Wichmann, Heinz-Erich] Klinikum Grosshadern, D-80336 Munich, Germany. [Wichmann, Heinz-Erich] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Wichmann, Heinz-Erich] Tech Univ Munich, Inst Med Stat & Epidemiol, D-81675 Munich, Germany. [Zeller, Tanja] German Ctr Cardiovasc Res DZHK eV, D-20246 Hamburg, Germany. 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[Bergmann, Sven] Univ Lausanne, Dept Med Genet, CH-1015 Lausanne, Switzerland. [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, DK-5230 Odense, Denmark. [Jukema, J. W.] Interuniv Cardiol Inst Netherlands, NL-3511 EP Utrecht, Netherlands. [Jukema, J. W.] Durrer Ctr Cardiogenet Res, NL-1105 AZ Amsterdam, Netherlands. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Lindgren, Cecilia M.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lindgren, Cecilia M.] Univ Oxford, Big Data Inst, S Parks Rd, Oxford OX1 2JD, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Kilpelainen, TO (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Univ Pk 1,DIKU Bldg, DK-2100 Copenhagen, Denmark.; Kilpelainen, TO; Loos, RJF (reprint author), Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.; Kilpelainen, TO; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM tuomas.kilpelainen@sund.ku.dk; ruth.loos@mssm.edu RI Hicks, Andrew/E-9518-2017; Grallert, Harald/B-3424-2013; Sarzynski, Mark/A-9798-2014; Bouchard, Claude/A-7637-2009; Ladwig, Karl-Heinz/B-5351-2014; Colaus, PsyColaus/K-6607-2013; Feitosa, Mary/K-8044-2012; Grarup, Niels/K-2807-2015; mangino, massimo/F-5134-2011; Gaunt, Tom/O-3918-2014; Fox, Laura /C-6249-2016; Peters, Annette/A-6117-2011; Slagboom, P. Eline/R-4790-2016; OI Hicks, Andrew/0000-0001-6320-0411; Menni, Cristina/0000-0001-9790-0571; Kristiansson, Kati/0000-0003-4688-107X; Gieger, Christian/0000-0001-6986-9554; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Mannisto, Satu/0000-0002-8668-3046; Mellstrom, Dan/0000-0003-2761-3723; Meisinger, Christa/0000-0002-9026-6544; Hedman, Asa/0000-0001-5413-204X; Vandenput, Liesbeth/0000-0002-1712-6131; Jorgensen, Torben/0000-0001-9453-2830; Allison, Matthew/0000-0003-0777-8272; Ladwig, Karl-Heinz/0000-0003-0710-1720; Feitosa, Mary/0000-0002-0933-2410; Grarup, Niels/0000-0001-5526-1070; mangino, massimo/0000-0002-2167-7470; Gaunt, Tom/0000-0003-0924-3247; Slagboom, P. Eline/0000-0002-2875-4723; Vestergaard, Henrik/0000-0003-3090-269X; Timpson, Nicholas/0000-0002-7141-9189; Lahti, Jari/0000-0002-4310-5297; Kleber, Marcus/0000-0003-0663-7275; Peters, Annette/0000-0001-6645-0985 FU Academy of Finland [41071, 117787, 118065, 121584, 124282, 126925, 129494, 129322, 129378, 130326, 134309, 134791, 136895, 139635, 250207, 263836, 286284, 263924]; Ahokas Foundation; ALF/LUA research grant in Gothenburg; Amgen; Augustinus Foundation; Becket Foundation; Bristol-Myers Squibb; British Heart Foundation programme [PG/13/66/30442, PG/07/131/24254]; Canadian Institutes of Health Research [FRCN-CCT-83028]; Centre for Medical Systems Biology; Danish Centre for Health Technology Assessment; Danish Council for Independent Research [DFF-1333-00124, DFF-1331-00730B]; Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Department of Health Policy Research Programme [0090049]; Diabetes UK; Donald W. Reynolds Foundation; Dutch Arthritis Association [DAA 2010_017]; Dutch government [NWO 184.021.007]; Emil Aaltonen Foundation; Erasmus MC; Erasmus University; European Commission [FP6-LSHG-CT-2006-018947, FP6-LSHG-CT-2006-01947, HEALTH-F2-2008-201865-GEFOS, FP7-201668, FP7-223004, FP7-259679, FP7-305739, FP7-IDEAS-ERC-323195]; European Regional Development Fund; EUROSPAN; Faculty of Biology and Medicine of Lausanne; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Society; Finnish Foundation of Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish National Institute for Health and Welfare; Finnish Special Governmental Subsidy for Health Sciences; Finska Lakaresallskapet; Folkhalsan Research Foundation; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; German Center for Diabetes Research (DZD); German Federal Ministry of Education and Research; GlaxoSmithKline; Goran Gustafsson Foundation; Heart Foundation of Northern Sweden; Helmholtz Zentrum Munchen; Ib Henriksen Foundation; Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007]; Italian Ministry of Health [ICS110.1/RF97.71]; John W. Barton Sr. Chair in Genetics and Nutrition; Juho Vainio Foundation; King's College London; Knut and Alice Wallenberg Foundation; Turku University Hospital Medical Fund [X51001, 9M048, 9N035]; Leiden University Medical Centre; Li Ka Shing Foundation; Liv och Halsa; Local Government Pensions Institution; Ludwig-Maximilians-Universitat; Lundbeck Foundation; Lundberg Foundation; Medical Research Council [MC_U106179471, MC_UU_12013/3, MC_UU_12013/8]; Medical Research Council-GlaxoSmithKline pilot programme grant [G0701863]; Ministry of Education, Culture and Science of the Netherlands; Ministry of health, Welfare and Sports of the Netherlands; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Danish Ministry of Internal Affairs and Health; Munich Center of Health Sciences; Municipality of Rotterdam; National Cancer Institute [CA047988]; National Eye Institute; National Institute on Aging (Intramural research programme) [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, 263MD9164, 263 MD 821336]; National Institute for Health Research; National Institutes of Health [DK52431, HG004399, HG004446, CA087969, CA055075, DK058845, CA65725, CA49449, CA67262, CA50385, UO1CA098233]; Netherlands Brain Foundation (HersenStichting Nederland); Netherlands Consortium for Healthy Aging [050-060-810]; Netherlands Genomics Initiative; Netherlands Heart Foundation [2001 D 032]; Netherlands Organization for Scientific Research [175-010-2005-011, 904-61-095, 911-03-012, 911-03-016, 917-66-344]; Netherlands Organization for the Health Research and Development; National Heart, Lung, and Blood Institute [5R01HL068891, 5R01HL087700, R01HL117078, HHSN26800625226C, HHSN268200782096C, HL-043851, HL-045670, HL080467, N01-HC95159, 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, N02-HL-64278, N01-HC-65226, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-088451, R00-HL-098459, U01-HG007033, UL1-RR-24156, UL1-RR-25005, UL1-TR-000040, UL1-TR-001079]; National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases [1R01DK080015, R01DK089256, 5R01DK068336, 5R01DK075681, 5R01DK07568102]; Novo Nordisk; Novo Nordisk Foundation; New York Obesity Nutrition Research Center Pilot and Feasilibity Grant [DK-26687]; Orion-Farmos Research Foundation; Pfizer Inc.; Paavo Nurmi Foundation; Pahlssons Foundation; Research Foundation of Copenhagen County; Roche Pharmaceuticals; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Samfundet Folkhalsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South Tyrolean Sparkasse Foundation; Swedish Diabetes Association; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation [20140422]; Swedish Research Council [2012-1397]; Swiss Institute of Bioinformatics; Swiss National Science Foundation [3100AO-116323/1, 33CSCO-122661, 33CS30-139468, 33CS30-148401]; Tampere Tuberculosis Foundation; Torsten and Ragnar Soderberg's Foundation; Umea University Career Development Award; Unilever Colworth; Wellcome Trust [WT064890, WT089062, WT090532, WT098017, WT098051, WT091551, 081917/Z/07/Z, 086596/Z/08/Z]; Wellcome Trust Centre for Human Genetics core funding [090532]; Wissenschaftsoffensive TMO; Yrjo Jahnsson Foundation; Kuopio University Hospital Medical Fund; Tampere University Hospital Medical Fund FX The full list of acknowledgements appears in the Supplementary Information. Funding for this study was provided by the Academy of Finland (41071, 117787, 118065, 121584, 124282, 126925, 129494, 129322, 129378, 130326, 134309, 134791, 136895, 139635, 250207, 263836, 286284 and 263924); Ahokas Foundation; ALF/LUA research grant in Gothenburg; Amgen; Augustinus Foundation; Becket Foundation; Bristol-Myers Squibb; British Heart Foundation programme (PG/13/66/30442 and PG/07/131/24254); Canadian Institutes of Health Research (FRCN-CCT-83028); Centre for Medical Systems Biology; Danish Centre for Health Technology Assessment; Danish Council for Independent Research (DFF-1333-00124 and DFF-1331-00730B); Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Department of Health Policy Research Programme (0090049); Diabetes UK; Donald W. Reynolds Foundation; Dutch Arthritis Association (DAA 2010_017); Dutch government (NWO 184.021.007); Emil Aaltonen Foundation; Erasmus MC; Erasmus University; European Commission (FP6-LSHG-CT-2006-018947, FP6-LSHG-CT-2006-01947, HEALTH-F2-2008-201865-GEFOS, FP7-201668, FP7-223004, FP7-259679, FP7-305739 and FP7-IDEAS-ERC-323195); European Regional Development Fund; EUROSPAN; Faculty of Biology and Medicine of Lausanne; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Society; Finnish Foundation of Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish National Institute for Health and Welfare; Finnish Special Governmental Subsidy for Health Sciences; Finska Lakaresallskapet; Folkhalsan Research Foundation; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; German Center for Diabetes Research (DZD); German Federal Ministry of Education and Research; GlaxoSmithKline; Goran Gustafsson Foundation; Heart Foundation of Northern Sweden; Helmholtz Zentrum Munchen; Ib Henriksen Foundation; Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Italian Ministry of Health (ICS110.1/RF97.71); John W. Barton Sr.; r Chair in Genetics and Nutrition; Juho Vainio Foundation; King's College London; Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001, 9M048, 9N035); Leiden University Medical Centre; Li Ka Shing Foundation; Liv och Halsa; Local Government Pensions Institution; Ludwig-Maximilians-Universitat; Lundbeck Foundation; Lundberg Foundation; Medical Research Council (MC_U106179471, MC_UU_12013/3, and MC_UU_12013/8); Medical Research Council-GlaxoSmithKline pilot programme grant (G0701863); Ministry of Education, Culture and Science of the Netherlands; Ministry of health, Welfare and Sports of the Netherlands; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Danish Ministry of Internal Affairs and Health; Munich Center of Health Sciences; Municipality of Rotterdam; National Cancer Institute (CA047988); National Eye Institute; National Institute on Aging (Intramural research programme, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, 263MD9164 and 263 MD 821336); National Institute for Health Research; National Institutes of Health (DK52431, HG004399, HG004446, CA087969, CA055075, DK058845, CA65725, CA49449, CA67262, CA50385 and UO1CA098233); Netherlands Brain Foundation (HersenStichting Nederland); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Heart Foundation (2001 D 032); Netherlands Organization for Scientific Research (175-010-2005-011, 904-61-095, 911-03-012, 911-03-016, 917-66-344 and 911-03-012); Netherlands Organization for the Health Research and Development; National Heart, Lung, and Blood Institute (5R01HL068891, 5R01HL087700, R01HL117078, HHSN26800625226C, HHSN268200782096C, HL-043851, HL-045670, HL080467, N01-HC95159, 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, N02-HL-64278, N01-HC-65226, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-088451, R00-HL-098459, U01-HG007033, UL1-RR-24156, UL1-RR-25005, UL1-TR-000040 and UL1-TR-001079); National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases (1R01DK080015, R01DK089256, 5R01DK068336, 5R01DK075681 and 5R01DK07568102); Novo Nordisk; Novo Nordisk Foundation; New York Obesity Nutrition Research Center Pilot and Feasilibity Grant (DK-26687); Orion-Farmos Research Foundation; Pfizer Inc.; Paavo Nurmi Foundation; Pahlssons Foundation; Research Foundation of Copenhagen County; Roche Pharmaceuticals; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Samfundet Folkhalsan; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; South Tyrolean Sparkasse Foundation; Swedish Diabetes Association; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140422); Swedish Research Council (2012-1397); Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 33CSCO-122661, 33CS30-139468 and 33CS30-148401); Tampere Tuberculosis Foundation; Torsten and Ragnar Soderberg's Foundation; Umea University Career Development Award; Unilever Colworth; Wellcome Trust (WT064890, WT089062, WT090532, WT098017, WT098051, WT091551, 081917/Z/07/Z and 086596/Z/08/Z); Wellcome Trust Centre for Human Genetics core funding (090532); Wissenschaftsoffensive TMO; Yrjo Jahnsson Foundation. NR 70 TC 3 Z9 3 U1 6 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10494 DI 10.1038/ncomms10494 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0EQ UT WOS:000371012200001 PM 26833098 ER PT J AU Lu, YC Day, FR Gustafsson, S Buchkovich, ML Na, JB Bataille, V Cousminer, DL Dastani, Z Drong, AW Esko, T Evans, DM Falchi, M Feitosa, MF Ferreira, T Hedman, AK Haring, R Hysi, PG Iles, MM Justice, AE Kanoni, S Lagou, V Li, R Li, X Locke, A Lu, C Magi, R Perry, JRB Pers, TH Qi, QB Sanna, M Schmidt, EM Scott, WR Shungin, D Teumer, A Vinkhuyzen, AAE Walker, RW Westra, HJ Zhang, MF Zhang, WH Zhao, JH Zhu, ZH Afzal, U Ahluwalia, TS Bakker, SJL Bellis, C Bonnefond, A Borodulin, K Buchman, AS Cederholm, T Choh, AC Choi, HJ Curran, JE de Groot, LCPGM De Jager, PL Dhonukshe-Rutten, RAM Enneman, AW Eury, E Evans, DS Forsen, T Friedrich, N Fumeron, F Garcia, ME Gartner, S Han, BG Havulinna, AS Hayward, C Hernandez, D Hillege, H Ittermann, T Kent, JW Kolcic, I Laatikainen, T Lahti, J Leach, IM Lee, CG Lee, JY Liu, T Liu, YF Lobbens, S Loh, M Lyytikainen, LP Medina-Gomez, C Michaelsson, K Nalls, MA Nielson, CM Oozageer, L Pascoe, L Paternoster, L Polasek, O Ripatti, S Sarzynski, MA Shin, CS Narancic, NS Spira, D Srikanth, P Steinhagen-Thiessen, E Sung, YJ Swart, KMA Taittonen, L Tanaka, T Tikkanen, E van der Velde, N van Schoor, NM Verweij, N Wright, AF Yu, L Zmuda, JM Eklund, N Forrester, T Grarup, N Jackson, AU Kristiansson, K Kuulasmaa, T Kuusisto, J Lichtner, P Luan, JA Mahajan, A Mannisto, S Palmer, CD Ried, JS Scott, RA Stancakova, A Wagner, PJ Demirkan, A Doring, A Gudnason, V Kiel, DP Kuhnel, B Mangino, M Mcknight, B Menni, C O'Connell, JR Oostra, BA Shuldiner, AR Song, KJ Vandenput, L van Duijn, CM Vollenweider, P White, CC Boehnke, M Boettcher, Y Cooper, RS Forouhi, NG Gieger, C Grallert, H Hingorani, A Jorgensen, T Jousilahti, P Kivimaki, M Kumari, M Laakso, M Langenberg, C Linneberg, A Luke, A Mckenzie, CA Palotie, A Pedersen, O Peters, A Strauch, K Tayo, BO Wareham, NJ Bennett, DA Bertram, L Blangero, J Bluher, M Bouchard, C Campbell, H Cho, NH Cummings, SR Czerwinski, SA Demuth, I Eckardt, R Eriksson, JG Ferrucci, L Franco, OH Froguel, P Gansevoort, RT Hansen, T Harris, TB Hastie, N Heliovaara, M Hofman, A Jordan, JM Jula, A Kahonen, M Kajantie, E Knekt, PB Koskinen, S Kovacs, P Lehtimaki, T Lind, L Liu, YM Orwoll, ES Osmond, C Perola, M Perusse, L Raitakari, OT Rankinen, T Rao, DC Rice, TK Rivadeneira, F Rudan, I Salomaa, V Sorensen, TIA Stumvoll, M Tonjes, A Towne, B Tranah, GJ Tremblay, A Uitterlinden, AG van der Harst, P Vartiainen, E Viikari, JS Vitart, V Vohl, MC Volzke, H Walker, M Wallaschofski, H Wild, S Wilson, JF Yengo, L Bishop, DT Borecki, IB Chambers, JC Cupples, LA Dehghan, A Deloukas, P Fatemifar, G Fox, C Furey, TS Franke, L Han, JL Hunter, DJ Karjalainen, J Karpe, F Kaplan, RC Kooner, JS McCarthy, MI Murabito, JM Morris, AP Bishop, JAN North, KE Ohlsson, C Ong, KK Prokopenko, I Richards, JB Schadt, EE Spector, TD Widen, E Willer, CJ Yang, J Ingelsson, E Mohlke, KL Hirschhorn, JN Pospisilik, JA Zillikens, MC Lindgren, C Kilpelainen, TO Loos, RJF AF Lu, Yingchang Day, Felix R. Gustafsson, Stefan Buchkovich, Martin L. Na, Jianbo Bataille, Veronique Cousminer, Diana L. Dastani, Zari Drong, Alexander W. Esko, Tonu Evans, David M. Falchi, Mario Feitosa, Mary F. Ferreira, Teresa Hedman, Asa K. Haring, Robin Hysi, Pirro G. Iles, Mark M. Justice, Anne E. Kanoni, Stavroula Lagou, Vasiliki Li, Rui Li, Xin Locke, Adam Lu, Chen Magi, Reedik Perry, John R. B. Pers, Tune H. Qi, Qibin Sanna, Marianna Schmidt, Ellen M. Scott, William R. Shungin, Dmitry Teumer, Alexander Vinkhuyzen, Anna A. E. Walker, Ryan W. Westra, Harm-Jan Zhang, Mingfeng Zhang, Weihua Zhao, Jing Hua Zhu, Zhihong Afzal, Uzma Ahluwalia, Tarunveer Singh Bakker, Stephan J. L. Bellis, Claire Bonnefond, Amelie Borodulin, Katja Buchman, Aron S. Cederholm, Tommy Choh, Audrey C. Choi, Hyung Jin Curran, Joanne E. de Groot, Lisette C. P. G. M. De Jager, Philip L. Dhonukshe-Rutten, Rosalie A. M. Enneman, Anke W. Eury, Elodie Evans, Daniel S. Forsen, Tom Friedrich, Nele Fumeron, Frederic Garcia, Melissa E. Gartner, Simone Han, Bok-Ghee Havulinna, Aki S. Hayward, Caroline Hernandez, Dena Hillege, Hans Ittermann, Till Kent, Jack W. Kolcic, Ivana Laatikainen, Tiina Lahti, Jari Leach, Irene Mateo Lee, Christine G. Lee, Jong-Young Liu, Tian Liu, Youfang Lobbens, Stephane Loh, Marie Lyytikainen, Leo-Pekka Medina-Gomez, Carolina Michaelsson, Karl Nalls, Mike A. Nielson, Carrie M. Oozageer, Laticia Pascoe, Laura Paternoster, Lavinia Polasek, Ozren Ripatti, Samuli Sarzynski, Mark A. Shin, Chan Soo Narancic, Nina Smolej Spira, Dominik Srikanth, Priya Steinhagen-Thiessen, Elisabeth Sung, Yun Ju Swart, Karin M. A. Taittonen, Leena Tanaka, Toshiko Tikkanen, Emmi van der Velde, Nathalie van Schoor, Natasja M. Verweij, Niek Wright, Alan F. Yu, Lei Zmuda, Joseph M. Eklund, Niina Forrester, Terrence Grarup, Niels Jackson, Anne U. Kristiansson, Kati Kuulasmaa, Teemu Kuusisto, Johanna Lichtner, Peter Luan, Jian'an Mahajan, Anubha Mannisto, Satu Palmer, Cameron D. Ried, Janina S. Scott, Robert A. Stancakova, Alena Wagner, Peter J. Demirkan, Ayse Doring, Angela Gudnason, Vilmundur Kiel, Douglas P. Kuhnel, Brigitte Mangino, Massimo Mcknight, Barbara Menni, Cristina O'Connell, Jeffrey R. Oostra, Ben A. Shuldiner, Alan R. Song, Kijoung Vandenput, Liesbeth van Duijn, Cornelia M. Vollenweider, Peter White, Charles C. Boehnke, Michael Boettcher, Yvonne Cooper, Richard S. Forouhi, Nita G. Gieger, Christian Grallert, Harald Hingorani, Aroon Jorgensen, Torben Jousilahti, Pekka Kivimaki, Mika Kumari, Meena Laakso, Markku Langenberg, Claudia Linneberg, Allan Luke, Amy Mckenzie, Colin A. Palotie, Aarno Pedersen, Oluf Peters, Annette Strauch, Konstantin Tayo, Bamidele O. Wareham, Nicholas J. Bennett, David A. Bertram, Lars Blangero, John Bluher, Matthias Bouchard, Claude Campbell, Harry Cho, Nam H. Cummings, Steven R. Czerwinski, Stefan A. Demuth, Ilja Eckardt, Rahel Eriksson, Johan G. Ferrucci, Luigi Franco, Oscar H. Froguel, Philippe Gansevoort, Ron T. Hansen, Torben Harris, Tamara B. Hastie, Nicholas Heliovaara, Markku Hofman, Albert Jordan, Joanne M. Jula, Antti Kahonen, Mika Kajantie, Eero Knekt, Paul B. Koskinen, Seppo Kovacs, Peter Lehtimaki, Terho Lind, Lars Liu, Yongmei Orwoll, Eric S. Osmond, Clive Perola, Markus Perusse, Louis Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rice, Treva K. Rivadeneira, Fernando Rudan, Igor Salomaa, Veikko Sorensen, Thorkild I. A. Stumvoll, Michael Tonjes, Anke Towne, Bradford Tranah, Gregory J. Tremblay, Angelo Uitterlinden, Andre G. van der Harst, Pim Vartiainen, Erkki Viikari, Jorma S. Vitart, Veronique Vohl, Marie-Claude Volzke, Henry Walker, Mark Wallaschofski, Henri Wild, Sarah Wilson, James F. Yengo, Loic Bishop, D. Timothy Borecki, Ingrid B. Chambers, John C. Cupples, L. Adrienne Dehghan, Abbas Deloukas, Panos Fatemifar, Ghazaleh Fox, Caroline Furey, Terrence S. Franke, Lude Han, Jiali Hunter, David J. Karjalainen, Juha Karpe, Fredrik Kaplan, Robert C. Kooner, Jaspal S. McCarthy, Mark I. Murabito, Joanne M. Morris, Andrew P. Bishop, Julia A. N. North, Kari E. Ohlsson, Claes Ong, Ken K. Prokopenko, Inga Richards, J. Brent Schadt, Eric E. Spector, Tim D. Widen, Elisabeth Willer, Cristen J. Yang, Jian Ingelsson, Erik Mohlke, Karen L. Hirschhorn, Joel N. Pospisilik, John Andrew Zillikens, M. Carola Lindgren, Cecilia Kilpelainen, Tuomas Oskari Loos, Ruth J. F. TI y New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk SO NATURE COMMUNICATIONS LA English DT Article ID GENOME-WIDE ASSOCIATION; MASS INDEX; INSULIN-RESISTANCE; COMMON VARIANTS; GENETIC ARCHITECTURE; SUSCEPTIBILITY LOCI; IDENTIFIES COMMON; PROVIDES INSIGHTS; ENERGY-BALANCE; CUTANEOUS NEVI AB To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P < 5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk. C1 [Lu, Yingchang; Walker, Ryan W.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Walker, Ryan W.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Day, Felix R.; Perry, John R. B.; Zhao, Jing Hua; Luan, Jian'an; Scott, Robert A.; Forouhi, Nita G.; Langenberg, Claudia; Wareham, Nicholas J.; Ong, Ken K.; Kilpelainen, Tuomas Oskari; Loos, Ruth J. F.] Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge Biomed Campus, Cambridge CB2 0QQ, England. [Gustafsson, Stefan; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Sci Life Lab, S-75085 Uppsala, Sweden. [Gustafsson, Stefan; Hedman, Asa K.; Ingelsson, Erik] Uppsala Univ, Dept Med Sci, Mol Epidemiol, S-75185 Uppsala, Sweden. [Buchkovich, Martin L.; Furey, Terrence S.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Na, Jianbo] Icahn Sch Med Mt Sinai, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Bataille, Veronique] West Herts NHS Trust, Hemel Hempstead HP2 4AD, Herts, England. [Bataille, Veronique; Falchi, Mario; Hysi, Pirro G.; Sanna, Marianna; Mangino, Massimo; Menni, Cristina; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Cousminer, Diana L.; Ripatti, Samuli; Tikkanen, Emmi; Kristiansson, Kati; Wagner, Peter J.; Palotie, Aarno; Perola, Markus; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, FI-00290 Helsinki, Finland. [Dastani, Zari; Li, Rui; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Human Genet, Montreal, PQ H3T 1E2, Canada. [Drong, Alexander W.; Ferreira, Teresa; Hedman, Asa K.; Lagou, Vasiliki; Magi, Reedik; Mahajan, Anubha; McCarthy, Mark I.; Morris, Andrew P.; Prokopenko, Inga; Lindgren, Cecilia] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Esko, Tonu; Magi, Reedik; Perola, Markus] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Esko, Tonu; Palmer, Cameron D.; Hunter, David J.; Hirschhorn, Joel N.; Lindgren, Cecilia] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA. [Esko, Tonu; Pers, Tune H.; Palmer, Cameron D.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Esko, Tonu; Pers, Tune H.; Palmer, Cameron D.; Hirschhorn, Joel N.] Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Esko, Tonu; Pers, Tune H.; Palmer, Cameron D.; Hirschhorn, Joel N.] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA. [Esko, Tonu; Pers, Tune H.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Evans, David M.] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia. [Evans, David M.; Paternoster, Lavinia; Sorensen, Thorkild I. A.; Fatemifar, Ghazaleh] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Falchi, Mario; Sanna, Marianna; Prokopenko, Inga] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Feitosa, Mary F.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Haring, Robin; Friedrich, Nele; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Haring, Robin] European Univ Appl Sci, Fac Appl Publ Hlth, D-18055 Rostock, Germany. [Iles, Mark M.; Bishop, D. Timothy; Bishop, Julia A. N.] Univ Leeds, Canc Res UK Leeds Ctr, Leeds Inst Canc & Pathol, Leeds LS9 7TF, W Yorkshire, England. [Justice, Anne E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England. [Kanoni, Stavroula; Ripatti, Samuli; Palotie, Aarno; Deloukas, Panos] Wellcome Trust Sanger Inst, Human Genet, Cambridge CB10 1SA, England. [Lagou, Vasiliki; Karpe, Fredrik; McCarthy, Mark I.; Prokopenko, Inga] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Li, Xin; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Locke, Adam; Jackson, Anne U.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Lu, Chen; White, Charles C.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Pers, Tune H.; Ahluwalia, Tarunveer Singh; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Sorensen, Thorkild I. A.; Kilpelainen, Tuomas Oskari] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, DK-2100 Copenhagen, Denmark. [Pers, Tune H.] Broad Inst MIT & Harvard, Med & Populat Genet Program, Cambridge, MA 02142 USA. [Pers, Tune H.] Statens Serum Inst, Dept Epidemiol Res, DK-2100 Copenhagen, Denmark. [Qi, Qibin; Kaplan, Robert C.] Albert Einstein Coll Med, Dept Epidemiol & Popualt Hlth, Bronx, NY 10461 USA. [Schmidt, Ellen M.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Scott, William R.; Zhang, Weihua; Afzal, Uzma; Loh, Marie; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Scott, William R.; Zhang, Weihua; Afzal, Uzma; Oozageer, Laticia; Chambers, John C.; Kooner, Jaspal S.] Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England. [Shungin, Dmitry] Lund Univ, Ctr Diabet, Dept Clin Sci, Genet & Mol Epidemiol Unit,Skane Univ Hosptial, S-20502 Malmo, Sweden. [Shungin, Dmitry] Umea Univ, Dept Publ Hlth & Clin Med, Med Unit, S-90187 Umea, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, S-90185 Umea, Sweden. [Teumer, Alexander; Ittermann, Till; Volzke, Henry] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17475 Greifswald, Germany. [Vinkhuyzen, Anna A. E.; Zhu, Zhihong; Yang, Jian] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. [Westra, Harm-Jan; De Jager, Philip L.; Walker, Mark] Broad Inst Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02446 USA. [Westra, Harm-Jan] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02446 USA. [Westra, Harm-Jan] Harvard Univ, Sch Med, Boston, MA 02446 USA. [Westra, Harm-Jan] Partners Ctr Personalized Genet Med, Boston, MA 02446 USA. [Zhang, Mingfeng] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Ahluwalia, Tarunveer Singh] Univ Copenhagen, Fac Hlth & Med Sceinces, Copenhagen Prospect Studies Asthma Childhood, DK-2200 Copenhagen, Denmark. [Ahluwalia, Tarunveer Singh] Gentofte Univ Hosp, Danish Pediat Asthma Ctr, DK-2200 Copenhagen, Denmark. [Ahluwalia, Tarunveer Singh] Steno Diabet Ctr AS, DK-2820 Gentofte, Denmark. [Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-9700 RB Groningen, Netherlands. [Bellis, Claire; Kent, Jack W.] Texas Biomed Res Inst, Dept Genet, San Antonio, TX 78245 USA. [Bonnefond, Amelie; Eury, Elodie; Lobbens, Stephane; Froguel, Philippe; Yengo, Loic] CNRS UMR 8199, F-59019 Lille, France. [Bonnefond, Amelie; Eury, Elodie; Lobbens, Stephane; Froguel, Philippe; Yengo, Loic] European Genom Inst Diabet, F-59000 Lille, France. [Bonnefond, Amelie; Eury, Elodie; Lobbens, Stephane; Froguel, Philippe; Yengo, Loic] Univ Lille 2, F-59000 Lille, France. [Borodulin, Katja; Havulinna, Aki S.; Laatikainen, Tiina; Eklund, Niina; Kristiansson, Kati; Mannisto, Satu; Wagner, Peter J.; Jousilahti, Pekka; Eriksson, Johan G.; Heliovaara, Markku; Jula, Antti; Kajantie, Eero; Knekt, Paul B.; Koskinen, Seppo; Perola, Markus; Salomaa, Veikko; Vartiainen, Erkki] Natl Inst Hlth & Welf, FI-00271 Helsinki, Finland. [Buchman, Aron S.; Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Cederholm, Tommy] Uppsala Univ, Dept Publ Hlth & Caring Sci, Clin Nutr & Metab, S-75185 Uppsala, Sweden. [Choh, Audrey C.; Czerwinski, Stefan A.; Towne, Bradford] Wright State Univ, Boonshoft Sch Med, Lifespan Hlth Res Ctr, Dayton, OH 45420 USA. [Choi, Hyung Jin] Seoul Natl Univ, Coll Med, Dept Anat, Seoul 03080, South Korea. [Curran, Joanne E.; Blangero, John] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX 78520 USA. [de Groot, Lisette C. P. G. M.; Dhonukshe-Rutten, Rosalie A. M.] Wageningen Univ, Dept Human Nutr, NL-6700 EV Wageningen, Netherlands. [De Jager, Philip L.; Fox, Caroline] Harvard Univ, Sch Med, Boston, MA 02115 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Enneman, Anke W.; Medina-Gomez, Carolina; van der Velde, Nathalie; Rivadeneira, Fernando; Uitterlinden, Andre G.; Zillikens, M. Carola] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Evans, Daniel S.; Cummings, Steven R.; Tranah, Gregory J.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Forsen, Tom; Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, FI-00014 Helsinki, Finland. [Fumeron, Frederic] Ctr Rech Cordeliers, INSERM, UMR S 1138, F-75006 Paris, France. [Fumeron, Frederic] Univ Paris 06, Sorbonne Univ, Ctr Rech Cordeliers, UMR S 1138, F-75006 Paris, France. [Fumeron, Frederic] Univ Paris 05, Sorbonne Paris Cite, Ctr Rech Cordeliers, UMR S 1138, F-75006 Paris, France. [Fumeron, Frederic] Univ Paris Diderot, Sorbonne Paris Cite, Ctr Rech Cordeliers, UMR S 1138, F-75006 Paris, France. [Garcia, Melissa E.; Harris, Tamara B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Gartner, Simone] Univ Med Greifswald, Dept Med A, D-17475 Greifswald, Germany. [Han, Bok-Ghee; Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Osong Hlth Technol Adm Complex, Chungcheongbuk Do 370914, South Korea. [Hayward, Caroline; Wright, Alan F.; Hastie, Nicholas; Vitart, Veronique; Wilson, James F.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hernandez, Dena; Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hillege, Hans; Leach, Irene Mateo; Verweij, Niek; van der Harst, Pim; Franke, Lude] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Kolcic, Ivana; Polasek, Ozren] Univ Split, Dept Publ Hlth, Fac Med, Split 21000, Croatia. [Laatikainen, Tiina] Hosp Dist North Karelia, FI-80210 Joensuu, Finland. [Laatikainen, Tiina] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, FI-70211 Kuopio, Finland. [Lahti, Jari; Eriksson, Johan G.] Folkhalsan Res Ctr, FI-00290 Helsinki, Finland. [Lahti, Jari] Univ Helsinki, Inst Behav Sci, FI-00014 Helsinki, Finland. [Lee, Christine G.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA. [Lee, Christine G.] Vet Affairs Med Ctr, Res Serv, Portland, OR 97239 USA. [Liu, Tian] Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany. [Liu, Tian] Max Planck Inst Human Dev, D-14194 Berlin, Germany. [Liu, Youfang; Jordan, Joanne M.] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC 27599 USA. [Loh, Marie] ASTAR, TLGM, 8A Biomed Grove,Immunos,Level 5, Singapore 138648, Singapore. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, FI-33014 Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Fimlab Labs, Dept Clin Chem, FI-33520 Tampere, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, FI-33520 Tampere, Finland. [Medina-Gomez, Carolina; van Duijn, Cornelia M.; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Zillikens, M. Carola] NCHA, NGI, Rotterdam, Netherlands. [Medina-Gomez, Carolina; Franco, Oscar H.; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Michaelsson, Karl] Uppsala Univ, Dept Surg Sci, Orthoped, S-75185 Uppsala, Sweden. [Nielson, Carrie M.; Srikanth, Priya] Oregon Hlth & Sci Univ, Sch Publ Hlth, Portland, OR 97239 USA. [Nielson, Carrie M.; Srikanth, Priya; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97239 USA. [Pascoe, Laura] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Polasek, Ozren; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland. [Ripatti, Samuli; Tikkanen, Emmi] Univ Helsinki, Hjelt Inst, FI-00014 Helsinki, Finland. [Sarzynski, Mark A.; Bouchard, Claude; Rankinen, Tuomo] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Shin, Chan Soo] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 03080, South Korea. [Narancic, Nina Smolej] Inst Anthropol Res, Zagreb 10000, Croatia. [Spira, Dominik; Steinhagen-Thiessen, Elisabeth; Demuth, Ilja; Eckardt, Rahel] Charite, Res Grp Geriatr, Berlin Aging Study 2, D-13347 Berlin, Germany. [Spira, Dominik; Steinhagen-Thiessen, Elisabeth] Charite, Lipid Clin, Interdisciplinary Metab Ctr, D-13353 Berlin, Germany. [Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Swart, Karin M. A.; van Schoor, Natasja M.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands. [Swart, Karin M. A.; van Schoor, Natasja M.] Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, NL-1081 BT Amsterdam, Netherlands. [Taittonen, Leena] Univ Oulu, Dept Pediat, FI-90014 Oulu, Finland. [Taittonen, Leena] Vaasa Cent Hosp, Dept Pediat, FI-65100 Vaasa, Finland. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21225 USA. [Zmuda, Joseph M.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Forrester, Terrence; Mckenzie, Colin A.] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Mona JMAAW15, Jamaica. [Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio 70210, Finland. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Kuopio 70029, Finland. [Lichtner, Peter] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. [Ried, Janina S.; Kuhnel, Brigitte; Gieger, Christian; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Stancakova, Alena] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland. [Stancakova, Alena] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Demirkan, Ayse; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Doring, Angela] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, D-85764 Neuherberg, Germany. [Doring, Angela; Kuhnel, Brigitte; Gieger, Christian; Grallert, Harald; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, D-85764 Neuherberg, Germany. [Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Kiel, Douglas P.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kiel, Douglas P.] Inst Aging Res Hebrew Senior Life, Boston, MA 02131 USA. [Kuhnel, Brigitte; Gieger, Christian; Grallert, Harald; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Mcknight, Barbara] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Mcknight, Barbara] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98109 USA. [Mcknight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [O'Connell, Jeffrey R.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med,Div Endocrinol D, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21042 USA. [Song, Kijoung] GlaxoSmithKline, Genet Projects Clin Platforms & Sci, Philadelphia, PA 19112 USA. [Vandenput, Liesbeth; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res,Dept Internal Med & Clin N, S-41345 Gothenburg, Sweden. [van Duijn, Cornelia M.] Ctr Med Syst Biol, NL-2300 Leiden, Netherlands. [Vollenweider, Peter] Univ Hosp Lausanne CHUV, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Vollenweider, Peter] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Boettcher, Yvonne; Bluher, Matthias; Kovacs, Peter; Stumvoll, Michael] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany. [Boettcher, Yvonne; Bluher, Matthias; Stumvoll, Michael; Tonjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Cooper, Richard S.; Luke, Amy; Tayo, Bamidele O.] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA. [Grallert, Harald] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany. [Hingorani, Aroon] UCL, Inst Cardiovasc Sci, London WC1E 6BT, England. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark. [Jorgensen, Torben] Aalborg Univ, Fac Med, DK-9220 Aalborg, Denmark. [Jorgensen, Torben] Res Ctr Prevent & Hlth, DK-2600 Capital Region Denmark, Denmark. [Kivimaki, Mika; Kumari, Meena; Langenberg, Claudia] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England. [Linneberg, Allan] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [Palotie, Aarno] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Strauch, Konstantin] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Bertram, Lars] Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, London W6 8RP, England. [Bertram, Lars] Med Univ Lubeck, Inst Neurogenet, Lubeck Interdisciplinary Platform Genome Analyt, D-23562 Lubeck, Germany. [Bertram, Lars] Med Univ Lubeck, Inst Integrat & Expt Genom, Lubeck Interdisciplinary Platform Genome Analyt, D-23562 Lubeck, Germany. [Cho, Nam H.] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 443721, Kyoung Gi, South Korea. [Demuth, Ilja] Charite, Inst Med & Human Genet, D-13353 Berlin, Germany. [Hansen, Torben] Univ Southern Denmark, Fac Hlth Sci, DK-5000 Odense, Denmark. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, FI-33521 Tampere, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, FI-33014 Tampere, Finland. [Kajantie, Eero] Helsinki Univ Hosp, Childrens Hosp, FI-00029 Helsinki, Finland. [Kajantie, Eero] Univ Helsinki, FI-00029 Helsinki, Finland. [Kajantie, Eero] Oulu Univ Hosp, MRC Oulu, Dept Obstet & Gynecol, FI-90029 Oulu, Finland. [Kajantie, Eero] Univ Oulu, FI-90029 Oulu, Finland. [Lind, Lars] Uppsala Univ, Dept Med Sci, S-75185 Uppsala, Sweden. [Liu, Yongmei] Wake Forest Sch Med, Ctr Human Genet, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Osmond, Clive] Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England. [Perusse, Louis; Tremblay, Angelo] Univ Laval, Dept Kinesiol, Quebec City, PQ G1V 0A6, Canada. [Perusse, Louis; Vohl, Marie-Claude] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ G1V 0A6, Canada. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FI-20521 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FI-20520 Turku, Finland. [Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Sorensen, Thorkild I. A.] Bispebjerg & Frederiksberg Hosp, Inst Prevent Med, DK-2000 Frederiksberg, Denmark. [van der Harst, Pim] Netherlands Heart Inst, Interuniv Cardiol Inst Netherlands, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands. [Vohl, Marie-Claude] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Viikari, Jorma S.] Univ Turku, Dept Med, FI-20521 Turku, Finland. [Vohl, Marie-Claude] Univ Laval, Sch Nutr, Quebec City, PQ G1V 0A6, Canada. [Volzke, Henry; Wallaschofski, Henri] DZHK German Ctr Cardiovasc Res, D-17475 Greifswald, Germany. [Volzke, Henry] DZD German Ctr Diabet Res, D-17475 Greifswald, Germany. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Wild, Sarah] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Borecki, Ingrid B.] Regeneron Pharmaceut Inc, Regeneron Genet Ctr, Analyt Genet Grp, Tarrytown, NY 10591 USA. [Chambers, John C.; Kooner, Jaspal S.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. [Cupples, L. Adrienne; Fox, Caroline] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Dehghan, Abbas] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Furey, Terrence S.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Han, Jiali] Melvin & Bren Simon Canc Ctr, Richard M Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA. [Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Karpe, Fredrik; McCarthy, Mark I.] Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Murabito, Joanne M.] NHLBIs & Boston Univ Framingham Heart Study, Framingham, MA 01702 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3GA, Merseyside, England. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Ong, Ken K.] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1B 5JU, England. [Ong, Ken K.] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res, London SE1 1E7, England. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Div Endocrinol, Montreal, PQ H3T 1E2, Canada. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Schadt, Eric E.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Ingelsson, Erik] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA. [Pospisilik, John Andrew] Max Planck Inst Immunobiol & Epigenet, Dept Epigenet, D-76108 Freiburg, Germany. [Lindgren, Cecilia] Univ Oxford, Big Data Inst, Oxford OX3 7LJ, England. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA.; Loos, RJF (reprint author), Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge Biomed Campus, Cambridge CB2 0QQ, England.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.; Loos, RJF (reprint author), Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. EM ruth.loos@mssm.edu RI Polasek, Ozren/B-6002-2011; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Grallert, Harald/B-3424-2013; Colaus, PsyColaus/K-6607-2013; Verweij, Niek/A-4499-2017; Sarzynski, Mark/A-9798-2014; Bertram, Lars/K-3889-2015; Yang, Jian/A-5852-2010; Yengo, Loic/D-2692-2017; Grarup, Niels/K-2807-2015; mangino, massimo/F-5134-2011; Franke, Lude/P-7036-2016; Karjalainen, Juha/P-8624-2016; Peters, Annette/A-6117-2011; Deloukas, Panos/B-2922-2013; Bouchard, Claude/A-7637-2009 OI Polasek, Ozren/0000-0002-5765-1862; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Bertram, Lars/0000-0002-0108-124X; Yang, Jian/0000-0003-2001-2474; Yengo, Loic/0000-0002-4272-9305; Grarup, Niels/0000-0001-5526-1070; mangino, massimo/0000-0002-2167-7470; Franke, Lude/0000-0002-5159-8802; Deloukas, Panos/0000-0001-9251-070X; FU Aase and Ejner Danielsens Foundation; Academy of Finland; Agency for Health Care Policy Research; Ahokas Foundation; ALFEDIAM; ALK-Abello A/S (Horsholm, Denmark); Althingi (the Icelandic Parliament); ANR ('Agence Nationale de la 359 Recherche'); American Heart Association; Ardix Medical; Arthritis Research UK; Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie; AstraZeneca; Australian Research Council; Bayer Diagnostics; BBSRC; Becton Dickinson; BMBF (DEEP); Boehringer Ingelheim Foundation; Boston University School of Medicine; British Heart Foundation; British Skin Foundation; Canadian Institutes of Health Research; Cancer Research UK; Cardionics; Centers for Disease Control and Prevention/Association of Schools of Public Health; Chief Scientist Office of the Scottish Government; Cohortes Sante TGIR; CMSB; CPER ('Contrat de Projets Etat-Region'); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research; Danish Medical Research Council; Department of Health, UK; Deutsche Forschungsgemeinschaft; Deutshe Forschungsgemeinschaft [SFB992]; DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland); Diabetes UK; Dutch Dairy Association (NZO); Dutch Kidney Foundation; Dutch Inter University Cardiology Institute Netherlands (ICIN); Emil Aaltonen Foundation; ENGAGE consortium; Food Standards Agency, UK; Erasmus Medical Center; Erasmus University; Estonian Government; European Commission; European Community's Seventh Framework Programme; European Research Council; European Research Council [ERC-StG-281641]; European Union framework program 6 EUROSPAN project; European Union; European Union (EU_FP7_NoE 'Epigenesys'); Faculty of Biology and Medicine of Lausanne; Federal State of Mecklenburg-West Pomerania; Federal Ministry of Education and Research (German Obesity Biomaterial Bank); Finnish Cardiovascular Research Foundation; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish Special Governmental Subsidy for Health Sciences; Finska Lakaresallskapet; Folkhalsan Research Foundation; German Bundesministerium fuer Forschung und Technology; German Diabetes Association; German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF); German Research Council; GlaxoSmithKline; Goran Gustafsson Foundation; Health and Safety Executive, UK; Helmholtz Zentrum Munchen-German Research Center for Environmental Health; Hjartavernd (the Icelandic Heart Association); Illinois Department of Public Health; INSERM (Reseaux en Sante Publique, Interactions entre les determinants de la sante); Integrated Research and Treatment Centre (IFB); Juho Vainio Foundation; John D and Catherine T MacArthur Foundation Research Networks; John W. Barton Sr Chair in Genetics and Nutrition; Kompetenznetz Adipositas; King's College London; Knut och Alice Wallenberg Foundation; Kuopio University Hospital Medical Fund; Tampere University Hospital Medical Fund; Turku University Hospital Medical Fund; Kuopio University Hospital; La Fondation de France; Li Ka Shing Foundation; Liv och Halsa; Local Government Pensions Institution (KEVA); Ludwig-Maximilians-Universitat; Lundbeck Foundation; Lundberg Foundation; Max-Planck Institute; Medical Research Council, UK; MEKOS Laboratories Denmark; Merck Sante; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs and Social Ministry of the Federal State of Mecklenburg-West Pomerania; Ministry of Economic Affairs, Agriculture and Innovation, The Netherlands; Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport of the Republic of Croatia; MRC Centre for Causal Analyses in Translational Epidemiology (MRC CAiTE); MRC-GlaxoSmithKline; MRC Human Genetics Unit; Munich Center of Health Sciences (MC Health); Municipality of Rotterdam; National Center for Advancing Translational Sciences, CTSI; National Center for Research Resources (NCRR); National Genome Research Institute, Korean Center for Disease Control and Prevention; National Heart Lung and Blood Institute (NHLBI); National Heart, Lung and Blood Institute's Framingham Heart Study; National Institute for Health and Welfare (THL); National Institute for Health Research (NIHR); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health; National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC); National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA); Netherlands Consortium Healthy Ageing (NCHA); Netherlands Genomics Initiative (NGI); Netherlands Heart Foundation; Netherlands Organisation for Scientific Research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); Novo Nordisk; Novo Nordisk Foundation; ONIVINS; Orion-Farmos Research Foundation; Paavo Nurmi Foundation; Pierre Fabre; Research Centre for Prevention and Health, the Capital Region of Denmark; Research Institute for Diseases in the Elderly (RIDE); Research into Ageing, UK; Roche; Royal Swedish Academy of Science; Russian Foundation for Basic Research; Sanger Institute; Samfundet Folkhalsan; SFD ('Societe Francophone du 358 Diabete'); Siemens Healthcare; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland (KELA); State of Bavaria; Stroke Association, UK; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council for Infrastructures; Swiss National Science Foundation; Sylvia AMP; Charles Viertel Charitable Foundation; Tampere Tuberculosis Foundation; Timber Merchant Vilhelm Bangs Foundation; Topcon; Torsten and Ragnar Soderberg's Foundation; Translational Genomics Research Institute; Unilever UK; University Cancer Research Fund at UNC Chapel Hill; University of Eastern Finland; University of Maryland General Clinical Research Center; Uppsala University; Uppsala University Hospital; USDA National Institute of Food and Agriculture; VA Clinical Science Research and Development; Velux Foundation; VU University Medical Center; Wageningen University; Wellcome Trust FX A full list of acknowledgements can be found in the Supplementary Notes. This work was supported by the following: Aase and Ejner Danielsens Foundation; Academy of Finland; Agency for Health Care Policy Research; Ahokas Foundation; ALFEDIAM; ALK-Abello A/S (Horsholm, Denmark); Althingi (the Icelandic Parliament); ANR ('Agence Nationale de la 359 Recherche'); American Heart Association; Ardix Medical; Arthritis Research UK; Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie; AstraZeneca; Australian Research Council; Bayer Diagnostics; BBSRC; Becton Dickinson; BMBF (DEEP); Boehringer Ingelheim Foundation; Boston University School of Medicine; British Heart Foundation; British Skin Foundation; Canadian Institutes of Health Research; Cancer Research UK; Cardionics; Centers for Disease Control and Prevention/Association of Schools of Public Health; Chief Scientist Office of the Scottish Government; Cohortes Sante TGIR; CMSB; CPER ('Contrat de Projets Etat-Region'); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research; Danish Medical Research Council; Department of Health, UK; Deutsche Forschungsgemeinschaft; Deutshe Forschungsgemeinschaft (SFB992); DHFD (Diabetes Hilfs- und Forschungsfonds Deutschland); Diabetes UK; Dutch Dairy Association (NZO); Dutch Kidney Foundation; Dutch Inter University Cardiology Institute Netherlands (ICIN); Emil Aaltonen Foundation; ENGAGE consortium; Food Standards Agency, UK; Erasmus Medical Center; Erasmus University; Estonian Government; European Commission; European Community's Seventh Framework Programme; European Research Council; European Research Council (ERC-StG-281641); European Union framework program 6 EUROSPAN project; European Union; European Union (EU_FP7_NoE 'Epigenesys'); Faculty of Biology and Medicine of Lausanne; Federal State of Mecklenburg-West Pomerania; Federal Ministry of Education and Research (German Obesity Biomaterial Bank); Finnish Cardiovascular Research Foundation; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish Special Governmental Subsidy for Health Sciences; Finska Lakaresallskapet; Folkhalsan Research Foundation; German Bundesministerium fuer Forschung und Technology; German Diabetes Association; German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF); German Research Council; GlaxoSmithKline; Goran Gustafsson Foundation; Health and Safety Executive, UK; Helmholtz Zentrum Munchen-German Research Center for Environmental Health; Hjartavernd (the Icelandic Heart Association); Illinois Department of Public Health; INSERM (Reseaux en Sante Publique, Interactions entre les determinants de la sante); Integrated Research and Treatment Centre (IFB); Juho Vainio Foundation; John D and Catherine T MacArthur Foundation Research Networks; John W.; r Barton Sr Chair in Genetics and Nutrition; Kompetenznetz Adipositas; King's College London; Knut och Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds; Kuopio University Hospital; La Fondation de France; Li Ka Shing Foundation; Liv och Halsa; Local Government Pensions Institution (KEVA); Ludwig-Maximilians-Universitat; Lundbeck Foundation; Lundberg Foundation; Max-Planck Institute; Medical Research Council, UK; MEKOS Laboratories Denmark; Merck Sante; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs and Social Ministry of the Federal State of Mecklenburg-West Pomerania; Ministry of Economic Affairs, Agriculture and Innovation, The Netherlands; Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport of the Republic of Croatia; MRC Centre for Causal Analyses in Translational Epidemiology (MRC CAiTE); MRC-GlaxoSmithKline; MRC Human Genetics Unit; Munich Center of Health Sciences (MC Health); Municipality of Rotterdam; National Center for Advancing Translational Sciences, CTSI; National Center for Research Resources (NCRR); National Genome Research Institute, Korean Center for Disease Control and Prevention; National Heart Lung and Blood Institute (NHLBI); National Heart, Lung and Blood Institute's Framingham Heart Study; National Institute for Health and Welfare (THL); National Institute for Health Research (NIHR); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health; National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC); National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA); Netherlands Consortium Healthy Ageing (NCHA); Netherlands Genomics Initiative (NGI); Netherlands Heart Foundation; Netherlands Organisation for Scientific Research (NWO); Netherlands Organization for the Health Research and Development (ZonMw); Novo Nordisk; Novo Nordisk Foundation; ONIVINS; Orion-Farmos Research Foundation; Paavo Nurmi Foundation; Pierre Fabre; Research Centre for Prevention and Health, the Capital Region of Denmark; Research Institute for Diseases in the Elderly (RIDE); Research into Ageing, UK; Roche; Royal Swedish Academy of Science; Russian Foundation for Basic Research; Sanger Institute; Samfundet Folkhalsan; SFD ('Societe Francophone du 358 Diabete'); Siemens Healthcare; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland (KELA); State of Bavaria; Stroke Association, UK; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Research Council; Swedish Research Council for Infrastructures; Swiss National Science Foundation; Sylvia & Charles Viertel Charitable Foundation; Tampere Tuberculosis Foundation; Timber Merchant Vilhelm Bangs Foundation; Topcon; Torsten and Ragnar Soderberg's Foundation; Translational Genomics Research Institute; Unilever UK; University Cancer Research Fund at UNC Chapel Hill; University of Eastern Finland; University of Maryland General Clinical Research Center; Uppsala University; Uppsala University Hospital; USDA National Institute of Food and Agriculture; VA Clinical Science Research and Development; Velux Foundation; VU University Medical Center; Wageningen University; Wellcome Trust. NR 70 TC 12 Z9 12 U1 6 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10495 DI 10.1038/ncomms10495 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0EQ UT WOS:000371012200002 PM 26833246 ER PT J AU Ma, L Chen, ZH Huang, DW Kutty, G Ishihara, M Wang, HH Abouelleil, A Bishop, L Davey, E Deng, R Deng, XL Fan, L Fantoni, G Fitzgerald, M Gogineni, E Goldberg, JM Handley, G Hu, XJ Huber, C Jiao, XL Jones, K Levin, JZ Liu, YQ Macdonald, P Melnikov, A Raley, C Sassi, M Sherman, BT Song, XH Sykes, S Tran, B Walsh, L Xia, Y Yang, J Young, S Zeng, QD Zheng, X Stephens, R Nusbaum, C Birren, BW Azadi, P Lempicki, RA Cuomo, CA Kovacs, JA AF Ma, Liang Chen, Zehua Huang, Da Wei Kutty, Geetha Ishihara, Mayumi Wang, Honghui Abouelleil, Amr Bishop, Lisa Davey, Emma Deng, Rebecca Deng, Xilong Fan, Lin Fantoni, Giovanna Fitzgerald, Michael Gogineni, Emile Goldberg, Jonathan M. Handley, Grace Hu, Xiaojun Huber, Charles Jiao, Xiaoli Jones, Kristine Levin, Joshua Z. Liu, Yueqin Macdonald, Pendexter Melnikov, Alexandre Raley, Castle Sassi, Monica Sherman, Brad T. Song, Xiaohong Sykes, Sean Tran, Bao Walsh, Laura Xia, Yun Yang, Jun Young, Sarah Zeng, Qiandong Zheng, Xin Stephens, Robert Nusbaum, Chad Birren, Bruce W. Azadi, Parastoo Lempicki, Richard A. Cuomo, Christina A. Kovacs, Joseph A. TI Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts SO NATURE COMMUNICATIONS LA English DT Article ID MAJOR SURFACE GLYCOPROTEIN; TIME PCR ASSAY; F-SP. CARINII; CELL-WALL; CANDIDA-ALBICANS; BETA-GLUCAN; PNEUMONIA; EXPRESSION; INFECTION; GENES AB Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses. C1 [Ma, Liang; Kutty, Geetha; Wang, Honghui; Bishop, Lisa; Davey, Emma; Deng, Rebecca; Deng, Xilong; Fantoni, Giovanna; Gogineni, Emile; Handley, Grace; Huber, Charles; Liu, Yueqin; Sassi, Monica; Song, Xiaohong; Walsh, Laura; Xia, Yun; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145,10 Ctr Dr, Bethesda, MD 20892 USA. [Chen, Zehua; Abouelleil, Amr; Fan, Lin; Fitzgerald, Michael; Goldberg, Jonathan M.; Levin, Joshua Z.; Macdonald, Pendexter; Melnikov, Alexandre; Sykes, Sean; Young, Sarah; Zeng, Qiandong; Nusbaum, Chad; Birren, Bruce W.; Cuomo, Christina A.] Broad Inst Harvard & Massachusetts Inst Technol, Genome Sequencing & Anal Program, Cambridge, MA 02142 USA. [Huang, Da Wei; Hu, Xiaojun; Jiao, Xiaoli; Jones, Kristine; Raley, Castle; Sherman, Brad T.; Tran, Bao; Yang, Jun; Zheng, Xin; Stephens, Robert; Lempicki, Richard A.] Leidos BioMed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. [Ishihara, Mayumi; Azadi, Parastoo] Univ Georgia, Complex Carbohydrate Res Ctr, 220 Riverbend Rd, Athens, GA 30602 USA. [Huang, Da Wei] NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. [Goldberg, Jonathan M.] Harvard Univ, Dept Infect & Immunol Dis, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. RP Ma, L; Kovacs, JA (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145,10 Ctr Dr, Bethesda, MD 20892 USA.; Cuomo, CA (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Genome Sequencing & Anal Program, Cambridge, MA 02142 USA. EM liang.ma@nih.gov; cuomo@broadinstitute.org; jkovacs@nih.gov OI Cuomo, Christina/0000-0002-5778-960X FU Intramural Research Program of the US National Institutes of Health Clinical Center; National Institute of Allergy and Infectious Diseases; National Cancer Institute, the National Institutes of Health [HHSN261200800001E]; National Human Genome Research Institute [U54HG003067]; National Institutes of Health (NIH/NCRR) [1 P41 RR018502-01]; Chongqing Medical University (Chongqing, China); Public Health Bureau of Guangzhou City [2009-YB-089009]; Department of Public Health, Guangdong Province, China [2012513]; China Scholarship Council FX This project has been funded in whole or in part with federal funds from the Intramural Research Program of the US National Institutes of Health Clinical Center; the National Institute of Allergy and Infectious Diseases; the National Cancer Institute, the National Institutes of Health, under Contract No. HHSN261200800001E; the National Human Genome Research Institute (grant U54HG003067 to the Broad Institute); and the National Institutes of Health (NIH/NCRR)-funded grant entitled `Integrated Technology Resource for Biomedical Glycomics' (grant 1 P41 RR018502-01) to the Complex Carbohydrate Research Center. Y.X. was supported by a scholarship from the Chongqing Medical University (Chongqing, China). X.D was supported by the Public Health Bureau of Guangzhou City (grant 2009-YB-089009) and the Department of Public Health, Guangdong Province (grant 2012513), China. X.S. was supported by the China Scholarship Council. We thank Rene Costello and Howard Mostowski for their support of the animal studies; Michail Lionakis for providing Candida-infected mouse tissue; Chad Steele for providing the dectin-Fc construct; Peter Walzer and Michael Linke for providing antibody RA-E7; the Broad Institute Genomics Platform for Illumina sequencing of DNA and RNA samples; Carsten Russ and Sinead Chapman for coordination of Illumina sequencing at the Broad Institute; Jennifer Troyer for coordination of Pacific Bioscience sequencing at Leidos Inc.; Zuoming Deng and Biswajit Das for help with genome assembly; Alexander Li and Lily Lin for assistance with rDNA PCR; Jing Zhang for assistance with DNA hybridization; Margaret Priest for assistance with annotation; Lucia Alvarado-Balderrama for assistance with genome data submission and release; Rhys Farrer for assistance with displaying synteny; and Henry Masur, June Kwon-Chung, Peter Williamson, John Bennett and Christopher Desjardins for reviewing the manuscript. NR 75 TC 10 Z9 10 U1 8 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10740 DI 10.1038/ncomms10740 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0NZ UT WOS:000371037200002 PM 26899007 ER PT J AU Weyemi, U Redon, CE Choudhuri, R Aziz, T Maeda, D Boufraqech, M Parekh, PR Sethi, TK Kasoji, M Abrams, N Merchant, A Rajapakse, VN Bonner, WM AF Weyemi, Urbain Redon, Christophe E. Choudhuri, Rohini Aziz, Towqir Maeda, Daisuke Boufraqech, Myriem Parekh, Palak R. Sethi, Taresh K. Kasoji, Manjula Abrams, Natalie Merchant, Anand Rajapakse, Vinodh N. Bonner, William M. TI The histone variant H2A.X is a regulator of the epithelial-mesenchymal transition SO NATURE COMMUNICATIONS LA English DT Article ID E-CADHERIN; COLORECTAL-CANCER; BREAST-CANCER; CARCINOMA METASTASIS; TUMOR-CELLS; DNA-DAMAGE; STEM-CELLS; EXPRESSION; PLASTICITY; GENE AB The epithelial-mesenchymal transition (EMT), considered essential for metastatic cancer, has been a focus of much research, but important questions remain. Here, we show that silencing or removing H2A.X, a histone H2A variant involved in cellular DNA repair and robust growth, induces mesenchymal-like characteristics including activation of EMT transcription factors, Slug and ZEB1, in HCT116 human colon cancer cells. Ectopic H2A.X re-expression partially reverses these changes, as does silencing Slug and ZEB1. In an experimental metastasis model, the HCT116 parental and H2A.X-null cells exhibit a similar metastatic behaviour, but the cells with re-expressed H2A.X are substantially more metastatic. We surmise that H2A.X re-expression leads to partial EMT reversal and increases robustness in the HCT116 cells, permitting them to both form tumours and to metastasize. In a human adenocarcinoma panel, H2A.X levels correlate inversely with Slug and ZEB1 levels. Together, these results point to H2A.X as a regulator of EMT. C1 [Weyemi, Urbain; Redon, Christophe E.; Choudhuri, Rohini; Aziz, Towqir; Maeda, Daisuke; Parekh, Palak R.; Sethi, Taresh K.; Rajapakse, Vinodh N.; Bonner, William M.] NCI, Dev Therapeut Branch, Mol Pharmacol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. [Boufraqech, Myriem] NCI, Dev Therapeut Branch, Mol Pharmacol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kasoji, Manjula; Abrams, Natalie; Merchant, Anand] NCI, Ctr Canc Res Collaborat Bioinformat Resource, 37 Convent Dr, Bethesda, MD 20892 USA. RP Weyemi, U; Bonner, WM (reprint author), NCI, Dev Therapeut Branch, Mol Pharmacol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM weyemiurbain@yahoo.fr; bonnerw@mail.nih.gov RI Weyemi, Urbain/E-2083-2016; Boufraqech, Myriem/E-4823-2016; Abrams, Natalie/F-4845-2011 OI Abrams, Natalie/0000-0001-9698-2819 FU National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program; Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health FX We thank Drs Simone Difilippantonio, Diana Haines and Joseph D. Kalen, Mr. Nimit Patel, Mrs. Christina Robinson and the other members of the Laboratory of Animal Sciences Program (National Cancer Institute, Frederick) for help with animal maintenance, tail vein injections experiments and histological analysis. We are grateful to Drs Farhoud Faraji, Andrea Baechler, Anjali A. Shukla and Sudhir Varma for their helpful discussions. We also thank Mrs Jennifer E. Dwyer and Mrs Shelley Hoover of the Laboratory of Cancer Biology and Genetics (National Cancer Institute) for help with scanning of immunohistochemistry slides. We are indebted to members of the LMT/Affymetrix Group, NCI-Frederick, MD, USA, for their help with microarray runs (Affymetrix GeneChip Human Gene 2.0 ST array). We are particularly grateful to Drs Karen M. Wolcott, Subhadra Banerjee and Ludmila Krymskaya, for help with flow cytometry (cells sorting). Finally, we thank Mr Owen K. Smith for the critical reading of the manuscript; Mrs Houria Balmakhtar for help with experiments; and Mr. Parthav Jailwala for help with microarray data analysis. This work was supported by the National Institute of Allergy and Infectious Diseases, Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. NR 67 TC 6 Z9 6 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD FEB PY 2016 VL 7 AR 10711 DI 10.1038/ncomms10711 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DF0NG UT WOS:000371035200012 PM 26876487 ER PT J AU Turnell, A Rasmussen, V Butow, P Juraskova, I Kirsten, L Wiener, L Patenaude, A Hoekstra-Weebers, J Grassi, L AF Turnell, Adrienne Rasmussen, Victoria Butow, Phyllis Juraskova, Ilona Kirsten, Laura Wiener, Lori Patenaude, Andrea Hoekstra-Weebers, Josette Grassi, Luigi CA IPOS Res Comm TI An exploration of the prevalence and predictors of work-related well-being among psychosocial oncology professionals: An application of the job demands-resources model SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE Cancer; Oncology; Psychosocial oncology; Burnout; Work engagement; Job demands-resources ID FAMILY CONFLICT; BURNOUT; HEALTH; ENGAGEMENT; SUPERVISION; INDICATORS; VALIDATION AB Objective: Burnout is reportedly high among oncology healthcare workers. Psychosocial oncologists may be particularly vulnerable to burnout. However, their work engagement may also be high, counteracting stress in the workplace. This study aimed to document the prevalence of both burnout and work engagement, and the predictors of both, utilizing the job demands-resources (JD-R) model, within a sample of psychosocial oncologists. Method: Psychosocial-oncologist (N = 417) clinicians, recruited through 10 international and national psychosocial-oncology societies, completed an online questionnaire. Measures included demographic and work characteristics, burnout (the MBI-HSS Emotional Exhaustion (EE) and Depersonalization (DP) subscales), the Utrecht Work Engagement Scale, and measures of job demands and resources. Results: High EE and DP was reported by 20.2 and 6.6% of participants, respectively, while 95.3% reported average to high work engagement. Lower levels of job resources and higher levels of job demands predicted greater burnout, as predicted by the JD-R model, but the predicted interaction between these characteristics and burnout was not significant. Higher levels of job resources predicted higher levels of work engagement. Significance of results: Burnout was surprisingly low and work engagement high in this sample. Nonetheless, one in five psychosocial oncologists have high EE. Our results suggest that both the positive (resources) and negative (demands) aspects of this work environment have an on impact burnout and engagement, offering opportunities for intervention. Theories such as the JD-R model can be useful in guiding research in this area. C1 [Turnell, Adrienne; Rasmussen, Victoria; Butow, Phyllis; Juraskova, Ilona] Univ Sydney, Sch Psychol, Level 6 North,Lifehouse C39Z, Sydney, NSW 2006, Australia. [Butow, Phyllis; Juraskova, Ilona; Kirsten, Laura] Univ Sydney, Sch Psychol, Ctr Med Psychol & Evidence Based Decis Making, Sydney, NSW 2006, Australia. [Butow, Phyllis; Juraskova, Ilona] Univ Sydney, Psychooncol Cooperat Res Grp, Sydney, NSW 2006, Australia. [Kirsten, Laura] Sydney West Canc Network, Nepean Canc Care Ctr, Sydney, NSW, Australia. [Wiener, Lori] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patenaude, Andrea] Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. [Hoekstra-Weebers, Josette] Univ Groningen, Univ Med Ctr Groningen, Wenckebach Inst, Groningen, Netherlands. [Grassi, Luigi] Int Psychooncol Soc, Charlottesville, VA USA. RP Butow, P (reprint author), Univ Sydney, Sch Psychol, Level 6 North,Lifehouse C39Z, Sydney, NSW 2006, Australia. EM phyllis.butow@sydney.edu.au FU International Psycho-Oncology Society; International Society of Paediatric Oncology; American Psychosocial Oncology Society; British Psychosocial Oncology Society; Canadian Association of Psychosocial Oncology; Dutch Society for Psychosocial Oncology; Oncology Social Work Australia; Australian Psychosocial Oncology Society; Australian Psycho-OncologyCo-Operative Research Group; British Faculty for Oncology and Palliative Care FX We would like to thank the International Psycho-Oncology Society, International Society of Paediatric Oncology, American Psychosocial Oncology Society, British Psychosocial Oncology Society, Canadian Association of Psychosocial Oncology, Dutch Society for Psychosocial Oncology, Oncology Social Work Australia, Australian Psychosocial Oncology Society, Australian Psycho-OncologyCo-Operative Research Group, and the British Faculty for Oncology and Palliative Care for their support of this study. NR 44 TC 0 Z9 0 U1 1 U2 10 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 EI 1478-9523 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD FEB PY 2016 VL 14 IS 1 BP 33 EP 41 DI 10.1017/S1478951515000693 PG 9 WC Health Policy & Services SC Health Care Sciences & Services GA DE8BI UT WOS:000370860400006 PM 26653250 ER PT J AU Hagberg, KW Sahasrabuddhe, VV McGlynn, KA Jick, SS AF Hagberg, Katrina Wilcox Sahasrabuddhe, Vikrant V. McGlynn, Katherine A. Jick, Susan S. TI Does Angiotensin-Converting Enzyme Inhibitor and -Blocker Use Reduce the Risk of Primary Liver Cancer? A Case-Control Study Using the UK Clinical Practice Research Datalink SO PHARMACOTHERAPY LA English DT Article DE angiotensin-converting enzyme inhibitors; ACE inhibitors; beta-blockers; antihypertensives; liver cancer ID PRACTICE RESEARCH DATABASE; HEPATOCELLULAR-CARCINOMA INCIDENCE; DIABETES-MELLITUS; MEDICAL THERAPY; MORTALITY; PREVENTION; CIRRHOSIS; LIGATION; GROWTH; COHORT AB Study ObjectiveIt has been suggested that use of the antihypertensive drugs angiotensin-converting enzyme (ACE) inhibitors and -blockers may decrease the risk of primary liver cancer; thus, the objective of this study was to evaluate whether use of ACE inhibitors and/or -blockers is associated with a lower risk of liver cancer. DesignNested case-control study. Data SourceUnited Kingdom Clinical Practice Research Datalink. PatientsWe identified 490 cases with hypertension and a first-time (incident) diagnosis of primary liver cancer between 1988 and 2011. To account for an induction period, the index date was defined as the date of the first recorded liver cancer diagnosis minus 1year. Controls were selected from patients with hypertension in the CPRD during the study period with a recorded diagnosis of hypertension who had no diagnosis of liver cancer and were free of any other cancer (except nonmelanoma skin cancer) before the index date; they were matched up to a 4:1 ratio to cases based on index date (same index date as that of their matched case), age (same year of birth), sex, general practice, and number of years of recorded history in the CPRD before the index date (1909 controls). Both cases and controls were required to have at least 2years of recorded activity in the database before the index date. Measurements and Main ResultsExposure was defined as receipt of two or more prescriptions for ACE inhibitors and/or -blockers before the index date; the reference group was nonuse (0-1 prescription) of ACE or -blocker prescriptions before the index date. We also examined the effect of duration of use and, separately, the effect of individual drugs within each medication class on risk of liver cancer, and conducted analyses restricted to patients without liver disease or diabetes mellitus. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). No association was found between use of ACE inhibitors and/or -blockers and the risk of liver cancer compared with nonuse (adjusted OR 1.14, 95% CI 0.85-1.55). No significant differences were noted in risk by duration of use or by individual drugs, or after restricting the analyses to patients without diabetes or liver disease. ConclusionUse of ACE inhibitors and/or -blockers was not associated with reduced risk of primary liver cancer compared with nonuse of these drugs in persons with hypertension. C1 [Hagberg, Katrina Wilcox; Jick, Susan S.] Boston Collaborat Drug Surveillance Program, Lexington, MA 02421 USA. [Hagberg, Katrina Wilcox; Jick, Susan S.] Boston Univ, Sch Publ Hlth, Lexington, MA 02421 USA. [Sahasrabuddhe, Vikrant V.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hagberg, KW (reprint author), Boston Collaborat Drug Surveillance Program, Lexington, MA 02421 USA.; Hagberg, KW (reprint author), Boston Univ, Sch Publ Hlth, Lexington, MA 02421 USA. EM khagberg@bu.edu RI CPRD, CPRD/B-9594-2017 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD FX This project was funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 25 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD FEB PY 2016 VL 36 IS 2 BP 187 EP 195 DI 10.1002/phar.1704 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DF2BW UT WOS:000371145500008 PM 26846893 ER PT J AU Taha, AY Chang, LS Chen, M AF Taha, Ameer Y. Chang, Lisa Chen, Mei TI Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Review DE Graded reduction; Polyunsaturated fatty acids (PUFAs); Docosahexaenoic acid (DHA); Alpha-linolenic acid; Threshold; Brain DHA metabolism ID POLYUNSATURATED FATTY-ACIDS; ARACHIDONIC-ACID; NUTRITIONAL DEPRIVATION; ADULT-RATS; UNANESTHETIZED RAT; BIPOLAR DISORDER; DEFICIENT DIET; HALF-LIVES; PHOSPHOLIPIDS; TURNOVER AB Background: This study tested the dietary level of alpha-linolenic acid (alpha-LNA, 18:3n-3) required to maintain brain C-14-Docosahexaenoic acid (DHA, 22:6n-3) metabolism and concentration following graded alpha-LNA reduction. Methods: Fischer-344 (CDF) male rat pups (18-21 days old) were randomized to the AlN-93G diet containing as a % of total fatty acids, 4.6% ("n-3 adequate"), 3.6%, 2.7%, 0.9% or 0.2% ("n-3 deficient") alpha-LNA for 15 weeks. Rats were intravenously infused with C-14-DHA to steady state for 5 min, serial blood samples collected to obtain plasma, and brains excised following microwave fixation. Labeled and unlabeled DHA concentrations were measured in plasma and brain to calculate the incorporation coefficient, k*, and incorporation rate, J(in). Results: Compared to 4.6% alpha-LNA controls, k* was significantly increased in ethanolamine glycerophospholipids in the 0.2% alpha-LNA group. Circulating unesterified DHA and brain incorporation rates (J(in)) were significantly reduced at 0.2% alpha-LNA. Brain total lipid and phospholipid DHA concentrations were reduced at or below 0.9% alpha-LNA. Conclusion: Threshold changes for brain DHA metabolism and concentration were maintained at or below 0.9% dietary alpha-LNA, suggesting the presence of homeostatic mechanisms to maintain brain DHA metabolism when dietary alpha-LNA intake is low. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Taha, Ameer Y.] Univ Calif Davis, Coll Agr & Environm Sci, Dept Food Sci & Technol, RMI North, Davis, CA 95616 USA. [Chang, Lisa; Chen, Mei] NIA, Brain Physiol & Metab Sect, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Taha, AY (reprint author), Univ Calif Davis, Coll Agr & Environm Sci, Dept Food Sci & Technol, RMI North, Davis, CA 95616 USA. EM ataha@ucdavis.edu FU National Institute on Aging Intramural Research Program; UC Davis College of Agriculture and Environmental Sciences Start-up Funds FX This study was funded by the National Institute on Aging Intramural Research Program, and the UC Davis College of Agriculture and Environmental Sciences Start-up Funds to A.Y.T. NR 55 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 EI 1532-2823 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD FEB PY 2016 VL 105 BP 26 EP 34 DI 10.1016/j.plefa.2015.12.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA DE8RB UT WOS:000370903200004 PM 26869088 ER PT J AU Khincha, PP Savage, SA AF Khincha, Payal P. Savage, Sharon A. TI Neonatal manifestations of inherited bone marrow failure syndromes SO SEMINARS IN FETAL & NEONATAL MEDICINE LA English DT Review DE Neonate; Cytopenia; Cancer; Bone marrow failure; Fanconi anemia; Dyskeratosis congenita ID DIAMOND-BLACKFAN ANEMIA; SEVERE CONGENITAL NEUTROPENIA; ACUTE MYELOGENOUS LEUKEMIA; ABSENT RADIUS SYNDROME; G-CSF THERAPY; DYSKERATOSIS-CONGENITA; FANCONI-ANEMIA; AMEGAKARYOCYTIC THROMBOCYTOPENIA; CLINICAL PRESENTATION; MOLECULAR PATHOGENESIS AB The inherited bone marrow failure syndromes (IBMFS) are a rare yet clinically important cause of neonatal hematological and non-hematological manifestations. Many of these syndromes, such as Fanconi anemia, dyskeratosis congenita and Diamond-Blackfan anemia, confer risks of multiple medical complications later in life, including an increased risk of cancer. Some IBMFS may present with cytopenias in the neonatal period whereas others may present only with congenital physical abnormalities and progress to pancytopenia later in life. A thorough family history and detailed physical examination are integral to the work-up of any neonate in whom there is a high index of suspicion for an IBMFS. Correct detection and diagnosis of these disorders is important for appropriate long-term medical surveillance and counseling not only for the patient but also for appropriate genetic counselling of their families regarding recurrence risks in future children and generations. Published by Elsevier Ltd. C1 [Khincha, Payal P.; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E 454, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr,Room 6E 454, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural NIH HHS [ZIA CP010144-15] NR 84 TC 0 Z9 0 U1 2 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1744-165X EI 1878-0946 J9 SEMIN FETAL NEONAT M JI Semin. Fetal Neonatal Med. PD FEB PY 2016 VL 21 IS 1 BP 57 EP 65 DI 10.1016/j.siny.2015.12.003 PG 9 WC Pediatrics SC Pediatrics GA DE8SD UT WOS:000370906100009 PM 26724991 ER PT J AU Golpanian, S Schulman, IH Ebert, RF Heldman, AW DiFede, DL Yang, PC Wu, JC Bolli, R Perin, EC Moye, L Simari, RD Wolf, A Hare, JM AF Golpanian, Samuel Schulman, Ivonne H. Ebert, Ray F. Heldman, Alan W. DiFede, Darcy L. Yang, Phillip C. Wu, Joseph C. Bolli, Roberto Perin, Emerson C. Moye, Lem Simari, Robert D. Wolf, Ariel Hare, Joshua M. CA Cardiovasc Cell Therapy TI Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease SO STEM CELLS TRANSLATIONAL MEDICINE LA English DT Review DE Stem cell; Cardiovascular disease; Cell dosage; Route of administration ID ACUTE MYOCARDIAL-INFARCTION; CHRONIC ISCHEMIC CARDIOMYOPATHY; MARROW MONONUCLEAR-CELLS; NONISCHEMIC DILATED CARDIOMYOPATHY; CARDIOSPHERE-DERIVED CELLS; POSEIDON RANDOMIZED-TRIAL; RESTORE CARDIAC-FUNCTION; TRANSENDOCARDIAL INJECTION; VENTRICULAR-FUNCTION; PROGENITOR CELLS AB An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions. C1 [Golpanian, Samuel; Schulman, Ivonne H.; Heldman, Alan W.; DiFede, Darcy L.; Wolf, Ariel; Hare, Joshua M.] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 USA. [Golpanian, Samuel] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Schulman, Ivonne H.; Heldman, Alan W.; Hare, Joshua M.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Ebert, Ray F.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yang, Phillip C.; Wu, Joseph C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Bolli, Roberto] Univ Louisville, Sch Med, Louisville, KY 40292 USA. [Perin, Emerson C.] Baylor Coll Med, Med Ctr, Texas Heart Inst, CHI St Lukes Hlth, Houston, TX 77030 USA. [Moye, Lem] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, 1200 Herman Pressler,E-1009, Houston, TX 77030 USA. [Simari, Robert D.] Univ Kansas, Sch Med, Kansas City, KS USA. RP Moye, L (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, 1200 Herman Pressler,E-1009, Houston, TX 77030 USA. EM lemmoye@msn.com FU NIH [UM1 HL113460, R01 HL084275, R01 HL110737, 5 UM1 HL087318] FX This work was supported by the NIH (Grants UM1 HL113460, R01 HL084275, and R01 HL110737 and cooperative agreement Grant 5 UM1 HL087318). The views expressed in the present report are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute, the NIH, or the U.S. federal government. NR 42 TC 9 Z9 9 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 2157-6564 EI 2157-6580 J9 STEM CELL TRANSL MED JI Stem Cells Transl. Med. PD FEB PY 2016 VL 5 IS 2 BP 186 EP 191 DI 10.5966/sctm.2015-0101 PG 6 WC Cell & Tissue Engineering SC Cell Biology GA DE8VI UT WOS:000370914400007 PM 26683870 ER PT J AU Zhang, XX Guo, ZJ Li, J Ito, Y Sun, WJ AF Zhang, Xinxin Guo, Zengjun Li, Jing Ito, Yoichiro Sun, Wenji TI A new quantitation method of protodioscin by HPLC-ESI-MS/MS in rat plasma and its application to the pharmacokinetic study SO STEROIDS LA English DT Article DE Protodioscin; Ginsenoside Rb-1; HPLC-MS/MS; Pharmacokinetics; Rat plasma ID MASS-SPECTROMETRY; ARREST; CELLS; MS AB A specific high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS method) was established for determining the concentration of protodioscin (PG) in rat plasma after intragastric administration of its standard form. Ginsenoside Rb-1 was selected as the internal standard (IS). The plasma sample was prepared using one-step deproteinization procedure by adding three parts of acetonitrile to precipitate proteins. The chromatographic separation was accomplished on an Inersil ODS-3 C-18 column (250 x 4.6 mm, 5 mu m) with a mobile phase composed with acetonitrile and water containing 0.1% formic acid under a gradient elution mode at a flow rate of 1 mL min(-1). A 3:1 portion of the eluent after a microsplit was detected on a triple quadrupole tandem mass spectrometer coupled with electrospray ionization (ESI) in positive ion and multiple reaction monitoring (MRM) scanning modes. The mass transitions were selected as 888.1 -> 1050.2 for PG and 948.2 -> 1110.3 for IS, respectively. After careful validation, the plasma samples were always stable under different storage conditions. These analytical results rendered sensitive, selective, and reliable values by this established method which displayed high accuracy, adequate extracted recoveries, and almost negligible matrix effects. This method was applied to the pharmacokinetic studies on PG level in the rat plasma and its pharmacokinetic effect. The results of our studies suggest that the present method may be a useful tool for further clinical study of PG. (C) 2015 Published by Elsevier C1 [Zhang, Xinxin; Guo, Zengjun] Xi An Jiao Tong Univ, Coll Pharm, Xian 710061, Peoples R China. [Li, Jing; Sun, Wenji] Northwest Univ, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China. [Ito, Yoichiro] NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Sun, WJ (reprint author), Northwest Univ, Biomed Key Lab Shaanxi Prov, Xian 710069, Peoples R China.; Ito, Y (reprint author), NHLBI, Lab Bioseparat Technol, Biochem & Biophys Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov; swj@nwu.edu.cn FU Intramural NIH HHS [Z99 HL999999] NR 17 TC 2 Z9 2 U1 8 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD FEB PY 2016 VL 106 BP 62 EP 69 DI 10.1016/j.steroids.2015.12.009 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DF2RH UT WOS:000371191000008 PM 26703445 ER PT J AU Hoang, CD AF Hoang, Chuong D. TI Surgical controversies in mesothelioma: MesoVATS addresses the role of surgical debulking SO TRANSLATIONAL LUNG CANCER RESEARCH LA English DT Editorial Material DE Mesothelioma; pleurectomy; VATS ID MALIGNANT-PLEURAL-MESOTHELIOMA; PHASE-III; PLEURECTOMY; CISPLATIN AB Contemporary multi-modality treatment of malignant mesothelioma remains challenging. The merits of surgical resection and the particular extent of resection continue to be debated topics. To date few randomized surgical trials have been completed to address many lingering issues concerning surgery in mesothelioma. Recently, the MesoVATS trial shows us that a minimally invasive thoracoscopic procedure for curative resection in mesothelioma is of limited benefit. Results of ongoing clinical trials are awaited. C1 [Hoang, Chuong D.] NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr Room,4-3940,Mail Code 1201, Bethesda, MD 20892 USA. RP Hoang, CD (reprint author), NCI, Thorac & GI Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr Room,4-3940,Mail Code 1201, Bethesda, MD 20892 USA. EM chuong.hoang@nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2218-6751 EI 2226-4477 J9 TRANSL LUNG CANCER R JI Transl. Lung Cancer Res. PD FEB PY 2016 VL 5 IS 1 BP 82 EP 84 DI 10.3978/j.issn.2218-6751.2015.06.04 PG 3 WC Oncology SC Oncology GA DF1XT UT WOS:000371133700009 PM 26958496 ER PT J AU Hernandez, BA Sandoval-Jaime, C Sosnovtsev, SV Green, KY Gutierrez-Escolano, AL AF Alvarado Hernandez, Beatriz Sandoval-Jaime, Carlos Sosnovtsev, Stanislav V. Green, Kim Y. Lorena Gutierrez-Escolano, Ana TI Nucleolin promotes in vitro translation of feline calicivirus genomic RNA SO VIROLOGY LA English DT Article DE FCV; Translation; Nucleolin; AGRO100; Aptamer; RNA virus; UTRs ID SURFACE-EXPRESSED NUCLEOLIN; 3' UNTRANSLATED REGION; RIBOSOMAL-PROTEIN L26; CELL-CYCLE ARREST; C VIRUS NS5B; MESSENGER-RNA; BINDING-PROTEIN; LIFE-CYCLE; ENTRY SITE; REPLICATION AB Feline calicivirus depends on host-cell proteins for its replication. We previously showed that knockdown of nucleolin (NCL), a phosphoprotein involved in ribosome biogenesis, resulted in the reduction of FCV protein synthesis and virus yield. Here, we found that NCL may not be involved in FCV binding and entry into cells, but it binds to both ends of the FCV genomic RNA, and stimulates its translation in vitro. AGRO100, an aptamer that specifically binds and inactivates NCL, caused a strong reduction in FCV protein synthesis. This effect could be reversed by the addition of full-length NCL but not by a Delta rNCL, lacking the N-terminal domain. Consistent with this, FCV infection of CrFK cells stably expressing Delta rNCL led to a reduction in virus protein translation. These results suggest that NCL is part of the FCV RNA translational complex, and that the N-terminal part of the protein is required for efficient FCV replication. (C) 2015 Elsevier Inc. All rights reserved. C1 [Alvarado Hernandez, Beatriz; Lorena Gutierrez-Escolano, Ana] IPN, Ctr Invest & Estudios Avanzados, Dept Infectom & Patogenesis Mol, Ave IPN 2508 Col San Pedro Zacatenco Mexico, Mexico City 07360, DF, Mexico. [Sandoval-Jaime, Carlos] Univ Nacl Autonoma Mexico, Inst Biotecnol, Dept Genet Desarrollo & Fisiol Mol, Cuernavaca 62191, Morelos, Mexico. [Sosnovtsev, Stanislav V.; Green, Kim Y.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Gutierrez-Escolano, AL (reprint author), IPN, Ctr Invest & Estudios Avanzados, Dept Infectom & Patogenesis Mol, Ave IPN 2508 Col San Pedro Zacatenco Mexico, Mexico City 07360, DF, Mexico. EM alonso@cinvestav.mx FU CONACyT [154767]; ICyTDF [ICYTDF/247/12]; Division of Intramural Research, NIAID, National Institutes of Health, U. S. Department of Health and Human Services FX We thank Rosa del Angel for helpful suggestions during the development of this research. We also thank Beatriz Gomez and Carlos A. Santiago for technical assistance. This work was supported by Grants 154767 from CONACyT and ICYTDF/247/12 from ICyTDF and in part, from the Division of Intramural Research, NIAID, National Institutes of Health, U. S. Department of Health and Human Services. NR 69 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB PY 2016 VL 489 BP 51 EP 62 DI 10.1016/j.virol.2015.12.001 PG 12 WC Virology SC Virology GA DE8NG UT WOS:000370892100006 PM 26707270 ER PT J AU Shrimp, JH Sorum, AW Garlick, JM Guasch, L Nicklaus, MC Meier, JL AF Shrimp, Jonathan H. Sorum, Alexander W. Garlick, Julie M. Guasch, Laura Nicklaus, Marc C. Meier, Jordan L. TI Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300 SO ACS MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Acetylation; acetyltransferase; epigenetics; probes; PAINS; pan-assay interference; reversible covalent inhibitor ID DRUG DISCOVERY; HISTONE ACETYLATION; ASSAY INTERFERENCE; IDENTIFICATION; PAINS; ELECTROPHILES; SELECTIVITY; CYSTEINES; PROTEOMES; PROBES AB C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and synthetic derivatization was used to develop a clickable analogue (C646-yne) that inhibits p300 similarly to the parent compound and enables enrichment of bound proteins. LC-MS/MS identified the major covalent targets of C646-yne as highly abundant cysteine-containing proteins, and follow-up studies found that C646 can inhibit tubulin polymerization in vitro. Finally, we provide evidence that thiol reactivity of C646 may limit its ability to antagonize acetylation in cells. These findings should enable a more precise interpretation of studies utilizing C646 as a chemical probe of KAT activity and suggest that an underappreciated liability of electrophile-containing inhibitors is a reduction in their cellular potency due to consumption by abundant protein and metabolite thiol sinks. C1 [Shrimp, Jonathan H.; Sorum, Alexander W.; Garlick, Julie M.; Guasch, Laura; Nicklaus, Marc C.; Meier, Jordan L.] NCI, Biol Chem Lab, Ft Detrick, MD 21702 USA. RP Meier, JL (reprint author), NCI, Biol Chem Lab, Ft Detrick, MD 21702 USA. EM jordan.meier@nih.gov RI Meier, Jordan/N-2608-2014; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research [ZIA BC011488-02] FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC011488-02). NR 29 TC 6 Z9 6 U1 4 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-5875 J9 ACS MED CHEM LETT JI ACS Med. Chem. Lett. PD FEB PY 2016 VL 7 IS 2 BP 151 EP 155 DI 10.1021/acsmedchemlett.5b00385 PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DD8ZP UT WOS:000370215700006 PM 26985290 ER PT J AU Yaggi, HK Mittleman, MA Bravata, DM Concato, J Ware, J Stoney, CM Redline, S AF Yaggi, Henry Klar Mittleman, Murray A. Bravata, Dawn M. Concato, John Ware, James Stoney, Catherine M. Redline, Susan TI Reducing cardiovascular risk through treatment of obstructive sleep apnea: 2 methodological approaches SO AMERICAN HEART JOURNAL LA English DT Article ID POSITIVE AIRWAY PRESSURE; SELF-DETERMINATION THEORY; HEALTH-CARE UTILIZATION; STROKE; INDIVIDUALS; ADHERENCE; DIAGNOSIS; HYPOPNEA; THERAPY; COHORT AB Obstructive sleep apnea (OSA) significantly impacts cardiovascular health, demonstrated by observational investigations showing an independently increased risk of ischemic heart disease, diabetes, hypertension, congestive heart failure, acute coronary syndrome, stroke, cardiovascular mortality, and all-cause mortality. Positive airway pressure (PAP), a medical therapy for sleep apnea, reverses airway obstruction and may help reduce cardiovascular risk. Prior to planning large phase III randomized controlled trials to test the impact of PAP on cardiovascular outcomes, several gaps in knowledge need to be addressed. This article describes 2 independent studies that worked collaboratively to fill these gaps. The populations, design features, and relative benefits/challenges of the 2 studies (SleepTight and BestAIR) are described. Both studies were encouraged to have multidisciplinary teams with expertise in behavioral interventions to improve PAP compliance. Both studies provide key information that will be useful to the research community in future large-scale, event-driven, randomized trials to evaluate the efficacy and/or effectiveness of strategies to identify and treat significant OSA for decreasing risk of major adverse cardiovascular events in high-risk patients. C1 [Yaggi, Henry Klar; Concato, John] Yale Univ, Sch Med, Dept Med, 300 Cedar St, New Haven, CT 06520 USA. [Yaggi, Henry Klar; Concato, John] VA Connecticut HCS, VA Clin Epidemiol Res Ctr, West Haven, CT USA. [Mittleman, Murray A.] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess, Boston, MA USA. [Mittleman, Murray A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Bravata, Dawn M.] Richard L Roudebush VA Med Ctr, VA Ctr Excellence Implementing Evidence Based Pra, Indianapolis, IN USA. [Bravata, Dawn M.] Indiana Sch Med, Dept Med, Indianapolis, IN USA. [Bravata, Dawn M.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Ware, James] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Stoney, Catherine M.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Div Sleep Med, Boston, MA 02215 USA. RP Yaggi, HK (reprint author), Yale Univ, Sch Med, Dept Med, 300 Cedar St, New Haven, CT 06520 USA. EM henry.yaggi@yale.edu FU National Institutes of Health/National Heart, Lung and Blood Institute [U34HL105285, U34HL105277] FX Supported by the National Institutes of Health/National Heart, Lung and Blood Institute (Grant Nos. U34HL105285 and U34HL105277). NR 26 TC 2 Z9 2 U1 2 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD FEB PY 2016 VL 172 BP 135 EP 143 DI 10.1016/j.ahj.2015.07.033 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DD1CS UT WOS:000369659400017 PM 26856225 ER PT J AU Haring, B Wu, CY Coker, LH Seth, A Snetselaar, L Manson, JE Rossouw, JE Wassertheil-Smoller, S AF Haring, Bernhard Wu, Chunyuan Coker, Laura H. Seth, Arjun Snetselaar, Linda Manson, JoAnn E. Rossouw, Jacques E. Wassertheil-Smoller, Sylvia TI Hypertension, Dietary Sodium, and Cognitive Decline: Results From the Women's Health Initiative Memory Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE antihypertensive treatment; blood pressure; cognitive decline; dietary sodium; hypertension ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; CONJUGATED EQUINE ESTROGENS; AMERICAN-HEART-ASSOCIATION; BLOOD-PRESSURE; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; POTASSIUM EXCRETION; ALZHEIMER-DISEASE; CLINICAL-TRIAL AB BACKGROUND To investigate the relationships of hypertension, antihypertensive treatment, and sodium intake on cognitive decline in older women. METHODS Prospective follow-up of 6,426 cognitively intact women aged 65-79 years enrolled in the Women's Health Initiative Memory Study (WHIMS) with a median follow-up of 9.1 years. Dietary sodium intake was determined by food frequency questionnaires. Hypertension was defined as self-report of current drug therapy for hypertension. Blood pressure (BP) control was assessed by treatment for hypertension and clinic measurement of systolic BP >= 140 mm Hg or diastolic BP >= 90 mm Hg at baseline. Cognitive functioning was assessed annually by global cognitive screening, neurocognitive, and neuropsychiatric evaluations. Cognitive decline was identified by the incidence of mild cognitive impairment (MCI) or probable dementia (PD). Cox proportional hazards analyses were used to calculate hazard ratios (HRs). RESULTS Hypertension was associated with an increased risk for cognitive decline (HR 1.20; 95% confidence interval (CI) 1.04, 1.39; P = 0.02). Among women with antihypertensive medication, those with BP >= 140/90 mm Hg (uncontrolled BP) were at highest risk for developing cognitive decline (HR 1.30; 95% CI 1.05, 1.60) compared to women without treatment and BP <140/90 mm Hg (controlled BP). Sodium intake >1,500 mg/day did not alter the risk for cognitive decline in hypertensive women or women with antihypertensive treatment (P-for interaction = 0.96 or 0.97). CONCLUSIONS Women with antihypertensive treatment and uncontrolled BP showed highest risk estimates for developing cognitive decline compared to non-hypertensive women. Sodium intake did not modify the risk for cognitive decline in women with hypertension or receiving antihypertensive medication. C1 [Haring, Bernhard] Univ Wurzburg, Comprehens Heart Failure Ctr, Dept Internal Med 1, Wurzburg, Bavaria, Germany. [Wu, Chunyuan] Fred Hutchinson Canc Res Ctr, Womens Hlth Initiat, 1124 Columbia St, Seattle, WA 98104 USA. [Coker, Laura H.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [Seth, Arjun; Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Snetselaar, Linda] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med,Dept Med, Boston, MA 02115 USA. [Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Haring, B (reprint author), Univ Wurzburg, Comprehens Heart Failure Ctr, Dept Internal Med 1, Wurzburg, Bavaria, Germany. EM haring_b@ukw.de FU National Heart, Lung, and Blood Institute, National Institutes of Health; U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 41 TC 2 Z9 3 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0895-7061 EI 1941-7225 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2016 VL 29 IS 2 BP 202 EP 216 DI 10.1093/ajh/hpv081 PG 15 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DD8RG UT WOS:000370194000008 PM 26137952 ER PT J AU Solomon, AJ Schindler, MK Howard, DB Watts, R Sati, P Nickerson, JP Reich, DS AF Solomon, Andrew J. Schindler, Matthew K. Howard, Diantha B. Watts, Richard Sati, Pascal Nickerson, Joshua P. Reich, Daniel S. TI "Central vessel sign" on 3T FLAIR* MRI for the differentiation of multiple sclerosis from migraine SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; PARENCHYMAL VEINS; MS LESIONS; DIAGNOSIS; BRAIN; PREVALENCE; MISDIAGNOSIS; MORPHOLOGY; 7T AB ObjectiveThe diagnosis of multiple sclerosis (MS) presently relies on radiographic assessments of imperfect specificity. Recent data using T2* methodology for the detection of the central vessel sign (CVS) in MS lesions suggests this novel MRI technique may distinguish MS from other disorders. Our aim was to determine if evaluation for CVS on 3T FLAIR* MRI differentiates MS from migraine. MethodsPatients with MS or migraine and a prior brain MRI demonstrating at least two hyperintense lesions 3mm were recruited. Exclusion criteria included any additional comorbidity known to cause brain MRI abnormalities. 3T MRI was performed in each participant with administration of gadopentetate dimeglumine, and FLAIR* images were generated in postprocessing. The total number of discrete ovoid lesions 3mm were counted on FLAIR, per participant, and subsequently evaluated for presence of CVS on FLAIR*. An exploratory method evaluating for CVS in a maximum of 12 lesions per subject was also completed. ResultsTen participants with MS and 10 with migraine completed the study. The median percentage (quartiles) of lesions in MS participants with CVS was 84 (79, 94) compared to 22 (15, 54) in migraine (P=0.008). In a subanalysis by brain region, in the subcortical and deep white matter, the median percentage (quartiles) of lesions in MS participants with CVS was 88 (81, 100) compared to 19 (11, 54) in migraine (P=0.004). This difference was not identified in juxtacortical, periventricular, or infratentorial regions. InterpretationIdentification of CVS using FLAIR* on 3T MRI helps differentiate MS from migraine, particularly in the subcortical and deep white matter. C1 [Solomon, Andrew J.] Univ Vermont, Coll Med, Dept Neurol Sci, Burlington, VT USA. [Schindler, Matthew K.; Sati, Pascal; Reich, Daniel S.] NIAID, Translat Neuroradiol Unit, Div Neuroimmunol & Neurovirol, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Howard, Diantha B.] Vermont Ctr Clin & Translat Sci, Burlington, VT USA. [Watts, Richard; Nickerson, Joshua P.] Univ Vermont, Coll Med, Dept Radiol, Burlington, VT USA. RP Solomon, AJ (reprint author), 1 South Prospect St, Burlington, VT 05401 USA. EM andrew.solomon@uvm.edu NR 39 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD FEB PY 2016 VL 3 IS 2 BP 82 EP 87 DI 10.1002/acn3.273 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DD9SA UT WOS:000370264700002 PM 26900578 ER PT J AU Kolb, SJ Coffey, CS Yankey, JW Krosschell, K Arnold, WD Rutkove, SB Swoboda, KJ Reyna, SP Sakonju, A Darras, BT Shell, R Kuntz, N Castro, D Iannaccone, ST Parsons, J Connolly, AM Chiriboga, CA McDonald, C Burnette, WB Werner, K Thangarajh, M Shieh, PB Finanger, E Cudkowicz, ME McGovern, MM McNeil, DE Finkel, R Kaye, E Kingsley, A Renusch, SR McGovern, VL Wang, XQ Zaworski, PG Prior, TW Burghes, AHM Bartlett, A Kissel, JT AF Kolb, Stephen J. Coffey, Christopher S. Yankey, Jon W. Krosschell, Kristin Arnold, W. David Rutkove, Seward B. Swoboda, Kathryn J. Reyna, Sandra P. Sakonju, Ai Darras, Basil T. Shell, Richard Kuntz, Nancy Castro, Diana Iannaccone, Susan T. Parsons, Julie Connolly, Anne M. Chiriboga, Claudia A. McDonald, Craig Burnette, W. Bryan Werner, Klaus Thangarajh, Mathula Shieh, Perry B. Finanger, Erika Cudkowicz, Merit E. McGovern, Michelle M. McNeil, D. Elizabeth Finkel, Richard Kaye, Edward Kingsley, Allison Renusch, Samantha R. McGovern, Vicki L. Wang, Xueqian Zaworski, Phillip G. Prior, Thomas W. Burghes, Arthur H. M. Bartlett, Amy Kissel, John T. CA NeuroNEXT Clinical Trial Network NN101 SMA Biomarker Investigators TI Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article ID ELECTRICAL-IMPEDANCE MYOGRAPHY; SMN2 COPY NUMBER; NATURAL-HISTORY; SINGLE NUCLEOTIDE; CLINICAL-TRIALS; GENE SMN2; PROTEIN; SURVIVAL; SEVERITY; SMA AB ObjectiveThis study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA). MethodsThis prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. ResultsEnrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 2.2 mV) was significantly reduced compared to controls (5.5 +/- 2.0 mV). Electrical impedance myography (EIM) high-frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. InterpretationBy the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit. C1 [Kolb, Stephen J.; Arnold, W. David; Kingsley, Allison; Bartlett, Amy; Kissel, John T.] Ohio State Univ, Dept Neurol, Wexner Med Ctr, Hamilton Hall,Room 337B,1645 Neil Ave, Columbus, OH 43210 USA. [Kolb, Stephen J.; Renusch, Samantha R.; McGovern, Vicki L.; Wang, Xueqian; Burghes, Arthur H. M.] Ohio State Univ, Dept Biol Chem & Pharmacol, Wexner Med Ctr, Hamilton Hall,Room 337B,1645 Neil Ave, Columbus, OH 43210 USA. [Coffey, Christopher S.; Yankey, Jon W.] Univ Iowa, Dept Biostat, NeuroNEXT Data Coordinating Ctr, Iowa City, IA USA. [Krosschell, Kristin] Northwestern Univ, Feinberg Sch Med, Dept Phys Therapy, Chicago, IL 60611 USA. [Krosschell, Kristin] Northwestern Univ, Dept Human Movement Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Krosschell, Kristin] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA. [Arnold, W. David] Ohio State Univ, Wexner Med Ctr, Dept Phys Med & Rehabil, Columbus, OH 43210 USA. [Rutkove, Seward B.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Swoboda, Kathryn J.; Reyna, Sandra P.; Sakonju, Ai] Univ Utah, Dept Neurol, Salt Lake City, UT USA. [Swoboda, Kathryn J.; Reyna, Sandra P.; Sakonju, Ai] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Swoboda, Kathryn J.; Reyna, Sandra P.; Cudkowicz, Merit E.; McGovern, Michelle M.] Massachusetts Gen Hosp, Dept Neurol, NeuroNEXT Clin Coordinating Ctr, Boston, MA 02114 USA. [Darras, Basil T.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Shell, Richard] Nationwide Childrens Hosp, Columbus, OH USA. [Kuntz, Nancy] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. [Castro, Diana; Iannaccone, Susan T.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Parsons, Julie] Univ Colorado, Sch Med, Childrens Hosp Colorado, Aurora, CO USA. [Connolly, Anne M.] Washington Univ, Sch Med, St Louis, MO USA. [Chiriboga, Claudia A.] Columbia Coll Phys & Surg, Dept Neurol, New York, NY USA. [McDonald, Craig] Univ Calif Davis, Davis, CA 95616 USA. [Burnette, W. Bryan] Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA. [Werner, Klaus] SUNY Upstate Med Ctr, Syracuse, NY USA. [Thangarajh, Mathula] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Shieh, Perry B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Finanger, Erika] Dorenbecher Childrens Hosp, Portland, OR USA. [McNeil, D. Elizabeth] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Finkel, Richard] Nemours Childrens Hosp, Orlando, FL USA. [Kaye, Edward] Sarepta Therapeut, Cambridge, MA USA. [Zaworski, Phillip G.] PharmOptima, Portage, MI USA. [Prior, Thomas W.] Ohio State Wexner Med Ctr, Dept Mol Pathol, Columbus, OH USA. RP Kolb, SJ (reprint author), Ohio State Univ, Dept Neurol, Wexner Med Ctr, Hamilton Hall,Room 337B,1645 Neil Ave, Columbus, OH 43210 USA.; Kolb, SJ (reprint author), Ohio State Univ, Dept Biol Chem & Pharmacol, Wexner Med Ctr, Hamilton Hall,Room 337B,1645 Neil Ave, Columbus, OH 43210 USA. EM stephen.kolb@osumc.edu OI Arnold, W. David/0000-0001-9889-7036 FU NCATS NIH HHS [UL1 TR000445]; NICHD NIH HHS [K12 HD001097, U54 HD087011]; NINDS NIH HHS [K08 NS067282, U01 NS077179, U01 NS077352, U01 NS079163, U10 NS077267] NR 37 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD FEB PY 2016 VL 3 IS 2 BP 132 EP 145 DI 10.1002/acn3.283 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DD9SA UT WOS:000370264700007 PM 26900585 ER PT J AU Robles, AI Ryan, BM AF Robles, A. I. Ryan, B. M. TI KRT81 miR-SNP rs3660 is associated with risk and survival of NSCLC SO ANNALS OF ONCOLOGY LA English DT Letter ID GENETIC-VARIATION; LUNG-CANCER C1 [Robles, A. I.; Ryan, B. M.] NCI CCR, Human Carcinogenesis Lab, Natl Inst Hlth, Bethesda, MD USA. RP Ryan, BM (reprint author), NCI CCR, Human Carcinogenesis Lab, Natl Inst Hlth, Bethesda, MD USA. EM ryanb@mail.nih.gov FU Intramural NIH HHS NR 4 TC 1 Z9 1 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD FEB PY 2016 VL 27 IS 2 BP 360 EP 361 DI 10.1093/annonc/mdv552 PG 3 WC Oncology SC Oncology GA DD8TF UT WOS:000370199100027 PM 26578733 ER PT J AU Bernard-Gauthier, V Bailey, JJ Liu, ZB Wangler, B Wangler, C Jurkschat, K Perrin, DM Schirrmacher, R AF Bernard-Gauthier, Vadim Bailey, Justin J. Liu, Zhibo Waengler, Bjoern Waengler, Carmen Jurkschat, Klaus Perrin, David M. Schirrmacher, Ralf TI From Unorthodox to Established: The Current Status of F-18-Trifluoroborate- and F-18-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging SO BIOCONJUGATE CHEMISTRY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO EVALUATION; PROSTATE-CANCER; HYDROLYTIC STABILITY; GOLD NANOPARTICLES; FLUORIDE-ACCEPTOR; BOMBESIN ANALOGS; PROSTHETIC GROUP; BUILDING-BLOCKS; CLICK-CHEMISTRY AB Unorthodox F-18-labeling strategies not employing the formation of a carbon-18F bond are seldom found in radiochemistry. Historically, the formation of a boron- or silicon-F-18 bond has been introduced very early on into the repertoire of labeling chemistries, but is without translation into any clinical radiotracer besides inorganic B[F-18]F-4(-) for brain tumor diagnosis. For many decades these labeling methodologies were forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006, two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3 labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat, and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other noncanonical strategies to introduce 18F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of F-18 radiolabeling. B- and Si-based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence 1E, will be the focus of this contribution over other noncanonical labeling methods. Peptides for tumor imaging especially lend themselves favorably toward one-step labeling via IE, but small molecules have been described as well, taking advantage of these new approaches, and have been used successfully for brain imaging. This Review gives an account of both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries, and the first encouraging preclinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome. C1 [Bernard-Gauthier, Vadim; Bailey, Justin J.; Schirrmacher, Ralf] Univ Alberta, Dept Oncol, Div Oncol Imaging, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada. [Liu, Zhibo] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Waengler, Bjoern] Heidelberg Univ, Med Fac Mannheim, Mol Imaging & Radiochem & Biomed Chem, D-68167 Mannheim, Germany. [Waengler, Carmen] Heidelberg Univ, Med Fac Mannheim, Dept Clin Radiol & Nucl Med, D-68167 Mannheim, Germany. [Jurkschat, Klaus] Tech Univ Dortmund, Dept Chem & Chem Biol, D-44227 Dortmund, Germany. [Perrin, David M.] Univ British Columbia, Dept Chem, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. RP Schirrmacher, R (reprint author), Univ Alberta, Dept Oncol, Div Oncol Imaging, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada.; Perrin, DM (reprint author), Univ British Columbia, Dept Chem, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. EM dperrin@chem.ubc.ca; schirrma@ualberta.ca NR 79 TC 6 Z9 6 U1 10 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD FEB PY 2016 VL 27 IS 2 BP 267 EP 279 DI 10.1021/acs.bioconjchem.5b00560 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA DE4ES UT WOS:000370582600002 PM 26566577 ER PT J AU Sato, K Gorka, AP Nagaya, T Michie, MS Nani, RR Nakamura, Y Coble, VL Vasalatiy, OV Swenson, RE Choyke, PL Schnermann, MJ Kobayashi, H AF Sato, Kazuhide Gorka, Alexander P. Nagaya, Tadanobu Michie, Megan S. Nani, Roger R. Nakamura, Yuko Coble, Vince L. Vasalatiy, Olga V. Swenson, Rolf E. Choyke, Peter L. Schnermann, Martin J. Kobayashi, Hisataka TI Role of Fluorophore Charge on the In Vivo Optical Imaging Properties of Near-Infrared Cyanine Dye/Monoclonal Antibody Conjugates SO BIOCONJUGATE CHEMISTRY LA English DT Article ID GUIDED CANCER-SURGERY; KILLER-REPORTER ADENOVIRUS; FLUORESCENCE; FUTURE; DYES AB Near-infrared (NIR) fluorophores have several advantages over visible-light fluorophores, including superior light penetration in tissue and lower autofluorescence. We recently demonstrated that a new class of NIR cyanine dyes containing a novel C4'-O-alkyl linker exhibit greater chemical stability and excellent optical properties relative to existing C4'-O-aryl variants. We synthesized two NIR cyanine dyes with the same core structure but different indolenine substituents: FNIR-774 bearing four sulfonate groups and FNIR-Z-759 bearing a combination of two sulfonates and two quaternary ammonium cations, resulting in an anionic (-3) or monocationic (+1) charge, respectively. In this study, we compare the in vitro and in vivo optical imaging properties of monoclonal antibody (mAb) conjugates of FNIR-774 and FNIR-Z-759 with panitumumab (pan) at antibody-to-dye ratios of 1:2 or 1:5. Conjugates of both dyes demonstrated similar quenching capacity, stability, and brightness in target cells in vitro. However, FNIR-Z-759 conjugates showed significantly lower background in mice, resulting in higher tumor-to background ratio. Thus, FNIR-Z-759 conjugates appear to have superior in vivo imaging characteristics compared with FNIR774 conjugates, especially in the abdominal region, regardless of the dye-mAb ratio. These results suggest that zwitterionic cyanine dyes are a promising class of fluorophores for improving in vivo optical imaging with antibody NIR dye conjugates. C1 [Sato, Kazuhide; Nagaya, Tadanobu; Nakamura, Yuko; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Gorka, Alexander P.; Nani, Roger R.; Schnermann, Martin J.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Coble, Vince L.; Vasalatiy, Olga V.; Swenson, Rolf E.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA.; Schnermann, MJ (reprint author), NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. EM martin.schnermann@nih.gov; kobayash@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 29 TC 5 Z9 5 U1 12 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD FEB PY 2016 VL 27 IS 2 BP 404 EP 413 DI 10.1021/acs.bioconjchem.5b00492 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA DE4ES UT WOS:000370582600015 PM 26444497 ER PT J AU Rajkowska, G Clarke, G Mahajan, G Licht, CMM van de Werd, HJJM Yuan, P Stockmeier, CA Manji, HK Uylings, HBM AF Rajkowska, Grazyna Clarke, Gerard Mahajan, Gouri Licht, Camilla M. M. van de Werd, Henri J. J. M. Yuan, Peter Stockmeier, Craig A. Manji, Husseini K. Uylings, Harry B. M. TI Differential effect of lithium on cell number in the hippocampus and prefrontal cortex in adult mice: a stereological study SO BIPOLAR DISORDERS LA English DT Article DE adult neurogenesis; astrocytes; bipolar disorder; glia; lithium; neurons; stereology ID GRAY-MATTER VOLUME; MAJOR-DEPRESSIVE-DISORDER; BIPOLAR-DISORDER; OPTICAL FRACTIONATOR; CORTICAL AREAS; BRAIN; NEUROGENESIS; NEURONS; SCHIZOPHRENIA; MORPHOMETRY AB ObjectivesNeuroimaging studies have revealed lithium-related increases in the volume of gray matter in the prefrontal cortex (PFC) and hippocampus. Postmortem human studies have reported alterations in neuronal and glial cell density and size in the PFC of lithium-treated subjects. Rodents treated with lithium exhibit cell proliferation in the dentate gyrus (DG) of the hippocampus. However, it is not known whether hippocampal and PFC volume are also increased in these animals or whether cell number in the PFC is altered. MethodsUsing stereological methods, this study estimated the total numbers of neurons and glia, and the packing density of astrocytes in the DG and PFC of normal adult mice treated with lithium, and evaluated the total volume of these regions and the entire neocortex. ResultsLithium treatment increased the total numbers of neurons and glia in the DG (by 25% and 21%, respectively) and the density of astrocytes but did not alter total numbers in the PFC. However, the volumes of the hippocampus and its subfields, the PFC and its subareas, and the entire neocortex were not altered by lithium. ConclusionsBoth neuronal and glial cells accounted for lithium-induced cell proliferation in the DG. That the numbers of neurons and glia were unchanged in the PFC is consistent with the view that this region is not a neurogenic zone. Further studies are required to clarify the impact of lithium treatment on the PFC under pathological conditions and to investigate the dissociation between increased cell proliferation and unchanged volume in the hippocampus. C1 [Rajkowska, Grazyna; Clarke, Gerard; Mahajan, Gouri; Stockmeier, Craig A.] Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, 2500 North State St, Jackson, MS 39216 USA. [Clarke, Gerard] Natl Univ Ireland Univ Coll Cork, Dept Psychiat, Cork, Ireland. [Clarke, Gerard] Natl Univ Ireland Univ Coll Cork, Alimentary Pharmabiot Ctr, Cork, Ireland. [Licht, Camilla M. M.; van de Werd, Henri J. J. M.; Uylings, Harry B. M.] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Licht, Camilla M. M.] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Yuan, Peter; Manji, Husseini K.] NIMH, Lab Mol Pathophysiol & Expt Therapeut, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Janssen Res & Dev LLC, Johnson & Johnson, Titusville, NJ USA. RP Rajkowska, G (reprint author), Univ Mississippi, Med Ctr, Dept Psychiat & Human Behav, 2500 North State St, Jackson, MS 39216 USA. EM grajkowska@umc.edu FU [MH61578]; [P30 GM103328] FX This work was supported by grants MH61578 and P30 GM103328. NR 62 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD FEB PY 2016 VL 18 IS 1 BP 41 EP 51 DI 10.1111/bdi.12364 PG 11 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DE6AV UT WOS:000370715800004 PM 26842627 ER PT J AU Forlenza, OV Aprahamian, I Radanovic, M Talib, LL Camargo, MZA Stella, F Machado-Vieira, R Gattaz, WF AF Forlenza, Orestes V. Aprahamian, Ivan Radanovic, Marcia Talib, Leda L. Camargo, Marina Z. A. Stella, Florindo Machado-Vieira, Rodrigo Gattaz, Wagner F. TI Cognitive impairment in late-life bipolar disorder is not associated with Alzheimer's disease pathological signature in the cerebrospinal fluid SO BIPOLAR DISORDERS LA English DT Article DE Alzheimer's disease; biomarkers; bipolar disorder; cerebrospinal fluid; dementia; mild cognitive impairment ID CARDIOVASCULAR-DISEASE; DEPRESSIVE DISORDER; ELDERLY-PATIENTS; MOOD DISORDERS; RATING-SCALE; OLDER-ADULTS; DEMENTIA; RISK; METAANALYSIS; RELIABILITY AB ObjectivesCognitive impairment is a common feature of late-life bipolar disorder (BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease (AD) bio-signature in the cerebrospinal fluid (CSF), defined as a combination of low concentrations of the amyloid-beta peptide (A(1-42)) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. MethodsSeventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment (BD-MCI; n=16) and the comparison groups comprised patients with dementia due to AD (n=17), patients with amnestic MCI (aMCI; n=14), and cognitively healthy older adults (control group; n=25). CSF samples were obtained by lumbar puncture and concentrations of A(1-42), T-tau and P-tau were determined. ResultsCSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD-MCI subjects from aMCI subjects and controls. BD-MCI patients had a non-significant reduction in CSF A(1-42) compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD-MCI patients were similar to those in controls, and significantly lower than those in AD. ConclusionsCognitively impaired patients with BD do not display the so-called AD bio-signature in the CSF. We therefore hypothesize that cognitive deterioration in BD is not associated with the classical pathophysiological mechanisms observed in AD, i.e., amyloid deposition and hyperphosphorylation of microtubule-associated tau protein. C1 [Forlenza, Orestes V.; Aprahamian, Ivan; Radanovic, Marcia; Talib, Leda L.; Camargo, Marina Z. A.; Stella, Florindo; Machado-Vieira, Rodrigo; Gattaz, Wagner F.] Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, Lab Neurosci LIM 27, Rua Dr Ovidio Pires de Campos 785, BR-05403010 Sao Paulo, SP, Brazil. [Aprahamian, Ivan] Univ Estadual Paulista, UNESP, Jundiai Med Sch, Dept Internal Med, Sao Paulo, SP, Brazil. [Stella, Florindo] Univ Estadual Paulista, UNESP, Biosci Inst, Sao Paulo, SP, Brazil. [Machado-Vieira, Rodrigo] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Forlenza, OV (reprint author), Univ Sao Paulo, Fac Med, Dept & Inst Psychiat, Lab Neurosci LIM 27, Rua Dr Ovidio Pires de Campos 785, BR-05403010 Sao Paulo, SP, Brazil. EM forlenza@usp.br RI MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Gattaz, Wagner/0000-0001-5215-4077 FU Fundacao de Amparo a Pesquisa de Sao Paulo (FAPESP, Brazil) [09/52825-8]; Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS) e JNK Empreendimentos e Incorporacoes FX Rodolfo Braga Ladeira, Jouce Gabriela de Almeida, and Tatiana Nakabayashia made substantive contributions to data collection and analysis. Financial support was provided by the Fundacao de Amparo a Pesquisa de Sao Paulo (FAPESP Grant no. 09/52825-8, Brazil), Associacao Beneficente Alzira Denise Hertzog da Silva (ABADHS) e JNK Empreendimentos e Incorporacoes. NR 49 TC 1 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD FEB PY 2016 VL 18 IS 1 BP 63 EP 70 DI 10.1111/bdi.12360 PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DE6AV UT WOS:000370715800006 PM 26876913 ER PT J AU Marachelian, A Desai, A Balis, F Katzenstein, H Qayed, M Armstrong, M Neville, KA Cohn, SL Bush, M Gunawan, R Lim, AP Smith, MA Smith, LM AF Marachelian, Araz Desai, Ami Balis, Frank Katzenstein, Howard Qayed, Muna Armstrong, Michael Neville, Kathleen A. Cohn, Susan L. Bush, Mark Gunawan, Rudy Lim, Allison Pecha Smith, Malcolm A. Smith, L. Mary TI Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE ch14.18; Dinutuximab; Pharmacokinetics; Safety; Tolerability; Unituxin ID COLONY-STIMULATING FACTOR; PHASE-I; ANTIBODY; CHILDREN; TRANSPLANTATION; INTERLEUKIN-2 AB Dinutuximab (Unituxin (TM); ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products. In this randomized, two-sequence crossover study, 28 patients aged a parts per thousand currency sign8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEMA (R) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUC(inf)) and maximum concentration (C (max)). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h). Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUC(inf) (0.96; 90 % CI 0.88-1.04) and C (max) (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported. Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences. C1 [Marachelian, Araz] Univ So Calif, Childrens Hosp Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. [Desai, Ami; Balis, Frank] Childrens Hosp Philadelphia, 3401 Civ Ctr Blvd, Philadelphia, PA 19104 USA. [Katzenstein, Howard] Vanderbilt Univ, Sch Med, 2200 Pierce Ave,397 PRB, Nashville, TN 37232 USA. [Qayed, Muna] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, 1405 Clifton Rd NE, Atlanta, GA 30322 USA. [Qayed, Muna] Emory Univ, Sch Med, 1405 Clifton Rd NE, Atlanta, GA 30322 USA. [Armstrong, Michael] Duke Univ, DUMC 102382, Durham, NC 27710 USA. [Neville, Kathleen A.] Univ Arkansas Med Sci, Arkansas Childrens Hosp, 1 Childrens Way,Slot 512-23, Little Rock, AR 72202 USA. [Cohn, Susan L.] Univ Chicago, Dept Pediat, KCBD, 900 E 57th St,Rm 5100, Chicago, IL 60637 USA. [Bush, Mark] Wingate Univ, Sch Pharm, 515 N Main St, Wingate, NC 28174 USA. [Gunawan, Rudy] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA. [Lim, Allison Pecha; Smith, L. Mary] United Therapeut Corp, 55 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. [Smith, Malcolm A.] NCI, 9609 Med Ctr Dr,MSC 9739, Bethesda, MD 20892 USA. RP Marachelian, A (reprint author), Univ So Calif, Childrens Hosp Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM amarachelian@chla.usc.edu OI Cohn, Susan/0000-0001-5749-7650 FU United Therapeutics Corporation FX Writing assistance was provided by Julia D'Ambrosio, PhD, of SciStrategy Communications. This study was sponsored by United Therapeutics Corporation. NR 15 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2016 VL 77 IS 2 BP 405 EP 412 DI 10.1007/s00280-015-2955-9 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DD8DO UT WOS:000370155300020 PM 26791869 ER PT J AU Li, M Tse, LA Chan, WC Kwok, CH Leung, SL Wu, C Yu, WC Yu, ITS Yu, CHT Wang, F Sung, H Yang, XHR AF Li, Mengjie Tse, Lap Ah Chan, Wing-cheong Kwok, Chi-hei Leung, Siu-lan Wu, Cherry Yu, Wai-cho Yu, Ignatius Tak-sun Yu, Chloe Hui-Tung Wang, Feng Sung, Hyuna Yang, Xiaohong R. TI Evaluation of breast cancer risk associated with tea consumption by menopausal and estrogen receptor status among Chinese women in Hong Kong SO CANCER EPIDEMIOLOGY LA English DT Article DE Tea consumption; Breast cancer; Menopausal status; Estrogen receptor status ID GREEN TEA; MEDICINAL BENEFITS; HEALTH; COHORT; MECHANISMS; PREVENTION; SINGAPORE; DRINKING; CATECHIN; COFFEE AB Purpose: Experimental studies implicate tea and tea polyphenols may be preventive against breast cancer, but evidence from epidemiological studies has been inconsistent. We conducted a hospital-based case-control study to evaluate the role of tea especially green tea in breast cancer etiology. Methods: We consecutively recruited 756 incident breast cancer cases and 789 hospital controls who had completed information on tea consumption. We calculated odds ratios (ORs) for tea consumption using unconditional multivariable logistic regression. We further conducted stratified analyses to assess whether the effect of tea consumption varied by menopausal status and estrogen receptor (ER). Results: Overall, 439 (58.1%) breast cancer cases and 434 (55.0%) controls reported habits of regular tea drinking, showing an adjusted OR of 1.01 (95% CI: 0.78-1.31) and 1.20 (95% CI: 0.80-1.78) for any tea and green tea drinking, respectively. Regular tea drinking was significantly associated with a lower risk for breast cancer in pre-menopausal women (OR = 0.62, 95% CI: 0.40-0.97) but an increased risk in postmenopausal women (OR = 1.40, 95% CI: 1.00-1.96). The positive association among postmenopausal women was strongest among ER-negative green tea drinkers (OR = 2.99, 95% CI: 1.26-7.11). Conclusions: Tea or green tea drinking was not associated with overall breast cancer risk, which may be masked by the differential effect in pre-and post-menopausal women. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Li, Mengjie; Tse, Lap Ah; Yu, Ignatius Tak-sun; Wang, Feng] Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Sha Tin, Hong Kong, Peoples R China. [Chan, Wing-cheong] North Dist Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Kwok, Chi-hei] Princess Margaret Hosp, Dept Oncol, Hong Kong, Hong Kong, Peoples R China. [Leung, Siu-lan] Pamela Youde Nethersole Eastern Hosp, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Wu, Cherry] North Dist Hosp, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. [Yu, Wai-cho] Princess Margaret Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Yu, Chloe Hui-Tung] Univ Hong Kong, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. [Sung, Hyuna; Yang, Xiaohong R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Tse, LA (reprint author), Chinese Univ Hong Kong, JC Sch Publ Hlth & Primary Care, Sch Publ Hlth & Primary Care 4 F, Prince Wales Hosp, Sha Tin, Hong Kong, Peoples R China. EM shelly@cuhk.edu.hk RI Yu, Ignatius Tak Sun/A-9936-2008 FU Research Grants Council of Hong Kong [474811] FX This work was supported by Research Grants Council of Hong Kong [Grant number 474811]. The authors are grateful to Miss Yinshan Magdalene Leung, Hiu-man Tess Tsoi, Hung-kuen Ivy Hsu, Kit-Ping Apple Kwok for their assistance in patients' recruitment and data collection. We would also like to acknowledge Ying-lun Jonathan Chan, Chui-shan Yip, Wing-chi Fung for their contribution to data entry and management. NR 33 TC 2 Z9 3 U1 15 U2 32 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD FEB PY 2016 VL 40 BP 73 EP 78 DI 10.1016/j.canep.2015.11.013 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA DD8HM UT WOS:000370167000011 PM 26680603 ER PT J AU Murphy, G Abnet, CC Freedman, ND AF Murphy, Gwen Abnet, Christian C. Freedman, Neal D. TI Pernicious Anemia: Time to Justify Endoscopic Monitoring? Reply SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Letter ID CANCER C1 [Murphy, Gwen; Abnet, Christian C.; Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Murphy, G (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD FEB PY 2016 VL 14 IS 2 BP 322 EP 323 DI 10.1016/j.cgh.2015.09.025 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DE1GY UT WOS:000370376300029 PM 26435071 ER PT J AU Wilson, EM Kattakuzhy, S Sidharthan, S Sims, Z Tang, L McLaughlin, M Price, A Nelson, A Silk, R Gross, C Akoth, E Mo, HM Subramanian, GM Pang, PS McHutchison, JG Osinusi, A Masur, H Kohli, A Kottilil, S AF Wilson, Eleanor M. Kattakuzhy, Sarah Sidharthan, Sreetha Sims, Zayani Tang, Lydia McLaughlin, Mary Price, Angie Nelson, Amy Silk, Rachel Gross, Chloe Akoth, Elizabeth Mo, Hongmei Subramanian, G. Mani Pang, Phillip S. McHutchison, John G. Osinusi, Anu Masur, Henry Kohli, Anita Kottilil, Shyam TI Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE hepatitis C; direct-acting antiviral agents; retreatment; sofosbuvir; ledipasvir ID NS5A INHIBITOR GS-5885; HEPATITIS-C; VIROLOGICAL RESPONSE; CLINICAL-TRIAL; RIBAVIRIN; RESISTANCE; DASABUVIR; CIRRHOSIS; LEDIPASVIR/SOFOSBUVIR; ABT-450/R-OMBITASVIR AB Background. The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. Methods. In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR](12)). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. Results. Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 x 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. Conclusions. In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants. C1 [Wilson, Eleanor M.; Kattakuzhy, Sarah; Tang, Lydia; Price, Angie; Nelson, Amy; Silk, Rachel; Gross, Chloe; Akoth, Elizabeth; Kottilil, Shyam] Univ Maryland, Inst Human Virol, Div Infect Dis, Baltimore, MD 21201 USA. [Wilson, Eleanor M.; Sidharthan, Sreetha; Masur, Henry; Kohli, Anita] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Sims, Zayani; McLaughlin, Mary] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mo, Hongmei; Subramanian, G. Mani; Pang, Phillip S.; McHutchison, John G.; Osinusi, Anu] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Kohli, Anita] Creighton Univ, St Josephs Hosp & Med Ctr, Dept Hepatol, Phoenix, AZ USA. RP Kottilil, S (reprint author), Univ Maryland, Inst Human Virol, Div Clin Care & Res, Rm S222,725 W Lombard St, Baltimore, MD 21201 USA. EM skottilil@ihv.umaryland.edu OI Wilson, Eleanor/0000-0002-4855-514X FU NIAID, Clinical Center, NIH; Gilead Sciences, Inc.; German Research Foundation, clinical research unit [KFO 129] FX The study sponsor was the Regulatory Compliance and Human Participants Protection Branch of NIAID. The study sponsor also reviewed and approved the study through a peer-review process and study management. The study sponsor did not design nor play a role in designing the study; collecting, analyzing, or interpreting the data; or preparing, reviewing, approving, or submitting the manuscript. This research was supported, in part, by a collaborative research and development agreement between NIAID, Clinical Center, NIH, and Gilead Sciences, Inc., and by the German Research Foundation, clinical research unit KFO 129. These entities did not have a role in the writing of the manuscript or decision to submit for publication. NR 24 TC 7 Z9 7 U1 1 U2 2 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 FEB 1 PY 2016 VL 62 IS 3 BP 280 EP 288 DI 10.1093/cid/civ874 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DD8VS UT WOS:000370205600006 PM 26521268 ER PT J AU Herold, BC Chen, BA Salata, RA Marzinke, MA Kelly, CW Dezzutti, CS McGowan, I Galaska, B Levy, L Piper, JM Hillier, S Hendrix, CW AF Herold, Betsy C. Chen, Beatrice A. Salata, Robert A. Marzinke, Mark A. Kelly, Clifton W. Dezzutti, Charlene S. McGowan, Ian Galaska, Beth Levy, Lisa Piper, Jeanna M. Hillier, Sharon Hendrix, Craig W. CA MTN-011 Study Team TI Impact of Sex on the Pharmacokinetics and Pharmacodynamics of 1% Tenofovir Gel SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE MTN-011; tenofovir gel; pharmacokinetics; post-coital; HIV ID SIMPLEX-VIRUS INFECTION; INTRAVAGINAL RING; PREEXPOSURE PROPHYLAXIS; DISOPROXIL FUMARATE; HIV-INFECTION; DOUBLE-BLIND; ANTIRETROVIRAL PROPHYLAXIS; ANTIVIRAL ACTIVITY; SEMINAL PLASMA; MICROBICIDE AB Background. Tenofovir (TFV) gel partially protected against human immunodeficiency virus (HIV) in one but not subsequent trials. The disappointing results were attributed largely to poor adherence. However, timing of gel application relative to sex may impact pharmacokinetics and contribute to outcomes. Thus, we conducted a single-dose pharmacokinetic study of TFV gel applied 1 or 24 hours before or 1 hour before and 1 hour after (BAT) sex and compared results with dosing without sex. Methods. Twenty-four couples were enrolled; cervicovaginal lavage (CVL) and tissue were collected 2 hours after sex with matching timed collections at no sex visits and assayed for drug concentrations and CVL anti-HIV activity. Results. Compared with dosing without sex, median TFV concentrations after sex decreased 72% and 78% (P<.001) in CVL, 75% and 71% (P<.001) in vaginal tissue, and 75% (P=.06) and 55% (P<.001) in cervical tissue with -1 hour and -24 hour dosing, respectively. Median concentration of TFV-diphosphate also decreased significantly in cervical tissue with -1 hour, dosing. BAT dosing resulted in drug levels at least as great as those in the absence of sex. Percent inhibition of HIV infection by post-coital CVL increased significantly from median (interquartile range) of 55% (54%) in the absence of gel to 99% (7%), 77% (57%), and 100% (0.4%) with -1 hour, -24 hour, or BAT dosing, respectively, and correlated significantly with drug concentration. Conclusions. Timing of TFV gel application relative to sex significantly impacts drug levels. BAT dosing or sustained delivery may be optimal for preexposure prophylaxis. C1 [Herold, Betsy C.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Herold, Betsy C.] Albert Einstein Coll Med, Dept Microbiol Immunol, Bronx, NY 10461 USA. [Chen, Beatrice A.; Dezzutti, Charlene S.; McGowan, Ian; Galaska, Beth; Hillier, Sharon] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA 15260 USA. [Salata, Robert A.] Case Western Reserve, Dept Med, Cleveland, OH USA. [Marzinke, Mark A.; Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Dept Med Clin Pharmacol, Baltimore, MD USA. [Kelly, Clifton W.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, 1124 Columbia St, Seattle, WA 98104 USA. [Levy, Lisa] Family Hlth Int 360, Durham, NC USA. [Piper, Jeanna M.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. RP Herold, BC (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM betsy.herold@einstein.yu.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU Microbicide Trials Network - National Institute of Allergy and Infectious Diseases (NIAID) [UM1AI068633, UM1AI068615, UM1AI106707]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Mental Health, all components of the US NIH; NIAID [U19AI03461] FX This study was supported by the Microbicide Trials Network, which is is funded by the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068633, UM1AI068615, UM1AI106707), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the US NIH. The anti-HSV studies were supported by NIAID U19AI03461 (B. C. H.). NR 31 TC 1 Z9 1 U1 2 U2 4 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 FEB 1 PY 2016 VL 62 IS 3 BP 375 EP 382 DI 10.1093/cid/civ913 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DD8VS UT WOS:000370205600020 PM 26508513 ER PT J AU Freeman, ML Mudd, JC Shive, CL Younes, SA Panigrahi, S Sieg, SF Lee, SA Hunt, PW Calabrese, LH Gianella, S Rodriguez, B Lederman, MM AF Freeman, Michael L. Mudd, Joseph C. Shive, Carey L. Younes, Souheil-Antoine Panigrahi, Soumya Sieg, Scott F. Lee, Sulggi A. Hunt, Peter W. Calabrese, Leonard H. Gianella, Sara Rodriguez, Benigno Lederman, Michael M. TI CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; CMV; coinfection; CD8 T-cell expansion; inflammation ID INTIMA-MEDIA THICKNESS; ANTIRETROVIRAL THERAPY; CYTOMEGALOVIRUS-SEROPOSITIVITY; INDIVIDUALS; ACTIVATION; DISEASE; CD4(+); ALPHA; ATHEROSCLEROSIS; INTERLEUKIN-7 AB Background. Persistent CD8 T-cell expansion, low CD4/CD8 T-cell ratios, and heightened inflammation persist in antiretroviral therapy (ART)-treated human immunodeficiency virus (HIV) infection and are associated with increased risk of morbid outcomes. We explored the role of cytomegalovirus (CMV) infection in CD8 lymphocytosis and inflammation in ART-treated HIV infection. Methods. Absolute CD4 and CD8 T-cell counts were abstracted from clinical records and compared among 32 HIV-infected CMV-seronegative subjects, 126 age, CD4 and gender-matched HIV-infected CMV-seropositive subjects, and among 21 HIV-uninfected controls (9 CMV-negative, 12 CMV-positive). Plasma inflammatory indices were measured in a subset by ELISA. Results. Median CD8 counts/mu L were higher in HIV-positive/CMV-positive patients (795) than in HIV-positive/CMV-negative subjects (522, P=.006) or in healthy controls (451, P=.0007), whereas CD8 T-cell counts were similar to controls' levels in HIV-positive/CMV-negative subjects. Higher plasma levels of IP-10 (P=.0011), TNF-RII (P=.0002), and D-dimer (P=.0444) were also found in coinfected patients than in HIV-positive/CMV-negative subjects. Conclusions. CMV infection is associated with higher CD8 T-cell counts, resultant lower CD4/CD8 ratios, and increased systemic inflammation in ART-treated HIV infection. CMV infection may contribute to risk for morbid outcomes in treated HIV infection. C1 [Freeman, Michael L.; Mudd, Joseph C.; Shive, Carey L.; Younes, Souheil-Antoine; Panigrahi, Soumya; Sieg, Scott F.; Rodriguez, Benigno; Lederman, Michael M.] Case Western Reserve Univ, Dept Med, Div Infect Dis & HIV Med, Ctr AIDS Res,Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Shive, Carey L.] Vet Adm Med Ctr, 10701 East Blvd, Cleveland, OH 44106 USA. [Lee, Sulggi A.; Hunt, Peter W.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Calabrese, Leonard H.] Cleveland Clin Fdn, Dept Rheumat & Immunol Dis, Cleveland, OH USA. [Gianella, Sara] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA. [Mudd, Joseph C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Sch Med, 2061 Cornell Rd, Cleveland, OH 44106 USA. EM mxl6@case.edu FU Case Western Reserve University (CWRU) Center for AIDS Research [AI036219]; CWRU Clinical Trials Unit [AI069501]; Richard J. Fasenmyer Foundation FX This work was supported by the Case Western Reserve University (CWRU) Center for AIDS Research (AI036219) and the CWRU Clinical Trials Unit (AI069501), and by funding from the Richard J. Fasenmyer Foundation. NR 42 TC 16 Z9 16 U1 2 U2 6 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 FEB 1 PY 2016 VL 62 IS 3 BP 392 EP 396 DI 10.1093/cid/civ840 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DD8VS UT WOS:000370205600022 PM 26400999 ER PT J AU Arron, ST Raymond, AK Yanik, EL Castenson, D McCulloch, CE Clarke, CA Paddock, LE Niu, XL Engels, EA AF Arron, Sarah T. Raymond, Amanda K. Yanik, Elizabeth L. Castenson, David McCulloch, Charles E. Clarke, Christina A. Paddock, Lisa E. Niu, Xiaoling Engels, Eric A. TI Melanoma Outcomes in Transplant Recipients With Pretransplant Melanoma SO DERMATOLOGIC SURGERY LA English DT Article ID MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; SKIN-CANCER; ORGAN; EPIDEMIOLOGY; RISK AB BACKGROUNDThere are limited data on outcomes in transplant recipients with a history of pretransplant melanoma.OBJECTIVETo determine whether pretransplant melanoma is associated with differences in survival or posttransplant melanoma risk.MATERIALS AND METHODSWe evaluated the outcomes of 185,039 US transplant recipients from the Transplant Cancer Match Study. We also evaluated the impact of transplantation on 141,441 patients with melanoma identified in cancer registries.RESULTSThere were 336 transplant recipients (0.18%) with pretransplant melanoma; they had increased risk of melanoma-specific mortality (hazard ratio [HR], 27; 95% confidence interval [CI], 11-64, p < .0001), overall mortality (HR, 1.3; 95% CI, 1.0-1.5, p = .02), and incident melanoma (HR, 5.4; 95% CI, 2.9-9.8, p < .0001) after transplant, compared with recipients without pretransplant melanoma. The 10-year absolute risk difference was 2.97% for melanoma-specific mortality, 3.68% for incident melanoma, and 14.32% for overall mortality. Among the 141,441 patients with melanoma in the general population, 68 (0.05%) subsequently received a transplant. Transplantation increased melanoma-specific mortality, but not significantly (HR, 1.7; 95% CI, 0.61-4.5, p = .32).CONCLUSIONPretransplant melanoma is associated with increased melanoma-specific mortality, overall mortality, and incident melanoma after transplant. Nonetheless, the rarity of melanoma-related events supports the current practice for listing transplant candidates with a history of melanoma. C1 [Arron, Sarah T.; Raymond, Amanda K.] Univ Calif San Francisco, Dept Dermatol, 1701 Divisadero St,Third Floor,Box 316, San Francisco, CA 94115 USA. [Yanik, Elizabeth L.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Castenson, David] Informat Management Serv Inc, Rockville, MD USA. [McCulloch, Charles E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94115 USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Paddock, Lisa E.] Rutgers Sch Publ Hlth, Piscataway, NJ USA. [Paddock, Lisa E.; Niu, Xiaoling] New Jersey Dept Hlth, Canc Epidemiol Serv, Trenton, NJ USA. RP Arron, ST (reprint author), Univ Calif San Francisco, Dept Dermatol, 1701 Divisadero St,Third Floor,Box 316, San Francisco, CA 94115 USA. EM arrons@derm.ucsf.edu OI Yanik, Elizabeth/0000-0002-5835-0201 FU cancer registry: the state of California; cancer registry: the state of Colorado; cancer registry: the state of Connecticut; cancer registry: the state of Georgia; cancer registry: the state of Hawaii; cancer registry: the state of Iowa; cancer registry: the state of Illinois; cancer registry: the state of Michigan; cancer registry: the state of New Jersey; cancer registry: the state of New York; cancer registry: the state of North Carolina; cancer registry: the state of Texas; cancer registry: the state of Utah; cancer registry: the state of Seattle-Puget Sound area of Washington; Information Management Services; Intramural Research Program of the National Cancer Institute; Arbor Research Collaborative for Health in Ann Arbor, MI [HHSH234200537009C]; Minneapolis Medical Research Foundation in Minneapolis, MN [HHSH250201000018C]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: California [1U58 DP000807-01]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Colorado [U58 DP000848-04]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Georgia [5U58DP003875-01]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Illinois [5658DP000805-04]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Michigan [5U58DP000812-03]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: New Jersey [5U58/DP003931-02]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: New York [U58DP003879]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: North Carolina [U58DP000832]; National Program of Cancer Registry of the Centers for Disease Control and Prevention: Texas [5U58DP000824-04]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: California [HHSN261201000036C, HHSN261201000035C, HHSN261201000034C]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: Connecticut [HHSN261201000024C]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: Hawaii [HHSN261201000037C, N01-PC-35137, N01-PC-35139]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: Iowa [HSN261201000032C, N01-PC-35143]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: New Jersey [HHSN261201300021I, N01-PC-2013-00021]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: Seattle-Puget Sound [N01-PC-35142]; Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: Utah [HHSN261201000026C]; state of California; state of Colorado; state of Connecticut; state of Illinois; state of Iowa; state of New Jersey; state of New York (Cancer Surveillance Improvement Initiative) [14-2491]; state of Texas; state of Washington; state of Fred Hutchinson Cancer Research Center in Seattle, WA; American Society for Dermatologic Surgery Cutting Edge Research Grant Program FX The authors acknowledge the support and assistance provided by individuals at the Health Resources and Services Administration (Monica Lin), the SRTR (Ajay Israni, Bertram Kasiske, Paul Newkirk, Jon Snyder), and the following cancer registries: the states of California, Colorado (Jack Finch), Connecticut (Lou Gonsalves), Georgia (Rana Bayakly), Hawaii (Brenda Hernandez), Iowa (Charles Lynch), Illinois (Lori Koch), Michigan (Glenn Copeland), New Jersey, New York (Amy Kahn), North Carolina (Chandrika Rao), Texas (Melanie Williams), and Utah (Janna Harrell), and the Seattle-Puget Sound area of Washington (Margaret Madeleine). The authors also thank analysts at Information Management Services for programming support (Matthew Chaloux, Michael Curry, Ruth Parsons) and Ryutaro Hirose for critical feedback on this manuscript. Supported in part by the Intramural Research Program of the National Cancer Institute. During the initial period when registry linkages were performed, the SRTR was managed by Arbor Research Collaborative for Health in Ann Arbor, MI (contract HHSH234200537009C); beginning in September 2010, the SRTR was managed by Minneapolis Medical Research Foundation in Minneapolis, MN (HHSH250201000018C). The following cancer registries were supported by the National Program of Cancer Registries of the Centers for Disease Control and Prevention: California (agreement 1U58 DP000807-01), Colorado (U58 DP000848-04), Georgia (5U58DP003875-01), Illinois (5658DP000805-04), Michigan (5U58DP000812-03), New Jersey (5U58/DP003931-02), New York (U58DP003879), North Carolina (U58DP000832), and Texas (5U58DP000824-04). The following cancer registries were supported by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute: California (contracts HHSN261201000036C, HHSN261201000035C, and HHSN261201000034C), Connecticut (HHSN261201000024C), Hawaii (HHSN261201000037C, N01-PC-35137, and N01-PC-35139), Iowa (HSN261201000032C and N01-PC-35143), New Jersey (HHSN261201300021I, N01-PC-2013-00021), Seattle-Puget Sound (N01-PC-35142), and Utah (HHSN261201000026C). Additional support was provided by the states of California, Colorado, Connecticut, Illinois, Iowa, New Jersey, New York (Cancer Surveillance Improvement Initiative 14-2491), Texas, and Washington, as well as the Fred Hutchinson Cancer Research Center in Seattle, WA. A. K. Raymond is funded by the American Society for Dermatologic Surgery Cutting Edge Research Grant Program. S. T. Arron and A. K. Raymond contributed equally to this work. The views expressed in this paper are those of the authors and should not be interpreted to reflect the views or policies of the National Cancer Institute, Health Resources and Services Administration, SRTR, cancer registries, or their contractors. NR 14 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD FEB PY 2016 VL 42 IS 2 BP 157 EP 166 DI 10.1097/DSS.0000000000000602 PG 10 WC Dermatology; Surgery SC Dermatology; Surgery GA DD5PM UT WOS:000369976300003 PM 26818209 ER PT J AU Mertan, FV Berman, R Szajek, K Pinto, PA Choyke, PL Turkbey, B AF Mertan, Francesca V. Berman, Rose Szajek, Kathryn Pinto, Peter A. Choyke, Peter L. Turkbey, Baris TI Evaluating the Role of mpMRI in Prostate Cancer Assessment SO EXPERT REVIEW OF MEDICAL DEVICES LA English DT Review DE focal therapy; MRI; biopsy; prostate cancer; PIRADS ID FUSION-GUIDED BIOPSY; PHYSICIAN PRACTICE PATTERNS; ACTIVE SURVEILLANCE COHORT; ASSOCIATION GALLUP SURVEY; GAUSSIAN WATER DIFFUSION; CONTRAST-ENHANCED MRI; RADS SCORING SYSTEM; NO PREVIOUS BIOPSY; MULTIPARAMETRIC MRI; FOCAL THERAPY AB Prostate cancer is the most common malignancy among American men. The role of multi-parametric MRI has recently gained more importance in detection of prostate cancer, its targeted biopsy, and focal therapy guidance. In this review, uses of multi-parametric MRI in prostate cancer assessment and treatment are discussed. C1 [Mertan, Francesca V.; Berman, Rose; Szajek, Kathryn; Choyke, Peter L.; Turkbey, Baris] NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. [Szajek, Kathryn] Mt St Marys Univ, Dept Sci, Emmitsburg, MD USA. [Pinto, Peter A.] NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. RP Turkbey, B (reprint author), NCI, Mol Imaging Program, NIH, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA.; Turkbey, B (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Room B3B85, Bethesda, MD 20892 USA. EM turkbeyi@mail.nih.gov NR 89 TC 1 Z9 1 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1743-4440 EI 1745-2422 J9 EXPERT REV MED DEVIC JI Expert Rev. Med. Devices PD FEB 1 PY 2016 VL 13 IS 2 BP 129 EP 141 DI 10.1586/17434440.2016.1134311 PG 13 WC Engineering, Biomedical SC Engineering GA DE5VL UT WOS:000370700900003 PM 26690507 ER PT J AU Abdelmegeed, MA Choi, Y Ha, SK Song, BJ AF Abdelmegeed, Mohamed A. Choi, Youngshim Ha, Seung-Kwon Song, Byoung-Joon TI Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Liver; Aging; CYP2E1; Steatohepatitis; Apoptosis; Fibrosis; Nitroxidative stress ID POSTTRANSLATIONAL PROTEIN MODIFICATIONS; FATTY LIVER-DISEASE; AGE-RELATED-CHANGES; OXIDATIVE STRESS; MITOCHONDRIAL DYSFUNCTION; NONALCOHOLIC STEATOHEPATITIS; HEME OXYGENASE-1; MOUSE-LIVER; RAT-LIVER; LIFE-SPAN AB The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2el-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. In contrast, the aging-related nitroxidative changes were very low in aged Cyp2el-null mice. These results suggest that CYP2E1 is important in causing aging-dependent hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging related liver disease. Published by Elsevier Inc. C1 [Abdelmegeed, Mohamed A.; Choi, Youngshim; Ha, Seung-Kwon; Song, Byoung-Joon] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bj.song@nih.gov FU Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism; KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program); Korea Research institute of Bioscience and Biotechnology, Republic of Korea FX This research was supported by the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism and by a Grant to Youngshim Choi from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), and Korea Research institute of Bioscience and Biotechnology, Republic of Korea. We are thankful to Dr. Frank J. Gonzalez (National Cancer Institute, NIH, Bethesda, MD, USA) and Dr. James P. Hardwick (Northeastern Ohio University College of Medicine, Rootstown, OH) for providing the WT and Cyp2el-null mice and the polyclonal antibodies to different P450 isoforms, respectively. We also thank Dr. Klaus Gawrisch for supporting this study. NR 78 TC 7 Z9 7 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB PY 2016 VL 91 BP 188 EP 202 DI 10.1016/j.freeradbiomed.2015.12.016 PG 15 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA DD8MQ UT WOS:000370181400018 PM 26703967 ER PT J AU Edmonson, CA Ziats, MN Rennert, OM AF Edmonson, Catherine A. Ziats, Mark N. Rennert, Owen M. TI A Non-inflammatory Role for Microglia in Autism Spectrum Disorders SO FRONTIERS IN NEUROLOGY LA English DT Article DE autism spectrum disorder; neurodevelopment; microglia; glia; neurodevelopmental disorders ID MATERNAL IMMUNE ACTIVATION; GENE-EXPRESSION; SYNAPSE ELIMINATION; PREFRONTAL CORTEX; BRAIN-DEVELOPMENT; IN-VIVO; CNS; CHILDREN; BEHAVIOR; REVEALS AB Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, difficulties with language, and repetitive/restricted behaviors. The etiology of ASD is still largely unclear, but immune dysfunction and abnormalities in synaptogenesis have repeatedly been implicated as contributing to the disease phenotype. However, an understanding of how and if these two processes are related has not firmly been established. As non-inflammatory roles of microglia become increasingly recognized as critical to normal neurodevelopment, it is important to consider how dysfunction in these processes might explain the seemingly disparate findings of immune dysfunction and aberrant synaptogenesis seen in ASD. In this review, we highlight research demonstrating the importance of microglia to the development of normal neural networks, review recent studies demonstrating abnormal microglia in autism, and discuss how the relationship between these processes may contribute to the development of autism and other neurodevelopmental disorders at the cellular level. C1 [Edmonson, Catherine A.] Univ Florida, Coll Med, Gainesville, FL USA. [Edmonson, Catherine A.; Ziats, Mark N.; Rennert, Owen M.] NICHHD, NIH, Bethesda, MD 20892 USA. [Ziats, Mark N.] Baylor Coll Med, Med Scientist Training Program, Houston, TX 77030 USA. RP Rennert, OM (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM rennerto@mail.nih.gov FU Intramural Research Program (IRP) of the National Institute of Child Health and Human Development, NIH; NIH-Cambridge Biomedical Scholars Program; Baylor College of Medicine Medical Scientist Training Program FX This work was supported by the Intramural Research Program (IRP) of the National Institute of Child Health and Human Development, NIH. MZ was also supported by the NIH-Cambridge Biomedical Scholars Program, and the Baylor College of Medicine Medical Scientist Training Program. NR 51 TC 3 Z9 3 U1 1 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2295 J9 FRONT NEUROL JI Front. Neurol. PD FEB 1 PY 2016 VL 7 AR 9 DI 10.3389/fneur.2016.00009 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DE2BQ UT WOS:000370431600001 PM 26869989 ER PT J AU Anderson, MJ Southon, E Tessarollo, L Lewandoski, M AF Anderson, Matthew J. Southon, Eileen Tessarollo, Lino Lewandoski, Mark TI Fgf3-Fgf4-cis: A new mouse line for studying Fgf functions during mouse development SO GENESIS LA English DT Article DE FGF; FGF3; FGF4; genetic redundancy; mouse development; presomitic mesoderm; axis extension ID FIBROBLAST-GROWTH-FACTOR; EMBRYONIC STEM-CELLS; INNER-EAR; PROTOONCOGENE INT-2; HOMOLOGOUS FACTORS; LIMB DEVELOPMENT; REVEALS; MORPHOGENESIS; REQUIREMENTS; INACTIVATION AB The fibroblast growth factor (FGF) family consists of 22 ligands in mice and humans. FGF signaling is vital for embryogenesis and, when dysregulated, can cause disease. Loss-of-function genetic analysis in the mouse has been crucial for understanding FGF function. Such analysis has revealed that multiple Fgfs sometimes function redundantly. Exploring such redundancy between Fgf3 and Fgf4 is currently impossible because both genes are located on chromosome 7, about 18.5 kb apart, making the frequency of interallelic cross-over between existing mutant alleles too infrequent to be practicable. Therefore, we retargeted Fgf3 and Fgf4 in cis, generating an Fgf3 null allele and a conditional Fgf4 allele, subject to Cre inactivation. To increase the frequency of cis targeting, we used an F1 embryonic stem cell line that contained 129/SvJae (129) and C57BL/6J (B6) chromosomes and targeting constructs isogenic to the 129 chromosome. We confirmed cis targeting by assaying for B6/129 allele-specific single-nucleotide polymorphisms. We demonstrated the utility of the Fgf3-Fgf4(flox)-cis mouse line by showing that the caudal axis extension defects found in the Fgf3 mutants worsen when Fgf4 is also inactivated. This Fgf3-Fgf4(flox)-cis line will be useful to study redundancy of these genes in a variety of tissues and stages in development. genesis 54:91-98, 2016. Published 2016. This article is a US Government work and is in the public domain in the USA. C1 [Anderson, Matthew J.; Lewandoski, Mark] NCI, Canc & Dev Biol Lab, 1050 Boyles St,Box B, Frederick, MD 21702 USA. [Southon, Eileen; Tessarollo, Lino] NCI, Mouse Canc Genet Program, 1050 Boyles St,Box B, Frederick, MD 21702 USA. RP Lewandoski, M (reprint author), NCI, Canc & Dev Biol Lab, 1050 Boyles St,Box B, Frederick, MD 21702 USA.; Lewandoski, M (reprint author), NCI, 1050 Boyles St,Box B, Frederick, MD 21702 USA. EM lewandom@mail.nih.gov FU Center for Cancer Research of the Intramural Research Program of the National Institutes of Health, National Cancer Institute FX Contract grant sponsor: Center for Cancer Research of the Intramural Research Program of the National Institutes of Health, National Cancer Institute NR 34 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-954X EI 1526-968X J9 GENESIS JI Genesis PD FEB PY 2016 VL 54 IS 2 BP 91 EP 98 DI 10.1002/dvg.22913 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA DE4QD UT WOS:000370613700004 PM 26666435 ER PT J AU Meier, TB Bergamino, M Bellgowan, PSF Teague, TK Ling, JM Jeromin, A Mayer, AR AF Meier, Timothy B. Bergamino, Maurizio Bellgowan, Patrick S. F. Teague, T. K. Ling, Josef M. Jeromin, Andreas Mayer, Andrew R. TI Longitudinal Assessment of White Matter Abnormalities Following Sports-Related Concussion SO HUMAN BRAIN MAPPING LA English DT Article DE diffusion tensor imaging; mTBI; fractional anisotropy; tau ID TRAUMATIC BRAIN-INJURY; TENSOR IMAGING FINDINGS; COLLEGIATE FOOTBALL PLAYERS; CEREBROSPINAL-FLUID; NCAA CONCUSSION; NERVOUS-SYSTEM; DIFFUSION; BIOMARKERS; RECOVERY; ADOLESCENTS AB There is great interest in developing physiological-based biomarkers such as diffusion tensor imaging to aid in the management of concussion, which is currently entirely dependent on clinical judgment. However, the time course for recovery of white matter abnormalities following sportsrelated concussion (SRC) is unknown. We collected diffusion tensor imaging and behavioral data in forty concussed collegiate athletes on average 1.64 days (T1; n = 33), 8.33 days (T2; n = 30), and 32.15 days post-concussion (T3; n = 26), with healthy collegiate contact-sport athletes (HA) serving as controls (n = 46). We hypothesized that fractional anisotropy (FA) would be increased acutely and partially recovered by one month post-concussion. Mood symptoms were assessed using structured interviews. FA differences were assessed using both traditional and subject-specific analyses. An exploratory analysis of tau plasma levels was conducted in a subset of participants. Results indicated that mood symptoms improved over time post-concussion, but remained elevated at T3 relative to HA. Across both group and subject-specific analyses, concussed athletes exhibited increased FA in several white matter tracts at each visit post-concussion with no longitudinal evidence of recovery. Increased FA at T1 and T3 was significantly associated with an independent, real-world outcome measure for return-to-play. Finally, we observed a nonsignificant trend for reduced tau in plasma of concussed athletes at T1 relative to HA, with tau significantly increasing by T2. These results suggest white matter abnormalities following SRC may persist beyond one month and have potential as an objective biomarker for concussion outcome. (C) 2015 Wiley Periodicals, Inc. C1 [Meier, Timothy B.] Med Coll Wisconsin, Dept Neurosurg, Milwaukee, WI 53226 USA. [Meier, Timothy B.; Ling, Josef M.; Mayer, Andrew R.] Lovelace Biomed & Environm Res Inst, Mind Res Network, Albuquerque, NM USA. [Meier, Timothy B.; Bergamino, Maurizio] Laureate Inst Brain Res, Tulsa, OK USA. [Bellgowan, Patrick S. F.] NINDS, NIH, North Bethesda, MD USA. [Teague, T. K.] Univ Oklahoma, Coll Med, Dept Surg, Tulsa, OK USA. [Teague, T. K.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. [Teague, T. K.] Univ Oklahoma, Coll Pharm, Dept Pharmaceut Sci, Tulsa, OK USA. [Teague, T. K.] Oklahoma State Univ, Ctr Hlth Sci, Dept Biochem & Microbiol, Tulsa, OK USA. [Jeromin, Andreas] Quanterix Corp, Lexington, MA USA. [Mayer, Andrew R.] Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA. [Meier, Timothy B.; Mayer, Andrew R.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Meier, TB (reprint author), Neurosci Res Ctr, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM tmeier@mcw.edu RI Teague, Kent/A-2527-2008 OI Teague, Kent/0000-0002-4680-5440 FU Laureate Institute for Brain Research FX Contract grant sponsor: Laureate Institute for Brain Research NR 54 TC 0 Z9 0 U1 2 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2016 VL 37 IS 2 BP 833 EP 845 DI 10.1002/hbm.23072 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DD9KB UT WOS:000370243000030 PM 26663463 ER PT J AU Pichard, DC Cardones, AR Chu, EY Dahut, WL Kong, HH AF Pichard, Dominique C. Cardones, Adela R. Chu, Emily Y. Dahut, William L. Kong, Heidi H. TI Sorafenib-Induced Eruption Mimicking Erythema Multiforme SO JAMA DERMATOLOGY LA English DT Letter ID RENAL-CELL CARCINOMA C1 [Pichard, Dominique C.; Kong, Heidi H.] NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,MSC 1908, Bethesda, MD 20892 USA. [Cardones, Adela R.] Duke Univ, Med Ctr, Dept Dermatol, Durham, NC USA. [Chu, Emily Y.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Dahut, William L.] NCI, Genitourinary Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kong, HH (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,MSC 1908, Bethesda, MD 20892 USA. EM Heidi.Kong@nih.gov OI Kong, Heidi/0000-0003-4424-064X NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6068 EI 2168-6084 J9 JAMA DERMATOL JI JAMA Dermatol. PD FEB PY 2016 VL 152 IS 2 BP 227 EP 228 DI 10.1001/jamadermatol.2015.2930 PG 3 WC Dermatology SC Dermatology GA DE4AT UT WOS:000370572300027 PM 26422655 ER PT J AU Zhao, N Nociti, FH Duan, P Prideaux, M Zhao, H Foster, BL Somerman, MJ Bonewald, LF AF Zhao, Ning Nociti, Francisco H., Jr. Duan, Peipei Prideaux, Matthew Zhao, Hong Foster, Brian L. Somerman, Martha J. Bonewald, Lynda F. TI Isolation and Functional Analysis of an Immortalized Murine Cementocyte Cell Line, IDG-CM6 SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE DENTAL CEMENTUM; CEMENTOCYTES; IDG-CM6; OPG; RANKL; SCLEROSTIN ID BONE-FORMATION; IN-VITRO; MECHANICAL STRAIN; RANKL EXPRESSION; ROS 17/2.8; OSTEOCYTES; MICE; LOCALIZATION; SCLEROSTIN; DIFFERENTIATION AB The dental cementum covering the tooth root is similar to bone in several respects but remains poorly understood in terms of development and differentiation of cementoblasts, as well as the potential function(s) of cementocytes residing in the cellular cementum. It is not known if the cementocyte is a dynamic actor in cementum metabolism, comparable to the osteocyte in the bone. Cementocytes exhibit irregular spacing and lacunar shape, with fewer canalicular connections compared with osteocytes. Immunohistochemistry and quantitative PCR (qPCR) revealed that the in vivo expression profile of cementocytes paralleled that of osteocytes, including expression of dentin matrix protein 1 (Dmp1/DMP1), Sost/sclerostin, E11/gp38/podoplanin, Tnfrsf11b (osteoprotegerin [OPG]), and Tnfsf11 (receptor activator of NF-B ligand [RANKL]). We used the Immortomouse(+/-); Dmp1-GFP(+/-) mice to isolate cementocytes as Dmp1-expressing cells followed by immortalization using the interferon (IFN)--inducible promoter driving expression of a thermolabile large T antigen to create the first immortalized line of cementocytes, IDG-CM6. This cell line reproduced the expression profile of cementocytes observed in vivo, including alkaline phosphatase activity and mineralization. IDG-CM6 cells expressed higher levels of Tnfrsf11b and lower levels of Tnfsf11 compared with IDG-SW3 osteocytes, and under fluid flow shear stress, IDG-CM6 cells significantly increased OPG while decreasing RANKL, leading to a significantly increased OPG/RANKL ratio, which would inhibit osteoclast activation. These studies indicate similarities yet potentially important differences in the function of cementocytes compared with osteocytes and support cementocytes as mechanically responsive cells. (c) 2015 American Society for Bone and Mineral Research. C1 [Zhao, Ning; Duan, Peipei; Prideaux, Matthew; Zhao, Hong; Bonewald, Lynda F.] Univ Missouri, Sch Dent, Dept Oral & Craniofacial Sci, Kansas City, MO 64110 USA. [Zhao, Ning; Foster, Brian L.; Somerman, Martha J.] Shanghai Jiao Tong Univ, Shanghai Hosp 9, Sch Med, Shanghai Key Lab Stomatol,Dept Orthodont, Shanghai 200030, Peoples R China. [Nociti, Francisco H., Jr.] NIAMSD, Lab Oral Connect Tissue Biol, NIAMS, NIH, Bethesda, MD 20892 USA. [Duan, Peipei] West China Coll Stomatol, State Key Lab Oral Dis, Dept Orthodont, Piracicaba, SP, Brazil. [Prideaux, Matthew] Univ Adelaide, Ctr Orthopaed & Trauma Res, Bone Cell Biol Grp, Adelaide, SA, Australia. [Foster, Brian L.] Ohio State Univ, Coll Dent, Div Biosci, Columbus, OH 43210 USA. RP Bonewald, LF (reprint author), 650 East 25th St, Kansas City, MO 64108 USA. EM bonewaldl@umkc.edu FU NIAMS/NIH; National Natural Science Funds of China [81000420]; [PO1 AR046758] FX This work was supported by grant PO1 AR046758 (to LB), by the Intramural Research Program of NIAMS/NIH (to MJS), and by National Natural Science Funds of China (grant no. 81000420 to NZ). The authors thank Yixia Xie, LeAnn Tiede-Lewis, Vladimir Dusevich, and Jennifer Rosser (University of Missouri-Kansas City, Kansas City, MO, USA) and Alyssa Coulter and KC Hemstreet (NIAMS/NIH) for their assistance in these studies. NR 50 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD FEB PY 2016 VL 31 IS 2 BP 430 EP 442 DI 10.1002/jbmr.2690 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD8NE UT WOS:000370182900020 PM 26274352 ER PT J AU Magidson, V He, J Ault, JG O'Connell, CB Yang, NC Tikhonenko, I McEwen, BF Sui, HX Khodjakov, A AF Magidson, Valentin He, Jie Ault, Jeffrey G. O'Connell, Christopher B. Yang, Nachen Tikhonenko, Irina McEwen, Bruce F. Sui, Haixin Khodjakov, Alexey TI Unattached kinetochores rather than intrakinetochore tension arrest mitosis in taxol-treated cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SPINDLE ASSEMBLY CHECKPOINT; VERTEBRATE SOMATIC-CELLS; MICROTUBULE ATTACHMENT; ELECTRON-MICROSCOPY; FREEZE-SUBSTITUTION; DEPENDENT CHANGES; OUTER PLATE; PROTEINS; ANAPHASE; SWITCH AB Kinetochores attach chromosomes to the spindle microtubules and signal the spindle assembly checkpoint to delay mitotic exit until all chromosomes are attached. Light microscopy approaches aimed to indirectly determine distances between various proteins within the kinetochore (termed Delta) suggest that kinetochores become stretched by spindle forces and compact elastically when the force is suppressed. Low Delta is believed to arrest mitotic progression in taxol-treated cells. However, the structural basis of Delta remains unknown. By integrating same-kinetochore light microscopy and electron microscopy, we demonstrate that the value of Delta is affected by the variability in the shape and size of outer kinetochore domains. The outer kinetochore compacts when spindle forces are maximal during metaphase. When the forces are weakened by taxol treatment, the outer kinetochore expands radially and some kinetochores completely lose microtubule attachment, a condition known to arrest mitotic progression. These observations offer an alternative interpretation of intrakinetochore tension and question whether Delta plays a direct role in the control of mitotic progression. C1 [Magidson, Valentin; He, Jie; Ault, Jeffrey G.; O'Connell, Christopher B.; Yang, Nachen; Tikhonenko, Irina; McEwen, Bruce F.; Sui, Haixin; Khodjakov, Alexey] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [McEwen, Bruce F.; Sui, Haixin] SUNY Albany, Sch Publ Hlth, Albany, NY 12201 USA. [Khodjakov, Alexey] Rensselaer Polytech Inst, Troy, NY 12180 USA. [Magidson, Valentin] NCI, Frederick, MD 21702 USA. [O'Connell, Christopher B.] Univ Connecticut, Storrs, CT 06269 USA. RP Sui, HX; Khodjakov, A (reprint author), New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA.; Sui, HX (reprint author), SUNY Albany, Sch Publ Hlth, Albany, NY 12201 USA.; Khodjakov, A (reprint author), Rensselaer Polytech Inst, Troy, NY 12180 USA. EM haixin.sui@health.ny.gov FU National Institutes of Health [GM059363, GM101026] FX This work was supported by the National Institutes of Health grants GM059363 to A. Khodjakov and GM101026 to H. Sui. The electron microscopy was enabled by the use of the Wadsworth Center's Electron Microscopy Core Facility. NR 39 TC 5 Z9 5 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 1 PY 2016 VL 212 IS 3 BP 307 EP 319 DI 10.1083/jcb.201412139 PG 13 WC Cell Biology SC Cell Biology GA DE2WM UT WOS:000370487900008 PM 26833787 ER PT J AU Jia, XY Wang, MT Shao, YH Konig, G Brooks, BR Zhang, JZH Mei, Y AF Jia, Xiangyu Wang, Meiting Shao, Yihan Koenig, Gerhard Brooks, Bernard R. Zhang, John Z. H. Mei, Ye TI Calculations of Solvation Free Energy through Energy Reweighting from Molecular Mechanics to Quantum Mechanics SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID HYDRATION FREE-ENERGIES; BENNETTS ACCEPTANCE RATIO; POLARIZABLE FORCE-FIELD; LENNARD-JONES PARAMETERS; BINDING FREE-ENERGY; DYNAMICS SIMULATIONS; CONSTANT-PH; THERMODYNAMIC INTEGRATION; PERTURBATION CALCULATIONS; EXPLICIT SOLVENT AB In this work, the solvation free energies of 20 organic molecules from the 4th Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL4) have been calculated. The sampling of phase space is carried out at a molecular mechanical level, and the associated free energy changes are estimated using the Bennett Acceptance:Ratio (BAR). Then the quantum mechanical (QM) corrections are computed through the indirect Non-Boltzmann Bennett's acceptance ratio (NBB) or the thermodynamics perturbation (TP) method. We show that BAR+TP gives a minimum analytic variance for the calculated solvation free energy at the Gaussian limit and performs slightly better than NBB in practice. Furthermore, the expense of the QM calculations in TP is only half of that in NBB, We also show that defining the biasing potential as the difference of the solute solvent interaction energy, instead of the total energy, can converge the calculated solvation free energies much faster but possibly to different values. Based on the experimental solvation free energies which have been published before, it is discovered in this study that BLYP yields better results than MP2 and some other later functionals such as B3LYP, M06-2X, and omega B97X-D. C1 [Jia, Xiangyu; Wang, Meiting; Zhang, John Z. H.; Mei, Ye] E China Normal Univ, State Key Lab Precis Spect, Shanghai 200062, Peoples R China. [Jia, Xiangyu; Wang, Meiting; Zhang, John Z. H.; Mei, Ye] E China Normal Univ, Dept Phys, Shanghai 200062, Peoples R China. [Jia, Xiangyu; Wang, Meiting; Zhang, John Z. H.; Mei, Ye] E China Normal Univ, Inst Theoret & Computat Sci, Shanghai 200062, Peoples R China. [Shao, Yihan] Q Chem Inc, 6601 Owens Dr,Suite 105, Pleasanton, CA 94588 USA. [Koenig, Gerhard; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, 5635 Fishers Lane,T-900 Suite, Rockville, MD 20852 USA. [Zhang, John Z. H.; Mei, Ye] NYU Shanghai, NYU ECNU Ctr Computat Chem, Shanghai 200062, Peoples R China. RP Mei, Y (reprint author), E China Normal Univ, State Key Lab Precis Spect, Shanghai 200062, Peoples R China.; Mei, Y (reprint author), E China Normal Univ, Dept Phys, Shanghai 200062, Peoples R China.; Mei, Y (reprint author), E China Normal Univ, Inst Theoret & Computat Sci, Shanghai 200062, Peoples R China.; Mei, Y (reprint author), NYU Shanghai, NYU ECNU Ctr Computat Chem, Shanghai 200062, Peoples R China. EM ymei@phy.ecnu.edu.cn RI MEI, Ye/C-5843-2009 OI MEI, Ye/0000-0002-3953-8508 FU National Natural Science Foundation of China [21173082, 21433004]; Large Instruments Open Foundation of East China Normal University FX We thank Dr. Stefan Boresch and Dr. Michael Shirts for helpful discussions. This work is supported by the National Natural Science Foundation of China (Grant Nos. 21173082 and 21433004) and the Large Instruments Open Foundation of East China Normal University. We also thank the Supercomputer Center of East China Normal University for CPU time support. NR 124 TC 8 Z9 8 U1 7 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 EI 1549-9626 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD FEB PY 2016 VL 12 IS 2 BP 499 EP 511 DI 10.1021/acs.jctc.5b00920 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DD7OB UT WOS:000370112900005 PM 26731197 ER PT J AU Blair, RJR AF Blair, Robert J. R. TI The Neurobiology of Impulsive Aggression SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID BORDERLINE PERSONALITY-DISORDER; VENTROMEDIAL PREFRONTAL CORTEX; CALLOUS-UNEMOTIONAL TRAITS; ORBITAL FRONTAL-CORTEX; DECISION-MAKING; ORBITOFRONTAL CORTEX; NEURAL MECHANISMS; PROACTIVE AGGRESSION; PERIAQUEDUCTAL GRAY; PSYCHOPATHIC TRAITS AB This selective review provides a model of the neurobiology of impulsive aggression from a cognitive neuroscience perspective. It is argued that prototypical cases of impulsive aggression, those associated with anger, involve the recruitment of the acute threat response system structures; that is, the amygdala, hypothalamus, and periaqueductal gray. It is argued that whether the recruitment of these structures results in impulsive aggression or not reflects the functional roles of ventromedial frontal cortex and dorsomedial frontal and anterior insula cortex in response selection. It is also argued that impulsive aggression may occur because of impaired decision making. The aggression may not be accompanied by anger, but it will reflect disrupted evaluation of the rewards/benefits of the action. C1 [Blair, Robert J. R.] NIMH, Sect Affect Cognit Neurosci, NIH, US Dept HHS, Bethesda, MD 20852 USA. RP Blair, RJR (reprint author), NIMH, Sect Affect Cognit Neurosci, NIH, US Dept HHS, Bethesda, MD 20852 USA. EM JamesBlair@mail.nih.gov FU National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health under grant number 1-ZIA-MH002860-08. NR 71 TC 3 Z9 3 U1 12 U2 21 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2016 VL 26 IS 1 SI SI BP 4 EP 9 DI 10.1089/cap.2015.0088 PG 6 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA DE0DH UT WOS:000370294600003 PM 26465707 ER PT J AU Farmer, CA Kaat, AJ Mazurek, MO Lainhart, JE DeWitt, MB Cook, EH Butter, EM Aman, MG AF Farmer, Cristan A. Kaat, Aaron J. Mazurek, Micah O. Lainhart, Janet E. DeWitt, Mary Beth Cook, Edwin H. Butter, Eric M. Aman, Michael G. TI Confirmation of the Factor Structure and Measurement Invariance of the Children's Scale of Hostility and Aggression: Reactive/Proactive in Clinic-Referred Children With and Without Autism Spectrum Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID TESTING MEASUREMENT INVARIANCE; OF-FIT INDEXES; PROACTIVE AGGRESSION; REACTIVE AGGRESSION; DOUBLE-BLIND; BEHAVIOR; ADOLESCENTS; RELIABILITY; PSYCHIATRY; CHECKLIST AB Objective: The measurement of aggression in its different forms (e.g., physical and verbal) and functions (e.g., impulsive and instrumental) is given little attention in subjects with developmental disabilities (DD). In this study, we confirm the factor structure of the Children's Scale for Hostility and Aggression: Reactive/Proactive (C-SHARP) and demonstrate measurement invariance (consistent performance across clinical groups) between clinic-referred groups with and without autism spectrum disorder (ASD). We also provide evidence of the construct validity of the C-SHARP. Methods: Caregivers provided C-SHARP, Child Behavior Checklist (CBCL), and Proactive/Reactive Rating Scale (PRRS) ratings for 644 children, adolescents, and young adults 2-21 years of age. Five types of measurement invariance were evaluated within a confirmatory factor analytic framework. Associations among the C-SHARP, CBCL, and PRRS were explored. Results: The factor structure of the C-SHARP had a good fit to the data from both groups, and strict measurement invariance between ASD and non-ASD groups was demonstrated (i.e., equivalent structure, factor loadings, item intercepts and residuals, and latent variance/covariance between groups). The C-SHARP Problem Scale was more strongly associated with CBCL Externalizing than with CBCL Internalizing, supporting its construct validity. Subjects classified with the PRRS as both Reactive and Proactive had significantly higher C-SHARP Proactive Scores than those classified as Reactive only, who were rated significantly higher than those classified by the PRRS as Neither Reactive nor Proactive. A similar pattern was observed for the C-SHARP Reactive Score. Conclusions: This study provided evidence of the validity of the C-SHARP through confirmation of its factor structure and its relationship with more established scales. The demonstration of measurement invariance demonstrates that differences in C-SHARP factor scores were the result of differences in the construct rather than to error or unmeasured/nuisance variables. These data suggest that the C-SHARP is useful for quantifying subtypes of aggressive behavior in children, adolescents, and young adults with DD. C1 [Farmer, Cristan A.; Kaat, Aaron J.; Aman, Michael G.] Ohio State Univ, Dept Psychol, Columbus, OH USA. [Farmer, Cristan A.] NIMH, Dept Pediat & Dev Neurosci, Bethesda, MD 20892 USA. [Kaat, Aaron J.] Northwestern Univ, Dept Med Social Sci, Chicago, IL 60611 USA. [Mazurek, Micah O.] Univ Missouri, Dept Hlth Psychol, Columbia, MO USA. [Lainhart, Janet E.] Univ Utah, Dept Child Psychiat, Salt Lake City, UT USA. [Lainhart, Janet E.] Univ Wisconsin, Waisman Ctr, Madison, WI 53705 USA. [DeWitt, Mary Beth] Childrens Med Ctr Dayton, Dayton, OH USA. [Cook, Edwin H.] Univ Illinois, Dept Psychiat, Chicago, IL 60680 USA. [Butter, Eric M.] Nationwide Childrens Hosp, Dept Psychol, Columbus, OH USA. RP Farmer, CA (reprint author), 10 Ctr Dr MSC1255, Bethesda, MD 20892 USA. EM cristan.farmer@nih.gov OI Mazurek, Micah/0000-0001-7715-6538; Kaat, Aaron/0000-0001-8147-1899 FU Graduate School of the Ohio State University; Organization for Autism Research [P50 HD055751, R01 MH080826, R01 MH097464] FX This work was supported by an alumni grant from the Graduate School of the Ohio State University (to Cristan Farmer), a graduate student grant from the Organization for Autism Research (to Cristan Farmer), P50 HD055751 (to Edwin Cook), and R01 MH080826 and R01 MH097464 (to Janet Lainhart, formerly at University of Utah). NR 36 TC 0 Z9 0 U1 4 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2016 VL 26 IS 1 SI SI BP 10 EP 18 DI 10.1089/cap.2015.0098 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA DE0DH UT WOS:000370294600004 PM 26744772 ER PT J AU Stoddard, J Sharif-Askary, B Harkins, EA Frank, HR Brotman, MA Penton-Voak, IS Maoz, K Bar-Haim, Y Munafo, M Pine, DS Leibenluft, E AF Stoddard, Joel Sharif-Askary, Banafsheh Harkins, Elizabeth A. Frank, Heather R. Brotman, Melissa A. Penton-Voak, Ian S. Maoz, Keren Bar-Haim, Yair Munafo, Marcus Pine, Daniel S. Leibenluft, Ellen TI An Open Pilot Study of Training Hostile Interpretation Bias to Treat Disruptive Mood Dysregulation Disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID INFORMATION-PROCESSING MECHANISMS; FACIAL EXPRESSIONS; BIPOLAR DISORDER; AGGRESSIVE-BEHAVIOR; AMYGDALA RESPONSES; LABELING DEFICITS; IRRITABILITY; CHILDREN; EMOTION; ANXIETY AB Objective: Irritability in disruptive mood dysregulation disorder (DMDD) may be associated with a biased tendency to judge ambiguous facial expressions as angry. We conducted three experiments to explore this bias as a treatment target. We tested: 1) whether youth with DMDD express this bias; 2) whether judgment of ambiguous faces can be altered in healthy youth by training; and 3) whether such training in youth with DMDD is associated with reduced irritability and associated changes in brain function. Methods: Participants in all experiments made happy versus angry judgments of faces that varied along a happy to angry continuum. These judgments were used to quantify a balance point, the facial expression at which a participant's judgment switches from predominantly happy to predominantly angry. We first compared balance points in youth with DMDD (n=63) versus healthy youth (n=26). We then conducted a double-blind, randomized controlled trial of active versus sham balance-point training in 19 healthy youth. Finally, we piloted open, active balance-point training in 14 youth with DMDD, with 10 completing an implicit functional MRI (fMRI) face-emotion processing task. Results: Relative to healthy youth, DMDD youth manifested a shifted balance point, expressed as a tendency to classify ambiguous faces as angry rather than happy. In both healthy and DMDD youth, active training is associated with a shift in balance point toward more happy judgments. In DMDD, evidence suggests that active training may be associated with decreased irritability and changes in activation in the lateral orbitofrontal cortex. Conclusions:These results set the stage for further research on computer-based treatment targeting interpretation bias of angry faces in DMDD. Such treatment may decrease irritability and alter neural responses to subtle expressions of happiness and anger. C1 [Stoddard, Joel; Sharif-Askary, Banafsheh; Harkins, Elizabeth A.; Frank, Heather R.; Brotman, Melissa A.; Leibenluft, Ellen] NIMH, Sect Bipolar Spectrum Disorders, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Penton-Voak, Ian S.; Munafo, Marcus] Univ Bristol, Sch Expt Psychol, Bristol, Avon, England. [Maoz, Keren; Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Bar-Haim, Yair] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Munafo, Marcus] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England. [Munafo, Marcus] Univ Bristol, UK Ctr Tobacco & Alcohol Studies, Bristol, Avon, England. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Emot & Dev Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Stoddard, J (reprint author), 9000 Rockville Pike MSC 2670,Bldg 15K, Bethesda, MD 20892 USA. EM joel.stoddard@nih.gov RI Brotman, Melissa/H-7409-2013 FU National Institute of Mental Health (National Institutes of Health [NIH]), Division of Intramural Research FX This study was supported by the National Institute of Mental Health (National Institutes of Health [NIH]), Division of Intramural Research, and was conducted under NIH Clinical Study Protocols 00-M-0198 (ClinicalTrials.gov # NCT00006177) and 02-M-0021 (ClinicalTrials.gov # NCT00025935). NR 49 TC 5 Z9 5 U1 4 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 EI 1557-8992 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD FEB 1 PY 2016 VL 26 IS 1 SI SI BP 49 EP 57 DI 10.1089/cap.2015.0100 PG 9 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA DE0DH UT WOS:000370294600008 PM 26745832 ER PT J AU Kim, IC Bang, G Lee, JH Kim, KP Kim, YH Kim, HK Chung, J AF Kim, Il Chan Bang, Geul Lee, Jeong Hwa Kim, Kwang Pyo Kim, Young Hwan Kim, Hark Kyun Chung, Jinsoo TI Low C24-OH and C22-OH sulfatides in human renal cell carcinoma (vol 49, pg 409, 2014) SO JOURNAL OF MASS SPECTROMETRY LA English DT Correction C1 [Kim, Il Chan; Kim, Young Hwan] Korea Basic Sci Inst, Div Mass Spectrometry Res, Ochang 363883, South Korea. [Bang, Geul] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Lee, Jeong Hwa; Kim, Kwang Pyo] Kyung Hee Univ, Coll Appl Sci, Dept Appl Chem, Yong In City 446701, South Korea. [Kim, Hark Kyun; Chung, Jinsoo] Natl Canc Ctr, Goyang 410769, Gyeonggi, South Korea. RP Kim, IC (reprint author), Korea Basic Sci Inst, Div Mass Spectrometry Res, Ochang 363883, South Korea. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-5174 EI 1096-9888 J9 J MASS SPECTROM JI J. Mass Spectrom. PD FEB PY 2016 VL 51 IS 2 BP 182 EP 182 DI 10.1002/jms.3736 PG 1 WC Biochemical Research Methods; Chemistry, Analytical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA DE5AP UT WOS:000370643000011 PM 26889935 ER PT J AU Polimeni, JR Bhat, H Witzel, T Benner, T Feiweier, T Inati, SJ Renvall, V Heberlein, K Wald, LL AF Polimeni, Jonathan R. Bhat, Himanshu Witzel, Thomas Benner, Thomas Feiweier, Thorsten Inati, Souheil J. Renvall, Ville Heberlein, Keith Wald, Lawrence L. TI Reducing Sensitivity Losses Due to Respiration and Motion in Accelerated Echo Planar Imaging by Reordering the Autocalibration Data Acquisition SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE GRAPPA; high-resolution fMRI; high-field fMRI; parallel imaging; image reconstruction ID GEOMETRIC DISTORTION; HUMAN BRAIN; 3 T; RESONANCE; NMR; MRI; ROBUST; GRAPPA; COIL AB Purpose: To reduce the sensitivity of echo-planar imaging (EPI) auto-calibration signal (ACS) data to patient respiration and motion to improve the image quality and temporal signal-to-noise ratio (tSNR) of accelerated EPI time-series data. Methods: ACS data for accelerated EPI are generally acquired using segmented, multishot EPI to distortion-match the ACS and time-series data. The ACS data are, therefore, typically collected over multiple TR periods, leading to increased vulnerability to motion and dynamic B-0 changes. The fast low-angle excitation echo-planar technique (FLEET) is adopted to reorder the ACS segments so that segments within any given slice are acquired consecutively in time, thereby acquiring ACS data for each slice as rapidly as possible. Results: Subject breathhold and motion phantom experiments demonstrate that artifacts in the ACS data reduce tSNR and produce tSNR discontinuities across slices in the accelerated EPI time-series data. Accelerated EPI data reconstructed using FLEET-ACS exhibit improved tSNR and increased tSNR continuity across slices. Additionally, image quality is improved dramatically when bulk motion occurs during the ACS acquisition. Conclusion: FLEET-ACS provides reduced respiration and motion sensitivity in accelerated EPI, which yields higher tSNR and image quality. Benefits are demonstrated in both conventional-resolution 3T and high-resolution 7T EPI timeseries data. (C) 2015 Wiley Periodicals, Inc. C1 [Polimeni, Jonathan R.; Witzel, Thomas; Renvall, Ville; Wald, Lawrence L.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Bhat, Himanshu; Heberlein, Keith] Siemens Med Solut USA Inc, Charlestown, MA USA. [Benner, Thomas; Feiweier, Thorsten] Siemens AG, Healthcare Sect, Erlangen, Bavaria, Germany. [Inati, Souheil J.] NIMH, Bethesda, MD 20892 USA. [Wald, Lawrence L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Polimeni, JR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM jonp@nmr.mgh.harvard.edu RI Renvall, Ville/M-4165-2013; Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009 OI Renvall, Ville/0000-0002-4070-7030; Polimeni, Jonathan/0000-0002-1348-1179; FU NIH National Institute for Biomedical Imaging and Bioengineering [P41-EB015896, K01-EB011498]; NIH National Center for Research Resources [P41-RR14075, S10-RR023401, S10-RR019307, S10-RR023043, S10-RR019371, S10-RR020948]; NIH Blueprint for Neuroscience Research [U01-MH093765] FX Grant sponsor: NIH National Institute for Biomedical Imaging and Bioengineering; Grant numbers: P41-EB015896, K01-EB011498; Grant sponsor: NIH National Center for Research Resources; Grant number: P41-RR14075, S10-RR023401, S10-RR019307, S10-RR023043, S10-RR019371, S10-RR020948; Grant sponsor: the NIH Blueprint for Neuroscience Research; Grant number: U01-MH093765. NR 40 TC 12 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2016 VL 75 IS 2 BP 665 EP 679 DI 10.1002/mrm.25628 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DE4KG UT WOS:000370597000020 PM 25809559 ER PT J AU Passeri, E Jones-Brando, L Bordon, C Sengupta, S Wilson, AM Primerano, A Rapoport, JL Ishizuka, K Kano, S Yolken, RH Sawa, A AF Passeri, Eleonora Jones-Brando, Lorraine Bordon, Claudia Sengupta, Srona Wilson, Ashley M. Primerano, Amedeo Rapoport, Judith L. Ishizuka, Koko Kano, Shin-ichi Yolken, Robert H. Sawa, Akira TI Infection and characterization of Toxoplasma gondii in human induced neurons from patients with brain disorders and healthy controls SO MICROBES AND INFECTION LA English DT Article DE Toxoplasma gondii; Induced neuronal cells; Cysts; Tachyzoites; Schizophrenia; Brain disorders ID FUNCTIONAL-NEURONS; BIPOLAR DISORDER; ANTIBODIES; SCHIZOPHRENIA; FIBROBLASTS; CELLS; CONVERSION; DISEASES; RISK AB Toxoplasma gondii is a protozoan parasite capable of establishing persistent infection within the brain. Serological studies in humans have linked exposure to Toxoplasma to neuropsychiatric disorders. However, serological studies have not elucidated the related molecular mechanisms within neuronal cells. To address this question, we used human induced neuronal cells derived from peripheral fibroblasts of healthy individuals and patients with genetically-defined brain disorders (i.e. childhood-onset schizophrenia with disease-associated copy number variations). Parasite infection was characterized by differential detection of tachyzoites and tissue cysts in induced neuronal cells. This approach may aid study of molecular mechanisms underlying individual predisposition to Toxoplasma infection linked to neuropathology of brain disorders. (C) 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. C1 [Passeri, Eleonora; Sengupta, Srona; Wilson, Ashley M.; Primerano, Amedeo; Ishizuka, Koko; Kano, Shin-ichi; Sawa, Akira] Johns Hopkins Univ, Sch Med, Dept Psychiat, 600 N Wolfe St, Baltimore, MD 21287 USA. [Passeri, Eleonora; Sengupta, Srona; Wilson, Ashley M.; Primerano, Amedeo; Ishizuka, Koko; Kano, Shin-ichi; Sawa, Akira] Johns Hopkins Univ, Sch Med, Dept Behav Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. [Jones-Brando, Lorraine; Bordon, Claudia; Yolken, Robert H.] Johns Hopkins Univ, Sch Med, Pediat, 600 N Wolfe St, Baltimore, MD 21287 USA. [Rapoport, Judith L.] Magnuson Clin Ctr, Natl Inst Mental Hlth, Room 3N202,MSC 1600, Bethesda, MD 20814 USA. RP Yolken, RH; Sawa, A (reprint author), 600 N Wolfe St, Baltimore, MD 21287 USA. EM rhyolken@gmail.com; asawa1@jhmi.edu RI Ishizuka, Koko/L-2071-2014; Kano, Shin-ichi/F-4144-2015 OI Kano, Shin-ichi/0000-0002-5171-3436 FU USPHS [MH-084018, MH-094268, MH-069853, MH-085226, MH-088753, MH-092443, MH-105660]; RUSK/S-R Foundations; NARSAD; Maryland Stem Cell Research Fund; Stanley Medical Research Institute FX We thank Drs. Pamela Talalay and Nao Gamo for critical reading of the manuscript. We thank Ms. Yukiko Y. Lema for organizing the manuscript and figures. This work was supported by USPHS grants of MH-084018 (A.S.), MH-094268 Silvio O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), MH-092443 (A.S.), MH-105660 (A.S., K.I.), RUSK/S-R Foundations (A.S.), NARSAD (A.S., S.K., K.I.), Maryland Stem Cell Research Fund (A.S., K.I) and a grant from the Stanley Medical Research Institute. NR 31 TC 1 Z9 1 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 EI 1769-714X J9 MICROBES INFECT JI Microbes Infect. PD FEB PY 2016 VL 18 IS 2 BP 153 EP 158 DI 10.1016/j.micinf.2015.09.023 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DE1GP UT WOS:000370375400010 PM 26432947 ER PT J AU Florea, AD Townsley, DM Dumitriu, B Winkler, T Valdez, J Bolan, C Dunbar, C Young, N Braylan, RC Calvo, KR AF Florea, Alina Dulau Townsley, Danielle M. Dumitriu, Bogdan Winkler, Thomas Valdez, Janet Bolan, Charles Dunbar, Cynthia Young, Neal Braylan, Raul C. Calvo, Katherine R. TI Multilineage Bone Marrow Response to Eltrombopag in Aplastic Anemia SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 [Florea, Alina Dulau; Townsley, Danielle M.; Dumitriu, Bogdan; Winkler, Thomas; Valdez, Janet; Bolan, Charles; Dunbar, Cynthia; Young, Neal; Braylan, Raul C.; Calvo, Katherine R.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1357 BP 342A EP 342A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502365 ER PT J AU Florea, AD Young, N Maric, I Braylan, RC AF Florea, Alina Dulau Young, Neal Maric, Irina Braylan, Raul C. TI Expression of Glycosylphosphatidylinositol (GPI) Anchor Protein (AP) in Bone Marrows of Normal Subjects and Aplastic Anemia Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Clones, as Determined by Fluorescent Aerolysin (FLAER) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1356 BP 342A EP 342A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502364 ER PT J AU Gong, SY Ganapathi, KA McCall, CM Crane, GM Xi, LQ Raffeld, M Pittaluga, S Duffield, AS Jaffe, ES AF Gong, Shunyou Ganapathi, Karthik A. McCall, Chad M. Crane, Genevieve M. Xi, Liqiang Raffeld, Mark Pittaluga, Stefania Duffield, Amy S. Jaffe, Elaine S. TI EBV plus Marginal Zone Lymphoma in Immunocompromised Patients: Report of Five Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1376 BP 347A EP 347A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502384 ER PT J AU Kallen, ME Townley, DM Dumitriu, B Hsu, AP Ganapathi, KA Wang, WX Bolan, C Holland, SM Young, NS Calvo, KR AF Kallen, Michael E. Townley, Danielle M. Dumitriu, Bogdan Hsu, Amy P. Ganapathi, Karthik A. Wang, Weixin Bolan, Charles Holland, Steven M. Young, Neal S. Calvo, Katherine R. TI Bone Marrow Failure in Telomere Disease in Comparison to Aplastic Anemia and GATA2 Deficiency SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bethesda, MD 20892 USA. NCI, 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1405 BP 355A EP 355A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502413 ER PT J AU Schmidt, J Salaverria, I Gong, SY Pittaluga, S Gonzalez, B Balague, O Marafioti, T Mozos, A Cabecadas, JM Bonzheim, I Fend, F Campo, E Jaffe, ES Quintanilla-Fend, L AF Schmidt, Janine Salaverria, Itziar Gong, Shunyou Pittaluga, Stefania Gonzalez, Blanca Balague, Olga Marafioti, Theresa Mozos, Anna Cabecadas, Jose M. Bonzheim, Irma Fend, Falko Campo, Elias Jaffe, Elaine S. Quintanilla-Fend, Leticia TI The Genetic Landscape in Follicular Lymphoma, Pediatric Type SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Univ Hosp, Tubingen, Germany. IDIBAPS, Hosp Clin, Barcelona, Spain. NCI, Bethesda, MD 20892 USA. Barts & London NHS Trust, London, England. Hosp Santa Creu & Sant Pau, Barcelona, Spain. Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal. NR 0 TC 0 Z9 0 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1483 BP 376A EP 376A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502490 ER PT J AU Wake, LM Ahn, I Farooqui, M Hahn, J Tian, X Steller-Stevenson, M Marti, G Wiestner, A Maric, I AF Wake, Laura M. Ahn, Inhye Farooqui, Mohammed Hahn, Jamie Tian, Xin Steller-Stevenson, Maryalice Marti, Gerald Wiestner, Adrian Maric, Irina TI Dual Antibody Immunohistochemistry: A Cost-Efficient and Sensitive New Tool for the Detection of Minimal Residual CLL SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NIH, CC, DLM, Bldg 10, Bethesda, MD 20892 USA. US FDA, CDRH, Bethesda, MD 20014 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1507 BP 382A EP 382A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502513 ER PT J AU Xiao, WB Kuang, FL Sharma, S Hahn, J Stetler-Stevenson, M Raffeld, M Klion, A Maric, I AF Xiao, Wenbin Kuang, Fei Li Sharma, Sachein Hahn, Jamie Stetler-Stevenson, Maryalice Raffeld, Mark Klion, Amy Maric, Irina TI Hypereosinophilic Syndrome with Clonal T-cell Receptor Gene Rearrangement: A Retrospective Study of 51 Patients SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NCI, 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1519 BP 385A EP 385A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502525 ER PT J AU Xiao, WB Sanchez, GM Marrero, B de Jesus, AA Miniti, C Gong, SY Schafernak, KT Goldbach-Mansky, R Calvo, KR AF Xiao, Wenbin Sanchez, Gina Montealegre Marrero, Bernadette de Jesus, Adriana Almeida Miniti, Caterina Gong, Shunyou Schafernak, Kristian T. Goldbach-Mansky, Raphaela Calvo, Katherine R. TI Spectrum of Bone Marrow Features in CANDLE Syndrome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, CC, Bldg 10, Bethesda, MD 20892 USA. NIAMS, NIH, Bethesda, MD USA. NHLBI, Bldg 10, Bethesda, MD 20892 USA. Lurie Childrens Hosp, Chicago, IL USA. Phoenix Childrens Hosp, Phoenix, AZ 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1520 BP 385A EP 385A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302502526 ER PT J AU McCarthy, A Moreno, V Xu, NZ Kennedy, S Merino, MJ AF McCarthy, Aoife Moreno, Vanessa Xu Naizhen Kennedy, Susan Merino, Maria J. TI PD-L1 Expression in Intraocular Malignant Melanomas. Correlation with Morphologic Patterns and Outcome SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Royal Victoria Eye & Ear Hosp, Dublin, Ireland. 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1718 BP 433A EP 434A PG 2 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503191 ER PT J AU McCarthy, A Moreno, V Xu, NZ Kennedy, S Merino, MJ AF McCarthy, Aoife Moreno, Vanessa Xu Naizhen Kennedy, Susan Merino, Maria J. TI Intraocular Malignant Melanoma: Correlation of Morphological and Molecular Findings with Outcome in an Irish Cohort SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Royal Victoria Eye & Ear Hosp, Dublin, Ireland. NCI, 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1717 BP 433A EP 433A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503190 ER PT J AU Pineda, I Edwards, N Goldstein, D Ray-Chaudhury, A AF Pineda, Itzel Edwards, Nancy Goldstein, David Ray-Chaudhury, Abhik TI Expression of Nuclear Receptor NR4A3 in Multiple System Atrophy and Dementia With Lewy Bodies SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 [Pineda, Itzel; Edwards, Nancy; Goldstein, David; Ray-Chaudhury, Abhik] NINDS, NIH, Bldg 36,Rm 4D04, 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1726 BP 435A EP 435A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503199 ER PT J AU Adsay, V Roa, JC Basturk, O Torres, J Mucientes, F Del Pozo, M Villaseca, MA Aguayo, G Bellolio, ER Araya, JC Endo, B Lee, K Jang, KT Jang, JY Ohike, N Shimizu, M Hirabayashi, K Terris, B Zamboni, G Reid, M Xue, Y Bedolla, G Quigley, B Krasinskas, A Akkas, G Memis, B Klimstra, D Hruban, RH Zhu, B Van Dyke, AL Koshiol, J AF Adsay, Volkan Roa, Juan Carlos Basturk, Ocla Torres, Javiera Mucientes, Francisco Del Pozo, Maeva Villaseca, Miguel A. Aguayo, Gloria Bellolio, Enrique R. Araya, Juan Carlos Endo, Baru Lee, KyoungBun Jang, Kee-Taek Jang, Jin-Young Ohike, Nobu Shimizu, Michio Hirabayashi, Kenichi Terris, Benoit Zamboni, Giuseppe Reid, Michelle Xue, Yue Bedolla, Gabriela Quigley, Brian Krasinskas, Alyssa Akkas, Gizem Memis, Bahar Klimstra, David Hruban, Ralph H. Zhu, Bin Van Dyke, Alison L. Koshiol, Jill TI Epithelial Atypia in the Gallbladder: Diagnosis and Classification in an International Consensus Study SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Emory, Atlanta, GA USA. Pontificia Univ, Santiago, Chile. MSKCC, New York, NY USA. Yokohama City Univ, Yokohama, Kanagawa 232, Japan. SNU, Seoul, South Korea. SMC, Seoul, South Korea. Hakujikai Hosp, Tokyo, Japan. Hosp Cochin, Paris, France. Univ Verona, I-37100 Verona, Italy. JHU, Baltimore, MD USA. NIH, Bldg 10, 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1738 BP 438A EP 439A PG 2 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503211 ER PT J AU Roa, JC Basturk, O Torres, J Mucientes, F Del Pozo, M Villaseca, MA Aguayo, G Bellolio, ER Araya, JC Endo, I Jang, KT Lee, K Jang, JY Ohike, N Shimizu, M Hirabayashi, K Terris, B Zamboni, G Reid, M Xue, Y Bedolla, G Quigley, B Krasinskas, AM Akkas, G Memis, B Klimstra, D Hruban, RH Zhu, B Van Dyke, AL Koshiol, J Adsay, V AF Roa, Juan Carlos Basturk, Olca Torres, Javiera Mucientes, Francisco Del Pozo, Maeva Villaseca, Miguel A. Aguayo, Gloria Bellolio, Enrique R. Araya, Juan Carlos Endo, Itaru Jang, Kee-Taek Lee, KyoungBun Jang, Jin-Young Ohike, Nobu Shimizu, Michio Hirabayashi, Kenichi Terris, Benoit Zamboni, Giuseppe Reid, Michelle Xue, Yue Bedolla, Gabriela Quigley, Brian Krasinskas, Alyssa M. Akkas, Gizem Memis, Bahar Klimstra, David Hruban, Ralph H. Zhu, Bin Van Dyke, Alison L. Koshiol, Jill Adsay, Volkan TI Marked Geographic Differences in the Pathologic Diagnosis of Non-Invasive (Tis) vs Minimally Invasive (T1) Gallbladder Cancer: Santiago Consensus Conference Highlights the Need for the Unifying Category "Early Gallbladder Cancer" (EGBC) SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Pontificia Univ, Santiago, Chile. MSKCC, New York, NY USA. Yokohama City Univ, Yokohama, Kanagawa 232, Japan. SMC, Seoul, South Korea. SNU, Seoul, South Korea. Hakujikai Hosp, Tokyo, Japan. Tokai Univ, Tokyo 151, Japan. Hop Cochin, 27 Rue Faubourg St Jacques, F-75674 Paris, France. Univ Verona, I-37100 Verona, Italy. Emory Univ, Atlanta, GA 30322 USA. JHU, Baltimore, MD USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1772 BP 447A EP 447A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503245 ER PT J AU Killian, J Arcila, ME Batlevi, C Ladanyi, M Meltzer, P Ptashkin, R Younes, A AF Killian, Jonathan Arcila, Maria E. Batlevi, Connie Ladanyi, Marc Meltzer, Paul Ptashkin, Ryan Younes, Anas TI Utility of Oral Fluid (Saliva) for Molecular Profiling in Hematologic Malignancy SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1803 BP 455A EP 455A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503276 ER PT J AU Felisiak-Golabek, A Wasag, B Wang, ZF Czapiewski, P Biernat, W Lasota, J Miettinen, M AF Felisiak-Golabek, Anna Wasag, Bartosz Wang, Zengfeng Czapiewski, Piotr Biernat, Wojciech Lasota, Jerzy Miettinen, Markku TI Inactivation of BRCA1 Associated Protein-1 (BAP1) in Mesothelioma. Immunohistochemical and Molecular Genetic Study of 94 Cases SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Med Univ Gdansk, Gdansk, Poland. 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 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 1862 BP 470A EP 470A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503335 ER PT J AU Varma, H Faust, PL Nagy, PL Iglesias, AD Lagana, SM Wou, K Hirano, M Mansukhani, M Hoff, KE Copeland, WC Naini, AB AF Varma, Hemant Faust, Phyllis L. Nagy, Peter L. Iglesias, Alejandro D. Lagana, Stephen M. Wou, Karen Hirano, Michio Mansukhani, Mahesh Hoff, Kirsten E. Copeland, William C. Naini, Ali B. TI Whole-Exome Sequencing Identifies a Homozygous POLG2 Missense Variant in an Infant with Fulminant Hepatic Failure and Mitochondrial DNA Depletion SO MODERN PATHOLOGY LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Columbia Univ, Med Ctr, New York, NY USA. New York Presbyterian Hosp, New York, NY USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2016 VL 29 SU 2 MA 2079 BP 523A EP 523A PG 1 WC Pathology SC Pathology GA DE0GI UT WOS:000370302503552 ER PT J AU Levy, BR Ferrucci, L Zonderman, AB Slade, MD Troncoso, J Resnick, SM AF Levy, Becca R. Ferrucci, Luigi Zonderman, Alan B. Slade, Martin D. Troncoso, Juan Resnick, Susan M. TI A Culture-Brain Link: Negative Age Stereotypes Predict Alzheimer's Disease Biomarkers SO PSYCHOLOGY AND AGING LA English DT Article DE age stereotypes; perceptions of aging; social cognition; Alzheimer's disease; brain ID OLDER-ADULTS; HIPPOCAMPAL VOLUME; SELF-PERCEPTIONS; AGING BLSA; STRESS; MEMORY; METAANALYSIS; MODEL; TIME; DISCRIMINATION AB Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer's disease. To consider this possibility, we drew on dementia-free participants, in the Baltimore Longitudinal Study of Aging, whose age stereotypes were assessed decades before yearly magnetic resonance images and brain autopsies were performed. Those holding more-negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss and significantly greater accumulation of neurofibrillary tangles and amyloid plaques, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the pathology of Alzheimer's disease. C1 [Levy, Becca R.] Yale Univ, Social & Behav Sci Div, Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, Gerontol Res Ctr, Bethesda, MD 20892 USA. [Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Slade, Martin D.] Yale Univ, Dept Med, Sch Med, New Haven, CT 06520 USA. [Troncoso, Juan] Johns Hopkins Med Sch, Dept Pathol, Baltimore, MD USA. [Troncoso, Juan] Johns Hopkins Med Sch, Dept Neurol, Baltimore, MD USA. [Resnick, Susan M.] NIA, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Levy, BR (reprint author), Yale Univ, Social & Behav Sci Div, Sch Publ Hlth, 60 Coll St, New Haven, CT 06520 USA. EM becca.levy@yale.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU National Institute on Aging, National Institutes of Health; Yale School of Public Health (National Institute on Aging) [R01AG032284]; Johns Hopkins University Alzheimer's Disease Research Center (National Institute on Aging) [AG 05146]; Johns Hopkins University Alzheimer's Disease Research Center [HHSN-260-2004-00012C] FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health; the Yale School of Public Health (National Institute on Aging Grant R01AG032284); and the Johns Hopkins University Alzheimer's Disease Research Center (National Institute on Aging Grant AG 05146 and Research and Development Contract HHSN-260-2004-00012C). We thank C. Davatzikos of Johns Hopkins Medical School for his hippocampal volume analyses and R. J. O'Brien of Duke University School of Medicine for his autopsy analyses. We also thank the Baltimore Longitudinal Study of Aging participants and staff for their contributions to our studies. NR 60 TC 10 Z9 10 U1 2 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 EI 1939-1498 J9 PSYCHOL AGING JI Psychol. Aging PD FEB PY 2016 VL 31 IS 1 BP 82 EP 88 DI 10.1037/pag0000062 PG 7 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA DE4AR UT WOS:000370572100009 PM 26641877 ER PT J AU Lungu, C Ahmad, OF AF Lungu, Codrin Ahmad, Omar F. TI Update on the Use of Botulinum Toxin Therapy for Focal and Task-Specific Dystonias SO SEMINARS IN NEUROLOGY LA English DT Article DE botulinum; dystonia; therapy; task-specific; focal dystonia ID PRIMARY WRITING TREMOR; MOVEMENT-DISORDERS; WRITERS CRAMP; SPASMODIC DYSPHONIA; MUSICIANS DYSTONIA; HAND DYSTONIA; YIPS; GOLFERS; EXPERIENCE; NEUROTOXIN AB Focal dystonia is defined by anatomical distribution and represents a distinct entity from generalized dystonia. Task-specific dystonia occurs in the context of specific patterns of movement. Botulinum neurotoxin (BoNT) injections are the treatment of choice in most cases. Several formulations are available; the approved indications, dosing, and some administration details, differ between them. The major forms of focal and task -specific dystonia are reviewed, along with the evidence for BoNT therapy, the expected benefit and side effects, and practical points guiding the injections. C1 [Lungu, Codrin; Ahmad, Omar F.] NINDS, Off Clin Director, NIH, Bldg 10,Rm 7D37,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. RP Lungu, C (reprint author), NINDS, Off Clin Director, NIH, Bldg 10,Rm 7D37,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA.; Lungu, C (reprint author), NINDS, NIH, Bldg 10,Rm 7D37,MSC 1428,10 Ctr Dr, Bethesda, MD 20892 USA. EM lunguci@ninds.nih.gov NR 46 TC 1 Z9 1 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD FEB PY 2016 VL 36 IS 1 BP 41 EP 46 DI 10.1055/s-0035-1571211 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA DE1NX UT WOS:000370394800008 PM 26866495 ER PT J AU Karp, BI Alter, K AF Karp, Barbara Illowsky Alter, Katharine TI Botulinum Toxin Treatment of Blepharospasm, Orofacial/Oromandibular Dystonia, and Hemifacial Spasm SO SEMINARS IN NEUROLOGY LA English DT Article DE blepharospasm; orofacial dystonia; oromandibular dystonia; hemifacial spasm; Meige's syndrome; botulinum toxin ID BENIGN ESSENTIAL BLEPHAROSPASM; LONG-TERM EFFICACY; QUALITY-OF-LIFE; DEEP BRAIN-STIMULATION; IDIOPATHIC OROMANDIBULAR DYSTONIA; CRANIAL-CERVICAL DYSTONIA; MEIGE-SYNDROME; FOLLOW-UP; MOVEMENT-DISORDERS; FACIAL-MUSCLES AB Blepharospasm is a focal dystonia characterized by involuntary, repetitive eye closure. Orofacial and oromandibular dystonia describe involuntary dystonic movements of orofacial and oromandibular musculature. Hemifacial spasm is characterized by repetitive synchronous contraction of facial nerve innervated muscles on one side of the face. In this article, the clinical presentation, epidemiology, and approaches to treatment are reviewed. Technical aspects of using botulinum toxin for treatment and reported outcomes are discussed. C1 [Karp, Barbara Illowsky] NINDS, Combined NeuroSci IRB, NIH, Bldg 31,Room B2 B32,9000 Rockville Pike, Bethesda, MD 20892 USA. [Alter, Katharine] Warren Grant Magnusen Clin Ctr, Dept Rehabil Med, Bethesda, MD USA. [Alter, Katharine] Eunice Shriver Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. RP Karp, BI (reprint author), NINDS, Combined NeuroSci IRB, NIH, Bldg 31,Room B2 B32,9000 Rockville Pike, Bethesda, MD 20892 USA.; Karp, BI (reprint author), NINDS, NIH, Bldg 31,Room B2 B32,9000 Rockville Pike, Bethesda, MD 20892 USA. EM karpb@ninds.nih.gov FU Intramural Research Program, National Institutes of Health FX This work was supported by the Intramural Research Program, National Institutes of Health. NR 80 TC 1 Z9 1 U1 0 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 EI 1098-9021 J9 SEMIN NEUROL JI Semin. Neurol. PD FEB PY 2016 VL 36 IS 1 BP 84 EP 91 DI 10.1055/s-0036-1571952 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DE1NX UT WOS:000370394800013 PM 26866500 ER PT J AU McLain, AC Sundaram, R Louis, GMB AF McLain, Alexander C. Sundaram, Rajeshwari Louis, Germaine M. Buck TI Modeling fecundity in the presence of a sterile fraction using a semi-parametric transformation model for grouped survival data SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article DE Cure fraction; fecundity; grouped survival; transformation models ID LONG-TERM SURVIVORS; PROPORTIONAL-HAZARDS; PREGNANCY; TIME; FECUNDABILITY; LIFE; PROBABILITY; INTERCOURSE; CONCEPTION AB The analysis of fecundity data is challenging and requires consideration of both highly timed and interrelated biologic processes in the context of essential behaviors such as sexual intercourse during the fertile window. Understanding human fecundity is further complicated by presence of a sterile population, i.e. couples unable to achieve pregnancy. Modeling techniques conducted to date have largely relied upon discrete time-to-pregnancy survival or day-specific probability models to estimate the determinants of time-to-pregnancy or acute effects, respectively. We developed a class of semi-parametric grouped transformation cure models that capture day-level variates purported to affect the cycle-level hazards of conception and, possibly, sterility. Our model's performance is assessed using simulation and longitudinal data from one of the few prospective cohort studies with preconception enrollment of women followed for 12 menstrual cycles at risk for pregnancy. C1 [McLain, Alexander C.; Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Executive Blvd,Room 7B05K, Bethesda, MD 20892 USA. RP McLain, AC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, 6100 Executive Blvd,Room 7B05K, Bethesda, MD 20892 USA. EM mclaina@mail.nih.gov OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of National Institute of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported in part by the Intramural Research Program of the National Institute of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 35 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD FEB PY 2016 VL 25 IS 1 BP 22 EP 36 DI 10.1177/0962280212438646 PG 15 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA DE5PZ UT WOS:000370685000002 PM 22374340 ER PT J AU Banerjee, P Dutta, S Pal, R AF Banerjee, Poulomi Dutta, Sunit Pal, Rajarshi TI Dysregulation of Wnt-Signaling and a Candidate Set of miRNAs Underlie the Effect of Metformin on Neural Crest Cell Development SO STEM CELLS LA English DT Article DE Embryonic stem cells; Neural crest; Epithelial to mesenchymal transition; Metformin; Wnt signaling; miRNA deregulation ID EMBRYONIC STEM-CELLS; N-CADHERIN SWITCH; MICRORNA REGULATION; ZEBRAFISH EMBRYOS; CANCER CELLS; MIGRATION; GENE; INDUCTION; DIFFERENTIATION; SPECIFICATION AB Neural crest cells (NCC) are a population of epithelial cells that arise from the dorsal tube and undergo epithelial-mesenchymal transition (EMT) eventually generating tissues from peripheral nervous system, melanocytes, craniofacial cartilage, and bone. The antidiabetic drug metformin reportedly inhibits EMT in physiological conditions like cancer and fibrosis. We hypothesize that perturbation of EMT may also contribute to developmental disabilities associated with neural crest (NC) development. To understand the molecular network underlying metformin action during NC formation, we first differentiated murine embryonic stem (ES) cells into NCC and characterized them by demonstrating spatiotemporal regulation of key markers. Metformin treatment prompted a delay in delamination of NCC by inhibiting key markers like Sox-1, Sox-9, HNK-1, and p-75. We then revealed that metformin impedes Wnt axis, a major signaling pathway active during NC formation via DVL-3 inhibition and impairment in nuclear translocation of beta-catenin. Concomitantly we identified and tested a candidate set of miRNAs that play a crucial role in NC cell fate determination. Further studies involving loss and gain of function confirmed that NCC specifiers like Sox-1 and Sox-9 are direct targets of miR-200 and miR-145, respectively and that they are essentially modulated by metformin. Our in vitro findings were strongly supported by in vivo studies in zebrafish. Given that metformin is a widely used drug, for the first time we demonstrate that it can induce a delayed onset of developmental EMT during NC formation by interfering with canonical Wnt signaling and mysregulation of miR-145 and miR-200. C1 [Banerjee, Poulomi; Pal, Rajarshi] Manipal Univ, Sch Regenerat Med, Bangalore 560065, Karnataka, India. [Dutta, Sunit] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Pal, R (reprint author), Manipal Univ, Sch Regenerat Med, Bangalore 560065, Karnataka, India. EM rajarshi.pal@manipal.edu FU Manipal University (MU), Manipal; NEI intramural research program; Department of Biotechnology, Ministry of Science and Technology, Govt. of India [BT/PR8394/MED/31/227/2013] FX We thank Dr. Mahendra S. Rao, New York Stem Cell Research Foundation, NY for critical comments and useful suggestions, Dr. Brian Brooks for support, and Dr. Valeria Zarelli for the reagents for in vivo work; Drs. Sanjeev Galande and P. Chandrashekar for lending DVL-3 and TCF-4 antibodies, respectively. We thank Qiagen for the free trial of Ingenuity Pathway Analysis software. We also thank Lithin K. Louis and Harshini Surendran for helping during manuscript preparation. Manipal University (MU), Manipal is gratefully acknowledged for the support in form of infrastructure and graduate fellowship to P.B.; R.P. is a faculty member with MU and S.D. is supported by the NEI intramural research program. This work was partially supported by a grant from the Department of Biotechnology, Ministry of Science and Technology, Govt. of India (# BT/PR8394/MED/31/227/2013). NR 60 TC 4 Z9 4 U1 6 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD FEB PY 2016 VL 34 IS 2 BP 334 EP 345 DI 10.1002/stem.2245 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA DE0ZA UT WOS:000370353200008 PM 26529121 ER PT J AU Stroncek, DF Tran, M Frodigh, SE David-Ocampo, V Ren, JQ Larochelle, A Sheikh, V Sereti, I Miller, JL Longin, K Sabatino, M AF Stroncek, David F. Minh Tran Frodigh, Sue Ellen David-Ocampo, Virginia Ren, Jiaqiang Larochelle, Andre Sheikh, Virginia Sereti, Irini Miller, Jeffery L. Longin, Kevin Sabatino, Marianna TI Preliminary evaluation of a highly automated instrument for the selection of CD34+cells from mobilized peripheral blood stem cell concentrates SO TRANSFUSION LA English DT Article ID ACUTE MYELOID-LEUKEMIA; NATURAL-KILLER-CELLS; HEMATOLOGICAL MALIGNANCIES; CLINIMACS DEVICE; CD34(+) CELLS; ADD-BACK; TRANSPLANTATION; THERAPY; TRIAL; GVHD AB BACKGROUNDCell selection is an important part of manufacturing cellular therapies. A new highly automated instrument, the CliniMACS Prodigy (Miltenyi Biotec), was evaluated for the selection of CD34+ cells from mobilized peripheral blood stem cell (PBSC) concentrates using monoclonal antibodies conjugated to paramagnetic particles. STUDY DESIGN AND METHODSPBSCs were collected by apheresis from 36 healthy subjects given granulocyte-colony-stimulating factor (G-CSF) or G-CSF plus plerixafor. CD34+ cells from 11 PBSC concentrates were isolated with the automated CliniMACS Prodigy and 25 with the semiautomated CliniMACS Plus Instrument. RESULTSThe proportion of CD34+ cells in the selected products obtained with the two instruments was similar: 93.62.6% for the automated and 95.7 +/- 3.3% for the semiautomated instrument (p>0.05). The recovery of CD34+ cells from PBSC concentrates was less for the automated than the semiautomated instrument (51.4 +/- 8.2% vs. 65.1 +/- 15.7%; p=0.019). The selected products from both instruments contained few and similar quantities of platelets (PLTs) and red blood cells. The depletion of CD3+ cells was less with the automated instrument (4.34 +/- 0.2 log depletion vs. 5.20 +/- 0.35 log depletion; p<1 x 10(-6)). Removal of PLTs from PBSC concentrates by washing was associated with better CD34+ cell recovery. We explored the reasons for lower CD34+ cell recovery by the Prodigy and found that the nonselected cells for the Prodigy contained more PLTs than those for the CliniMACS Plus. CONCLUSIONSCD34+ cells can be effectively selected from mobilized PBSC concentrates with the CliniMAC Prodigy, but the recovery of CD34+ cells and depletion of CD3+ cells was lower than with the semiautomated CliniMACS Plus Instrument. C1 [Stroncek, David F.; Minh Tran; Frodigh, Sue Ellen; David-Ocampo, Virginia; Ren, Jiaqiang; Sabatino, Marianna] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, 10 Ctr Dr MSC 1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. [Larochelle, Andre] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sheikh, Virginia; Sereti, Irini] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Miller, Jeffery L.] NIDDK, Mol Genom & Therapeut Sect, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Longin, Kevin] Miltenyi Biotec, Auburn, CA USA. RP Stroncek, DF (reprint author), NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, 10 Ctr Dr MSC 1184,Bldg 10,Room 3C720, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Department of Transfusion Medicine, Clinical Center; Intramural Programs National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD FX This study was supported with funds from the Department of Transfusion Medicine, Clinical Center, the Intramural Programs National Institute of Allergy and Infectious Diseases, the National Heart, Lung, and Blood Institute; and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD. NR 18 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0041-1132 EI 1537-2995 J9 TRANSFUSION JI Transfusion PD FEB PY 2016 VL 56 IS 2 BP 511 EP 517 DI 10.1111/trf.13394 PG 7 WC Hematology SC Hematology GA DD8KF UT WOS:000370174700033 PM 26505619 ER PT J AU Cai, T Notkins, AL AF Cai, Tao Notkins, Abner L. TI Pathophysiologic changes in IA-2/IA-2 beta null mice are secondary to alterations in the secretion of hormones and neurotransmitters SO ACTA DIABETOLOGICA LA English DT Review DE Type 1 diabetes (T1D); Autoantigen; Densecore vesicles (DCV); Glucose intolerance; Behavior and learning; Female infertility; Circadian rhythm ID PROTEIN-TYROSINE-PHOSPHATASE; DEPENDENT DIABETES-MELLITUS; INSULIN-SECRETION; CAENORHABDITIS-ELEGANS; TRANSMEMBRANE PROTEIN; TARGETED DISRUPTION; AUTOANTIGENS IA-2; RECEPTOR-TYPE; IA-2-BETA; FAMILY AB IA-2 and IA-2 beta are transmembrane proteins of dense-core vesicles (DCV). The deletion of these proteins results in a reduction in the number of DCV and the secretion of hormones and neurotransmitters. As a result, this leads to a variety of pathophysiologic changes. The purpose of this review is to describe these changes, which are characterized by glucose intolerance, female infertility, behavior and learning abnormalities and alterations in the diurnal circadian rhythms of blood pressure, heart rate, spontaneous physical activity and body temperature. These findings show that the deletion of IA-2 and IA-2 beta results in multiple pathophysiologic changes and represents a unique in vivo model for studying the effect of hormone and neurotransmitter reduction on known and still unrecognized targets. C1 [Cai, Tao; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, B30-Rm106, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Lab Sensory Biol, NIH, B30-Rm106, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov FU NIH FX We thank previous and current members of the laboratory and collaborators for their excellent contributions to the IA-2/IA-2 beta studies. This research was supported by the Intramural Research Program of the NIH. NR 27 TC 1 Z9 1 U1 1 U2 4 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 0940-5429 EI 1432-5233 J9 ACTA DIABETOL JI Acta Diabetol. PD FEB PY 2016 VL 53 IS 1 BP 7 EP 12 DI 10.1007/s00592-015-0750-z PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD6MI UT WOS:000370037900002 PM 25861885 ER PT J AU Liu, CK Lyass, A Larson, MG Massaro, JM Wang, N D'Agostino, RB Benjamin, EJ Murabito, JM AF Liu, Christine K. Lyass, Asya Larson, Martin G. Massaro, Joseph M. Wang, Na D'Agostino, Ralph B., Sr. Benjamin, Emelia J. Murabito, Joanne M. TI Biomarkers of oxidative stress are associated with frailty: the Framingham Offspring Study SO AGE LA English DT Article DE Frailty; Inflammation; Oxidative stress; Gait speed ID PERIPHERAL ARTERIAL-DISEASE; C-REACTIVE PROTEIN; OLDER-ADULTS; WOMENS HEALTH; GAIT SPEED; CARDIOVASCULAR-DISEASE; MOBILITY DISABILITY; PHYSICAL-ACTIVITY; GRIP STRENGTH; VITAMIN-D AB Cardiovascular disease and frailty frequently occur together. Both are associated with inflammation, which may be partially triggered by oxidative stress, especially in cardiovascular disease. We investigated whether inflammatory and oxidative stress biomarkers linked to cardiovascular disease were associated with frailty and the related outcome of gait speed. We report cross-sectional associations of biomarkers and frailty assessed at Framingham Offspring Study cycle eight. Participants >= 60 years were eligible if they had information on frailty and at least one of the following: C-reactive protein, interleukin-6, tumor necrosis factor receptor 2, 8-epi-FGF alpha isoprostanes (isoprostanes), lipoprotein phospholipase A2 (LpPLA2) mass or activity, osteoprotegerin, intracellular adhesion molecule-1, monocyte chemoattractant protein-1 or P-selectin. Stepwise logistic models were utilized for frailty and stepwise linear models for gait speed. Covariates included age, sex, body mass index, smoking, and co-morbidities. Odds ratios (ORs) and slope estimates (B) are reported per standard deviation increase of loge-transformed biomarker. Of the 1919 participants, 142 (7 %) were frail. In a stepwise model, frailty odds increased with higher interleukin-6 (OR 1.90, 95 % CI 1.51, 2.38), isoprostanes (OR 1.46, 95% CI 1.12, 1.92), and LpPLA2 mass (OR 1.29, 95 % CI 1.00, 1.65). Stepwise regression found that slower gait speeds were associated with interleukin-6 (B=-0.025 m/s, 95 % CI 0.04, -0.01), isoprostanes (B=-0.019, 95 % CI -0.03, -0.008), LpPLA2 mass (B=-0.016, 95 % CI -0.03, -0.004), and osteoprotegerin (B = -0.015, 95 % CI -0.03, -0.002, all p< 0.05). Interleukin-6, isoprostanes, and LpPLA2 mass were associated with greater frailty odds and slower gait speeds. Oxidative stress may be a mechanism contributing to frailty. C1 [Liu, Christine K.] Boston Univ, Sch Med, Dept Med, Sect Geriatr, 88 E Newton St,Robinson 2, Boston, MA 02118 USA. [Liu, Christine K.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Lyass, Asya; Larson, Martin G.; Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; Benjamin, Emelia J.; Murabito, Joanne M.] Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. [Lyass, Asya; Larson, Martin G.; Wang, Na; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Larson, Martin G.; Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Sect Prevent Med, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Liu, CK (reprint author), Boston Univ, Sch Med, Dept Med, Sect Geriatr, 88 E Newton St,Robinson 2, Boston, MA 02118 USA.; Murabito, JM (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM Christine.Liu@bmc.org; murabito@bu.edu FU National Institute on Aging at the National Institutes of Health [R01-AG029451, 1R01-AG028321]; National Heart, Lung and Blood Institute at the National Institutes of Health [1RO1-HL64753, R01-HL076784]; National Heart, Lung, and Blood Institute; Boston University [N01-HC-25195]; American Federation for Aging Research; John A. Hartford Foundation; U.S. Department of Agriculture [1950-51000-068-01S] FX This work was supported by the National Institute on Aging (grant number R01-AG029451 to JM Murabito, 1R01-AG028321 to EJB) and by the National Heart, Lung and Blood Institute (grant number 1RO1-HL64753, R01-HL076784 to EJB), both at the National Institutes of Health. The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (contract number N01-HC-25195). CKL was supported by the American Federation for Aging Research, the John A. Hartford Foundation, and the U.S. Department of Agriculture, under Agreement no. 1950-51000-068-01S. NR 56 TC 8 Z9 8 U1 5 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD FEB PY 2016 VL 38 IS 1 AR 1 DI 10.1007/s11357-015-9864-z PG 10 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA DD1PA UT WOS:000369692400001 PM 26695510 ER PT J AU Withers, K Biradavolu, M Jia, YJ Kapetanovic, S AF Withers, Keenan Biradavolu, Monica Jia, Yujiang Kapetanovic, Suad TI How Locally Specific Factors May Impact the Delivery of HIV-Related Services to the Severely Mentally Ill in Washington, DC SO AIDS PATIENT CARE AND STDS LA English DT Letter ID UNITED-STATES; ILLNESS; INDIVIDUALS C1 [Withers, Keenan; Kapetanovic, Suad] NIMH, NIH, Bethesda, MD 20892 USA. [Biradavolu, Monica] Amer Univ, Washington, DC 20016 USA. [Jia, Yujiang] DC HIV AIDS Hepatitis STD & TB Adm, Washington, DC USA. [Kapetanovic, Suad] Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA USA. RP Kapetanovic, S (reprint author), USC Dept Psychiat, 2250 Alcazar St,Suite 2200,Off 2250, Los Angeles, CA 90033 USA. EM kapetano@usc.edu NR 9 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 EI 1557-7449 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD FEB 1 PY 2016 VL 30 IS 2 BP 49 EP 50 DI 10.1089/apc.2015.0188 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DD2QV UT WOS:000369768200001 PM 26771866 ER PT J AU Akkina, R Allam, A Balazs, AB Blankson, JN Burnett, JC Casares, S Garcia, JV Hasenkrug, KJ Kashanchi, F Kitchen, SG Klein, F Kumar, P Luster, AD Poluektova, LY Rao, M Sanders-Beer, BE Shultz, LD Zack, JA AF Akkina, Ramesh Allam, Atef Balazs, Alejandro B. Blankson, Joel N. Burnett, John C. Casares, Sofia Garcia, J. Victor Hasenkrug, Kim J. Kashanchi, Fatah Kitchen, Scott G. Klein, Florian Kumar, Priti Luster, Andrew D. Poluektova, Larisa Y. Rao, Mangala Sanders-Beer, Brigitte E. Shultz, Leonard D. Zack, Jerome A. TI Improvements and Limitations of Humanized Mouse Models for HIV Research: NIH/NIAID "Meet the Experts" 2015 Workshop Summary SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS ENCEPHALITIS; BROADLY NEUTRALIZING ANTIBODIES; HEMATOPOIETIC STEM-CELLS; SCID-HU MOUSE; T-CELLS; BLT MICE; IN-VIVO; VAGINAL TRANSMISSION; INFECTIOUS-DISEASES; IMMUNE-RESPONSES AB The number of humanized mouse models for the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases has expanded rapidly over the past 8 years. Highly immunodeficient mouse strains, such as NOD/SCID/gamma chain(null) (NSG, NOG), support better human hematopoietic cell engraftment. Another improvement is the derivation of highly immunodeficient mice, transgenic with human leukocyte antigens (HLAs) and cytokines that supported development of HLA-restricted human T cells and heightened human myeloid cell engraftment. Humanized mice are also used to study the HIV reservoir using new imaging techniques. Despite these advances, there are still limitations in HIV immune responses and deficits in lymphoid structures in these models in addition to xenogeneic graft-versus-host responses. To understand and disseminate the improvements and limitations of humanized mouse models to the scientific community, the NIH sponsored and convened a meeting on April 15, 2015 to discuss the state of knowledge concerning these questions and best practices for selecting a humanized mouse model for a particular scientific investigation. This report summarizes the findings of the NIH meeting. C1 [Akkina, Ramesh] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Allam, Atef] Henry M Jackson Fdn Adv Mil Med, Silver Spring, MD USA. [Allam, Atef; Rao, Mangala] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Balazs, Alejandro B.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Blankson, Joel N.] Johns Hopkins Univ, Sch Med, Dept Med, Ctr AIDS Res, Baltimore, MD 21205 USA. [Burnett, John C.] Beckman Res Inst City Hope, Dept Mol & Cellular Biol, Duarte, CA USA. [Casares, Sofia] Naval Med Res Ctr, US Mil Malaria Vaccine Program, Silver Spring, MD USA. [Garcia, J. Victor] Univ N Carolina, Dept Med, Div Infect Dis, UNC Ctr AIDS Res, Chapel Hill, NC USA. [Hasenkrug, Kim J.] NIAID, Lab Persistent Viral Dis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Kashanchi, Fatah] George Mason Univ, Sch Syst Biol, Natl Ctr Biodef & Infect Dis, Manassas, VA USA. [Kitchen, Scott G.; Zack, Jerome A.] Univ Calif Los Angeles, AIDS Inst, Dept Med & Microbiol, Los Angeles, CA USA. [Kitchen, Scott G.; Zack, Jerome A.] Univ Calif Los Angeles, AIDS Inst, Dept Immunol & Mol Genet, Los Angeles, CA USA. [Klein, Florian] Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany. [Klein, Florian] Univ Cologne, CMMC, D-50931 Cologne, Germany. [Kumar, Priti] Yale Univ, Sch Med, Infect Dis Internal Med, New Haven, CT USA. [Luster, Andrew D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol,Ctr Immunol & Inf, Boston, MA 02115 USA. [Poluektova, Larisa Y.] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE USA. [Sanders-Beer, Brigitte E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Shultz, Leonard D.] Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. RP Sanders-Beer, BE (reprint author), NIAID, BSP, DAIDS, NIH,DHHS, 5601 Fishers Lane,Room 9G58, Rockville, MD 20852 USA. EM sandersbe@niaid.nih.gov OI Burnett, John/0000-0002-8817-6064 FU National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201100001G] FX The workshop was funded in whole with Federal funds from the National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201100001G. NR 76 TC 3 Z9 3 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB 1 PY 2016 VL 32 IS 2 BP 109 EP 119 DI 10.1089/aid.2015.0258 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DD2NY UT WOS:000369760500001 PM 26670361 ER PT J AU Del Prete, GQ Smedley, J Macallister, R Jones, GS Li, B Hattersley, J Zheng, J Piatak, M Keele, BF Hesselgesser, J Geleziunas, R Lifson, JD AF Del Prete, Gregory Q. Smedley, Jeremy Macallister, Rhonda Jones, Gregg S. Li, Bei Hattersley, Jillian Zheng, Jim Piatak, Michael, Jr. Keele, Brandon F. Hesselgesser, Joseph Geleziunas, Romas Lifson, Jeffrey D. TI Short Communication: Comparative Evaluation of Coformulated Injectable Combination Antiretroviral Therapy Regimens in Simian Immunodeficiency Virus-Infected Rhesus Macaques SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID TENOFOVIR DISOPROXIL FUMARATE; VIRAL RESERVOIR; RESIDUAL VIRUS; PHARMACOKINETICS; MODEL; AIDS; SUPPRESSION; SIVMAC251; SAFETY; ADULTS AB The use of nonhuman primate (NHP) models to study persistent residual virus and viral eradication strategies in combination antiretroviral therapy (cART)-treated individuals requires regimens that effectively suppress SIV replication to clinically relevant levels in macaques. We developed and evaluated two novel cART regimens in SIVmac239-infected rhesus macaques: (1) a triple regimen containing the nucleo(s/t)ide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate [TDF, prodrug of tenofovir (TFV, PMPA)] with the integrase strand transfer inhibitor dolutegravir (DTG) (n=3), or (2) a quad regimen containing the same three drugs plus the protease inhibitor darunavir (DRV) (n=3), with each regimen coformulated for convenient administration by a single daily subcutaneous injection. Plasma drug concentrations were consistent across animals within the triple and quad regimen-treated groups, although DTG levels were lower in the quad regimen animals. Time to achieve plasma viral loads stably <30 viral RNA copies/ml ranged from 12 to 20 weeks of treatment between animals, and viral loads <30 viral RNA copies/ml plasma were maintained through 40 weeks of follow-up on cART. Notably, although we show virologic suppression and development of viral resistance in a separate cohort of SIV-infected animals treated with oral DRV monotherapy, the addition of DRV in the quad regimen did not confer an apparent virologic benefit during early treatment, hence the quad regimen-treated animals were switched to the triple regimen after 4 weeks. This coformulated triple cART regimen can be safely, conveniently, and sustainably administered to durably suppress SIV replication to clinically relevant levels in rhesus macaques. C1 [Del Prete, Gregory Q.; Piatak, Michael, Jr.; Keele, Brandon F.; Lifson, Jeffrey D.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. [Smedley, Jeremy; Macallister, Rhonda] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Anim Sci Program, Frederick, MD USA. [Jones, Gregg S.; Li, Bei; Hattersley, Jillian; Zheng, Jim; Hesselgesser, Joseph; Geleziunas, Romas] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA. [Smedley, Jeremy] Washington Natl Primate Res Ctr, Div Primate Resources, Seattle, WA USA. [Macallister, Rhonda] Oregon Natl Primate Res Ctr, Beaverton, OR USA. RP Lifson, JD (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. EM lifsonj@mail.nih.gov OI Smedley, Jeremy/0000-0003-3369-4662 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. NR 20 TC 5 Z9 5 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB 1 PY 2016 VL 32 IS 2 BP 163 EP 168 DI 10.1089/aid.2015.0130 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DD2NY UT WOS:000369760500009 PM 26150024 ER PT J AU Carter, JM Landin, JD Gigante, ED Rieger, SP Diaz, MR Werner, DF AF Carter, Jenna M. Landin, Justine D. Gigante, Eduardo D. Rieger, Samuel P. Diaz, Marvin R. Werner, David F. TI Inhibitors of Calcium-Activated Anion Channels Modulate Hypnotic Ethanol Responses in Adult Sprague Dawley Rats SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Calcium-Activated Anion Channels; Ethanol; Sedation; Hypnosis; Anxiety ID PROTEIN-KINASE-C; HIPPOCAMPAL ASTROCYTES; CHLORIDE CHANNELS; CA2+ MOBILIZATION; GLUTAMATE RELEASE; TONIC INHIBITION; ROS GENERATION; EXPOSURE; ALCOHOL; ADOLESCENT AB BackgroundEthanol is widely known for its depressant effects; however, the underlying neurobiological mechanisms are not clear. Calcium-activated anion channels (CAACs) contribute to extracellular chloride levels and thus may be involved in regulating inhibitory mechanisms within the central nervous system. Therefore, we hypothesized that CAACs influence ethanol behavioral sensitivity by altering CAAC expression. MethodsWe assessed the role of CAACs in ethanol-induced loss of righting reflex (LORR) and locomotor activity using intracerebroventricular infusions of several nonselective CAAC blockers. CAAC expression was determined after ethanol exposure. ResultsEthanol-induced LORR (4.0g/kg, intraperitoneally [i.p.]) was significantly attenuated by all 4 CAAC blockers. Blocking CAACs did not impact ethanol's low-dose (1.5g/kg, i.p.) locomotor-impairing effects. Biochemical analysis of CAAC protein expression revealed that cortical Bestrophin1 (Best1) and Tweety1 levels were reduced as early as 30minutes following a single ethanol injection (3.5g/kg, intraperitoneally [i.p.]) and remained decreased 24hours later in P2 fractions. Cortical Best1 levels were also reduced following 1.5g/kg. However, CAAC expression was unaltered in the striatum following a single ethanol exposure. Ethanol did not affect Tweety2 levels in either brain region. ConclusionsThese results suggest that CAACs are a major target of ethanol invivo, and the regulation of these channels contributes to select behavioral actions of ethanol. C1 [Carter, Jenna M.; Landin, Justine D.; Gigante, Eduardo D.; Rieger, Samuel P.; Diaz, Marvin R.; Werner, David F.] SUNY Binghamton, Dept Psychol, Ctr Dev & Behav Neurosci, Binghamton, NY USA. [Gigante, Eduardo D.] NIDA, Dept Hlth & Human Serv, Intramural Res Program, NIH, Baltimore, MD USA. RP Werner, DF (reprint author), Binghamton Univ, Sci 4, 4400 Vestal Pkwy East, Binghamton, NY USA. EM dwerner@binghamton.edu FU National Institute on Alcohol Abuse and Alcoholism [AA019367]; Binghamton University's Center for Development and Behavioral Neuroscience and Psychology Department FX We would like to thank Dr. C. Fernando Valenzuela for comments and discussions during the course of this study and drafting of the manuscript. This work was supported by the National Institute on Alcohol Abuse and Alcoholism (AA019367 - Linda P. Spear - faculty recruitment of David F. Werner) and Binghamton University's Center for Development and Behavioral Neuroscience and Psychology Department. The authors declare no conflict of interests. NR 52 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2016 VL 40 IS 2 BP 301 EP 308 DI 10.1111/acer.12957 PG 8 WC Substance Abuse SC Substance Abuse GA DD5XT UT WOS:000369998900008 PM 26842249 ER PT J AU Hsieh, YH Kelen, GD Beck, KJ Kraus, CK Shahan, JB Laeyendecker, OB Quinn, TC Rothman, RE AF Hsieh, Yu-Hsiang Kelen, Gabor D. Beck, Kaylin J. Kraus, Chadd K. Shahan, Judy B. Laeyendecker, Oliver B. Quinn, Thomas C. Rothman, Richard E. TI Evaluation of hidden HIV infections in an urban ED with a rapid HIV screening program SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID CITY EMERGENCY-DEPARTMENT; OPT-OUT; MISSED OPPORTUNITIES; UNITED-STATES; VIRAL LOAD; ROUTINE; TRANSMISSION; PREVALENCE; SETTINGS AB Background: To investigate the prevalence of undiagnosed HIV infections in an emergency department (ED) with an established screening program. Methods: Evaluation of the prevalence and risk factors for HIV from an 8-week (June 24, 2007-August 18, 2007) identity-unlinked HIV serosurvey, conducted at the same time as an ongoing opt-in rapid oral-fluid HIV screening program. Testing facilitators offering 24/7 bedside rapid testing to patients aged 18 to 64 years, with concordant collection of excess sera collected as part of routine clinical procedures. Known HIV positivity was determined by (1) medical record review or self-report from the screening program and/or (2) presence of antiretrovirals in serum specimens. Results: Among 3207 patients, 1165 (36.3%) patients were offered an HIV test. Among those offered, 567 (48.7%) consented to testing. Concordance identity-unlinked study revealed that the prevalence of undiagnosed infections was as follows: 2.3% in all patients, 1.0% in those offered testing vs 3.0% in those not offered testing (P < .001); and 1.3% in those who declined testing compared with 0.4% in those who were tested (P = .077). Higher median viral loads were observed in those not offered testing (14255 copies/mL; interquartile range, 1147-64354) vs those offered testing (1865 copies/mL; interquartile range, undetectable-21786), but the difference was not statistically significant. Conclusions: High undiagnosed HIV prevalence was observed in ED patients who were not offered HIV testing and those who declined testing, compared with those who were tested. This indicates that even with an intensive facilitator-based rapid HIV screening model, significant missed opportunities remain with regard to identifying undiagnosed infections in the ED. (C) 2015 Elsevier Inc. All rights reserved. C1 [Hsieh, Yu-Hsiang; Kelen, Gabor D.; Beck, Kaylin J.; Shahan, Judy B.; Rothman, Richard E.] Johns Hopkins Univ, Dept Emergency Med, Sch Med, Baltimore, MD 21209 USA. [Kraus, Chadd K.] Lehigh Valley Hlth Network, Allentown, PA USA. [Laeyendecker, Oliver B.; Quinn, Thomas C.; Rothman, Richard E.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21209 USA. [Laeyendecker, Oliver B.; Quinn, Thomas C.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Hsieh, YH (reprint author), Johns Hopkins Univ, Dept Emergency Med, 5801 Smith Ave,Suite 3220 Davis Bldg, Baltimore, MD 21209 USA. EM yhsieh1@jhmi.edu OI Rothman, Richard/0000-0002-1017-9505; Kelen, Gabor/0000-0002-3236-8286 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Emergency Medicine Foundation/Society for Academic Emergency Medicine Medical Student Research Grant; Maryland Department of Health and Mental Hygiene; National Institutes of Health from National Institute of Allergy and Infectious Diseases [K01AI100681]; Gilead Focus Program FX The study was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Dr Kraus was supported by the 2007 Emergency Medicine Foundation/Society for Academic Emergency Medicine Medical Student Research Grant to conduct the identity-unlinked seroprevalence study. The Johns Hopkins University Department of Emergency Medicine HIV Testing Program was funded in part by grants from Maryland Department of Health and Mental Hygiene. Dr Hsieh is also supported in part by a National Institutes of Health award, K01AI100681 from National Institute of Allergy and Infectious Diseases, to study HIV testing in emergency departments using a modeling approach. Dr Rothman is currently supported in part by funding from the Gilead Focus Program, which does not fund this project. NR 27 TC 1 Z9 1 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0735-6757 EI 1532-8171 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD FEB PY 2016 VL 34 IS 2 BP 180 EP 184 DI 10.1016/j.ajem.2015.10.002 PG 5 WC Emergency Medicine SC Emergency Medicine GA DD1SE UT WOS:000369701200012 PM 26589466 ER PT J AU Zhou, CK Levine, PH Cleary, SD Hoffman, HJ Graubard, BI Cook, MB AF Zhou, Cindy Ke Levine, Paul H. Cleary, Sean D. Hoffman, Heather J. Graubard, Barry I. Cook, Michael B. TI Male Pattern Baldness in Relation to Prostate Cancer-Specific Mortality: A Prospective Analysis in the NHANES I Epidemiologic Follow-up Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort; male pattern baldness; prostate cancer mortality ID ENDOGENOUS SEX-HORMONES; ANDROGENETIC ALOPECIA; SERUM TESTOSTERONE; SCREENING TRIAL; RISK-FACTORS; MEN; HAIR; INSENSITIVITY; ASSOCIATIONS; LEVEL AB We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer-specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971-1974), we included 4,316 men who were 25-74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables used to calculate sample weights. During follow-up (median, 21 years), 3,284 deaths occurred; prostate cancer was the underlying cause of 107. In multivariable models, compared with no balding, any baldness was associated with a 56% higher risk of fatal prostate cancer (hazard ratio = 1.56; 95% confidence interval: 1.02, 2.37), and moderate balding specifically was associated with an 83% higher risk (hazard ratio = 1.83; 95% confidence interval: 1.15, 2.92). Conversely, patterned hair loss was not statistically significantly associated with all-cause mortality. Our analysis suggests that patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms. C1 [Zhou, Cindy Ke; Graubard, Barry I.; Cook, Michael B.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zhou, Cindy Ke; Levine, Paul H.; Cleary, Sean D.; Hoffman, Heather J.] George Washington Univ, Dept Epidemiol & Biostat, Milken Inst, Sch Publ Hlth, Washington, DC USA. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 7-E106,MSC 9774, Bethesda, MD 20892 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009; Zhou, Cindy /H-2165-2015 OI Cook, Michael/0000-0002-0533-7302; Zhou, Cindy /0000-0003-4814-4305 FU Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 54 TC 1 Z9 1 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2016 VL 183 IS 3 BP 210 EP 217 DI 10.1093/aje/kwv190 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD8QY UT WOS:000370193200005 PM 26764224 ER PT J AU Boonstra, PS Mukherjee, B Gruber, SB Ahn, J Schmit, SL Chatterjee, N AF Boonstra, Philip S. Mukherjee, Bhramar Gruber, Stephen B. Ahn, Jaeil Schmit, Stephanie L. Chatterjee, Nilanjan TI Tests for Gene-Environment Interactions and Joint Effects With Exposure Misclassification SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control; gene discovery; gene-environment independence; genome-wide association; modular methods; multiple testing; screening test; weighted hypothesis test ID GENOME-WIDE ASSOCIATION; LOGISTIC-REGRESSION; MEASUREMENT ERROR; WHOLE-GENOME; CANCER; DESIGNS; SUSCEPTIBILITY; OPPORTUNITIES; INDEPENDENCE; SIMULATION AB The number of methods for genome-wide testing of gene-environment (G-E) interactions continues to increase, with the aim of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods, assessed on the basis of family-wise type I error rate and power, depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting G-E interactions by evaluating the impact of exposure misclassification. We consider 7 single-step and modular screening methods for identifying G-E interaction at a genome-wide level and 7 joint tests for genetic association and G-E interaction, for which the goal is to discover new genetic susceptibility loci by leveraging G-E interaction when present. In terms of statistical power, modular methods that screen on the basis of the marginal disease-gene relationship are more robust to exposure misclassification. Joint tests that include main/marginal effects of a gene display a similar robustness, which confirms results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide searches for G-E interaction and joint tests in the presence of exposure misclassification. C1 [Boonstra, Philip S.; Mukherjee, Bhramar] Univ Michigan, Sch Publ Hlth, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI 48109 USA. [Ahn, Jaeil] Georgetown Univ, Med Ctr, Dept Biostat & Bioinformat, Washington, DC 20007 USA. [Gruber, Stephen B.; Schmit, Stephanie L.] Univ So Calif, Keck Sch Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Chatterjee, Nilanjan] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. RP Mukherjee, B (reprint author), Univ Michigan, Sch Publ Hlth, Dept Biostat, 1415 Washington Hts, Ann Arbor, MI 48109 USA. EM bhramar@umich.edu FU National Institutes of Health [P30 CA046592, R21 ES20811, U19 CA148107, P30 CA014089, T32 ES013678]; Intramural Research Program of the National Cancer Institute; National Science Foundation [DMS-1406712] FX This work was supported by the National Institutes of Health (grants P30 CA046592 to P.S.B.; R21 ES20811 to B.M.; U19 CA148107 to S.B.G., S.L.S., P.S.B., and B.M.; P30 CA014089 to S.B.G., S.L.S., and B.M.; T32 ES013678 to S.L.S.; the Intramural Research Program of the National Cancer Institute to N.C.) and the National Science Foundation (grant DMS-1406712 to B.M.). NR 57 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2016 VL 183 IS 3 BP 237 EP 247 DI 10.1093/aje/kwv198 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD8QY UT WOS:000370193200008 PM 26755675 ER PT J AU Lee, JH Goldspiel, BR Ryu, SJ Potti, GK AF Lee, Jun H. Goldspiel, Barry R. Ryu, Sujung Potti, Gopal K. TI Stability of tacrolimus solutions in polyolefin containers SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article ID SODIUM-CHLORIDE INJECTION AB Purpose. Results of a study to determine the stability of tacrolimus solutions stored in polyolefin containers under various temperature conditions are reported. Methods. Triplicate solutions of tacrolimus (0.001, 0.01, and 0.1 mg/mL) in 0.9% sodium chloride injection or 5% dextrose injection were prepared in polyolefin containers. Some samples were stored at room temperature (20-25 degrees C); others were refrigerated (2-8 degrees C) for 20 hours and then stored at room temperature for up to 28 hours. The solutions were analyzed: by stability-indicating high-performance liquid chromatography (HPLC) assay at specified time points over 48 hours. Solution pH was measured and containers were visually inspected at each time point. Stability was defined as retention of at least 90% of the initial tacrolimus concentration. Results. All tested solutions retained over 90% of the initial tacrolimus concentration at all time points, with the exception of the 0.001-mg/mL solution prepared in 0.9% sodium chloride injection, which was deemed unstable beyond 24 hours. At all evaluated concentrations, mean solution pH values did not change significantly over 48 hours; no particle formation was detected. Conclusion. During storage in polyolefin bags at room temperature, a 0.001-mg/mL solution of tacrolimus was stable for 24 hours when prepared in 0.9% sodium chloride injection and for at least 48 hours when prepared in 5% dextrose injection. Solutions of 0.01 and 0.1 mg/mL prepared in either diluent were stable for at least 48 hours, and the 0.01-mg/mL tacrolimus solution was also found to be stable throughout a sequential temperature protocol. C1 [Lee, Jun H.; Ryu, Sujung; Potti, Gopal K.] NIH, Pharmaceut Dev Sect, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Goldspiel, Barry R.] NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RP Goldspiel, BR (reprint author), NIH, Dept Pharm, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM bgoldspiel@nih.gov NR 6 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 1 PY 2016 VL 73 IS 3 BP 137 EP 142 DI 10.2146/ajhp150264 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DD4FO UT WOS:000369878100011 PM 26796907 ER PT J AU Dettmer, AM Kaburu, SSK Byers, KL Murphy, AM Soneson, E Wooddell, LJ Suomi, SJ AF Dettmer, Amanda M. Kaburu, Stefano S. K. Byers, Kristen L. Murphy, Ashley M. Soneson, Emma Wooddell, Lauren J. Suomi, Stephen J. TI First-Time Rhesus Monkey Mothers, and Mothers of Sons, Preferentially Engage in Face-to-Face Interactions With Their Infants SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE Macaca mulatta; mother-infant interaction; parity; infant sex; mutual gaze ID JAPANESE MACAQUES; INDIVIDUAL-DIFFERENCES; STRESS REACTIVITY; WILD CHIMPANZEES; MACACA-MULATTA; BIRTH-ORDER; SEX; COMMUNICATION; POPULATION; ATTACHMENT AB Face-to-face interactions between mothers and infants occur in both human and non-human primates, but there is large variability in the occurrence of these behaviors and the reason for this variability remains largely unexplored. Other types of maternal investment have been shown to be dependent on infant sex (e. g. milk production and maternal responsiveness) and maternal experience (e. g. symmetrical communication). Thus, we sought to determine whether variability in face-to-face interactions, that is, mutual gazing (MG), which are hypothesized to be important for later sociocognitive development, could be explained by these variables. We studied 28 semi-free ranging rhesus monkey (Macaca mulatta) mother-infant dyads (6 primiparous; 12 male infants) born and reared at the Laboratory of Comparative Ethology field station at the NIH Animal Center in Poolesville, MD, across the first 90 postnatal days. Infant sex (i. e. male) was a significant predictor of maternal grooming (beta +/- SE -0.359 +/- 0.164, Z = 2.19, P = 0.029) whereas both parity (i. e. first time mothers) and infant sex (i. e. male) significantly predictedMG(parity: beta +/- SE = -0.735 +/- 0.223, Z = -3.30, P< 0.001; infant sex: beta +/- SE = 0.436 +/- 0.201, Z = 2.17, P = 0.029). Separation from the mother (outside of arm's reach) was not influenced by parity or infant sex. Together with existing literature, these findings point toward differential maternal investment for sons versus daughters. Mothers may be investing differentially in sons, behaviorally, to ensure their future social competence and thus later reproductive success. Collectively, our findings add to the literature that is beginning to identify early life experiences that may lead to sex differences in neurological and behavioral development. (C) 2015 Wiley Periodicals, Inc. C1 [Dettmer, Amanda M.; Kaburu, Stefano S. K.; Byers, Kristen L.; Murphy, Ashley M.; Soneson, Emma; Wooddell, Lauren J.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, POB 529, Poolesville, MD 20837 USA. [Kaburu, Stefano S. K.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Soneson, Emma] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT USA. RP Dettmer, AM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, POB 529, Poolesville, MD 20837 USA. EM dettmera@mail.nih.gov FU Division of Intramural Research; National Institute of Child Health and Human Development [PO1HD064653] FX Contract grant sponsor: Division of Intramural Research; contract grant sponsor: National Institute of Child Health and Human Development; contract grant number: PO1HD064653. NR 61 TC 5 Z9 5 U1 7 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-2565 EI 1098-2345 J9 AM J PRIMATOL JI Am. J. Primatol. PD FEB PY 2016 VL 78 IS 2 BP 238 EP 246 DI 10.1002/ajp.22503 PG 9 WC Zoology SC Zoology GA DD5RV UT WOS:000369982900006 PM 26581804 ER PT J AU Brennan, DC Kopetskie, HA Sayre, PH Alejandro, R Cagliero, E Shapiro, AMJ Goldstein, JS DesMarais, MR Booher, S Bianchine, PJ AF Brennan, D. C. Kopetskie, H. A. Sayre, P. H. Alejandro, R. Cagliero, E. Shapiro, A. M. J. Goldstein, J. S. DesMarais, M. R. Booher, S. Bianchine, P. J. TI Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Scope: clinical research; practice; Discipline: islet transplantation; Focus: clinical trial; immunosuppressive regimens ID IMPROVEMENT; OUTCOMES; DISEASE; TRIAL; BP AB We report the long-term follow-up of the efficacy and safety of islet transplantation in seven type 1 diabetic subjects from the United States enrolled in the multicenter international Edmonton Protocol who had persistent islet function after completion of the Edmonton Protocol. Subjects were followed up to 12 years with serial testing for sustained islet allograft function as measured by C-peptide. All seven subjects demonstrated continued islet function longer than a decade from the time of first islet transplantation. One subject remained insulin independent without the need for diabetic medications or supplemental transplants. One subject who was insulin-independent for over 8 years experienced graft failure 10.9 years after the first islet transplant. The remaining six subjects demonstrated continued islet function upon trial completion, although three had received a supplemental islet transplant each. At trial completion, five subjects were receiving insulin and two remained insulin independent, although one was treated with liraglutide. The median hemoglobin A(1c) was 6.3% (45mmol/mol). All subjects experienced progressive decline in the C-peptide/glucose ratio. No patients experienced severe hypoglycemia, opportunistic infection, or lymphoma. Thus, although the rate and duration of insulin independence was low, the Edmonton Protocol was safe in the long term. Alternative approaches to islet transplantation are under investigation. C1 [Brennan, D. C.] Washington Univ, Sch Med, St Louis, MO USA. [Kopetskie, H. A.] Rho Fed Syst Div, Chapel Hill, NC USA. [Sayre, P. H.; DesMarais, M. R.] Immune Tolerance Network, San Francisco, CA USA. [Alejandro, R.] Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. [Cagliero, E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Shapiro, A. M. J.] Univ Alberta, Edmonton, AB, Canada. [Goldstein, J. S.; Booher, S.; Bianchine, P. J.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Brennan, DC (reprint author), Washington Univ, Sch Med, St Louis, MO USA. EM dbrennan@dom.wustl.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [NO1-AI-15416, HSN272200800029C]; Juvenile Diabetes Research Foundation FX Dr. Brennan is the guarantor of the work. The authors would like to thank the ITN040CT Trial Study Group and the investigators involved in the NIS01 trial. This research was performed as a project of the Immune Tolerance Network, an international clinical research consortium headquartered at the University of California San Francisco and supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (award numbers NO1-AI-15416 and HSN272200800029C) and the Juvenile Diabetes Research Foundation. NR 16 TC 17 Z9 17 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2016 VL 16 IS 2 BP 509 EP 517 DI 10.1111/ajt.13458 PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA DD3WL UT WOS:000369853900016 PM 26433206 ER PT J AU Coghill, AE Johnson, LG Berg, D Resler, AJ Leca, N Madeleine, MM AF Coghill, A. E. Johnson, L. G. Berg, D. Resler, A. J. Leca, N. Madeleine, M. M. TI Immunosuppressive Medications and Squamous Cell Skin Carcinoma: Nested Case-Control Study Within the Skin Cancer after Organ Transplant (SCOT) Cohort SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE clinical research; practice; immunosuppression; immune modulation; cancer; malignancy; neoplasia; skin; nonmelanoma; epidemiology ID KIDNEY-TRANSPLANTATION; MYCOPHENOLATE-MOFETIL; CYCLOSPORINE-A; RENAL-TRANSPLANTATION; TACROLIMUS FK506; UNITED-STATES; RISK-FACTORS; DNA-REPAIR; RECIPIENTS; AZATHIOPRINE AB Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n=170). Controls without SCSC (n=324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR]=2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR=0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR=0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Johnson, L. G.; Resler, A. J.; Madeleine, M. M.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Berg, D.; Leca, N.] Univ Washington, Dept Med, Seattle, WA USA. [Resler, A. J.; Madeleine, M. M.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. EM anna.coghill@nih.gov NR 56 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD FEB PY 2016 VL 16 IS 2 BP 565 EP 573 DI 10.1111/ajt.13596 PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA DD3WL UT WOS:000369853900022 PM 26824445 ER PT J AU Ahn, RS Moslehi, H Martin, MP Abad-Santos, M Bowcock, AM Carrington, M Liao, W AF Ahn, R. S. Moslehi, H. Martin, M. P. Abad-Santos, M. Bowcock, A. M. Carrington, M. Liao, W. TI Inhibitory KIR3DL1 alleles are associated with psoriasis SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Letter ID HLA-B; SUBTYPES; DISTINCT; DISEASE C1 [Ahn, R. S.; Moslehi, H.; Abad-Santos, M.; Liao, W.] Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St,Box 0808, San Francisco, CA 94143 USA. [Martin, M. P.; Carrington, M.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Martin, M. P.; Carrington, M.] Massachusetts Gen Hosp, MIT, Ragon Inst, Cambridge, MA USA. [Martin, M. P.; Carrington, M.] Harvard Univ, Cambridge, MA 02138 USA. [Bowcock, A. M.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. RP Ahn, RS (reprint author), Univ Calif San Francisco, Dept Dermatol, 2340 Sutter St,Box 0808, San Francisco, CA 94143 USA. EM richard.ahn@ucsf.edu OI Ahn, Richard/0000-0002-9698-2752; Bowcock, Anne/0000-0001-8691-9090 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; NIAMS NIH HHS [R01 AR050266, 2R01AR050266, K08 AR057763, K08AR057763, R01 AR065174, R01AR065174, T32 AR007175]; PHS HHS [HHSN261200800001E] NR 15 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD FEB PY 2016 VL 174 IS 2 BP 449 EP 451 DI 10.1111/bjd.14081 PG 3 WC Dermatology SC Dermatology GA DD6DO UT WOS:000370014600044 PM 26286807 ER PT J AU Orihuela, R McPherson, CA Harry, GJ AF Orihuela, Ruben McPherson, Christopher A. Harry, Gaylia Jean TI Microglial M1/M2 polarization and metabolic states SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; AMYOTROPHIC-LATERAL-SCLEROSIS; MONOCYTE-DERIVED MACROPHAGES; DENDRITIC CELL ACTIVATION; GENE-EXPRESSION PROFILES; INNATE HOST-DEFENSE; FACTOR-KAPPA-B; IN-VIVO; NITRIC-OXIDE; ALTERNATIVE ACTIVATION AB Microglia are critical nervous system-specific immune cells serving as tissue-resident macrophages influencing brain development, maintenance of the neural environment, response to injury and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison with peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by LPS or IFN- to an M1 phenotype for expression of pro-inflammatory cytokines or by IL-4/IL-13 to an M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and their relationship to mitochondrial metabolism. Additional supporting experimental data are provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL-13 (M2) polarization. Linked ArticlesThis article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit C1 [Orihuela, Ruben; McPherson, Christopher A.; Harry, Gaylia Jean] NIEHS, Neurotoxicol Grp, Natl Toxicol Program Lab, NIH, 111 TW Alexander Dr,MD E1-07, Res Triangle Pk, NC 27709 USA. RP Harry, GJ (reprint author), NIEHS, Neurotoxicol Grp, Natl Toxicol Program Lab, NIH, 111 TW Alexander Dr,MD E1-07, Res Triangle Pk, NC 27709 USA.; Harry, GJ (reprint author), NIEHS, 111 TW Alexander Dr,MD E1-07, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Division National Toxicology Program, National Institute of Environmental Health Sciences [1Z01ES101623, ES021164] FX This work was supported by the Division National Toxicology Program, National Institute of Environmental Health Sciences (nos. 1Z01ES101623 and ES021164). NR 203 TC 31 Z9 33 U1 14 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD FEB PY 2016 VL 173 IS 4 SI SI BP 649 EP 665 DI 10.1111/bph.13139 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DD6AI UT WOS:000370005700003 PM 25800044 ER PT J AU Smith, TG Castro, KM Troeschel, AN Arora, NK Lipscomb, J Jones, SM Treiman, KA Hobbs, C McCabe, RM Clauser, SB AF Smith, Tenbroeck G. Castro, Kathleen M. Troeschel, Alyssa N. Arora, Neeraj K. Lipscomb, Joseph Jones, Shelton M. Treiman, Katherine A. Hobbs, Connie McCabe, Ryan M. Clauser, Steven B. TI The rationale for patient-reported outcomes surveillance in cancer and a reproducible method for achieving it SO CANCER LA English DT Editorial Material DE patient-reported outcomes; quality of life; surveillance; symptoms ID COLORECTAL-CANCER; CLINICAL-PRACTICE; CARE; QUALITY; SURVIVORS; ONCOLOGY; FATIGUE; SYSTEM; POLICY; PAIN AB Patient-reported outcomes (PROs) measure quality of life, symptoms, patient functioning, and patient perceptions of care; they are essential for gaining a full understanding of cancer care and the impact of cancer on people's lives. Repeatedly captured facility-level and/or population-level PROs (PRO surveillance) could play an important role in quality monitoring and improvement, benchmarking, advocacy, policy making, and research. This article describes the rationale for PRO surveillance and the methods of the Patient Reported Outcomes Symptoms and Side Effects Study (PROSSES), which is the first PRO study to use the American College of Surgeons Commission on Cancer's Rapid Quality Reporting System to identify patients and manage study data flow. The American Cancer Society, the National Cancer Institute, the Commission on Cancer, and RTI International collaborated on PROSSES. PROSSES was conducted at 17 cancer programs that participated in the National Cancer Institute Community Cancer Centers Program among patients diagnosed with locoregional breast or colon cancer. The methods piloted in PROSSES were successful as demonstrated by high eligibility (93%) and response (61%) rates. Differences in clinical and demographic characteristics between respondents and nonrespondents were mostly negligible, with the exception that non-white individuals were somewhat less likely to respond. These methods were consistent across cancer centers and reproducible over time. If repeated and expanded, they could provide PRO surveillance data from patients with cancer on a national scale. Cancer 2016;122:344-351. (c) 2015 American Cancer Society. C1 [Smith, Tenbroeck G.; Troeschel, Alyssa N.] Amer Canc Soc, Behav Res Ctr, Intramural Res Dept, Atlanta, GA 30303 USA. [Castro, Kathleen M.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Arora, Neeraj K.; Clauser, Steven B.] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Lipscomb, Joseph] Emory Univ, Rollins Sch Publ Hlth, Hlth Policy & Management, Atlanta, GA 30322 USA. [Lipscomb, Joseph] Emory Univ, Winship Canc Inst, Populat Sci, Atlanta, GA 30322 USA. [Jones, Shelton M.; Treiman, Katherine A.; Hobbs, Connie] RTI Int, Res Triangle Pk, NC USA. [McCabe, Ryan M.] Amer Coll Surg, Natl Canc Data Base, Chicago, IL USA. RP Smith, TG (reprint author), Amer Canc Soc, Behav Res Ctr, Intramural Res Dept, Patient Reported Outcomes Res, 250 Williams St, Atlanta, GA 30303 USA. EM tenbroeck.smith@cancer.org NR 36 TC 3 Z9 3 U1 3 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 1 PY 2016 VL 122 IS 3 BP 344 EP 351 DI 10.1002/cncr.29767 PG 8 WC Oncology SC Oncology GA DC9HN UT WOS:000369532100005 PM 26619031 ER PT J AU Hakimi, AA Ostrovnaya, I Jacobsen, A Susztak, K Coleman, JA Russo, P Winer, AG Mano, R Sankin, AI Motzer, RJ Voss, MH Offit, K Purdue, M Pomerantz, M Freedman, M Choueiri, TK Hsieh, JJ Klein, RJ AF Hakimi, A. Ari Ostrovnaya, Irina Jacobsen, Anders Susztak, Katalin Coleman, Jonathan A. Russo, Paul Winer, Andrew G. Mano, Roy Sankin, Alexander I. Motzer, Robert J. Voss, Martin H. Offit, Kenneth Purdue, Mark Pomerantz, Mark Freedman, Matthew Choueiri, Toni K. Hsieh, James J. Klein, Robert J. TI Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma SO CANCER LA English DT Article DE biomarker; MET oncogene; renal cell carcinoma; The Cancer Genome Atlas (TCGA); variant ID SINGLE-NUCLEOTIDE POLYMORPHISMS; CANCER-RISK; GROWTH; ASSOCIATION; METHYLATION; RECURRENCE; ACCURACY; SURVIVAL; PATHWAY; GENES AB BACKGROUNDThe exonic single-nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). This finding was validated with The Cancer Genome Atlas (TCGA) cohort, and the biologic implications were explored. METHODSThe genotype status for rs11762213 was available for 272 patients. Paired tumor-normal data, genomic data, and clinical information were acquired from ccRCC TCGA data sets. Cancer-specific survival (CSS) was analyzed with the competing risk method, and Cox proportional hazards regression was used for the analysis of the time to recurrence (TTR). Multivariate competing risk models were fitted to adjust for the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTSThe variant allele of rs11762213 was detected in 10.3% of the cohort. After adjustments for the SSIGN score, the risk allele remained a significant predictor for adverse CSS (hazard ratio [HR], 3.88; 95% confidence interval [CI], 1.99-7.56; P<.0001) and for TTR (OR, 2.97; 95% CI, 1.43-6.2; P=.003). The mapping of rs11762213 to regulatory regions within the genome suggested that it might affect a DNA enhancer region. RNA and protein sequencing data for MET did not reveal differences in steady-state expression with stratification by risk allele. CONCLUSIONSThe exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification. Genomic analysis suggests that the single-nucleotide polymorphism may affect an enhancer region located in the coding region of MET. Further biological mechanistic interrogation is currently underway. Cancer 2016;122:402-410. (c) 2015 American Cancer Society. C1 [Hakimi, A. Ari; Ostrovnaya, Irina; Jacobsen, Anders; Coleman, Jonathan A.; Russo, Paul; Winer, Andrew G.; Mano, Roy; Sankin, Alexander I.; Motzer, Robert J.; Voss, Martin H.; Offit, Kenneth; Hsieh, James J.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Susztak, Katalin] Univ Penn, Philadelphia, PA 19104 USA. [Purdue, Mark] NCI, Bethesda, MD 20892 USA. [Pomerantz, Mark; Freedman, Matthew; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Klein, Robert J.] Mt Sinai Sch Med, New York, NY USA. RP Hakimi, AA (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, 353 East 68th St, New York, NY 10065 USA. EM hakimia@mskcc.org OI Mano, Roy/0000-0003-3855-0211; Jacobsen, Anders/0000-0001-6847-4980; Coleman, Jonathan/0000-0002-6428-7835 FU Paula Moss Trust for Research Into the Cure and Treatment of Kidney Cancer; Sidney Kimmel Center for Prostate and Urologic Cancers; Prostate Cancer Foundation; National Cancer Institute [T32 CA082088-12]; Stephen P. Hanson Family Fund Fellowship in Kidney Cancer; National Institutes of Health [U01 HG007033, R03 CA165082]; Trust Family Fund for Kidney Cancer Research; Dana-Farber Cancer Institute; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Carmel Family Cancer Research Fund; Michael Brigham Fund for Kidney Cancer Research FX This work was supported by the Paula Moss Trust for Research Into the Cure and Treatment of Kidney Cancer (to James J. Hsieh), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation, the National Cancer Institute (training grant T32 CA082088-12 to A. Ari Hakimi, Andrew G. Winer, and Alexander I. Sankin), the Stephen P. Hanson Family Fund Fellowship in Kidney Cancer (to A. Ari Hakimi, Andrew G. Winer, and Alexander I. Sankin), the National Institutes of Health (U01 HG007033 and R03 CA165082 to Robert J. Klein), the Trust Family and Michael Brigham Funds for Kidney Cancer Research (to Toni K. Choueiri), the Dana-Farber Cancer Institute (to Toni K. Choueiri), the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Carmel Family Cancer Research Fund (to Kenneth Offit). NR 30 TC 5 Z9 5 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD FEB 1 PY 2016 VL 122 IS 3 BP 402 EP 410 DI 10.1002/cncr.29765 PG 9 WC Oncology SC Oncology GA DC9HN UT WOS:000369532100013 PM 26505625 ER PT J AU Schwartz, K Ruterbusch, JJ Colt, JS Miller, DC Chow, WH Purdue, MP AF Schwartz, Kendra Ruterbusch, Julie J. Colt, Joanne S. Miller, David C. Chow, Wong-Ho Purdue, Mark P. TI Racial disparities in overall survival among renal cell carcinoma patients with young age and small tumors SO CANCER MEDICINE LA English DT Article DE Age; race; renal cell carcinoma; survival; tumor size ID SOCIOECONOMIC-STATUS; AFRICAN-AMERICANS; CANCER; STAGE; EPIDEMIOLOGY; SEGREGATION; DISEASE; HEALTH; MODE AB We examined the overall survival of a population- - based cohort of black and white patients with renal cell carcinoma ( RCC) to better understand the paradox of poorer RCC survival despite more frequent diagnosis at lower stage among blacks. Renal cell carcinoma patients ( 699 white, 252 black) diagnosed between 2002 and 2007 in metropolitan Detroit were followed for vital status in the Detroit Surveillance, Epidemiology and End Results ( SEER) registry. Hazard ratios ( HR) of death for black versus white race and 95% confidence intervals ( CIs) were calculated using Cox proportional hazard models stratified by demographic and prognostic factors, and in models successively adjusted for clinical factors, comorbidities, and socioeconomic factors. Mean follow- - up time was 88.4 months for white patients and 89.6 months for black patients ( P = 0.49), with 202 white deaths and 89 black deaths ( P = 0.06). While black race was weakly associated with poorer overall survival ( P = 0.053), black patients < 65 years at diagnosis or with tumors < 4 cm in size had significantly poorer survival than their white counterparts ( HR = 1.46, 95% CI 1.06- 2.01 and HR = 2.15, 95% CI 1.51- 3.06, respectively). The racial disparities within these two subgroups were minimally affected by adjustment for clinical/ treatment factors ( HR = 1.49, 95% CI 1.01- 2.19 and HR = 1.95, 95% CI 1.27- 2.99), but were substantially reduced when renal- - relevant comorbidities were added ( HR = 1.30, 95% CI 0.89- 1.91 and HR = 1.76, 95% CI 1.16- 2.66). After further adjustment for socioeconomic factors, the survival disparities were essentially null ( HR = 1.14, 95% CI 0.71- 1.85 and HR = 1.15, 95% CI 0.67- 1.98). In this population- - based sample of RCC patients, younger black patients and those with small tumors had poorer overall survival than whites. The disparity was explained primarily by racial differences in renal- - relevant comorbidities, particularly chronic renal failure, and socioeconomic deprivation. Future research should focus on younger patients and those with smaller tumors to better understand how these factors may contribute to the survival disparity. C1 [Schwartz, Kendra] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Schwartz, Kendra; Ruterbusch, Julie J.] Karmanos Canc Inst, Populat Studies & Dispar Res Program, Detroit, MI USA. [Ruterbusch, Julie J.] Wayne State Univ, Sch Med, Dept Oncol, Detroit, MI USA. [Colt, Joanne S.; Purdue, Mark P.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Miller, David C.] Univ Michigan, Dept Urol, Sch Med, Ann Arbor, MI USA. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA. RP Schwartz, K (reprint author), 320 E Canfield St,Suite 310, Detroit, MI 48201 USA. EM kensch@med.wayne.edu FU NCI [N02-CP-11004] FX This study was supported in part by NCI N02-CP-11004: U.S. Kidney Cancer Study. NR 27 TC 3 Z9 3 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD FEB PY 2016 VL 5 IS 2 BP 200 EP 208 DI 10.1002/cam4.578 PG 9 WC Oncology SC Oncology GA DD2HV UT WOS:000369744200007 PM 26710924 ER PT J AU Salsgiver, EL Fink, AK Knapp, EA LiPuma, JJ Olivier, KN Marshall, BC Saiman, L AF Salsgiver, Elizabeth L. Fink, Aliza K. Knapp, Emily A. LiPuma, John J. Olivier, Kenneth N. Marshall, Bruce C. Saiman, Lisa TI Changing Epidemiology of the Respiratory Bacteriology of Patients With Cystic Fibrosis SO CHEST LA English DT Article DE cystic fibrosis; Pseudomonas aeruginosa; registry; Staphylococcus aureus ID PSEUDOMONAS-AERUGINOSA INFECTION; RESISTANT STAPHYLOCOCCUS-AUREUS; NONTUBERCULOUS MYCOBACTERIA; STENOTROPHOMONAS-MALTOPHILIA; MOLECULAR EPIDEMIOLOGY; UNITED-STATES; MRSA; TRANSMISSION; ERADICATION; ACQUISITION AB BACKGROUND: Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions. METHODS: We performed a retrospective analysis using data reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2006 to 2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), Haemophilus influenzae, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010 to 2012, when the CFFPR collected NTM species. RESULTS: In 2012, the pathogens of highest prevalence and incidence were MSSA and P aeruginosa, followed by MRSA. The prevalence of A xylosoxidans and B cepacia complex were relatively low. From 2006 to 2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P aeruginosa and B cepacia complex, but significantly increased for MRSA. From 2010 to 2012, the annual percent change in overall prevalence of NTM and Mycobaterium avium complex increased. CONCLUSIONS: The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology. C1 [Salsgiver, Elizabeth L.; Saiman, Lisa] Columbia Univ, Med Ctr, New York, NY 10032 USA. [Fink, Aliza K.; Knapp, Emily A.; Marshall, Bruce C.] Cyst Fibrosis Fdn, Bethesda, MD USA. [LiPuma, John J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Olivier, Kenneth N.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Salsgiver, Elizabeth L.] Weill Cornell Med Ctr, New York, NY USA. RP Saiman, L (reprint author), Columbia Univ, Med Ctr, Dept Pediat, 650 W 168th St,PH 4 W Room 470, New York, NY 10032 USA. EM LS5@cumc.columbia.edu FU US Cystic Fibrosis Foundation; Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This study was supported by the US Cystic Fibrosis Foundation and, in part, by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 42 TC 6 Z9 6 U1 4 U2 18 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2016 VL 149 IS 2 BP 390 EP 400 DI 10.1378/chest.15-0676 PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DD1DC UT WOS:000369660400022 PM 26203598 ER PT J AU Cheng, LL Liu, J Li, B Liu, SM Li, XY Tu, HB AF Cheng, Linling Liu, Jun Li, Bing Liu, Shengming Li, Xianyan Tu, Hongbin TI Cigarette Smoke-Induced Hypermethylation of the GCLC Gene Is Associated With COPD SO CHEST LA English DT Article DE antioxidants; COPD; smoking ID OBSTRUCTIVE PULMONARY-DISEASE; MICROSOMAL EPOXIDE HYDROLASE; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; GLUTAMATE-CYSTEINE LIGASE; POSSIBLE MECHANISMS; DNA METHYLATION; GLUTATHIONE; SUSCEPTIBILITY; POLYMORPHISMS; EPIGENETICS AB BACKGROUND: Cigarette smoking is a major environmental contributor to COPD, but understanding its epigenetic regulation of oxidative genes involved in the pathogenesis of COPD remains elusive. METHODS: We analyzed DNA methylation on glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase M1 (GSTM1), glutathione S-transferase P1 (GSTP1), and superoxide dismutase 3 (SOD3) promoters in clinical samples from patients with COPD (current-smoker [CS-COPD]; ex-smoker [ES-COPD]) and subjects with normal pulmonary function (current-smoker [CS-NS]; ex-smoker [ES-NS]; never-smoker [NC]). Expression of GCLC messenger RNA (mRNA) and glutathione (GSH) synthesis in these clinical samples and human bronchial epithelial (BEAS-2B) cells stimulated by cigarette-smoke extract (CSE) was evaluated. GCLC mRNA and protein levels were measured to determine effects of demethylation and deacetylation agents on CSE-treated BEAS-2B cells. RESULTS: The DNA methylation level of the GCLC promoter was significantly increased in CS-COPD, CS-NS, and ES-COPD groups compared with ES-NS and NC groups. However, there were no significant differences in DNA methylation values of GSTM1, GSTP1, and SOD3 promoters among these groups. Expression of GCLC mRNA was downregulated in the lungs, and GSH levels decreased in plasma as a consequence of hypermethylation of the GCLC promoter. Similarly, CSE-treated BEAS-2B cells had hypermethylation of the GCLC gene, mRNA downregulation, and a decreased intracellular GSH level. GCLC expression in CSE-treated BEAS-2B cells was restored by the methylation inhibitor, 5-aza-2'-deoxycytidine, but not by the deacetylation agent, trichostatin A. CONCLUSIONS: Cigarette smoke-induced hypermethylation of the GCLC promoter is related to the initiation and progression of COPD. Our finding may provide a new strategy for COPD intervention by developing demethylation agents targeting GCLC hypermethylation. C1 [Cheng, Linling; Liu, Jun; Tu, Hongbin] Affiliated Hosp 1, Natl Clin Ctr Resp Dis, Guangzhou Inst Resp Dis, State Key Lab Resp Dis, Guangzhou, Guangdong, Peoples R China. [Li, Bing; Tu, Hongbin] Guangzhou Med Univ, Res Ctr Expt Med, Guangzhou, Guangdong, Peoples R China. [Liu, Shengming; Li, Xianyan] Jinan Univ, Affiliated Hosp 1, Dept Resp Med, Guangzhou, Guangdong, Peoples R China. [Tu, Hongbin] NIDDK, NIH, Bethesda, MD 20892 USA. RP Tu, HB (reprint author), NIH, 10-4D57,MSC-1372,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tuhongbin@mail.nih.gov FU National Natural Science Foundation of China [30800498]; Guangdong Natural Science Foundation [S2013010016665] FX This study was supported by grants from the National Natural Science Foundation of China [30800498] and Guangdong Natural Science Foundation [S2013010016665] NR 35 TC 1 Z9 1 U1 2 U2 7 PU AMER COLL CHEST PHYSICIANS PI GLENVIEW PA 2595 PATRIOT BLVD, GLENVIEW, IL 60026 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2016 VL 149 IS 2 BP 474 EP 482 DI 10.1378/chest.14-2309 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DD1DC UT WOS:000369660400030 PM 26087411 ER PT J AU Mueller, GA Randall, TA Glesner, J Pedersen, LC Perera, L Edwards, LL DeRose, EF Chapman, MD London, RE Pomes, A AF Mueller, G. A. Randall, T. A. Glesner, J. Pedersen, L. C. Perera, L. Edwards, L. L. DeRose, E. F. Chapman, M. D. London, R. E. Pomes, A. TI Serological, genomic and structural analyses of the major mite allergen Der p 23 SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE allergen; Der p 23; house dust mite; RNA-seq ID NMR CHEMICAL-SHIFTS; HOUSE-DUST MITES; RNA-SEQ DATA; DERMATOPHAGOIDES-PTERONYSSINUS; CARBOHYDRATE INTERACTIONS; ANTIGENIC STRUCTURE; PERITROPHIC MATRIX; INDOOR ALLERGENS; PROTEIN; IGE AB BackgroundDer p 23 was recently identified in a European population as a major allergen and potentially a chitin binding protein. ObjectiveThis study sought to assess the importance of Der p 23 among other Dermatophagoides allergens in a North American population and to determine the structure for functional characterization. MethodsIgE binding to Der p 23, Der p 1, Der p 2, Der p 5, Der p 7 and Der p 8 was measured by ELISA. RNA-seq data from D.pteronyssinus were compared as estimates of allergen expression levels. The structure was analysed by X-ray crystallography and NMR. ResultsDespite a high prevalence of Der p 23, (75% vs. 87% and 79% for Der p 1 and Der p 2, respectively), the anti-Der p 23 IgE levels were relatively low. The patient response to the 6 allergens tested was variable (n=47), but on average anti-Der p 1 and anti-Der p 2 together accounted for 85% of the specific IgE. In terms of abundance, the RNA expression level of Der p 23 is the lowest of the major allergens, thirty fold less than Der p 1 and sevenfold less than Der p 2. The structure of Der p 23 is a small, globular protein stabilized by two disulphide bonds, which is structurally related to allergens such as Blo t 12 that contain carbohydrate binding domains that bind chitin. Functional assays failed to confirm chitin binding by Der p 23. Conclusions and Clinical RelevanceDer p 23 accounts for a small percentage of the IgE response to mite allergens, which is dominated by Der p 1 and Der p 2. The prevalence and amount of specific IgE to Der p 23 and Der p 2 are disproportionately high compared to the expression of other Dermatophagoides allergens. C1 [Mueller, G. A.; Pedersen, L. C.; Perera, L.; Edwards, L. L.; DeRose, E. F.; London, R. E.] Genome Integr & Struct Biol Lab, 111 TW Alexander Dr MD MR01, Res Triangle Pk, NC 27709 USA. [Randall, T. A.] NIEHS, Integrat Bioinformat, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Glesner, J.; Chapman, M. D.; Pomes, A.] INDOOR Biotechnol Inc, Charlottesville, VA USA. RP Mueller, GA (reprint author), Genome Integr & Struct Biol Lab, 111 TW Alexander Dr MD MR01, Res Triangle Pk, NC 27709 USA. EM mueller3@niehs.nih.gov OI Pomes, Anna/0000-0002-8729-1829 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES102885-01, ZIA-ES102645]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01AI077653] FX Research in this publication was supported in part by Research Project Number Z01-ES102885-01 to REL, and ZIA-ES102645 to LCP in the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health, and in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI077653 (AP and MDC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Mr. Aaron Manning for help in protein purification, and Marjorie S. Morgan, S. Dean Rider, Jr., DiAnn L. Vyszenski-Moher and Larry G. Arlian from Wright State University for providing the D. pteronyssinus RNA. The authors also thank the NIH Intramural Sequencing Center, Comparative Sequence Group for expert technical assistance with high-throughput sequencing. NR 55 TC 6 Z9 6 U1 4 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0954-7894 EI 1365-2222 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD FEB PY 2016 VL 46 IS 2 BP 365 EP 376 DI 10.1111/cea.12680 PG 12 WC Allergy; Immunology SC Allergy; Immunology GA DD6TQ UT WOS:000370057800015 PM 26602749 ER PT J AU Fufaa, GD Weil, EJ Lemley, KV Knowler, WC Brosius, FC Yee, B Mauer, M Nelson, RG AF Fufaa, Gudeta D. Weil, E. Jennifer Lemley, Kevin V. Knowler, William C. Brosius, Frank C., III Yee, Berne Mauer, Michael Nelson, Robert G. TI Structural Predictors of Loss of Renal Function in American Indians with Type 2 Diabetes SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; ALBUMIN EXCRETION RATE; PIMA-INDIANS; FUNCTION DECLINE; NEPHROPATHY; PROGRESSION; MELLITUS; DISEASE; INJURY; MICROALBUMINURIA AB Background and objectives Diabetes is the leading cause of kidney failure in the United States, but early structural determinants of renal function loss in type 2 diabetes are poorly defined. We examined the association between morphometrically determined renal structural variables and loss of renal function in 111 American Indians with type 2 diabetes who volunteered for a research kidney biopsy at the end of a 6-year clinical trial designed to test the renoprotective efficacy of losartan versus placebo. Participants were subsequently followed in an observational study, in which annual measurements of GFR (iothalamate) initiated during the clinical trial were continued. Design, setting, participants, & measurements Renal function loss was defined as >= 40% loss of GFR from the research examination performed at the time of kidney biopsy. Associations with renal function loss were evaluated by Cox proportional hazards regression. Hazard ratios (HRs) were reported per 1-SD increment for each morphometric variable. Results Of 111 participants (82% women; baseline mean [+/- SD] age, 46 years old [+/- 10]; diabetes duration, 16 years [+/- 6]; hemoglobin A1c =9.4% [+/- 2.2]; GFR=147 ml/min [+/- 56]; median albumin-to-creatinine ratio, 41 mg/g [interquartile range, 13-158]), 51 (46%) developed renal function loss during a median follow-up of 6.6 years (interquartile range, 3.1-9.0). Fourteen had baseline GFR <90 ml/min, and three had baseline GFR <60 ml/min. Higher mesangial fractional volunie (HR, 2.27; 95% confidence interval [95% CI], 1.58 to 3.26), percentage of global glomerular sclerosis (HR, 1.63; 95% CI, 1.21 to 2.21), nonpodocyte cell number per glomerulus (HR, 1.50; 95% CI, 1.10 to 2.05), glomerular basement membrane width (HR, 1.48; 95% CI, 1.05 to 2.08), mean glomerular volume (HR, 1.42; 95% CI, 1.02 to 1.96), and podocyte foot process width (HR, 1.28; 95% CI, 1.03 to 1.60); lower glomerular filtration surface density (HR, 0.62; 95% CI, 0.41 to 0.94); and fewer endothelial fenestrations (HR, 0.68; 95% CI, 0.48 to 0.95) were each associated with GFR decline after adjustment for baseline age, sex, duration of diabetes, hemoglobin A1c, GFR, and treatment assignment during the clinical trial. Conclusions Quantitative measures of glomerular structure predict loss of renal function in type 2 diabetes. C1 [Fufaa, Gudeta D.; Weil, E. Jennifer; Knowler, William C.; Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ USA. [Lemley, Kevin V.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90033 USA. [Brosius, Frank C., III] Univ Michigan, Div Nephrol, Ann Arbor, MI 48109 USA. [Yee, Berne] Southwest Kidney Inst, Phoenix, AZ USA. [Mauer, Michael] Univ Minnesota, Dept Pediat & Med, Minneapolis, MN USA. RP Nelson, RG (reprint author), NIH, 1550 East Indian Sch Rd, Phoenix, AZ 85014 USA. EM rnelson@nih.gov FU Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases; American Diabetes Association Clinical Science Award [1-08-CR-42] FX This research was supported by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases and American Diabetes Association Clinical Science Award 1-08-CR-42. NR 43 TC 8 Z9 8 U1 1 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB PY 2016 VL 11 IS 2 BP 254 EP 261 DI 10.2215/CJN.05760515 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DD4FM UT WOS:000369877900009 PM 26792530 ER PT J AU Atta, MG Estrella, MM Skorecki, KL Kopp, JB Winkler, CA Wasser, WG Shemer, R Racusen, LC Kuperman, M Foy, MC Lucas, GM Fine, DM AF Atta, Mohamed G. Estrella, Michelle M. Skorecki, Karl L. Kopp, Jeffrey B. Winkler, Cheryl A. Wasser, Walter G. Shemer, Revital Racusen, Lorraine C. Kuperman, Michael Foy, Matthew C. Lucas, Gregory M. Fine, Derek M. TI Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID APOLIPOPROTEIN-L GENE; RISK VARIANTS; AFRICAN-AMERICANS; DISEASE; NEPHROPATHY; INFECTION; PROGRESSION; CLUSTER; TISSUE; CKD AB Background and objectives Prior studies have shown that the APOL1 risk alleles are associated with a greater risk of HIV-associated nephropathy and FSGS among blacks who are HIV positive. We sought to determine whether the APOL1 high risk genotype incrementally improved the-prediction of these underlying lesions beyond conventional clinical factors. Design, setting, participants, & measurements In a cross-sectional study, we analyzed data from 203 blacks who are HIV positive, underwent kidney biopsies between 1996 and 2011, and were genotyped for the APOL1 G1 and G2 alleles. Predictive logistic regression models with conventional clinical factors were compared with those that also included APOL1 genotype using receiver-operating curves and bootstrapping analyses with crossvalidation. Results The addition of APOL1 genotype to HIV related risk factors for kidney disease in a predictive model improved the prediction of non HIV associated nephropathy FSGS, specifically, increasing the c statistic from 0.65 to 0.74 (P=0.04). Although two risk alleles were significantly associated with higher odds of HIV-associated nephropathy, APOL1 genotype did not add incrementally to the prediction of this specific histopathology. Conclusions APOL1 genotype may provide additional diagnostic information to traditional clinical variables in predicting underlying FSGS spectrum lesions in blacks who are HIV positive. In contrast, although APOL1 risk genotype predicts HIV-associated nephropathy, it lacked a high c statistic sufficient for discrimination to eliminate the role of kidney biopsy in the clinical care of blacks who are HIV positive with nephrotic proteinuria or unexplained kidney disease. C1 [Atta, Mohamed G.; Estrella, Michelle M.; Lucas, Gregory M.; Fine, Derek M.] Johns Hopkins Univ, Sch Med, Dept Med, 1830 East Monument St,Suite 416, Baltimore, MD 21205 USA. [Racusen, Lorraine C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Skorecki, Karl L.; Shemer, Revital] Technion Israel Inst Technol, Rappaport Fac Med & Res Inst, Haifa, Israel. [Skorecki, Karl L.; Wasser, Walter G.; Shemer, Revital] Rambam Hlth Care Campus, Dept Med, Haifa, Israel. [Kopp, Jeffrey B.] NIDDK, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Winkler, Cheryl A.] Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD USA. [Kuperman, Michael] Baylor Univ, Med Ctr, Dept Pathol, Dallas, TX USA. [Foy, Matthew C.] Louisiana State Univ, Hlth Sci Ctr, Div Internal Med, Baton Rouge, LA 70803 USA. RP Atta, MG (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1830 East Monument St,Suite 416, Baltimore, MD 21205 USA. EM matta1@jhmi.edu FU National Cancer Institute (NCI); National Institutes of Health (NIH) [HHSN26120080001E]; NIH, NCI, Center for Cancer Research; Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH; NIH/NIDDK Grant [P01DK056492, K23DK081317]; Johns Hopkins University Center for AIDS Research Grant [P30AI094189]; Johns Hopkins-Technion Program of the American Technion Society; Israel Science Foundation Grant [2013504]; Ernest and Bonnie Beutler Grant Program at Rambam Health Care Campus; NIH/National Institute on Drug Abuse (NIDA) [K24DA035684, R01DA026770] FX This project has been funded, in part, with federal funds from National Cancer Institute (NCI), National Institutes of Health (NIH) Contract HHSN26120080001E. This research was supported, in part, by the Intramural Research Program of the NIH, NCI, Center for Cancer Research and the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. M.G.A. and D.M.F. are supported by NIH/NIDDK Grant P01DK056492. M.M.E. is supported by NIH/NIDDK Grant K23DK081317. M.M.E. and G.M.L. are supported by Johns Hopkins University Center for AIDS Research Grant P30AI094189. K.S. and D.M.F. are supported by a grant from the Johns Hopkins-Technion Program of the American Technion Society. K.S. is supported by Israel Science Foundation Grant 2013504 and the Ernest and Bonnie Beutler Grant Program at Rambam Health Care Campus. G.M.L. is supported by NIH/National Institute on Drug Abuse (NIDA) grants K24DA035684 and R01DA026770. NR 24 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD FEB PY 2016 VL 11 IS 2 BP 262 EP 270 DI 10.2215/CJN.07490715 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA DD4FM UT WOS:000369877900010 PM 26668025 ER PT J AU Dodd, LE AF Dodd, Lori E. TI Clinical trials during the Ebola crisis SO CLINICAL TRIALS LA English DT Editorial Material C1 [Dodd, Lori E.] NIAID, Biostat Res Branch, Div Clin Res, 5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NIAID, Biostat Res Branch, Div Clin Res, 5601 Fishers Lane,MSC 9820, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov NR 5 TC 1 Z9 2 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 5 EP 5 DI 10.1177/1740774515621509 PG 1 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700001 PM 26768571 ER PT J AU Proschan, MA Dodd, LE Price, D AF Proschan, Michael A. Dodd, Lori E. Price, Dionne TI Statistical considerations for a trial of Ebola virus disease therapeutics SO CLINICAL TRIALS LA English DT Article DE Barnard's test; Bayesian methods; beta-binomial distribution; conditional power; emerging infectious diseases; Fisher's exact test; group-sequential monitoring; non-informative prior ID CLINICAL-TRIALS; VACCINE TRIALS; TESTS AB The 2014 West African outbreak of Ebola virus ravaged Liberia, Sierra Leone, and Guinea, causing hemorrhagic fever and death. The need to identify effective therapeutics was acute. The usual drug development paradigm of phase I, followed by phase II, and then phase III trials would take too long. These and other factors led to the design of a clinical trial of Ebola virus disease therapeutics that differs from more conventional clinical trial designs. This article describes the Ebola virus disease medical countermeasures trial design and the thinking behind it. C1 [Proschan, Michael A.; Dodd, Lori E.] NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. [Price, Dionne] US FDA, Silver Spring, MD USA. RP Proschan, MA (reprint author), NIAID, 5601 Fishers Lane,Room 4C30,MSC 9820, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 13 TC 6 Z9 6 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 39 EP 48 DI 10.1177/1740774515620145 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700007 PM 26768567 ER PT J AU Kennedy, SB Neaton, JD Lane, HC Kieh, MWS Massaquoi, MBF Touchette, NA Nason, MC Follmann, DA Boley, FK Johnson, MP Larson, G Kateh, FN Nyenswah, TG AF Kennedy, Stephen B. Neaton, James D. Lane, H. Clifford Kieh, Mark W. S. Massaquoi, Moses B. F. Touchette, Nancy A. Nason, Martha C. Follmann, Dean A. Boley, Fatorma K. Johnson, Melvin P. Larson, Gregg Kateh, Francis N. Nyenswah, Tolbert G. TI Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges SO CLINICAL TRIALS LA English DT Article DE Ebola virus disease; clinical trials; Liberia; epidemics; emerging and re-emerging infections; infectious diseases; social mobilization; partnership ID HEALTH AB The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia. C1 [Kennedy, Stephen B.; Kieh, Mark W. S.; Massaquoi, Moses B. F.; Boley, Fatorma K.; Johnson, Melvin P.] Partnership Res Ebola Vaccines Liberia PREVAIL, Liberia US Clin Trials Partnership Program, Monrovia 100010, Montserrado Cty, Liberia. [Kennedy, Stephen B.; Massaquoi, Moses B. F.; Kateh, Francis N.; Nyenswah, Tolbert G.] Minist Hlth, Emergency Operat Ctr, Incident Management Syst, Monrovia, Liberia. [Neaton, James D.; Larson, Gregg] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Lane, H. Clifford; Touchette, Nancy A.; Nason, Martha C.; Follmann, Dean A.] NIAID, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Boley, Fatorma K.] LIBR, Margibi, Liberia. [Kateh, Francis N.; Nyenswah, Tolbert G.] Minist Hlth, Monrovia, Liberia. RP Kennedy, SB (reprint author), Partnership Res Ebola Vaccines Liberia PREVAIL, Liberia US Clin Trials Partnership Program, Monrovia 100010, Montserrado Cty, Liberia.; Kennedy, SB (reprint author), Minist Hlth, Emergency Operat Ctr, Incident Management Syst, Monrovia, Liberia. EM kennedys@lpgmc.org NR 12 TC 11 Z9 12 U1 3 U2 15 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 49 EP 56 DI 10.1177/1740774515621037 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700008 PM 26768572 ER PT J AU Nason, M AF Nason, Martha TI Statistics and logistics: Design of Ebola vaccine trials in West Africa SO CLINICAL TRIALS LA English DT Article C1 [Nason, Martha] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Nason, M (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mnason@niaid.nih.gov NR 11 TC 0 Z9 0 U1 1 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 87 EP 91 DI 10.1177/1740774515620612 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700014 PM 26768560 ER PT J AU Lane, HC Marston, HD Fauci, AS AF Lane, H. Clifford Marston, Hilary D. Fauci, Anthony S. TI Conducting clinical trials in outbreak settings: Points to consider SO CLINICAL TRIALS LA English DT Article C1 [Lane, H. Clifford; Marston, Hilary D.; Fauci, Anthony S.] NIAID, NIH, 10 Ctr Dr,MSC 1460, Bethesda, MD 20892 USA. RP Lane, HC (reprint author), NIAID, NIH, 10 Ctr Dr,MSC 1460, Bethesda, MD 20892 USA. EM Clane@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 5 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD FEB PY 2016 VL 13 IS 1 BP 92 EP 95 DI 10.1177/1740774515618198 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DD5UT UT WOS:000369990700015 PM 26768564 ER PT J AU Marina, RJ Sturgill, D Bailly, MA Thenoz, M Varma, G Prigge, MF Nanan, KK Shukla, S Haque, N Oberdoerffer, S AF Marina, Ryan J. Sturgill, David Bailly, Marc A. Thenoz, Morgan Varma, Garima Prigge, Maria F. Nanan, Kyster K. Shukla, Sanjeev Haque, Nazmul Oberdoerffer, Shalini TI TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing SO EMBO JOURNAL LA English DT Article DE alternative splicing; CTCF; DNA methylation; TET1; TET2 ID EMBRYONIC STEM-CELLS; POLYMERASE-II ELONGATION; EXON-INTRON STRUCTURE; GENOME-WIDE ANALYSIS; DNA-METHYLATION; RNA-POLYMERASE; MAMMALIAN DNA; CHROMATIN ORGANIZATION; BINDING PROTEIN; SEQUENCING DATA AB Intragenic 5-methylcytosine and CTCF mediate opposing effects on pre-mRNA splicing: CTCF promotes inclusion of weak upstream exons through RNA polymerase II pausing, whereas 5-methylcytosine evicts CTCF, leading to exon exclusion. However, the mechanisms governing dynamic DNA methylation at CTCF-binding sites were unclear. Here, we reveal the methylcytosine dioxygenases TET1 and TET2 as active regulators of CTCF-mediated alternative splicing through conversion of 5-methylcytosine to its oxidation derivatives. 5-hydroxymethylcytosine and 5-carboxylcytosine are enriched at an intragenic CTCF-binding sites in the CD45 model gene and are associated with alternative exon inclusion. Reduced TET levels culminate in increased 5-methylcytosine, resulting in CTCF eviction and exon exclusion. In vitro analyses establish the oxidation derivatives are not sufficient to stimulate splicing, but efficiently promote CTCF association. We further show genomewide that reciprocal exchange of 5-hydroxymethylcytosine and 5-methylcytosineat downstream CTCF-binding sites is a general feature of alternative splicing in naive and activated CD4(+) T cells. These findings significantly expand our current concept of the pre-mRNA "splicing code" to include dynamic intragenic DNA methylation catalyzed by the TET proteins. C1 [Marina, Ryan J.; Sturgill, David; Bailly, Marc A.; Thenoz, Morgan; Varma, Garima; Prigge, Maria F.; Nanan, Kyster K.; Shukla, Sanjeev; Haque, Nazmul; Oberdoerffer, Shalini] NCI, Ctr Canc Res, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Bailly, Marc A.] Merck Res Lab, Palo Alto, CA USA. [Varma, Garima] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Shukla, Sanjeev] Indian Inst Sci Educ & Res Bhopal, Dept Biol Sci, Bhopal 462066, India. [Haque, Nazmul] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Oberdoerffer, S (reprint author), NCI, Ctr Canc Res, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. EM shalini.oberdoerffer@nih.gov FU Intramural Research Program of NIH; National Cancer Institute; Center for Cancer Research FX We thank K. Lynch, T. Misteli, and P. Oberdoerffer for critical reading of this manuscript. We also thank A. Rao for helpful discussions and feedback. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). This work is supported by the Intramural Research Program of NIH, the National Cancer Institute, the Center for Cancer Research. NR 91 TC 4 Z9 4 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD FEB 1 PY 2016 VL 35 IS 3 BP 335 EP 355 DI 10.15252/embj.201593235 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DD5YF UT WOS:000370000100007 PM 26711177 ER PT J AU Park, S Ahuja, M Kim, MS Brailoiu, GC Jha, A Zeng, M Baydyuk, M Wu, LG Wassif, CA Porter, FD Zerfas, PM Eckhaus, MA Brailoiu, E Shin, DM Muallem, S AF Park, Soonhong Ahuja, Malini Kim, Min Seuk Brailoiu, G. Cristina Jha, Archana Zeng, Mei Baydyuk, Maryna Wu, Ling-Gang Wassif, Christopher A. Porter, Forbes D. Zerfas, Patricia M. Eckhaus, Michael A. Brailoiu, Eugen Shin, Dong Min Muallem, Shmuel TI Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV SO EMBO REPORTS LA English DT Article DE exocytosis; lysosomes; secretory organelles; TRPML1 channel ID PAROTID ACINAR-CELLS; GRANULE EXOCYTOSIS; GLUTAMATE RELEASE; AMYLASE RELEASE; TRP CHANNEL; PATHWAYS; PROTEINS; TRAFFICKING; CALCIUM; MODEL AB Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV. C1 [Park, Soonhong; Ahuja, Malini; Jha, Archana; Zeng, Mei; Muallem, Shmuel] NIDCR, Epithelial Signaling & Transport Sect Mol Physiol, NIH, Bethesda, MD USA. [Park, Soonhong; Shin, Dong Min] Yonsei Univ, Coll Dent, Dept Oral Biol, BK PLUS Project 12, Seoul 120749, South Korea. [Kim, Min Seuk] Wonkwang Univ, Dept Oral Physiol, Sch Dent, Iksan, South Korea. [Brailoiu, G. Cristina] Thomas Jefferson Univ, Jefferson Sch Pharm, Dept Pharmaceut Sci, Philadelphia, PA 19107 USA. [Baydyuk, Maryna; Wu, Ling-Gang] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Zerfas, Patricia M.; Eckhaus, Michael A.] NIH, Diagnost & Res Serv Branch, Div Vet Resources, Off Res Serv, Bldg 10, Bethesda, MD 20892 USA. [Brailoiu, Eugen] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19122 USA. RP Muallem, S (reprint author), NIDCR, Epithelial Signaling & Transport Sect Mol Physiol, NIH, Bethesda, MD USA.; Shin, DM (reprint author), Yonsei Univ, Coll Dent, Dept Oral Biol, BK PLUS Project 12, Seoul 120749, South Korea. EM dmshin@yuhs.ac; shmuel.muallem@nih.gov FU National Institutes of Health [HL090804, P30DA013429]; NIH/NIDCR [DE000735]; Intramural Research Program of NICHD; National Research Foundation of Korea (NRF) [NRF-2013K2A1A2049748]; NRF grants - Korea Government [NRF-2007-0056419, NRF-2015R1A2A1A15054157, NRF-2012R1A1A1038381] FX This work was supported in part by National Institutes of Health Grants HL090804 to E.B., P30DA013429 to the Center for Substance Abuse Research, Temple University (E.B.), NIH/NIDCR intramural grant DE000735 to S.M., the Intramural Research Program of NICHD to F.D.P., grant NRF-2013K2A1A2049748 under the framework of international cooperation program managed by National Research Foundation of Korea (NRF), and by NRF grants funded by the Korea Government (NRF-2007-0056419, NRF-2015R1A2A1A15054157, and NRF-2012R1A1A1038381). NR 52 TC 4 Z9 4 U1 6 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD FEB PY 2016 VL 17 IS 2 BP 266 EP 278 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DD5JV UT WOS:000369960600015 PM 26682800 ER PT J AU Naves, LA Daly, AF Dias, LA Yuan, B Zakir, JCO Barra, GB Palmeira, L Villa, C Trivellin, G Jreige, A Neto, FFC Liu, PF Pellegata, NS Stratakis, CA Lupski, JR Beckers, A AF Naves, Luciana A. Daly, Adrian F. Dias, Luiz Augusto Yuan, Bo Oliveira Zakir, Juliano Coelho Barra, Gustavo Barcellos Palmeira, Leonor Villa, Chiara Trivellin, Giampaolo Jreige Junior, Armindo Cavalcante Neto, Florencio Figueiredo Liu, Pengfei Pellegata, Natalia S. Stratakis, Constantine A. Lupski, James R. Beckers, Albert TI Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome SO ENDOCRINE LA English DT Article DE Giant; Pituitary adenoma; X-linked acrogigantism syndrome; FIPA; GPR101 ID PITUITARY-ADENOMAS; THERAPEUTIC RESPONSES; AIP MUTATION; GENE; MANAGEMENT; YOUNG AB X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for > 2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 x 23.9 x 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 x 58.1 x 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome. C1 [Naves, Luciana A.; Oliveira Zakir, Juliano Coelho] Univ Brasilia, Fac Med, Dept Endocrinol, Brasilia, DF, Brazil. [Cavalcante Neto, Florencio Figueiredo] Univ Brasilia, Fac Med, Dept Pathol, Brasilia, DF, Brazil. [Daly, Adrian F.; Palmeira, Leonor; Beckers, Albert] Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, Domaine Univ Sart Tilman, B-4000 Liege, Belgium. [Barra, Gustavo Barcellos] Lab Sabin Anal Clin Brasilia, Brasilia, DF, Brazil. [Villa, Chiara] Hop Foch, Dept Pathol, Suresnes, France. [Pellegata, Natalia S.] Helmholtz Zentrum Munchen, Inst Pathol, Neuherberg, Germany. [Yuan, Bo; Liu, Pengfei; Lupski, James R.] Baylor Coll Med, Dept Mol, Houston, TX 77030 USA. [Yuan, Bo; Liu, Pengfei; Lupski, James R.] Baylor Coll Med, Dept Human Genet, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Dias, Luiz Augusto] Fed Dist Base Hosp, Dept Neurosurg, Brasilia, DF, Brazil. [Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA. [Lupski, James R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Lupski, James R.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. RP Beckers, A (reprint author), Univ Liege, Ctr Hosp Univ Liege, Dept Endocrinol, Domaine Univ Sart Tilman, B-4000 Liege, Belgium. EM draluciananaves@gmail.com; albert.beckers@chu.ulg.ac.be RI Trivellin, Giampaolo/J-6583-2016; Daly, Adrian /E-2178-2011; OI Trivellin, Giampaolo/0000-0003-2384-4153; Daly, Adrian /0000-0001-6130-2975; Pellegata, Natalia S./0000-0002-8000-7784 FU CNPq; Fonds d'Investissement de Recherche Scientifique (FIRS) of the Centre Hospitalier Universitaire de Liege; US National Institute of Neurological Disorders and Stroke (NINDS) [R01NS058529]; National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) [U54 HG006542] FX We thank Nucleo de Apoio a Pesquisa and Instituto Sabin in Brasilia-Brazil, for sample preparations and for performing hormonal studies; Drs. Luiz Augusto Casulari and Dr. Roberpaulo Barboza Filho, for clinical assistance; Ms Doralice Rabello from Pathology Department of University of Brasilia, for preparing tissue samples; Prof Jean Francois Bonneville for discussions on the neuroradiological findings; Dr. Misu Lee for discussion and analysis of somatostatin receptor studies. We thank the CNPq for support. This study was assisted in part by a grant from Fonds d'Investissement de Recherche Scientifique (FIRS) of the Centre Hospitalier Universitaire de Liege to Prof. Albert Beckers. This work was supported in part by grants from the US National Institute of Neurological Disorders and Stroke (NINDS; R01NS058529) to JRL and National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI) (U54 HG006542) to the Baylor-Hopkins Center for Mendelian Genomics. NR 21 TC 10 Z9 10 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-008X EI 1559-0100 J9 ENDOCRINE JI Endocrine PD FEB PY 2016 VL 51 IS 2 BP 236 EP 244 DI 10.1007/s12020-015-0804-6 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD6WP UT WOS:000370065600007 PM 26607152 ER PT J AU Zhu, Y He, Q Aydin, C Rubera, I Tauc, M Chen, M Weinstein, LS Marshansky, V Juppner, H Bastepe, M AF Zhu, Yan He, Qing Aydin, Cumhur Rubera, Isabelle Tauc, Michel Chen, Min Weinstein, Lee S. Marshansky, Vladimir Jueppner, Harald Bastepe, Murat TI Ablation of the Stimulatory G Protein alpha-Subunit in Renal Proximal Tubules Leads to Parathyroid Hormone-Resistance With Increased Renal Cyp24a1 mRNA Abundance and Reduced Serum 1,25-Dihydroxyvitamin D SO ENDOCRINOLOGY LA English DT Article ID ALBRIGHT HEREDITARY OSTEODYSTROPHY; VITAMIN-D METABOLISM; PSEUDO-PSEUDOHYPOPARATHYROIDISM; MOUSE MODEL; MOLECULAR CHARACTERISTICS; PHOSPHATE HOMEOSTASIS; DOWN-REGULATION; GNAS GENE; KINASE-C; IN-VIVO AB PTH regulates serum calcium, phosphate, and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) levels by acting on bone and kidney. In renal proximal tubules (PTs), PTH inhibits reabsorption of phosphate and stimulates the synthesis of 1,25(OH)(2)D. The PTH receptor couples to multiple G proteins. We here ablated the alpha-subunit of the stimulatory G protein (Gs alpha) in mouse PTs by using Cre recombinase driven by the promoter of type-2 sodium-glucose cotransporter (Gs alpha(Sglt2KO) mice). Gs alpha(Sglt2KO) mice were normophosphatemic but displayed, relative to controls, hypocalcemia (1.19 +/- 0.01 vs 1.23 +/- 0.01 mmol/L; P < .05), reduced serum 1,25(OH)(2)D (59.3 +/- 7.0 vs 102.5 +/- 12.2 pmol/L; P < .05), and elevated serum PTH (834 +/- 133 vs 438 +/- 59 pg/mL; P < .05). PTH-induced elevation in urinary cAMP excretion was blunted in Gs alpha(Sglt2KO) mice (2-vs 4-fold over baseline in controls; P < .05). Relative to baseline in controls, PTH-induced reduction in serum phosphate tended to be blunted in Gs alpha(Sglt2KO) mice (-0.39 +/- 0.33 vs -1.34 +/- 0.36 mg/dL; P = .07). Gs alpha(Sglt2KO) mice showed elevated renal vitamin D 24-hydroxylase and bone fibroblast growth factor-23 (FGF23) mRNA abundance (similar to 3.4- and similar to 11-fold over controls, respectively; P < .05) and tended to have elevated serum FGF23 (829 +/- 76 vs 632 +/- 60 pg/mL in controls; P = .07). Heterozygous mice having constitutive ablation of the maternal Gs alpha allele (E1(m-/+)) (model of pseudohypoparathyroidism type-Ia), in which Gs alpha levels in PT are reduced, also exhibited elevated serum FGF23 (474 +/- 20 vs 374 +/- 27 pg/mL in controls; P < .05). Our findings indicate that Gs alpha is required in PTs for suppressing renal vitamin D 24-hydroxylase mRNA levels and for maintaining normal serum 1,25(OH)(2)D. C1 [Zhu, Yan; He, Qing; Aydin, Cumhur; Jueppner, Harald; Bastepe, Murat] Massachusetts Gen Hosp, Endocrine Unit, 55 Fruit St,Thier 10, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Aydin, Cumhur] Gulhane Mil Med Acad, Dept Endodont, TR-06018 Ankara, Turkey. [Rubera, Isabelle; Tauc, Michel] Univ Nice Sophia Antipolis, Fac Med, F-06107 Nice, France. [Chen, Min; Weinstein, Lee S.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Marshansky, Vladimir] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Marshansky, Vladimir] Kadmon Corp, Alexandria Ctr Life Sci, Mol Signaling, New York, NY 10016 USA. RP Bastepe, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 55 Fruit St,Thier 10, Boston, MA 02114 USA. EM bastepe@helix.mgh.harvard.edu RI Tauc, Michel/F-1530-2013 FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01DK073911, R01DK46718]; Intramural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grants R01DK073911 (to M.B.) and R01DK46718 (to H.J.) and the Intramural Research of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 61 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2016 VL 157 IS 2 BP 497 EP 507 DI 10.1210/en.2015-1639 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD5LT UT WOS:000369965900010 PM 26671181 ER PT J AU Berger, A Kablan, A Yao, C Ho, T Podyma, B Weinstein, LS Chen, M AF Berger, Alta Kablan, Ahmed Yao, Catherine Ho, Thuy Podyma, Brandon Weinstein, Lee S. Chen, Min TI G(s)alpha Deficiency in the Ventromedial Hypothalamus Enhances Leptin Sensitivity and Improves Glucose Homeostasis in Mice on a High-Fat Diet SO ENDOCRINOLOGY LA English DT Article ID PSEUDOHYPOPARATHYROIDISM TYPE 1A; ACTIVATED PROTEIN-KINASE; RECEPTOR MESSENGER-RNA; CENTRAL-NERVOUS-SYSTEM; MELANOCORTIN-4 RECEPTOR; BODY-WEIGHT; STEROIDOGENIC FACTOR-1; NEUROTROPHIC FACTOR; REDUCED ADIPOSITY; ENERGY-BALANCE AB In both mice and patients with Albright hereditary osteodystrophy, heterozygous inactivating mutations of G(s)alpha, a ubiquitously expressed G protein that mediates receptor-stimulated intracellular cAMP production, lead to obesity and insulin resistance but only when the mutation is present on the maternal allele. This parent-of-origin effect in mice was shown to be due to G(s)alpha imprinting in one or more brain regions. The ventromedial hypothalamus (VMH) is involved in the regulation of energy and glucose homeostasis, but the role of G(s)alpha in VMH on metabolic regulation is unknown. To examine this, we created VMH-specific G(s)alpha-deficient mice by mating G(s)alpha-floxed mice with SF1-cre mice. Heterozygotes with G(s)alpha mutation on either the maternal or paternal allele had a normal metabolic phenotype, and there was no molecular evidence of G(s)alpha imprinting, indicating that the parent-of-origin metabolic effects associated with G(s)alpha mutations is not due to G(s)alpha deficiency in VMH SF1 neurons. Homozygous VMH G(s)alpha knockout mice (VMHGsKO) showed no changes in body weight on either a regular or high-fat diet. However, glucose metabolism ( fasting glucose, glucose tolerance, insulin sensitivity) was significantly improved in male VMHGsKO mice, with the difference more dramatic on the high-fat diet. Inaddition, male VMHGsKO mice on the high-fat diet showed a greater anorexigenic effect and increased VMH signal transducer and activator of transcription-3 phosphorylation in response to leptin. These results indicate that VMHG(s)alpha/cyclic AMP signaling regulates glucose homeostasis and alters leptin sensitivity in mice, particularly in the setting of excess caloric intake. C1 [Berger, Alta; Kablan, Ahmed; Yao, Catherine; Ho, Thuy; Podyma, Brandon; Weinstein, Lee S.; Chen, Min] NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. [Berger, Alta] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Kablan, Ahmed] US Agcy Int Dev, Washington, DC 20004 USA. [Yao, Catherine] Stanford Univ, Sch Med, Palo Alto, CA 94305 USA. [Ho, Thuy] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. RP Weinstein, LS; Chen, M (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. EM leew@mail.nih.gov; minc@niddk.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Bethesda, Maryland) FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Bethesda, Maryland). NR 30 TC 3 Z9 3 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2016 VL 157 IS 2 BP 600 EP 610 DI 10.1210/en.2015-1700 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD5LT UT WOS:000369965900018 PM 26671183 ER PT J AU Glynn, E Thompson, B Vadrevu, S Lu, SS Kennedy, RT Ha, J Sherman, A Satin, LS AF Glynn, Eric Thompson, Benjamin Vadrevu, Suryakiran Lu, Shusheng Kennedy, Robert T. Ha, Joon Sherman, Arthur Satin, Leslie S. TI Chronic Glucose Exposure Systematically Shifts the Oscillatory Threshold of Mouse Islets: Experimental Evidence for an Early Intrinsic Mechanism of Compensation for Hyperglycemia SO ENDOCRINOLOGY LA English DT Article ID PANCREATIC BETA-CELL; INDUCED INSULIN-SECRETION; ATP CHANNEL TRAFFICKING; SENSITIVE K+ CHANNELS; ENDOPLASMIC-RETICULUM; LIVING CELLS; FALFA RATS; DIAZOXIDE; TURNOVER; FAILURE AB Mouse islets exhibit glucose-dependent oscillations in electrical activity, intracellular Ca2+ and insulin secretion. We developed a mathematical model in which a left shift in glucose threshold helps compensate for insulin resistance. To test this experimentally, we exposed isolated mouse islets to varying glucose concentrations overnight and monitored their glucose sensitivity the next day by measuring intracellular Ca2+, electrical activity, and insulin secretion. Glucose sensitivity of all oscillation modes was increased when overnight glucose was greater than 2.8mM. To determine whether threshold shifts were a direct effect of glucose or involved secreted insulin, the K-ATP opener diazoxide (Dz) was coapplied with glucose to inhibit insulin secretion. The addition of Dz or the insulin receptor antagonist s961 increased islet glucose sensitivity, whereas the K-ATP blocker tolbutamide tended to reduce it. This suggests insulin and glucose have opposing actions on the islet glucose threshold. To test the hypothesis that the threshold shifts were due to changes in plasma membrane K-ATP channels, we measured cell K-ATP conductance, which was confirmed to be reduced by high glucose pretreatment and further reduced by Dz. Finally, treatment of INS-1 cells with glucose and Dz overnight reduced high affinity sulfonylurea receptor (SUR1) trafficking to the plasma membrane vs glucose alone, consistent with insulin increasing K-ATP conductance by altering channel number. The results support a role for metabolically regulated K-ATP channels in the maintenance of glucose homeostasis. C1 [Glynn, Eric; Thompson, Benjamin; Vadrevu, Suryakiran; Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48105 USA. [Glynn, Eric; Thompson, Benjamin; Vadrevu, Suryakiran; Satin, Leslie S.] Univ Michigan, Brehm Diabet Res Ctr, Ann Arbor, MI 48105 USA. [Lu, Shusheng; Kennedy, Robert T.] Univ Michigan, Dept Chem, Ann Arbor, MI 48105 USA. [Ha, Joon; Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Satin, LS (reprint author), Univ Michigan, Brehm Diabet Res Ctr, Kellogg Eye Ctr, Sch Med, 5128 Brehm Tower,1000 Wall St, Ann Arbor, MI 48105 USA. EM lsatin@umich.edu RI Kennedy, Robert/G-9095-2016 OI Kennedy, Robert/0000-0003-2447-7471 FU National Institutes of Health (NIDDK); NIH [RO1DK46409, R37DK046960]; NIDDK [NIH5P60 DK20572] FX This work was supported by the Intramural Program of the National Institutes of Health (NIDDK) (A.S. and J.H.); L.S.S.'s lab was funded by the NIH Grant RO1DK46409. This work used the Chemistry Laboratory of the Michigan Diabetes Research and Training Center, funded by the NIDDK Grant NIH5P60 DK20572. Research in R.T.K.'s lab was supported by the NIH Grant R37DK046960. NR 51 TC 4 Z9 4 U1 3 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2016 VL 157 IS 2 BP 611 EP 623 DI 10.1210/en.2015-1563 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD5LT UT WOS:000369965900019 PM 26697721 ER PT J AU Ha, J Satin, LS Sherman, AS AF Ha, Joon Satin, Leslie S. Sherman, Arthur S. TI A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes SO ENDOCRINOLOGY LA English DT Article ID BETA-CELL MASS; Y GASTRIC BYPASS; PERIPHERAL INSULIN SENSITIVITY; LIFE-STYLE INTERVENTION; BARIATRIC SURGERY; GLUCOSE; REMISSION; HYPERINSULINEMIA; MECHANISM; PATHWAYS AB Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic beta-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing beta-cell mass. We add to that model regulation of 2 aspects of beta-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into "Starling's Law of the Pancreas," whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals. C1 [Ha, Joon; Sherman, Arthur S.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48105 USA. [Satin, Leslie S.] Univ Michigan, Brehm Diabet Res Ctr, Ann Arbor, MI 48105 USA. RP Sherman, AS (reprint author), NIDDK, Lab Biol Modeling, 12A South Dr,Room 4007, Bethesda, MD 20892 USA. EM arthurs@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Kidney Diseases); National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK46409] FX This work was supported by the Intramural Research Program of the National Institutes of Health (National Institute of Diabetes and Kidney Diseases) (A.S.S. and J.H.). L.S.S. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1DK46409. NR 47 TC 6 Z9 6 U1 2 U2 7 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2016 VL 157 IS 2 BP 624 EP 635 DI 10.1210/en.2015-1564 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD5LT UT WOS:000369965900020 PM 26709417 ER PT J AU Venkatasubramanian, S Tripathi, D Tucker, T Paidipally, P Cheekatla, S Welch, E Raghunath, A Jeffers, A Tvinnereim, AR Schechter, ME Andrade, BB Mackman, N Idell, S Vankayalapati, R AF Venkatasubramanian, Sambasivan Tripathi, Deepak Tucker, Torry Paidipally, Padmaja Cheekatla, Satyanarayana Welch, Elwyn Raghunath, Anjana Jeffers, Ann Tvinnereim, Amy R. Schechter, Melissa E. Andrade, Bruno B. Mackman, Nizel Idell, Steven Vankayalapati, Ramakrishna TI Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Apoptosis; IL-10; Macrophage; M; tuberculosis; Tissue factor ID MURINE PNEUMOCOCCAL PNEUMONIA; PROTEASE-ACTIVATED RECEPTORS; FACTOR C-MAF; MACROPHAGE DIFFERENTIATION; GENE-EXPRESSION; MOUSE MODEL; T-CELLS; MICE; IL-10; LUNG AB Tissue factor (TF) is a transmembrane glycoprotein that plays an essential role in hemostasis by activating coagulation. TF is also expressed by monocytes/macrophages as part of the innate immune response to infections. In the current study, we determined the role of TF expressed by myeloid cells during Mycobacterium tuberculosis (M. tb) infection by using mice lacking the TF gene in myeloid cells (TF) and human monocyte derived macrophages (MDMs). We found that during M. tb infection, a deficiency of TF in myeloid cells was associated with reduced inducible nitric oxide synthase (iNOS) expression, enhanced arginase 1 (Arg1) expression, enhanced IL-10 production and reduced apoptosis in infected macrophages, which augmented M. tb growth. Our results demonstrate that a deficiency of TF in myeloid cells promotes M2-like phenotype in M .tb infected macrophages. A deficiency in TF expression by myeloid cells was also associated with reduced fibrin deposition and increased matrix metalloproteases (MMP)-2 and MMP-9 mediated inflammation in M. tb infected lungs. Our studies demonstrate that TF expressed by myeloid cells has newly recognized abilities to polarize macrophages and to regulate M. tb growth. C1 [Venkatasubramanian, Sambasivan; Tripathi, Deepak; Paidipally, Padmaja; Cheekatla, Satyanarayana; Welch, Elwyn; Raghunath, Anjana; Tvinnereim, Amy R.; Vankayalapati, Ramakrishna] Univ Texas Hlth Ctr Tyler, Dept Pulm Immunol, 11937 US Highway 271, Tyler, TX 75708 USA. [Tucker, Torry; Jeffers, Ann; Idell, Steven] Univ Texas Hlth Ctr Tyler, Dept Cellular & Mol Biol, 11937 US Highway 271, Tyler, TX 75708 USA. [Mackman, Nizel] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Schechter, Melissa E.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Clin Monitoring Res Program, Clin Res Directorate, Frederick, MD USA. [Andrade, Bruno B.] Fundacao Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz CPqGM, Lab Immune Regulat, Investigat Med Branch, Salvador, BA, Brazil. [Andrade, Bruno B.] Brazilian Inst TB Res, Res Ctr, Salvador, BA, Brazil. RP Vankayalapati, R (reprint author), Univ Texas Hlth Ctr Tyler, Dept Pulm Immunol, 11937 US Highway 271, Tyler, TX 75708 USA. EM krishna.vankayalapati@uthct.edu FU National Institutes of Health [A1094692, A1085135]; Cain Foundation for Infectious Disease Research; Department of Pulmonary Immunology; RePORT India cohort (NIH-CRDF Global) part of the Indo-US vaccine program; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This work was supported by grants from the National Institutes of Health (A1094692 and A1085135) to R.V., and the Cain Foundation for Infectious Disease Research, and the Department of Pulmonary Immunology. This work was also supported by grants from RePORT India cohort (NIH-CRDF Global) which is part of the Indo-US vaccine program. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. NR 58 TC 4 Z9 4 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2016 VL 46 IS 2 BP 464 EP 479 DI 10.1002/eji.201545817 PG 16 WC Immunology SC Immunology GA DD5OA UT WOS:000369972300024 PM 26471500 ER PT J AU Allen, AM McRae-Clark, AL Carlson, S Saladin, ME Gray, KM Wetherington, CL Mckee, SA Allen, SS AF Allen, Alicia M. McRae-Clark, Aimee L. Carlson, Samantha Saladin, Michael E. Gray, Kevin M. Wetherington, Cora Lee Mckee, Sherry A. Allen, Sharon S. TI Determining Menstrual Phase in Human Biobehavioral Research: A Review With Recommendations SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE women; menstrual phase; sex hormones; methods; recommendations; review ID PREMENSTRUAL DYSPHORIC DISORDER; BRAIN ACTIVATION PATTERNS; URINARY-EXCRETION RATES; DRIED BLOOD SPOTS; CYCLE PHASE; OVARIAN ACTIVITY; HORMONAL CONTRACEPTIVES; ESTRONE GLUCURONIDE; SEX-DIFFERENCES; WOMEN AB Given the volume and importance of research focusing on menstrual phase, a review of the strategies being used to identify menstrual phase and recommendations that will promote methodological uniformity in the field is needed. We conducted a literature review via Ovid Medline and PsycINFO. Our goal was to review methods used to identify menstrual phase and subphases in biobehavioral research studies with women who had physiologically natural menstrual cycles. Therefore, we excluded articles that focused on any of the following: use of exogenous hormones, the postpartum period, menstrual-related problems (e.g., polycystic ovarian syndrome, endometriosis), and infertility/anovulation. We also excluded articles on either younger (<18 years old) or older (>45 years old) study samples. We initially identified a total of 1,809 articles. After our exclusionary criteria were applied, 146 articles remained, within which our review identified 6 different methods used to identify menstrual phase and subphases. The most common method used was self-report of onset of menses (145/146 articles) followed by urine luteinizing hormone testing (50/146 articles) and measurement of hormones (estradiol and/or progesterone) in blood samples (49/146 articles). Overall, we found a lack of consistency in the methodology used to determine menstrual phase and subphases. Weprovide several options to improve accuracy of phase identification, as well as to minimize costs and burden. Adoption of these recommendations will decrease misclassification within individual studies, facilitate cross-study comparisons, and enhance the reproducibility of results. C1 [Allen, Alicia M.; Carlson, Samantha; Allen, Sharon S.] Univ Minnesota, Dept Family Med & Community Hlth, Sch Med, Minneapolis, MN 55455 USA. [McRae-Clark, Aimee L.; Gray, Kevin M.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC USA. [Saladin, Michael E.] Med Univ S Carolina, Dept Hlth Sci & Res, Coll Hlth Profess, Charleston, SC USA. [Wetherington, Cora Lee] Natl Inst Drug Abuse, Bethesda, MD USA. [Mckee, Sherry A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. RP Allen, AM (reprint author), 717 Delaware St SE,Room 422, Minneapolis, MN 55414 USA. EM alle0299@umn.edu FU Specialized Center of Research (SCOR) on Sex Differences grants [P50-DA033942, P50-DA016511, P50-DA033945]; National Institute on Drug Abuse [K24DA038240]; Building Interdisciplinary Research Careers in Women's Health Grant from Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [K12HD055887]; Office of Research on Women's Health; National Institute on Aging, National Institutes of Health (NIH) FX Support for this project was provided by the following Specialized Center of Research (SCOR) on Sex Differences grants: P50-DA033942 (Sharon S. Allen and Alicia M. Allen), P50-DA016511 (Aimee L. McRae-Clark, Michael E. Saladin, and Kevin M. Gray), and P50-DA033945 (Sherry A. McKee). Additional support was provided by National Institute on Drug Abuse (K24DA038240; Aimee L. McRae-Clark), as well as the Building Interdisciplinary Research Careers in Women's Health Grant (K12HD055887; Alicia M. Allen) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Office of Research on Women's Health, and the National Institute on Aging, National Institutes of Health (NIH), administered by the University of Minnesota Deborah E. Powell Center for Women's Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. None of the authors have any conflicts of interest. NR 58 TC 1 Z9 1 U1 3 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 EI 1936-2293 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD FEB PY 2016 VL 24 IS 1 BP 1 EP 11 DI 10.1037/pha0000057 PG 11 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA DD6YQ UT WOS:000370071100001 PM 26570992 ER PT J AU Meyers, FJ Mathur, A Fuhrmann, CN O'Brien, TC Wefes, I Labosky, PA Duncan, DS August, A Feig, A Gould, KL Friedlander, MJ Schaffer, CB Van Wart, A Chalkley, R AF Meyers, Frederick J. Mathur, Ambika Fuhrmann, Cynthia N. O'Brien, Theresa C. Wefes, Inge Labosky, Patricia A. Duncan, D'Anne S. August, Avery Feig, Andrew Gould, Kathleen L. Friedlander, Michael J. Schaffer, Chris B. Van Wart, Audra Chalkley, Roger TI The origin and implementation of the Broadening Experiences in Scientific Training programs: an NIH common fund initiative SO FASEB JOURNAL LA English DT Article DE professional development; career development; Ph. D.; postdoctoral trainee AB Recent national reports and commentaries on the current status and needs of the U.S. biomedical research workforce have highlighted the limited career development opportunities for predoctoral and postdoctoral trainees in academia, yet little attention is paid to preparation for career pathways outside of the traditional faculty path. Recognizing this issue, in 2013, the U.S. National Institutes of Health (NIH) Common Fund issued a request for application titled" NIH Director's Biomedical Research Workforce Innovation Award: Broadening Experiences in Scientific Training (BEST)." These 5-yr 1-time grants, awarded to 17 single or partnering institutions, were designed to develop sustainable approaches to broaden graduate and postgraduate training, aimed at creating training programs that reflect the range of career options that trainees may ultimately pursue. These institutions have formed a consortium in order to work together to develop, evaluate, share, and disseminate best practices and challenges. This is a first report on the early experiences of the consortium and the scope of participating BEST programs. In this report, we describe the state of the U.S. biomedical workforce and development of the BEST award, variations of programmatic approaches to assist with program design without BEST funding, and novel approaches to engage faculty in career development programs. To test the effectiveness of these BEST programs, external evaluators will assess their outcomes not only over the 5 yr grant period but also for an additional 10 yr beyond award completion. C1 [Meyers, Frederick J.] Univ Calif Davis, Hlth Syst, Sacramento, CA 95817 USA. [Mathur, Ambika; Feig, Andrew] Wayne State Univ, Grad Sch, Detroit, MI USA. [Fuhrmann, Cynthia N.] Univ Massachusetts, Sch Med, Grad Sch Biomed Sci, Worcester, MA USA. [O'Brien, Theresa C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wefes, Inge] Univ Colorado, Grad Sch, Anschutz Med Campus, Denver, CO 80202 USA. [Labosky, Patricia A.] NIH, Div Program Coordinat Planning & Strateg Initiat, Bldg 10, Bethesda, MD 20892 USA. [Duncan, D'Anne S.; Gould, Kathleen L.; Chalkley, Roger] Vanderbilt Univ, Sch Med, Biomed Res Educ & Training, Nashville, TN 37232 USA. [Gould, Kathleen L.] Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37212 USA. [August, Avery] Cornell Univ, Dept Microbiol & Immunol, Ithaca, NY USA. [Schaffer, Chris B.] Cornell Univ, Dept Biomed Engn, Ithaca, NY USA. [Friedlander, Michael J.; Van Wart, Audra] Virginia Tech Caril Sch Med & Res Inst, Roanoke, VA USA. RP Chalkley, R (reprint author), Vanderbilt Univ, Sch Med, Biomed Res Educ & Training, Nashville, TN 37232 USA. EM roger.g.chalkley@vanderbilt.edu RI Schaffer, Chris/A-7409-2008; OI Schaffer, Chris/0000-0002-7800-9596; Feig, Andrew/0000-0002-5783-1097 FU NIGMS NIH HHS [R25 GM062459]; NIH HHS [DP7 OD018420, DP7 OD018421, DP7 OD018423, DP7 OD018425, DP7 OD018427, DP7 OD018428] NR 19 TC 4 Z9 4 U1 2 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2016 VL 30 IS 2 BP 507 EP 514 DI 10.1096/fj.15-276139 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DC7IA UT WOS:000369391900004 PM 26432783 ER PT J AU Clayton, JA AF Clayton, Janine Austin TI Studying both sexes: a guiding principle for biomedicine SO FASEB JOURNAL LA English DT Article DE gender; NIH; sex-based biology; inclusion; SABV ID RECEPTOR KNOCKOUT; BALANCE SEX; GENDER; CELL; MICE; NIH; REPRODUCIBILITY; CHROMOSOME; BEHAVIOR; SCIENCE AB In May 2014, the U.S. National Institutes of Health (NIH) announced that it will ensure that investigators account for sex as a biological variable (SABV) in NIH-funded preclinical research as part of the agency's rigor and transparency initiative. Herein, I describe in more detail the rationale behind the SABV policy component and provide additional detail about policy goals. In short, studying both sexes is a guiding principle in biomedical research that will expand knowledge toward turning discovery into health. NIH expects that considering SABV in preclinical research will help to build a knowledge base that better informs the design of clinical research and trials in humans. Integrating the practice of studying both sexes in preclinical research will, over time, expand our currently incomplete knowledge base that plays a critical role in informing the development of sex- and gender-appropriate medical care for women and men. C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. RP Clayton, JA (reprint author), NIH, Off Res Womens Hlth, 6707 Democracy Blvd,Suite 400, Bethesda, MD 20892 USA. EM janine.clayton@nih.gov NR 57 TC 20 Z9 21 U1 3 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2016 VL 30 IS 2 BP 519 EP 524 DI 10.1096/fj.15-279554 PG 6 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DC7IA UT WOS:000369391900006 PM 26514164 ER PT J AU Shi, J Miralles, F Birnbaumer, L Large, WA Albert, AP AF Shi, Jian Miralles, Francesc Birnbaumer, Lutz Large, William A. Albert, Anthony P. TI Store depletion induces Gaq-mediated PLCb1 activity to stimulate TRPC1 channels in vascular smooth muscle cells SO FASEB JOURNAL LA English DT Article DE electrophysiology; PLC activity; Ca2+ signaling; phosphoinositol signaling ID PROTEIN-KINASE-C; OPERATED CA2+ CHANNELS; PORTAL-VEIN MYOCYTES; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; CALCIUM-CHANNELS; ARTERY MYOCYTES; ANGIOTENSIN-II; ACTIVATION; ENTRY; STIM1 AB Depletion of sarcoplasmic reticulum (SR) Ca2+ stores activates store-operated channels (SOCs) composed of canonical transient receptor potential (TRPC) 1 proteins in vascular smooth muscle cells (VSMCs), which contribute to important cellular functions. We have previously shown that PKC is obligatory for activation of TRPC1 SOCs in VSMCs, and the present study investigates if the classic phosphoinositol signaling pathway involving Gaq-mediated PLC activity is responsible for driving PKC-dependent channel gating. The G-protein inhibitor GDP beta-S, anti-Gaq antibodies, the PLC inhibitor U73122, and the PKC inhibitor GF109203X all inhibited activation of TRPC1 SOCs, and U73122 and GF109203X also reduced storeoperated PKC-dependent phosphorylation of TRPC1 proteins. Three distinct SR Ca2+ store-depleting agents, 1,2-bis(2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid acetoxymethyl ester, cyclopiazonic acid, and N, N, N', N'-tetrakis(2-pyridylmethyl) ethane-1,2-diamineed, induced-translocations of the fluorescent biosensor GFP-PLCd1-PH from the cell membrane to the cytosol, which were inhibited by U73122. Knockdown of PLC beta 1 with small hairpin RNA reduced both store-operated PLC activity and stimulation of TRPC1 SOCs. Immunoprecipitation studies and proximity ligation assays revealed that store depletion induced interactions between TRPC1 and Gaq, and TRPC1 and PLC beta 1. We propose a novel activation mechanism for TRPC1 SOCs in VSMCs, in which store depletion induces formation of TRPC1-Gaq-PLC beta 1 complexes that lead to PKC stimulation and channel gating. C1 [Shi, Jian; Miralles, Francesc; Large, William A.; Albert, Anthony P.] Univ London, Inst Cardiovasc & Cell Sci, Vasc Biol Res Ctr, Cranmer Terrace, London SW17 0RE, England. [Miralles, Francesc] Univ London, Inst Med & Biomed Educ, London, England. [Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC USA. RP Shi, J (reprint author), Univ London, Inst Cardiovasc & Cell Sci, Vasc Biol Res Ctr, Cranmer Terrace, London SW17 0RE, England. EM jshi@sgul.ac.uk FU Biotechnology and Biological Sciences Research Council (Swindon, United Kingdom) [BB/J007226/1, BB/M018350/1]; U.S. National Institutes of Health Intramural Research Program [Z01-ES-101684] FX The authors thank Dr. Elena Sviderskaya for assistance with electroporation. This work was supported by the Biotechnology and Biological Sciences Research Council (Swindon, United Kingdom) (BB/J007226/1 and BB/M018350/1 to A.P.A.) and was also supported in part by the U.S. National Institutes of Health Intramural Research Program (Project Z01-ES-101684 to L.B.). NR 53 TC 3 Z9 4 U1 3 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2016 VL 30 IS 2 BP 702 EP 715 DI 10.1096/fj.15-280271 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DC7IA UT WOS:000369391900021 PM 26467792 ER PT J AU Quinn, MA Cidlowski, JA AF Quinn, Matthew A. Cidlowski, John A. TI Endogenous hepatic glucocorticoid receptor signaling coordinates sex-biased inflammatory gene expression SO FASEB JOURNAL LA English DT Article DE sexual dimorphism; liver; nanostring; inflammation; corticosteroid ID PRIMARY SJOGRENS-SYNDROME; UTERINE EPITHELIAL-CELLS; NF-KAPPA-B; GROWTH-HORMONE; GENDER-DIFFERENCES; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; ANTIINFLAMMATORY ACTION; ESTRADIOL ANTAGONISM; MOUSE-LIVER; IN-VIVO AB An individual's sex affects gene expression and many inflammatory diseases present in a sex-biased manner. Glucocorticoid receptors (GRs) are regulators of inflammatory genes, but their role in sex-specific responses is unclear. Our goal was to evaluate whether GR differentially regulates inflammatory gene expression in male and female mouse liver. Twenty-five percent of the 251 genes assayed by nanostring analysis were influenced by sex. Of these baseline sexually dimorphic inflammatory genes, 82% was expressed higher in female liver. Pathway analyses defined pattern-recognition receptors as the most sexually dimorphic pathway. We next exposed male and female mice to the proinflammatory stimulus LPS. Female mice had 177 genes regulated by treatment with LPS, whereas males had 149, with only 66% of LPS-regulated genes common between the sexes. To determine the contribution of GR to sexually dimorphic inflammatory genes we performed nanostring analysis on liver-specific GR knockout (LGRKO) mice in the presence or absence of LPS. Comparing LGRKO to GR(flox/flox) revealed that 36 genes required GR for sexually dimorphic expression, whereas 24 genes became sexually dimorphic in LGRKO. Fifteen percent of LPS-regulated genes in GR(flox/flox) were not regulated in male and female LGRKO mice treated with LPS. Thus, GR action is influenced by sex to regulate inflammatory gene expression. C1 [Quinn, Matthew A.; Cidlowski, John A.] NIEHS, Signal Transduct Lab, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Signal Transduct Lab, NIH, MD F3-07,POB 12233, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU NIH NIEHS FX The authors thank Dr. D. W. Cain for technical assistance and critical reading of the manuscript and the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences (NIEHS) Genomics Core for help with the nanostring analysis. This research was supported by the Intramural Research Program of the NIH NIEHS. The authors declare no conflicts of interest. NR 66 TC 1 Z9 1 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD FEB PY 2016 VL 30 IS 2 BP 971 EP 982 DI 10.1096/fj.15-278309 PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA DC7IA UT WOS:000369391900043 PM 26581598 ER PT J AU Cogliati, M Zani, A Rickerts, V McCormick, I Desnos-Ollivier, M Velegraki, A Escandon, P Ichikawa, T Ikeda, R Bienvenu, AL Tintelnot, K Tore, O Akcaglar, S Lockhart, S Tortorano, AM Varma, A AF Cogliati, Massinio Zani, Alberto Rickerts, Volker McCormick, Ilka Desnos-Ollivier, Marie Velegraki, Aristea Escandon, Patricia Ichikawa, Tomoe Ikeda, Reiko Bienvenu, Anne-Lise Tintelnot, Kathrin Tore, Okan Akcaglar, Sevim Lockhart, Shawn Tortorano, Anna Maria Varma, Ashok TI Multilocus sequence typing analysis reveals that Cryptococcus neoformans var. neoformans is a recombinant population SO FUNGAL GENETICS AND BIOLOGY LA English DT Article DE Cryptococcus; C. neoformans var. neoformans; C neoformans var. grubii; MLST; Recombination ID SPECIES COMPLEX; MATING-TYPE; MOLECULAR EPIDEMIOLOGY; GATTII; PCR; SEROTYPES; GENOTYPE; THAILAND AB Cryptococcus neoformans var. neoformans (serotype D) represents about 30% of the clinical isolates in Europe and is present less frequently in the other continents. It is the prevalent etiological agent in primary cutaneous cryptococcosis as well as in cryptococcal skin lesions of disseminated cryptococcosis. Very little is known about the genotypic diversity of this Cryptococcus subtype. The aim of this study was to investigate the genotypic diversity among a set of clinical and environmental C. neoformans var. neoformans isolates and to evaluate the relationship between genotypes, geographical origin and clinical manifestations. A total of 83 globally collected C neoformans var. neoformans isolates from Italy, Germany, France, Belgium, Denmark, Greece, Turkey, Thailand, Japan, Colombia, and the USA, recovered from different sources (primary and secondary cutaneous cryptococcosis, disseminated cryptococcosis, the environment, and animals), were included in the study. All isolates were confirmed to belong to genotype VNIV by molecular typing and they were further investigated by MLST analysis. Maximum likelihood phylogenetic as well as network analysis strongly suggested the existence of a recombinant rather than a clonal population structure. Geographical origin and source of isolation were not correlated with a specific MLST genotype. The comparison with a set of outgroup C neoformans var. grubii isolates provided clear evidence that the two varieties have different population structures. (C) 2016 Elsevier Inc. All rights reserved. C1 [Cogliati, Massinio; Zani, Alberto; Tortorano, Anna Maria] Univ Milan, Lab Micol Med, Dip Sci Biomed Salute, Via Pascal 36, I-20133 Milan, Italy. [Rickerts, Volker; McCormick, Ilka; Tintelnot, Kathrin] Robert Koch Inst, Sect Mycol, Berlin, Germany. [Desnos-Ollivier, Marie] Inst Pasteur, Ctr Natl Reference Mycoses Invas & Antifong, Unite Mycol, Paris, France. [Velegraki, Aristea] Univ Athens, Sch Med, Dept Microbiol, Athens 11528, Greece. [Escandon, Patricia] Inst Nacl Salud, Microbiol Grp, Bogota, Colombia. [Ichikawa, Tomoe; Ikeda, Reiko] Meiji Pharmaceut Univ, Dept Microbial Sci & Host Def, Tokyo, Japan. [Bienvenu, Anne-Lise] Hosp Civils Lyon, Inst Parasitol & Mycol Med, Lyon, France. [Bienvenu, Anne-Lise] Univ Lyon, Malaria Res Unit, Lyon, France. [Varma, Ashok] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Tore, Okan; Akcaglar, Sevim] Uludag Univ, Sch Med, Dept Med Microbiol, Bursa, Turkey. [Lockhart, Shawn] Ctr Dis Control & Prevent, Mycot Dis Branch, Antifungal & Fungal Reference Labs, Atlanta, GA USA. RP Cogliati, M (reprint author), Univ Milan, Lab Micol Med, Dip Sci Biomed Salute, Via Pascal 36, I-20133 Milan, Italy. EM massimo.cogliati@unimi.it OI Tortorano, Anna Maria/0000-0003-2093-8250 FU Intramural NIH HHS [Z99 AI999999]; NCRR NIH HHS [P41 RR001646] NR 39 TC 3 Z9 3 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1087-1845 EI 1096-0937 J9 FUNGAL GENET BIOL JI Fungal Genet. Biol. PD FEB PY 2016 VL 87 BP 22 EP 29 DI 10.1016/j.fgb.2016.01.003 PG 8 WC Genetics & Heredity; Mycology SC Genetics & Heredity; Mycology GA DD2UW UT WOS:000369778700003 PM 26768709 ER PT J AU Choy, JS Qadri, B Henry, L Shroff, K Bifarin, O Basrai, MA AF Choy, John S. Qadri, Bayan Henry, Leah Shroff, Kunal Bifarin, Olatomiwa Basrai, Munira A. TI A Genome-Wide Screen with Nicotinamide to Identify Sirtuin-Dependent Pathways in Saccharomyces cerevisiae SO G3-GENES GENOMES GENETICS LA English DT Article ID SISTER-CHROMATID COHESION; SPINDLE ASSEMBLY CHECKPOINT; HISTONE H2A VARIANT; LIFE-SPAN EXTENSION; BUDDING-YEAST; DNA-DAMAGE; PROTEIN DEACETYLASES; RETROGRADE TRANSPORT; CALORIE RESTRICTION; REMODELING COMPLEX AB Sirtuins are evolutionarily conserved NAD-dependent deacetylases that catalyze the cleavage of NAD(+) into nicotinamide (NAM), which can act as a pan-sirtuin inhibitor in unicellular and multicellular organisms. Sirtuins regulate processes such as transcription, DNA damage repair, chromosome segregation, and longevity extension in yeast and metazoans. The founding member of the evolutionarily conserved sirtuin family, SIR2, was first identified in budding yeast. Subsequent studies led to the identification of four yeast SIR2 homologs HST1, HST2, HST3, and HST4. Understanding the downstream physiological consequences of inhibiting sirtuins can be challenging since most studies focus on single or double deletions of sirtuins, and mating defects in SIR2 deletions hamper genome-wide screens. This represents an important gap in our knowledge of how sirtuins function in highly complex biological processes such as aging, metabolism, and chromosome segregation. In this report, we used a genome-wide screen to explore sirtuin-dependent processes in Saccharomyces cerevisiae by identifying deletion mutants that are sensitive to NAM. We identified 55 genes in total, 36 of which have not been previously reported to be dependent on sirtuins. We find that genome stability pathways are particularly vulnerable to loss of sirtuin activity. Here, we provide evidence that defects in sister chromatid cohesion renders cells sensitive to growth in the presence of NAM. The results of our screen provide a broad view of the biological pathways sensitive to inhibition of sirtuins, and advance our understanding of the function of sirtuins and NAD(+) biology. C1 [Choy, John S.; Qadri, Bayan; Henry, Leah; Shroff, Kunal; Bifarin, Olatomiwa] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Basrai, Munira A.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Choy, JS; Basrai, MA (reprint author), McCort Ward Hall Room 105,620 Michigan Ave North, Washington, DC 20064 USA.; Choy, JS; Basrai, MA (reprint author), Room B629,41 Medlars Dr, Bethesda, MD 20892 USA. EM choy@cua.edu; basraim@nih.gov FU National Cancer Institute, National Institutes of Health; Litovitz Family Fund FX We thank Charlie Boone for generously providing the nonessential yeast deletion collection, Kevin Hardwick, Douglas Koshland, and Satoshi Kawashima for yeast strains, the Choy and Basrai laboratory members for discussions, and Jack Warren for proofreading of the manuscript. The Intramural Research Program of the National Cancer Institute, National Institutes of Health, supports work in M.A.B.'s laboratory. J.S.C. gratefully acknowledges the Litovitz Family Fund for generously supporting work in his laboratory. NR 78 TC 0 Z9 0 U1 5 U2 8 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD FEB 1 PY 2016 VL 6 IS 2 BP 485 EP 494 DI 10.1534/g3.115.022244 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DD0FH UT WOS:000369595300023 ER PT J AU Doria-Rose, VP Levin, TR Palitz, A Conell, C Weiss, NS AF Doria-Rose, V. Paul Levin, Theodore R. Palitz, Albert Conell, Carol Weiss, Noel S. TI Ten-year incidence of colorectal cancer following a negative screening sigmoidoscopy: an update from the Colorectal Cancer Prevention (CoCaP) programme SO GUT LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; FLEXIBLE SIGMOIDOSCOPY; TASK-FORCE; COLONOSCOPY; RISK; MORTALITY; INTERVAL; PROTECTION; ENDOSCOPY; REDUCTION AB Objective To examine the rates of colorectal cancer (CRC) following a negative screening sigmoidoscopy. Design Cohort study. Setting An integrated healthcare delivery organisation in California, USA. Participants 72 483 men and women aged 50 years and above who had a negative screening sigmoidoscopy between 1994 and 1996. Those at elevated risk of CRC due to inflammatory bowel disease, prior polyps or CRC, or a strong family history of CRC were excluded. Main outcome measures Incidence rates of distal and proximal CRC. Standardised Incidence Ratios were used to compare annual incidence rates of distal and proximal CRC in the cohort to expected rates based on Surveillance, Epidemiology, and End Results data. Additionally, rate ratios (RR) and rate differences (RD) comparing the incidence rate of distal CRC in years 6+ postscreening with that in years 1-5 were calculated. Results Incidence rates of distal CRC were lower than those in the San Francisco Bay area population at large during each of the first 10 years postsigmoidoscopy screening. However, the incidence of distal CRC rose steadily, from 3 per 100 000 in the first year of follow-up to 40 per 100 000 in the 10th year. During the second half of follow-up, the rate of distal CRC was twice as high as in the first half (RR 2.08, 95% CI 1.38 to 3.16; RD 14 per 100 000 person-years, 95% CI 6 to 22). Conclusions Though still below population levels, the incidence of CRC during years 6-10 following a negative sigmoiodoscopy is appreciably higher than during the first 5 years. C1 [Doria-Rose, V. Paul] NCI, Div Canc Control & Populat Sci, Bethesda, MD USA. [Levin, Theodore R.; Conell, Carol] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Levin, Theodore R.; Palitz, Albert] Kaiser Permanente No Calif, Dept Gastroenterol, Walnut Creek, CA USA. [Weiss, Noel S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Weiss, Noel S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. RP Doria-Rose, VP (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, 9609 Med Ctr Dr,Room 3E438, Bethesda, MD 20892 USA. EM doriarop@mail.nih.gov OI Doria-Rose, Vincent/0000-0002-8802-5143 FU Kaiser Permanente Community Benefit Research Program; National Institutes of Health [R03CA92767] FX This work was supported by the Kaiser Permanente Community Benefit Research Program, and by grant R03CA92767 from the National Institutes of Health. NR 41 TC 1 Z9 1 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD FEB PY 2016 VL 65 IS 2 BP 271 EP 277 DI 10.1136/gutjnl-2014-307729 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DD6CC UT WOS:000370010400012 PM 25512639 ER PT J AU Lynch, PM Burke, CA Phillips, R Morris, JS Slack, R Wang, XM Liu, J Patterson, S Sinicrope, FA Rodriguez-Bigas, MA Half, E Bulow, S Latchford, A Clark, S Ross, WA Malone, B Hasson, H Richmond, E Hawk, E AF Lynch, Patrick M. Burke, Carol A. Phillips, Robin Morris, Jeffrey S. Slack, Rebecca Wang, Xuemei Liu, Jun Patterson, Sherri Sinicrope, Frank A. Rodriguez-Bigas, Miguel A. Half, Elizabeth Bulow, Steffen Latchford, Andrew Clark, Sue Ross, William A. Malone, Bonnie Hasson, Hennie Richmond, Ellen Hawk, Ernest TI An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis SO GUT LA English DT Article ID SPORADIC COLORECTAL ADENOMAS; PLACEBO-CONTROLLED TRIAL; COLON-CANCER PREVENTION; ALPHA-DIFLUOROMETHYLORNITHINE; ORNITHINE-DECARBOXYLASE; CHEMOPREVENTION; INHIBITION; ROFECOXIB; PIROXICAM; TUMORS AB Background and aim Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. Methods The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. Results 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was -13.0% for CXB+DFMO and -1.0% for CXB (p=0.69). Mean % change in adenoma burden was -40% (CXB+DFMO) vs -27% (CXB) (p=0.13). Video-based global polyp change was -0.80 for CXB+ DFMO vs -0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). Conclusions CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. C1 [Lynch, Patrick M.; Ross, William A.; Malone, Bonnie] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. [Burke, Carol A.; Hasson, Hennie] Cleveland Clin, Dept Gastroenterol & Hepatol, Cleveland, OH 44106 USA. [Phillips, Robin; Latchford, Andrew; Clark, Sue] St Marks Hosp, Polyposis Registry, City Rd, London EC1V 2PS, England. [Morris, Jeffrey S.; Slack, Rebecca; Wang, Xuemei] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Div Quantitat Sci, Houston, TX 77030 USA. [Liu, Jun] Univ Texas MD Anderson Canc Ctr, Dept Plast Surg, Houston, TX 77030 USA. [Patterson, Sherri] Univ Texas MD Anderson Canc Ctr, Dept Canc Prevent & Pop Sci, Houston, TX 77030 USA. [Sinicrope, Frank A.] Mayo Clin, Div Gastroenterol Hepatol & Oncol, Rochester, MN USA. [Rodriguez-Bigas, Miguel A.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Half, Elizabeth] Rambam Med Ctr, Gatroenterol Dept, Haifa, Israel. [Bulow, Steffen] Hvidovre Univ Hosp, Hvidovre, Denmark. [Richmond, Ellen] Natl Canc Inst, Canc Prevent Div, Gastrointestinal & Other Cancers Res Grp, Bethesda, MD USA. [Hawk, Ernest] Univ Texas MD Anderson Canc Ctr, Div OVP Canc Prevent & Populat Sci, Houston, TX 77030 USA. RP Lynch, PM (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr 1466, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM plynch@mdanderson.org FU Pfizer [P30CA016672]; Biostatistics Resource Group; US NCI [N01-CN95040] FX This trail was funded by Pfizer under the assigned award number P30CA016672, the Biostatistics Resource Group and US NCI (N01-CN95040). NR 31 TC 8 Z9 8 U1 2 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD FEB PY 2016 VL 65 IS 2 BP 286 EP U372 DI 10.1136/gutjnl-2014-307235 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DD6CC UT WOS:000370010400014 PM 25792707 ER PT J AU Song, MY Nishihara, R Wang, ML Chan, AT Qian, ZR Inamura, K Zhang, XH Ng, K Kim, SA Mima, K Sukawa, Y Nosho, K Fuchs, CS Giovannucci, EL Wu, K Ogino, S AF Song, Mingyang Nishihara, Reiko Wang, Molin Chan, Andrew T. Qian, Zhi Rong Inamura, Kentaro Zhang, Xuehong Ng, Kimmie Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Nosho, Katsuhiko Fuchs, Charles S. Giovannucci, Edward L. Wu, Kana Ogino, Shuji TI Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status SO GUT LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; VITAMIN-D; MICROSATELLITE INSTABILITY; COLON-CANCER; ADAPTIVE IMMUNITY; DNA METHYLATION; ASPIRIN USE; T-CELLS; PREVENTION AB Objective Evidence suggests protective effects of vitamin D and antitumour immunity on colorectal cancer risk. Immune cells in tumour microenvironment can convert 25-hydroxyvitamin D [25(OH)D] to bioactive 1 alpha, 25-dihydroxyvitamin D-3, which influences neoplastic and immune cells as an autocrine and paracrine factor. Thus, we hypothesised that the inverse association between vitamin D and colorectal cancer risk might be stronger for cancers with high-level immune response than those with low-level immune response. Design We designed a nested case-control study (318 rectal and colon carcinoma cases and 624 matched controls) within the Nurses' Health Study and Health Professionals Follow-up Study using molecular pathological epidemiology database. Multivariable conditional logistic regression was used to assess the association of plasma 25 (OH) D with tumour subtypes according to the degree of lymphocytic reaction, tumour-infiltrating T cells (CD3+, CD8+, CD45RO+ (PTPRC) and FOXP3+ cells), microsatellite instability or CpG island methylator phenotype. Results The association of plasma 25(OH)D with colorectal carcinoma differed by the degree of intratumoural periglandular reaction (p for heterogeneity=0.001); high 25(OH)D was associated with lower risk of tumour with high-level reaction (comparing the highest versus lowest tertile: OR 0.10; 95% CI 0.03 to 0.35; p for trend<0.001), but not risk of tumour with lower-level reaction (p for trend>0.50). A statistically non-significant difference was observed for the associations of 25(OH)D with tumour subtypes according to CD3+ T cell density (p for heterogeneity= 0.03; adjusted statistical significance level of alpha=0.006). Conclusions High plasma 25(OH)D level is associated with lower risk of colorectal cancer with intense immune reaction, supporting a role of vitamin D in cancer immunoprevention through tumour-host interaction. C1 [Song, Mingyang; Nishihara, Reiko; Giovannucci, Edward L.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Song, Mingyang; Wang, Molin; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko; Qian, Zhi Rong; Inamura, Kentaro; Ng, Kimmie; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nishihara, Reiko; Chan, Andrew T.; Qian, Zhi Rong; Inamura, Kentaro; Zhang, Xuehong; Ng, Kimmie; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Fuchs, Charles S.; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Zhang, Xuehong; Fuchs, Charles S.; Giovannucci, Edward L.; Ogino, Shuji] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 75 Francis St, Boston, MA 02115 USA. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Nosho, Katsuhiko] Sapporo Med Univ, Sch Med, Dept Gastroenterol Rheumatol & Clin Immunol, Sapporo, Hokkaido, Japan. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institutes of Health (NIH) [P01 CA87969, R01 CA49449, UM1 CA186107, P01 CA55075, UM1 CA167552, R03 CA176717, R01 CA137178, K24 DK098311, P50 CA127003]; US National Institutes of Health (NIH) (DF/HCC GI SPORE Developmental Project) [R01 CA151993, K07 CA190673, K07 CA148894]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation; Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad; Takashi Tsuruo Memorial Fund; Asian medical centre FX This work was supported by US National Institutes of Health (NIH) grants [P01 CA87969 to SE Hankinson; R01 CA49449 to SE Hankinson; UM1 CA186107 to MJ Stampfer; P01 CA55075 to WC Willett; UM1 CA167552 to WC Willett; R03 CA176717 to XZ; R01 CA137178 to ATC; K24 DK098311 to ATC; P50 CA127003 to CSF; DF/HCC GI SPORE Developmental Project to SO; R01 CA151993 to SO; K07 CA190673 to RN; and K07 CA148894 to KN], and grants from The Paula and Russell Agrusa Fund for Colorectal Cancer Research (to CSF), the Friends of the Dana-Farber Cancer Institute (SO), the Bennett Family Fund, and the Entertainment Industry Foundation. ATC is a Damon Runyon Clinical Investigator. MS is a trainee of the Harvard Transdisciplinary Research Center on Energetics and Cancer (TREC). KI is supported by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and by Takashi Tsuruo Memorial Fund. SAK is supported by an early exchange postdoctoral fellowship grant from Asian medical centre. NR 52 TC 12 Z9 13 U1 1 U2 12 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD FEB PY 2016 VL 65 IS 2 BP 296 EP 304 DI 10.1136/gutjnl-2014-308852 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DD6CC UT WOS:000370010400016 PM 25591978 ER PT J AU Sung, H Yang, HH Hu, N Su, H Taylor, PR Hyland, PL AF Sung, Hyuna Yang, Howard H. Hu, Nan Su, Hua Taylor, Philip R. Hyland, Paula L. TI Functional annotation of high-quality SNP biomarkers of gastric cancer susceptibility: the Yin Yang of PSCA rs2294008 SO GUT LA English DT Letter ID GENETIC-VARIATION; RISK C1 [Sung, Hyuna; Hu, Nan; Su, Hua; Taylor, Philip R.; Hyland, Paula L.] NCI, DCEG, NIH, Bethesda, MD 20892 USA. [Yang, Howard H.] NCI, Lab Populat Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hyland, PL (reprint author), NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. EM hylandpl@mail.nih.gov FU Intramural NIH HHS NR 5 TC 1 Z9 1 U1 1 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 EI 1468-3288 J9 GUT JI Gut PD FEB PY 2016 VL 65 IS 2 BP 361 EP 364 DI 10.1136/gutjnl-2015-310059 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DD6CC UT WOS:000370010400028 PM 26109531 ER PT J AU Gai, ND Sandfort, V Liu, ST Lima, JAC Bluemke, DA AF Gai, Neville D. Sandfort, Veit Liu, Songtao Lima, Joo A. C. Bluemke, David A. TI Dose correction for post-contrast T1 mapping of the heart: the MESA study SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE T1 mapping; Cardiac; Dose correction; Blood volume; Plasma volume ID CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL EXTRACELLULAR VOLUME; GD-DTPA RELAXIVITY; BLOOD-VOLUME; LOOK-LOCKER; RECOVERY; T-1; FIBROSIS; MOLLI; CARDIOMYOPATHY AB Post-contrast myocardial T1 (T1(myo,c)) values have been shown to be sensitive to myocardial fibrosis. Recent studies have shown differences in results obtained from T1(myo,c) and extracellular volume fraction (ECV) with respect to percentage fibrosis. By exploring the relationship between blood plasma volume and T1(myo,c), the underlying basis for the divergence can be explained. Furthermore, dose administration based on body mass index (BMI), age and gender can mitigate the divergence in results. Inter-subject comparison of T1(myo,c) required adjustment for dose (in mmol/kg), time and glomerular filtration rate. Further adjustment for effective dose based on lean muscle mass reflected by blood/plasma volume was performed. A test case of 605 subjects from the MESA study who had undergone pre- and post-contrast T1 mapping was studied. T1(myo,c) values were compared between subjects with and without metabolic syndrome (MetS), between smoking and non-smoking subjects, and subjects with and without impaired glucose tolerance, before and after dose adjustment based on plasma volume. Comparison with ECV (which is dose independent), pre-contrast myocardial T1 and blood normalized myocardial T1 values was also performed to validate the correction. There were significant differences in T1(myo,c) (post plasma volume correction) and ECV between current and former smokers (p value 0.017 and 0.01, respectively) but not T1(myo,c) prior to correction (p = 0.12). Prior to dose adjustment for plasma volume, p value was < 0.001 for T1(myo,c) between MetS and non-MetS groups and was 0.13 between subjects with and without glucose intolerance; after adjustment for PV, p value was 0.63 and 0.99. Corresponding ECV p values were 0.44 and 0.99, respectively. Overall, ECV results showed the best agreement with PV corrected T1(myo,c) (mean absolute difference in p values = 0.073) and pre-contrast myocardial T1 in comparison with other measures (T1(myo,c) prior to correction, blood/plasma T1 value normalized myocardium). Weight-based contrast dosing administered in mmol/kg results in a bias in T1 values which can lead to erroneous conclusions. After adjustment for lean muscle mass based on plasma volume, results from T1(myo,c) were in line with ECV derived results. Furthermore, the use of a modified equivalent dose adjusted for BMI, age, sex and hematocrit can be adopted for quantitative imaging. C1 [Gai, Neville D.; Sandfort, Veit; Liu, Songtao; Bluemke, David A.] NIH, Radiol & Imaging Sci RAD&IS, Ctr Clin, 9000 Rockville Pike,Bldg 10, Bethesda, MD 20892 USA. [Lima, Joo A. C.] Johns Hopkins Med, Baltimore, MD USA. [Bluemke, David A.] NIBIB, Bethesda, MD USA. RP Gai, ND (reprint author), NIH, Radiol & Imaging Sci RAD&IS, Ctr Clin, 9000 Rockville Pike,Bldg 10, Bethesda, MD 20892 USA. EM gaind@cc.nih.gov OI Bluemke, David/0000-0002-8323-8086 FU NIH Clinical Center intramural research program FX This work was supported by the NIH Clinical Center intramural research program. NR 31 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 EI 1573-0743 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD FEB PY 2016 VL 32 IS 2 BP 271 EP 279 DI 10.1007/s10554-015-0754-3 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DD3GO UT WOS:000369810300007 PM 26362875 ER PT J AU Wilson, PA Kahana, SY Fernandez, MI Harper, GW Mayer, K Wilson, CM Hightow-Weidman, LB AF Wilson, Patrick A. Kahana, Shoshana Y. Fernandez, Maria Isabel Harper, Gary W. Mayer, Kenneth Wilson, Craig M. Hightow-Weidman, Lisa B. TI Sexual Risk Behavior Among Virologically Detectable Human Immunodeficiency Virus-Infected Young Men Who Have Sex With Men SO JAMA PEDIATRICS LA English DT Article ID HIV-POSITIVE MEN; UNITED-STATES; ANTIRETROVIRAL THERAPY; SCREENING-TEST; CARE; DISPARITIES; ADOLESCENT; BLACK; INTERVENTIONS; PREVALENCE AB IMPORTANCE Human immunodeficiency virus (HIV) diagnoses continue to increase among young men who have sex with men (YMSM). Many YMSM living with HIV engage in sexual risk behaviors, and those who have a detectable viral load can transmit HIV to sex partners. Understanding factors that are related to sexual risk taking among virologically detectable (VL+) YMSM can inform prevention and treatment efforts. OBJECTIVES To describe differences between virologically suppressed (VL-) and VL+ YMSM living with HIV and to identify correlates of condomless anal intercourse (CAI) and serodiscordant CAI among VL+ YMSM. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional survey conducted from December 1, 2009, through June 30, 2012, we studied 991 HIV-infected YMSM 15 to 26 years of age at 20 adolescent HIV clinics in the United States. Data analysis was conducted December 1, 2013, through July 31, 2015. MAIN OUTCOMES AND MEASURES Demographic, behavioral, and psychosocial assessments obtained using audio computer-assisted self-interviews. Viral load information was obtained via blood draw or medical record abstraction. RESULTS Of the 991 participants, 688 (69.4%) were VL+ and 458 (46.2%) reported CAI, with 310 (31.3%) reporting serodiscordant CAI in the past 3 months. The VL+ YMSM were more likely than the VL-YMSM to report CAI (detectable, 266 [54.7%]; suppressed, 91 [44.4%]; P =.01) and serodiscordant CAI (detectable, 187 [34.9%]; suppressed, 57 [25.0%]; P < .01). Multivariable analyses indicated that among VL+ YMSM, those reporting problematic substance use were more likely to report CAI (adjusted odds ratio [AOR], 1.46; 95% CI, 1.02-2.10) and serodiscordant CAI (AOR, 1.45; 95% CI, 1.06-1.99). Black VL+ YMSM were less likely to report CAI (AOR, 0.63; 95% CI, 0.44-0.90) or serodiscordant CAI (AOR, 0.66; 95% CI, 0.46-0.94) compared with other VL+ YMSM. In addition, VL+ YMSM who disclosed their HIV status to sex partners were more likely to report CAI compared with nondisclosing YMSM (AOR, 1.35; 95% CI, 1.01-1.81). Transgender participants were less likely to report CAI than cisgender participants (AOR, 0.35; 95% CI, 0.14-0.85). Last, VL+ YMSM who reported currently being employed were less likely to report serodiscordant CAI than those who were unemployed (AOR, 0.74; 95% CI, 0.55-0.99). CONCLUSIONS AND RELEVANCE Targeted multilevel interventions are needed to reduce HIV transmission risk behaviors among YMSM living with HIV, particularly among those who are VL+. C1 [Wilson, Patrick A.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Kahana, Shoshana Y.] NIDA, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. [Fernandez, Maria Isabel] Nova SE Univ, Coll Osteopath Med, Ft Lauderdale, FL 33314 USA. [Harper, Gary W.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Mayer, Kenneth] Harvard Univ, Sch Med, Fenway Inst, Boston, MA USA. [Wilson, Craig M.] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. [Hightow-Weidman, Lisa B.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. RP Wilson, PA (reprint author), Mailman Sch Publ Hlth, Dept Sociomed Sci, 722 W 168th St, New York, NY 10032 USA. EM pw2219@columbia.edu FU ATN of the National Institutes of Health through the National Institute of Child Health and Human Development [U01 HD 040533, U01 D 040474]; National Institute on Drug Abuse; National Institute on Mental Health FX This work was supported by grants U01 HD 040533 and U01 D 040474 from the ATN of the National Institutes of Health through the National Institute of Child Health and Human Development, with supplemental funding from the National Institute on Drug Abuse and the National Institute on Mental Health. NR 31 TC 3 Z9 3 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD FEB PY 2016 VL 170 IS 2 BP 125 EP 131 DI 10.1001/jamapediatrics.2015.3333 PG 7 WC Pediatrics SC Pediatrics GA DD1AT UT WOS:000369654000012 PM 26641367 ER PT J AU Sims, M Diez-Roux, AV Gebreab, SY Brenner, A Dubbert, P Wyatt, S Bruce, M Hickson, D Payne, T Taylor, H AF Sims, Mario Diez-Roux, Ana V. Gebreab, Samson Y. Brenner, Allison Dubbert, Patricia Wyatt, Sharon Bruce, Marino Hickson, DeMarc Payne, Tom Taylor, Herman TI Perceived discrimination is associated with health behaviours among African-Americans in the Jackson Heart Study SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID STRESSFUL LIFE EVENTS; RACIAL-DISCRIMINATION; PHYSICAL-ACTIVITY; RACIAL/ETHNIC DISCRIMINATION; CIGARETTE-SMOKING; SLEEP DURATION; SOCIAL-CLASS; ADULTS; DISPARITIES; DEPRESSION AB Background Using Jackson Heart Study data, we examined associations of multiple measures of perceived discrimination with health behaviours among African-Americans (AA). Methods The cross-sectional associations of everyday, lifetime and burden of discrimination with odds of smoking and mean differences in physical activity, dietary fat and sleep were examined among 4925 participants aged 35-84 years after adjustment for age and socioeconomic status (SES). Results Men reported slightly higher levels of everyday and lifetime discrimination than women and similar levels of burden of discrimination as women. After adjustment for age and SES, everyday discrimination was associated with more smoking and a greater percentage of dietary fat in men and women (OR for smoking: 1.13, 95% CI 1.00 to 1.28 and 1.19, 95% CI 1.05 to 1.34; mean difference in dietary fat: 0.37, p<0.05 and 0.43, p<0.01, in men and women, respectively). Everyday and lifetime discrimination were associated with fewer hours of sleep in men and women (mean difference for everyday discrimination: -0.08, p<0.05 and -0.18, p<0.001, respectively; and mean difference for lifetime discrimination: -0.08, p<0.05 and -0.24, p<0.001, respectively). Burden of discrimination was associated with more smoking and fewer hours of sleep in women only. Conclusions Higher levels of perceived discrimination were associated with select health behaviours among men and women. Health behaviours offer a potential mechanism through which perceived discrimination affects health in AA. C1 [Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Diez-Roux, Ana V.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Gebreab, Samson Y.] NHGRI, Cardiovasc & Inflammatory Dis Genom Branch, Metabol, Bethesda, MD 20892 USA. [Brenner, Allison] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Dubbert, Patricia] Univ Arkansas Med Sci, Coll Med, Dept Psychiat, North Little Rock, AR USA. [Wyatt, Sharon] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Bruce, Marino] Jackson State Univ, Dept Sociol & Criminol, Jackson, MS USA. [Hickson, DeMarc] My Bros Keeper Inc, Ctr Res Evaluat & Environm & Policy Change, Jackson, MS USA. [Payne, Tom] Univ Mississippi, Med Ctr, Dept Otolaryngol & Commun Sci, Jackson, MS 39216 USA. [Taylor, Herman] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. RP Sims, M (reprint author), Univ Mississippi, Med Ctr, Jackson Heart Study, Dept Med, 350 W Woodrow Wilson Dr, Jackson, MS 39213 USA. EM msims2@umc.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]; National Institute on Minority Health and Health Disparities (NIMHD); NHLBI [K01 HL08468-05]; NIMHD [P60MD002249, U54MD008176] FX The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). At the time of this work, MS was supported by Career Development Award K01 HL08468-05 from the NHLBI, and grants P60MD002249 and U54MD008176 from the NIMHD. NR 42 TC 4 Z9 4 U1 4 U2 9 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD FEB PY 2016 VL 70 IS 2 BP 187 EP 194 DI 10.1136/jech-2015-206390 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD5KH UT WOS:000369962000013 PM 26417003 ER PT J AU Cai, JW Zhang, LM Jones, RA Correll, JB Hatzakis, E Smith, PB Gonzalez, FJ Patterson, AD AF Cai, Jingwei Zhang, Limin Jones, Richard A. Correll, Jared B. Hatzakis, Emmanuel Smith, Philip B. Gonzalez, Frank J. Patterson, Andrew D. TI Antioxidant Drug Ternpol Promotes Functional Metabolic Changes in the Gut Microbiota SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE SCFAs; metabolomics; GC-MS; NMR; bomb calorimetry; tempol; obesity ID CHAIN FATTY-ACIDS; OBESITY; ACETATE; GLUCOSE; WEIGHT; RATS; ECOLOGY; IMPACTS; DISEASE; PROTEIN AB Recent studies have identified the important role of the gut microbiota in the pathogenesis and progression of obesity and related metabolic disorders. The antioxidant tempol was shown to prevent or reduce weight gain and modulate the gut microbiota community in mice; however, the mechanism by which tempol modulates weight gain/loss with respect to the host and gut microbiota has not been clearly established. Here we show that tempol (0, 1, 10, and 50 mg/kg p.o. for 5 days) decreased cecal bacterial fermentation and increased fecal energy excretion in a dose-dependent manner. Liver H-1 NMR-based metabolomics identified a dose dependent decrease in glycogen and glucose, enhanced glucogenic and ketogenic activity (tyrosine and phenylalanine), and increased activation of the glycolysis pathway. Serum H-1 NMR-based metabolomics indicated that tempol promotes enhanced glucose catabolism. Hepatic gene expression was significantly altered as demonstrated by an increase in Pepck and G6pase and a decrease in Hnf4a, ChREBP, Fabp1, and Cd36 mRNAs. No significant change in the liver and serum metabolomic profiles was observed in germ-free mice, thus establishing a significant role for the gut microbiota in mediating the beneficial metabolic effects of tempol. These results demonstrate that tempol modulates the gut microbial community and its function, resulting in reduced host energy availability and a significant shift in liver metabolism toward a more catabolic state. C1 [Cai, Jingwei; Zhang, Limin; Jones, Richard A.; Correll, Jared B.; Patterson, Andrew D.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, State Coll, PA 16802 USA. [Zhang, Limin] Chinese Acad Sci, Wuhan Inst Phys & Math, Natl Ctr Magnet Resonance Wuhan, CAS Key Lab Magnet Resonance Biol Syst,State Key, Wuhan 430071, Peoples R China. [Smith, Philip B.] Penn State Univ, Metabol Facil, Huck Inst Life Sci, State Coll, PA 16802 USA. [Hatzakis, Emmanuel] Penn State Univ, Dept Chem, State Coll, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Patterson, AD (reprint author), Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, State Coll, PA 16802 USA. EM adp117@psu.edu RI limin, zhang/O-8208-2016; Patterson, Andrew/G-3852-2012 OI limin, zhang/0000-0001-5689-948X; Patterson, Andrew/0000-0003-2073-0070 FU National Institute of Environmental Health Sciences [ES022186] FX This work was supported by National Institute of Environmental Health Sciences [ES022186 (ADP)]. NR 45 TC 3 Z9 3 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2016 VL 15 IS 2 BP 563 EP 571 DI 10.1021/acs.jproteome.5b00957 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DD2SE UT WOS:000369771700020 PM 26696396 ER PT J AU Gebregiworgis, T Nielsen, HH Massilamany, C Gangaplara, A Reddy, J Illes, Z Powers, R AF Gebregiworgis, Teklab Nielsen, Helle H. Massilamany, Chandirasegaran Gangaplara, Arunakumar Reddy, Jay Illes, Zsolt Powers, Robert TI A Urinary Metabolic Signature for Multiple Sclerosis and Neuromyelitis Optica SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE urine biomarkers; multiple sclerosis; neuromyelitis optica-spectrum disorder; NMR; metabolomics; multivariate statistics ID NMR METABOLOMICS; DIAGNOSTIC-CRITERIA; BIOMARKERS; DISEASE; PROTEOMICS; DISCOVERY; MICROBIOTA; DISORDERS; BRAIN AB Urine is a metabolite-rich biofluid that reflects the body's effort to maintain chemical and osmotic homeostasis. Clinical diagnosis routinely relies on urine samples because the collection process is easy and noninvasive. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). Nuclear magnetic resonance spectroscopy (NMR) has become a common approach for analyzing urinary metabolites for disease diagnosis and biomarker discovery. For illustration of the potential of urinary metabolites for diagnosing and treating MS patients, and for differentiating between MS and other illnesses, 38 urine samples were collected from healthy controls, MS patients, and neuromyelitis optica-spectrum disorder (NMO-SD) patients and analyzed with NMR, multivariate statistics, one-way ANOVA, and univariate statistics. Urine from MS patients exhibited a statistically distinct metabolic signature from healthy and NMO-SD controls. A total of 27 metabolites were differentially altered in the urine from MS and NMO-SD patients and were associated with synthesis and degradation of ketone bodies, amino acids, propionate and pyruvate metabolism, tricarboxylic acid cycle, and glycolysis. Metabolites altered in urine from MS patients were shown to be related to known pathogenic processes relevant to MS, including alterations in energy and fatty acid metabolism, mitochondrial activity, and the gut microbiota. C1 [Gebregiworgis, Teklab; Powers, Robert] Univ Nebraska, Dept Chem, Lincoln, NE 68588 USA. [Nielsen, Helle H.; Illes, Zsolt] Univ Southern Denmark, Odense Univ Hosp, Inst Clin Res, Dept Neurol, Odense, Denmark. [Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Reddy, Jay] Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Gangaplara, Arunakumar] NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Powers, R (reprint author), Univ Nebraska, Dept Chem, Lincoln, NE 68588 USA.; Illes, Z (reprint author), Univ Southern Denmark, Odense Univ Hosp, Inst Clin Res, Dept Neurol, Odense, Denmark.; Reddy, J (reprint author), Univ Nebraska, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. EM nreddy2@unl.edu; zsolt.illes@rsyd.dk; rpowers3@unl.edu RI Massilamany, Chandirasegaran/D-9305-2016; OI Massilamany, Chandirasegaran/0000-0002-0205-282X; Gangaplara, Arunakumar/0000-0001-6307-9391 FU National Institutes of Health (NIH), USA [P30 GM103335, HL114669]; NIH National Center for Research Resources [P20 RR-17675]; University of Nebraska Research Council; Scleroseforeningen (Denmark) [A-19412]; Lundbeckfonden (Denmark) [R118-A11472]; Odense University Hospital; National Institutes of Health [RR015468-01] FX This manuscript was supported in part by funds from the National Institutes of Health (NIH), USA (P30 GM103335, RP., J.R; HL114669, J.R.), NIH National Center for Research Resources (P20 RR-17675, J.R.), University of Nebraska Research Council (J.R., RP.), Scleroseforeningen (A-19412, Denmark, Z.I.), Lundbeckfonden (R118-A11472, Denmark, Z.I.), and a grant from Odense University Hospital (Z.I.). The research was performed in facilities renovated with support from the National Institutes of Health (RR015468-01). NR 42 TC 4 Z9 4 U1 6 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD FEB PY 2016 VL 15 IS 2 BP 659 EP 666 DI 10.1021/acs.jproteome.5b01111 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DD2SE UT WOS:000369771700029 PM 26759122 ER PT J AU Fleischhacker, S AF Fleischhacker, Sheila TI Emerging Opportunities for Registered Dietitian Nutritionists to Help Raise a Healthier Generation of Native American Youth SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE American Indians; Alaskan Natives; Food; Nutrition; Health disparities ID WEIGHT-LOSS PRACTICES; PARTICIPATORY RESEARCH; OBESITY PREVENTION; INDIAN COMMUNITIES; CARDIOVASCULAR RISK; PHYSICAL-ACTIVITY; CHILDREN; INTERVENTION; DISPARITIES; POPULATION C1 [Fleischhacker, Sheila] NIDDK, Off Nutr Res, NIH, US Dept HHS, Two Democracy Plaza,Room 635, Bethesda, MD 20892 USA. RP Fleischhacker, S (reprint author), NIDDK, Off Nutr Res, NIH, US Dept HHS, Two Democracy Plaza,Room 635, Bethesda, MD 20892 USA. EM sheila.fleischhacker@nih.gov FU Healthy Eating Research, a national program of the Robert Wood Johnson Foundation (RWJF) [66958]; National Institutes of Health (NIH), University of North Carolina Interdisciplinary Obesity Training Grant [T 32 MH75854-03]; Kate B. Reynolds Charitable Trust (KBR) FX Support was provided in part by Healthy Eating Research, a national program of the Robert Wood Johnson Foundation (RWJF) (ID #66958); the National Institutes of Health (NIH), University of North Carolina Interdisciplinary Obesity Training Grant (T 32 MH75854-03); and Kate B. Reynolds Charitable Trust (KBR). The content is solely the responsibility of the author and does not necessarily represent the official views of the RWJF, NIH, or KBR. NR 73 TC 1 Z9 1 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD FEB PY 2016 VL 116 IS 2 BP 219 EP 225 DI 10.1016/j.jand.2015.10.018 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DD0KH UT WOS:000369608400006 PM 26680608 ER PT J AU Wilson, MM Reedy, J Krebs-Smith, SM AF Wilson, Magdalena M. Reedy, Jill Krebs-Smith, Susan M. TI American Diet Quality: Where It Is, Where It Is Heading, and What It Could Be SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Diet quality; Healthy Eating Index; Healthy People 2020; 2010 Dietary Guidelines for Americans ID GUIDELINES; OBESITY AB Background Diet quality is critically important to the prevention of many types of chronic disease. The federal government provides recommendations for optimal diet quality through the Dietary Guidelines for Americans, and sets benchmarks for progress toward these recommendations through the Healthy People objectives. Objective This analysis estimated recent trends in American diet quality and compared those trends to the quality of diets that would meet the Healthy People 2020 objectives and the 2010 Dietary Guidelines for Americans in order to measure progress toward our national nutrition goals. Design This analysis used 24-hour recall data from the cross-sectional National Health and Nutrition Examination Survey, between the years of 1999-2000 and 2011-2012, to determine mean intakes of various dietary components for the US population over time. Mean intakes were estimated using the population ratio method, and diet quality was assessed using the Healthy Eating Index 2010 (HEI-2010). Results The mean HEI-2010 total score for the US population has increased from 49 in 1999-2000 to 59 in 2011-2012; continuing on that trajectory, it would reach a score of 65 by 2019-2020. A diet that meets the Healthy People 2020 objectives would receive a score of 74 and, by definition, a diet that meets the 2010 Dietary Guidelines for Americans would receive a score of 100. Trends in HEI-2010 component scores vary; all HEI-2010 component scores except sodium have increased over time. Conclusions Diet quality is improving over time, but not quickly enough to meet all of the Healthy People 2020 objectives. Whole fruit and empty calories are the only HEI-2010 components on track to meet their respective Healthy People 2020 targets. Furthermore, the country falls short of the 2010 Dietary Guidelines for Americans by a large margin in nearly every component of diet quality assessed by the HEI-2010. C1 [Wilson, Magdalena M.; Reedy, Jill; Krebs-Smith, Susan M.] NCI, Risk Factor Assessment Branch, Epidemiol & Genom Res Program, 9609 Med Ctr Dr,MSC 9762, Rockville, MD 20850 USA. RP Wilson, MM (reprint author), NCI, Risk Factor Assessment Branch, Epidemiol & Genom Res Program, 9609 Med Ctr Dr,MSC 9762, Rockville, MD 20850 USA. EM maggie.wilson@nih.gov OI Wilson, Magdalena/0000-0002-9438-8688 FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 1 Z9 1 U1 2 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 EI 2212-2680 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD FEB PY 2016 VL 116 IS 2 BP 302 EP + DI 10.1016/j.jand.2015.09.020 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DD0KH UT WOS:000369608400014 PM 26612769 ER PT J AU McDougall, J Ramsey, SD Radich, J AF McDougall, Jean Ramsey, Scott D. Radich, Jerald TI What Happens When Imatinib Goes Generic? SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material ID CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITORS; 24-MONTH FOLLOW-UP; DASATINIB; INTERFERON; RESISTANCE; BOSUTINIB; NILOTINIB; EFFICACY; SAFETY C1 [McDougall, Jean] Univ Washington, Pharmaceut Outcomes Res & Policy Program, Seattle, WA 98195 USA. [McDougall, Jean] Fred Hutchinson Canc Res Ctr, Hutchinson Inst Canc Outcomes Res, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Ramsey, Scott D.] Univ Washington, Sch Pharm, Sch Med, Seattle, WA 98195 USA. [Ramsey, Scott D.] Univ Washington, Inst Publ Hlth Genet, Seattle, WA 98195 USA. [Ramsey, Scott D.] Southwest Oncol Grp, Outcomes & Comparat Effectiveness Comm, Seattle, WA USA. [Ramsey, Scott D.] ISPOR, Washington, DC USA. [Radich, Jerald] Fred Hutchinson Canc Res Ctr, Mol Oncol Lab, Seattle, WA 98104 USA. Univ Washington, Sch Med, Med, Seattle, WA 98195 USA. [Radich, Jerald] Southwest Oncol Grp, Leukemia Translat Med Comm, Seattle, WA USA. [Radich, Jerald] NCI, NIH, Leukemia Steering Comm, Bethesda, MD 20892 USA. [Radich, Jerald] NIH, Genome Res Inst, Bethesda, MD USA. [Radich, Jerald] NCCN Chron Myelogenous Leukemia CML Panel, New York, NY USA. RP McDougall, J (reprint author), Univ Washington, Pharmaceut Outcomes Res & Policy Program, Seattle, WA 98195 USA. NR 30 TC 0 Z9 0 U1 0 U2 3 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD FEB PY 2016 VL 14 IS 2 BP 128 EP 131 PG 4 WC Oncology SC Oncology GA DD0UA UT WOS:000369634300004 PM 26850483 ER PT J AU Armitage, JO Wood, WC Longo, DL AF Armitage, James O. Wood, William C. Longo, Dan L. TI Real Personalized Medicine SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material ID HODGKINS-DISEASE; LYMPHOMA; RADIOTHERAPY; LEUKEMIA; CANCER; TRIAL; RISK C1 [Armitage, James O.] Univ Nebraska Med Ctr, Med, Omaha, NE 68198 USA. [Armitage, James O.] Amer & Royal Coll Phys, New York, NY USA. [Armitage, James O.] Amer Assoc Advancement Sci, Cambridge, MA USA. [Armitage, James O.] US Natl Canc Advisory Board, New York, NY USA. [Armitage, James O.] French Natl Canc Advisory Board, Naples, Italy. [Armitage, James O.; Wood, William C.] ASCO, Alexandria, VA USA. [Armitage, James O.] Amer Soc Blood & Marrow Transplantat, Arlington, VA USA. [Wood, William C.] Emory Univ, Sch Med, Surg, Atlanta, GA 30322 USA. [Wood, William C.] Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Global Hlth, Atlanta, GA USA. [Wood, William C.] PAACS, Gabon, Cameroon. [Wood, William C.] Int Prevent Res Inst Lyon, Lyon, France. [Wood, William C.] Africa Oxford Canc Fdn, Oxford, England. [Wood, William C.] Canc & Leukemia Grp B Breast Comm, Lake Success, NY USA. [Wood, William C.] Eastern Cooperat Oncol Grp, Breast Comm, New York, NY USA. [Wood, William C.] NCI Breast Intergrp, London, England. [Wood, William C.] Early Breast Canc Trialists Collaborat Grp Oxford, Oxford, England. [Wood, William C.] NCI Breast Canc Steering Comm, Pittsburgh, PA USA. [Wood, William C.] BIG NABCG, New York, NY USA. [Wood, William C.] Amer Coll Surg, New York, NY USA. [Wood, William C.] NCI, Bethesda, MD 20892 USA. [Wood, William C.] Soc Surg Oncol, Brussels, Belgium. [Wood, William C.] Southeastern Surg Congress, Atlanta, GA USA. [Wood, William C.] Georgia Surg Assoc, Atlanta, GA USA. [Wood, William C.] Atlanta Surg Assoc, Atlanta, GA USA. [Wood, William C.] Southern Surg Association, Palm Beach, FL USA. [Longo, Dan L.] Harvard Univ, Sch Med, Div Hematol, Brigham & Womens Hosp,Med, Cambridge, MA 02138 USA. [Longo, Dan L.] Amer Coll Physicians, New York, NY USA. [Longo, Dan L.] Assoc Amer Phys, College Pk, MD USA. [Longo, Dan L.] Amer Assoc Advancement Sci, New York, NY USA. RP Armitage, JO (reprint author), Univ Nebraska Med Ctr, Med, Omaha, NE 68198 USA. NR 14 TC 0 Z9 0 U1 0 U2 1 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD FEB PY 2016 VL 14 IS 2 BP 233 EP 236 PG 4 WC Oncology SC Oncology GA DD0UA UT WOS:000369634300012 PM 26850491 ER PT J AU Byrnes, C Lee, YT Meier, ER Rabel, A Sacks, DB Miller, JL AF Byrnes, Colleen Lee, Y. Terry Meier, Emily R. Rabel, Antoinette Sacks, David B. Miller, Jeffery L. TI Iron dose-dependent differentiation and enucleation of human erythroblasts in serum-free medium SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE erythropoiesis; serum-free media; holo-transferrin; haemoglobin; enucleation; iron ID RED-BLOOD-CELLS; HUMAN ERYTHROID PROGENITORS; HEMATOPOIETIC STEM-CELLS; FLOW-CYTOMETRIC ANALYSIS; BONE-MARROW CULTURE; EX-VIVO GENERATION; LIQUID CULTURE; IN-VITRO; EXPRESSION; PROLIFERATION AB Improvements in ex vivo generation of enucleated red blood cells are being sought for erythroid biology research, toward the ultimate goal of erythrocyte engineering for clinical use. Based upon the high levels of iron-saturated transferrin in plasma serum, it was hypothesized that terminal differentiation in serum-free media may be highly dependent on the concentration of iron. Here adult human CD34(+) cells were cultured in a serum-free medium containing dosed levels of iron-saturated transferrin (holo-Tf, 0.1-1.0mg/ml). Iron in the culture medium was reduced, but not depleted, with erythroblast differentiation into haemoglobinized cells. At the lowest holo-Tf dose (0.1mg/ml), terminal differentiation was significantly reduced and the majority of the cells underwent apoptotic death. Cell survival, differentiation and enucleation were enhanced as the holo-Tf dose increased. These data suggest that adequate holo-Tf dosing is critical for terminal differentiation and enucleation of human erythroblasts generated ex vivo in serum-free culture conditions. Published 2013. This article is a US Government work and is in the public domain in the USA. C1 [Byrnes, Colleen; Lee, Y. Terry; Meier, Emily R.; Rabel, Antoinette; Miller, Jeffery L.] Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. [Sacks, David B.] Warren Grant Magnuson Clin Ctr, Clin Chem Serv, Dept Lab Med, NIH, Bethesda, MD USA. [Meier, Emily R.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. RP Miller, JL (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. EM jm7f@nih.gov OI Sacks, David/0000-0003-3100-0735 FU Intramural Research Programmes of the National Institute of Diabetes and Digestive and Kidney Diseases FX The Intramural Research Programmes of the National Institute of Diabetes and Digestive and Kidney Diseases supported this study. NR 33 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-6254 EI 1932-7005 J9 J TISSUE ENG REGEN M JI J. Tissue Eng. Regen. Med. PD FEB PY 2016 VL 10 IS 2 BP E84 EP E89 DI 10.1002/term.1743 PG 6 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Engineering, Biomedical SC Cell Biology; Biotechnology & Applied Microbiology; Engineering GA DD7UX UT WOS:000370131300005 PM 23606586 ER PT J AU Alexander, R Parker, K Schwetz, T AF Alexander, Rashada Parker, Karen Schwetz, Tara TI Sexual and Gender Minority Health Research at the National Institutes of Health SO LGBT HEALTH LA English DT Article DE biomedical research; National Institutes of Health (NIH); sexual and gender minority; strategic plan AB Sexual and gender minority (SGM) populations experience many diseases and conditions at higher prevalence rates than their non-SGM counterparts. In 2009, the National Institutes of Health (NIH) commissioned an Institute of Medicine (IOM) report to better understand the health of SGM populations. Following the release of the report, NIH, including the National Cancer Institute (NCI), initiated new activities, and continued and expanded its existing efforts to advance the health of SGM individuals. Such efforts include various forms of outreach to solicit feedback, support of extramural researchers, analysis of the research portfolio to identify areas of opportunity, and the development of the NIH Strategic Plan for SGM Health Research. C1 [Alexander, Rashada] NIGMS, CRCB, NIH, Bethesda, MD USA. [Parker, Karen] NCI, OD, NIH, Bethesda, MD 20892 USA. [Parker, Karen; Schwetz, Tara] NIH, Off Director, Bldg 1,Room 257,1 Ctr Dr, Bethesda, MD 20892 USA. [Schwetz, Tara] NIH, Immediate Off Director IMOD, Bldg 10, Bethesda, MD 20892 USA. RP Parker, K (reprint author), NIH, Off Director, Bldg 1,Room 257,1 Ctr Dr, Bethesda, MD 20892 USA. EM klparker@mail.nih.gov FU NIH Sexual and Gender Minority Research Coordinating Committee; NIH Office of the Director; NIH Office of Equity, Diversity and Inclusion FX The authors would like to thank the NIH Sexual and Gender Minority Research Coordinating Committee, the NIH Office of the Director, and the NIH Office of Equity, Diversity and Inclusion for their collaborative efforts and support, which contributed to the information presented here. NR 16 TC 2 Z9 2 U1 1 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2325-8292 EI 2325-8306 J9 LGBT HEALTH JI LGBT Health PD FEB PY 2016 VL 3 IS 1 SI SI BP 7 EP 10 DI 10.1089/lgbt.2015.0107 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD0PY UT WOS:000369623100003 ER PT J AU Zhu, YY Hernandez, LM Mueller, P Dong, YQ Hirschfeld, S Forman, MR AF Zhu, Yeyi Hernandez, Ladia M. Mueller, Peter Dong, Yongquan Hirschfeld, Steven Forman, Michele R. TI Predictive Models for Characterizing Disparities in Exclusive Breastfeeding Performance in a Multi-ethnic Population in the US SO MATERNAL AND CHILD HEALTH JOURNAL LA English DT Article DE Breastfeeding promotion; Breastfeeding disparity; Breast-bottle feeding; Exclusive breastfeeding; Multi-ethnic population ID GESTATIONAL WEIGHT-GAIN; BODY-MASS INDEX; MATERNAL OBESITY; UNITED-STATES; PREGNANCY COMPLICATIONS; BIRTH-WEIGHT; DURATION; WOMEN; OVERWEIGHT; RECALL AB Objectives Maternal lactation performance varies across populations, yet the relative impact of maternal sociodemographics, perinatal factors, and birth outcomes on disparities in exclusive breastfeeding (XBR) outcomes is not well known. We aimed to develop predictive models and compare the relative contribution of predictors for XBR initiation and XBR a parts per thousand yen 6 months. Methods Infant feeding data were obtained from women with children aged 0-6 years (n = 1471) in a multi-ethnic cross-sectional study in the US (2011-2012). We compared discriminant ability of predictors for ever XBR and XBR a parts per thousand yen 6 months using discriminant function analysis, respectively. We also calculated adjusted ORs for factors associated with XBR outcomes and breast-bottle feeding (BrBot) subgroups. Results Maternal sociodemographics (education level, marital status, nativity, and age at childbirth) had greater discriminating abilities in predicting ever XBR and XBR a parts per thousand yen 6 months than birth outcomes and perinatal factors. Foreign-born women were two-fold more likely to initiate XBR but not necessarily continue to 6 months compared to their US-born counterparts. Factors associated with BrBot subgroups differed from those associated with XBR outcomes, whereas maternal age was the only predictor consistently associated with ever XBR, XBR a parts per thousand yen 6 months, and BrBot subgroups. The areas under the receiver operating characteristic curves for models predicting ever XBR and XBR a parts per thousand yen 6 months were 0.88 (95 % CI 0.85, 0.91) and 0.90 (95 % CI 0.88, 0.93), respectively. Conclusions Findings underscore the importance of educational, clinical, and social support to promote XBR in mothers with sociodemographic factors predictive of none or poor XBR outcomes. C1 [Zhu, Yeyi; Hernandez, Ladia M.; Dong, Yongquan; Forman, Michele R.] Univ Texas Austin, Dept Nutr Sci, Austin, TX 78703 USA. [Mueller, Peter] Univ Texas Austin, Dept Math, Austin, TX 78712 USA. [Zhu, Yeyi; Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Forman, Michele R.] Univ Texas Austin, Sch Human Ecol, Austin, TX 78712 USA. RP Zhu, YY (reprint author), Univ Texas Austin, Dept Nutr Sci, Austin, TX 78703 USA.; Zhu, YY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA.; Zhu, YY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Epidemiol Branch, Bethesda, MD 20852 USA. EM yeyi.zhu@nih.gov RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN275200800020C] FX Dr. Zhu carried out data collection, analysis and interpretation, and wrote the manuscript; Drs. Hernandez and Forman collected the data and revised the manuscript; Mr. Dong and Drs. Mueller and Forman contributed to data analysis and interpretation; Drs. Hirschfeld and Forman designed and supervised the research. The authors are grateful to the participants and other investigators and staff at all study sites (Johns Hopkins University, Baltimore, MD; Michigan State University, East Lansing, MI; Saint Louis University, Saint Louis, MO; University of California-Irvine, Irvine, CA; University of California-Los Angeles, Los Angeles, CA; University of Minnesota, Minneapolis, MN; University of Texas at Austin/Baylor College of Medicine, Austin/Houston, TX; University of Texas Health Science Center at San Antonio, San Antonio, TX). This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development award# HHSN275200800020C. NR 55 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1092-7875 EI 1573-6628 J9 MATERN CHILD HLTH J JI Matern. Child Health J. PD FEB PY 2016 VL 20 IS 2 BP 398 EP 407 DI 10.1007/s10995-015-1838-3 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DD3FK UT WOS:000369807300018 PM 26515468 ER PT J AU Haddad, D Krane, L Mirzazadeh, M Badlani, G AF Haddad, Devin Krane, Louis Mirzazadeh, Majid Badlani, Gopal TI TRENDS IN MESH USAGE AND RESIDENT INVOLVEMENT FOR VAGINAL SURGERY FROM THE NATIONAL SURGICAL QUALITY IMPROVEMENT PROGRAM SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 23-27, 2016 CL New Orleans, LA SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Haddad, Devin; Mirzazadeh, Majid; Badlani, Gopal] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Krane, Louis] NCI, 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 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2016 VL 35 SU 1 MA NM98 BP S81 EP S81 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DD2BF UT WOS:000369726700197 ER PT J AU Haddad, D Krane, L Badlani, G Mirzazadeh, M AF Haddad, Devin Krane, Louis Badlani, Gopal Mirzazadeh, Majid TI TRANSVAGINAL MESH INCREASES THE RISK OF BLEEDING AND ORGAN SURGICAL SITE INFECTION IN VAGINAL PELVIC RECONSTRUCTION SURGERY: RESULTS FROM A MULTI-INSTITUTIONAL PROSPECTIVELY MAINTAINED DATASET SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 23-27, 2016 CL New Orleans, LA SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Haddad, Devin; Badlani, Gopal; Mirzazadeh, Majid] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Krane, Louis] NCI, 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 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2016 VL 35 SU 1 MA M58 BP S43 EP S43 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DD2BF UT WOS:000369726700096 ER PT J AU Haddad, D Krane, L Badlani, G Mirzazadeh, M AF Haddad, Devin Krane, Louis Badlani, Gopal Mirzazadeh, Majid TI COMPARISON OF SURGICAL OUTCOMES IN BENIGN PROSTATIC HYPERTROPHY MANAGEMENT USING THE NATIONAL SURGICAL QUALITY IMPROVEMENT PROGRAM SO NEUROUROLOGY AND URODYNAMICS LA English DT Meeting Abstract CT Winter Meeting of the Society-of-Urodynamics-Female-Pelvic-Medicine-and-Urogenital-Reconstruct ion CY FEB 23-27, 2016 CL New Orleans, LA SP Soc Urodynam Female Pelv Med & Urogenital Reconstruct C1 [Haddad, Devin; Badlani, Gopal; Mirzazadeh, Majid] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Krane, Louis] NCI, 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 0733-2467 EI 1520-6777 J9 NEUROUROL URODYNAM JI Neurourol. Urodyn. PD FEB PY 2016 VL 35 SU 1 MA M42 BP S37 EP S37 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA DD2BF UT WOS:000369726700080 ER PT J AU Nelson, KB Blair, E AF Nelson, Karin B. Blair, Eve TI Prenatal Factors in Singletons With Cerebral Palsy Born at or Near Term SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material AB Cerebral palsy (CP) is a disorder of movement affecting activities of daily living that is due to nonprogressive cerebral defects acquired early in life. Gestational age at birth is strongly associated with CP (prevalence among term infants is approximately one-fortieth the prevalence among extremely preterm survivors). Controlled studies in human populations have shown important prenatal antecedents of CP. The current review article discusses the evidence that for children in developed countries who are born at or near term factors operating before labor begins are chief determinants of the risk of CP. It is noted that among infants with CP, major malformations are more frequent in infants born at term or at normal birth weight; the risk of an association of birth defects with CP is increased by a factor of 9 among infants born at or near term. Reasons for this high rate of anomalies at the normal time of delivery pattern in CP are still unclear. Birth defects most frequently associated with CP in term and near-term infants involve the brain and include structural abnormalities, aberrant growth, and prenatal destructive lesions. Congenital microcephaly is the most common birth defect in CP. Marked fetal growth restriction too is associated with an increased risk of CP. Neonates with poor growth are more likely to have birth defects, and infants with birth defects are more likely to have restricted growth. Thromboembolism, vascular disruption, and major hemodynamic shifts can contribute to malformations, including congenital limb amputation, and gastroschisis. Such events occurring early in pregnancy can cause brain lesions and later in pregnancy can cause cerebral infarction in a vascular territory. Perinatal stroke due to such cerebral infarction is a common cause of hemiplegic CP (most common type of CP in children born at or near term). Twins have a higher frequency of malformations and of CP than do singletons. Pathologic processes in the placenta are associated with CP, growth restriction, and some birth defects. Many birth defects have a genetic cause. A genetic component has been suspected for some infants with CP because a sibling also has the disorder. Malformations of the cerebral cortex are more common in babies who have birth complications than in controls. Cerebral palsy and its major predictors (birth defects, fetal growth restriction, and neonatal encephalopathy) are not etiologically uniform, and the effect of each predictive factor is likely to be related to its specific cause. The ability to offer a reliable prognosis and anticipate the need for special management may be improved by thorough evaluation of a growth-restricted fetus or neonate for birth defects. Information from placental investigations and rapid-turnaround microanalyses of biochemical and genetic markers are likely to inform future evaluation and treatment of neonates with restricted fetal growth or neurologic abnormalities. Greater understanding of CP is possible by clinical investigations along with research in genetics and genomics, teratology, and developmental neuroscience. C1 [Nelson, Karin B.] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Nelson, Karin B.] Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. [Blair, Eve] Univ Western Australia, Telethon Kids Inst, Subiaco, WA, Australia. RP Nelson, KB (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7828 EI 1533-9866 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD FEB PY 2016 VL 71 IS 2 BP 65 EP 66 DI 10.1097/01.ogx.0000480256.92761.c8 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DD4DS UT WOS:000369873300002 ER PT J AU Shapiro, AJ Zariwala, MA Ferkol, T Davis, SD Sagel, SD Dell, SD Rosenfeld, M Olivier, KN Milla, C Daniel, SJ Kimple, AJ Manion, M Knowles, MR Leigh, MW AF Shapiro, Adam J. Zariwala, Maimoona A. Ferkol, Thomas Davis, Stephanie D. Sagel, Scott D. Dell, Sharon D. Rosenfeld, Margaret Olivier, Kenneth N. Milla, Carlos Daniel, Sam J. Kimple, Adam J. Manion, Michele Knowles, Michael R. Leigh, Margaret W. CA Genetic Disorders Mucociliary Clea TI Diagnosis, Monitoring, and Treatment of Primary Ciliary Dyskinesia: PCD Foundation Consensus Recommendations Based on State of the Art Review SO PEDIATRIC PULMONOLOGY LA English DT Article DE primary ciliary dyskinesia; PCD; kartagener; consensus statement; PCD Foundation ID NASAL NITRIC-OXIDE; CYSTIC-FIBROSIS BRONCHIECTASIS; RANDOMIZED CONTROLLED-TRIAL; SITUS-INVERSUS TOTALIS; MUCOCILIARY CLEARANCE DISORDER; MULTIPLE MOTILE CILIA; INNER DYNEIN ARMS; LONG-TERM; KARTAGENERS-SYNDROME; IMMOTILE CILIA AB Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, rare lung disease resulting in chronic oto-sino-pulmonary disease in both children and adults. Many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials. This review article outlines consensus recommendations from PCD physicians in North America who have been engaged in a PCD centered research consortium for the last 10 years. These recommendations have been adopted by the governing board of the PCD Foundation to provide guidance for PCD clinical centers for diagnostic testing, monitoring, and appropriate short and long-term therapeutics in PCD patients. (C) 2015 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc. C1 [Shapiro, Adam J.] McGill Univ, Montreal Childrens Hosp, Dept Pediat, 2300 Tupper,D-380, Montreal, PQ H3H 1P3, Canada. [Zariwala, Maimoona A.] Univ N Carolina, Sch Med, Marsico Lung Inst, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Ferkol, Thomas] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Sagel, Scott D.] Indiana Univ, James Whitcomb Riley Hosp Children, Dept Pediat, Indianapolis, IN 46204 USA. [Sagel, Scott D.] Childrens Hosp Colorado, Dept Pediat, Aurora, CO USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Aurora, CO USA. [Dell, Sharon D.] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Dell, Sharon D.] Univ Toronto, Toronto, ON, Canada. [Rosenfeld, Margaret] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Rosenfeld, Margaret] Univ Washington, Seattle, WA 98195 USA. [Olivier, Kenneth N.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [Milla, Carlos] Stanford Univ, Dept Pediat, Palo Alto, CA 94304 USA. [Daniel, Sam J.] McGill Univ, Montreal Childrens Hosp, Dept Otolaryngol, Montreal, PQ H3H 1P3, Canada. [Kimple, Adam J.] Univ N Carolina, Sch Med, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. [Manion, Michele] PCD Fdn, Minneapolis, MN USA. [Knowles, Michael R.] Univ N Carolina, Dept Med, Marsico Lung Inst, Chapel Hill, NC USA. [Leigh, Margaret W.] Univ N Carolina, Dept Pediat, Marsico Lung Inst, Chapel Hill, NC USA. RP Shapiro, AJ (reprint author), McGill Univ, Montreal Childrens Hosp, Dept Pediat, 2300 Tupper,D-380, Montreal, PQ H3H 1P3, Canada. EM adam.shapiro@muhc.mcgill.ca FU National Institutes of Health (NIH) [U54HL096458, 5R01HL071798]; Genetic Disorders of Mucociliary Clearance is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN) [U54HL096458]; RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS; CTSA NIH/NCATS UNC [ULTR000083]; CTSA NIH/NCATS Colorado [UL1TR000154]; Intramural Research Program of NIH/NIAID FX National Institutes of Health (NIH), Number: U54HL096458, 5R01HL071798; The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and NHLBI; CTSA NIH/NCATS UNC ULTR000083; CTSA NIH/NCATS Colorado UL1TR000154; Intramural Research Program of NIH/NIAID. NR 164 TC 11 Z9 11 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-6863 EI 1099-0496 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD FEB PY 2016 VL 51 IS 2 BP 115 EP 132 DI 10.1002/ppul.23304 PG 18 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA DD8EM UT WOS:000370158000002 PM 26418604 ER PT J AU da Cunha, MG Rosalen, PL Franchin, M de Alencar, SM Ikegaki, M Ransom, T Beutler, JA AF da Cunha, Marcos Guilherme Rosalen, Pedro Luiz Franchin, Marcelo de Alencar, Severino Matias Ikegaki, Masaharu Ransom, Tanya Beutler, John Albert TI Antiproliferative Constituents of Geopropolis from the Bee Melipona scutellaris SO PLANTA MEDICA LA English DT Article DE Clusiaceae; geopropolis; Melipona scutellaris; cytotoxity; coumarins ID MAMMEA-AMERICANA L; 4-PHENYLCOUMARINS; DERIVATIVES; COUMARINS AB Fractionation of geopropolis from Melipona scutellaris, guided by antiproliferative activity against two colon cancer cell lines (COLO205 and KM12), led to the isolation of two new cinnamic acid esters, mammea-type coumarins 5,7-dihydroxy-6(3-methyl-2-butenyl)-8-(4-cinnamoyl-3-methyl-1-oxobutyl)-4-propyl-coumarin (1) and 5,7-dihydroxy-6-(4-cinnamoyl-3-methyl-1-oxobutyl)-4-phenylcoumarin (2), along with five known coumarins, mammeigin (3), hydroxymammeigin (4), mammeisin (5), cinnamoyloxy-mammeisin (6), and mammein (7), and the prenylated benzophenone ent-nemorosone (8). Among the isolated compounds, 5 and 7 showed the highest cell growth inhibition against COLO205 (GI(50) 9.7 and 10.7 mu M, respectively) and KM12 (GI(50) 12.0 and 10.9 mu M, respectively). The presence of these compounds suggests that plants of Clusiaceae family, especially the genera Kielmeyera and Clusia, are likely to be major sources of geopropolis produced by M. scutellaris. C1 [da Cunha, Marcos Guilherme; Rosalen, Pedro Luiz; Franchin, Marcelo] Univ Estadual Campinas, Piracicaba Dent Sch, Piracicaba, SP, Brazil. [de Alencar, Severino Matias] Univ Sao Paulo, Luiz de Queiroz Coll Agr, Piracicaba, SP, Brazil. [Ikegaki, Masaharu] Univ Fed Alfenas, Alfenas, MG, Brazil. [da Cunha, Marcos Guilherme; Ransom, Tanya; Beutler, John Albert] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Beutler, JA (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Bldg 560,Rm 11-82 NCI Frederick, Frederick, MD 21702 USA. EM beutlerj@mail.nih.gov RI Alencar, Severino/B-7743-2012; da Cunha, Marcos/F-5720-2014 OI Alencar, Severino/0000-0002-6637-7973; da Cunha, Marcos/0000-0003-0099-6189 FU NIH, National Cancer Institute, Center for Cancer Research; FAPESP [2011/23635-6, 2012/22002-2] FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and by FAPESP (#2011/23635-6 and #2012/22002-2). The authors are grateful to Mr. Jose Emidio Borges de Souza for providing the geopropolis samples. We thank D. Newman for help in documenting the samples, the Natural Products Support Group at NCI-Frederick, and S. Tarasov, M. Dyba (Biophysics Resource Core, Structural Biophysics Laboratory, CCR), and H. Bokesch (MTL) for assistance with high-resolution mass spectrometry as well as Kirk Gustafson for NMR support. We also thank Dr. Gordon Cragg for making the execution of this work possible. NR 20 TC 5 Z9 5 U1 8 U2 20 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 EI 1439-0221 J9 PLANTA MED JI Planta Med. PD FEB PY 2016 VL 82 IS 3 BP 190 EP 194 DI 10.1055/s-0035-1558142 PG 5 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA DD5FM UT WOS:000369948100002 PM 26544117 ER PT J AU Barb, JJ Oler, AJ Kim, HS Chalmers, N Wallen, GR Cashion, A Munson, PJ Ames, NJ AF Barb, Jennifer J. Oler, Andrew J. Kim, Hyung-Suk Chalmers, Natalia Wallen, Gwenyth R. Cashion, Ann Munson, Peter J. Ames, Nancy J. TI Development of an Analysis Pipeline Characterizing Multiple Hypervariable Regions of 16S rRNA Using Mock Samples SO PLOS ONE LA English DT Article ID CLINICAL MICROBIOLOGY; SEQUENCING PLATFORMS; DIVERSITY; IDENTIFICATION; PERFORMANCE; BACTERIA; PRIMERS AB Objectives There is much speculation on which hypervariable region provides the highest bacterial specificity in 16S rRNA sequencing. The optimum solution to prevent bias and to obtain a comprehensive view of complex bacterial communities would be to sequence the entire 16S rRNA gene; however, this is not possible with second generation standard library design and short-read next-generation sequencing technology. Methods This paper examines a new process using seven hypervariable or V regions of the 16S rRNA (six amplicons: V2, V3, V4, V6-7, V8, and V9) processed simultaneously on the Ion Torrent Personal Genome Machine (Life Technologies, Grand Island, NY). Four mock samples were amplified using the 16S Ion Metagenomics Kit (TM) (Life Technologies) and their sequencing data is subjected to a novel analytical pipeline. Results Results are presented at family and genus level. The Kullback-Leibler divergence (D-KL), a measure of the departure of the computed from the nominal bacterial distribution in the mock samples, was used to infer which region performed best at the family and genus levels. Three different hypervariable regions, V2, V4, and V6-7, produced the lowest divergence compared to the known mock sample. The V9 region gave the highest (worst) average D-KL while the V4 gave the lowest (best) average D-KL. In addition to having a high D-KL, the V9 region in both the forward and reverse directions performed the worst finding only 17% and 53% of the known family level and 12% and 47% of the genus level bacteria, while results from the forward and reverse V4 region identified all 17 family level bacteria. Conclusions The results of our analysis have shown that our sequencing methods using 6 hypervariable regions of the 16S rRNA and subsequent analysis is valid. This method also allowed for the assessment of how well each of the variable regions might perform simultaneously. Our findings will provide the basis for future work intended to assess microbial abundance at different time points throughout a clinical protocol. C1 [Barb, Jennifer J.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. [Oler, Andrew J.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Kim, Hyung-Suk; Cashion, Ann] NINR, NIH, Bethesda, MD 20892 USA. [Chalmers, Natalia] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Wallen, Gwenyth R.; Ames, Nancy J.] NIH, Ctr Clin, Dept Nursing, Bldg 10, Bethesda, MD 20892 USA. RP Barb, JJ (reprint author), NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM barbj@mail.nih.gov FU NIH; Clinical Center and NIH; National Institute of Nursing Research FX This research was supported by the Intramural Research Program of NIH, Clinical Center and NIH, National Institute of Nursing Research. NR 46 TC 4 Z9 4 U1 6 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 1 PY 2016 VL 11 IS 2 AR e0148047 DI 10.1371/journal.pone.0148047 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9NL UT WOS:000369548200055 PM 26829716 ER PT J AU Li, M Lin, SQ Craigie, R AF Li, Min Lin, Shiqiang Craigie, Robert TI Outer domains of integrase within retroviral intasomes are dispensible for catalysis of DNA integration SO PROTEIN SCIENCE LA English DT Article DE HIV-1; integration; integrase; intasomes ID PROTOTYPE FOAMY VIRUS; STRAND TRANSFER; MECHANISM; PRODUCT AB Retroviral DNA integration is mediated by nucleoprotein complexes (intasomes) comprising a pair of viral DNA ends synapsed by a tetramer of integrase. Current integrase inhibitors act on intasomes rather than free integrase protein. Structural and functional studies of intasomes are essential to understand their mechanism of action and how the virus can escape by mutation. To date, prototype foamy virus (PFV) is the only retrovirus for which high-resolution structures of intasomes have been determined. In the PFV intasome structure, only the core domains of the outer subunits are ordered; the N-terminal domain, C-terminal domain, and N-terminal extension domain are disordered. Are these missing domains required for function or are they dispensable? We have devised a strategy to assemble hetero-intasomes in which the outer domains are not present as a tool to assess the functional role of the missing domains for catalysis of integration. We find that the disordered domains of outer subunits are not required for intasome assembly or catalytic activity as catalytic core domains can substitute for the outer subunits in the case of both PFV and HIV-1 intasomes. C1 [Li, Min; Lin, Shiqiang; Craigie, Robert] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Craigie, R (reprint author), Bldg 5,Room 301,5 Mem Dr, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov FU NIDDK; NIH; AIDS Targeted Antiviral Program FX Grant sponsor: NIDDK; Grant sponsor: NIH; Grant sponsor: AIDS Targeted Antiviral Program. NR 15 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 EI 1469-896X J9 PROTEIN SCI JI Protein Sci. PD FEB PY 2016 VL 25 IS 2 BP 472 EP 478 DI 10.1002/pro.2837 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD3JW UT WOS:000369819500015 PM 26537415 ER PT J AU Makowski, MM Willems, E Fang, J Choi, J Zhang, TW Jansen, PWTC Brown, KM Vermeulen, M AF Makowski, Matthew M. Willems, Esther Fang, Jun Choi, Jiyeon Zhang, Tongwu Jansen, Pascal W. T. C. Brown, Kevin M. Vermeulen, Michiel TI An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations SO PROTEOMICS LA English DT Article DE Biomedicine; Melanoma; Telomerase; Transcription ID OPEN-ACCESS DATABASE; QUANTITATIVE PROTEOMICS; PROTEIN INTERACTIONS; CANCER; SUBUNITS; COMPLEX; IDENTIFICATION; ACTIVATION; EXPRESSION; HALLMARKS AB Aberrant telomerase reactivation in differentiated cells represents a major event in oncogenic transformation. Recurrent somatic mutations in the human telomerase reverse transcriptase (TERT) promoter region, predominantly localized to two nucleotide positions, are highly prevalent in many cancer types. Both mutations create novel consensus E26 transformation-specific (ETS) motifs and are associated with increased TERT expression. Here, we perform an unbiased proteome-wide survey of transcription factor binding at TERT promoter mutations in melanoma. We observe ELF1 binding at both mutations in vitro and we show that increased recruitment of GABP is enabled by the spatial architecture of native and novel ETS motifs in the TERT promoter region. We characterize the dynamics of competitive binding between ELF1 and GABP and provide evidence for ELF1 exclusion by transcriptionally active GABP. This study thus provides an important description of proteome-wide, mutation-specific binding at the recurrent, oncogenic TERT promoter mutations. C1 [Makowski, Matthew M.; Willems, Esther; Jansen, Pascal W. T. C.; Vermeulen, Michiel] Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Geert Grootepl 28, NL-6525 GA Nijmegen, Netherlands. [Vermeulen, Michiel] Canc Genom Netherlands, Utrecht, Netherlands. [Fang, Jun; Choi, Jiyeon; Zhang, Tongwu; Brown, Kevin M.] NIH, Lab Translat Genom, Div Canc Epidemiol & Genet, Bldg 10, Bethesda, MD 20892 USA. RP Vermeulen, M (reprint author), Radboud Univ Nijmegen, Radboud Inst Mol Life Sci, Geert Grootepl 28, NL-6525 GA Nijmegen, Netherlands. EM michiel.vermeulen@science.ru.nl OI Vermeulen, Michiel/0000-0003-0836-6894 FU DevCom FP7 Marie Curie ITN; Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health FX M.M. and M.V. received funding from the DevCom FP7 Marie Curie ITN. K.M.B., J.F., J.C., and T.Z. are supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health. NR 34 TC 8 Z9 8 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 EI 1615-9861 J9 PROTEOMICS JI Proteomics PD FEB PY 2016 VL 16 IS 3 SI SI BP 417 EP 426 DI 10.1002/pmic.201500327 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD7UL UT WOS:000370130000005 PM 26553150 ER PT J AU Uzasci, L Auh, S Cotter, RJ Nath, A AF Uzasci, Lerna Auh, Sungyoung Cotter, Robert J. Nath, Avindra TI Mass spectrometric phosphoproteome analysis of HIV-infected brain reveals novel phosphorylation sites and differential phosphorylation patterns SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Drug target; HIV-associated neurocognitive disorders; Phosphorylation; Protein kinase A; Proteomics ID IMMUNODEFICIENCY-VIRUS TYPE-1; COGNITIVE IMPAIRMENT; IMMUNE-RESPONSE; PROTEIN; TAT; CDK5; NEURODEGENERATION; QUANTIFICATION; NEUROTOXICITY; ENCEPHALITIS AB PurposeTo map the phosphoproteome and identify changes in the phosphorylation patterns in the HIV-infected and uninfected brain. Experimental designParietal cortex from individuals with and without HIV infection were lysed and trypsinized. The peptides were labeled with iTRAQ reagents, combined, phospho-enriched by titanium dioxide chromatography, and analyzed by LC-MS/MS with high resolution. ResultsOur phosphoproteomic workflow resulted in the identification of 112 phosphorylated proteins and 17 novel phosphorylation sites in all the samples that were analyzed. The phosphopeptide sequences were searched for kinase substrate motifs, which revealed potential kinases involved in important signaling pathways. The site-specific phosphopeptide quantification showed that peptides from neurofilament medium polypeptide, myelin basic protein, and 2-3-cyclic nucleotide-3 phosphodiesterase have relatively higher phosphorylation levels during HIV infection. Conclusions and clinical relevanceThis study has enriched the global phosphoproteome knowledge of the human brain by detecting novel phosphorylation sites on neuronal proteins and identifying differentially phosphorylated brain proteins during HIV infection. Kinases that lead to unusual phosphorylations could be therapeutic targets for the treatment of HIV-associated neurocognitive disorders. C1 [Uzasci, Lerna; Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, 10 Ctr Dr,Bldg 10,Rm 7C-103, Bethesda, MD 20892 USA. [Uzasci, Lerna; Cotter, Robert J.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Auh, Sungyoung] NINDS, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Uzasci, L (reprint author), NINDS, Sect Infect Nervous Syst, NIH, 10 Ctr Dr,Bldg 10,Rm 7C-103, Bethesda, MD 20892 USA. EM luzasci1@jhu.edu FU NINDS [R01NS039253]; NIH FX The authors dedicate this work to the memory of their beloved colleague Dr. Robert J. Cotter, who died on November 12, 2012. RJC and LU were supported by grant R01NS039253 from the NINDS. AN and SA are supported by intramural NIH funds. We wish to thank the Johns Hopkins University School of Medicine Mass Spectrometry and Proteomics Facility for technical assistance, Dr. Wenxue Li for discussion, and Drs. Ronald Schnaar and Stefani Thomas for the critical reading of the manuscript. NR 42 TC 2 Z9 2 U1 2 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD FEB PY 2016 VL 10 IS 2 SI SI BP 126 EP 135 DI 10.1002/prca.201400134 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD3UL UT WOS:000369848400003 PM 26033855 ER PT J AU Rasmussen, V Turnell, A Butow, P Juraskova, I Kirsten, L Wiener, L Patenaude, A Hoekstra-Weebers, J Grassi, L AF Rasmussen, Victoria Turnell, Adrienne Butow, Phyllis Juraskova, Ilona Kirsten, Laura Wiener, Lori Patenaude, Andrea Hoekstra-Weebers, Josette Grassi, Luigi CA IPOS Res Committee TI Burnout among psychosocial oncologists: an application and extension of the effort-reward imbalance model SO PSYCHO-ONCOLOGY LA English DT Article ID CAREER-SUSTAINING BEHAVIORS; SELF-REPORTED HEALTH; PROFESSIONAL PSYCHOLOGISTS; OVER-COMMITMENT; MENTAL-HEALTH; WORK; NURSES; OVERCOMMITMENT; STRESS AB ObjectivesBurnout is a significant problem among healthcare professionals working within the oncology setting. This study aimed to investigate predictors of emotional exhaustion (EE) and depersonalisation (DP) in psychosocial oncologists, through the application of the effort-reward imbalance (ERI) model with an additional focus on the role of meaningful work in the burnout process. MethodsPsychosocial oncology clinicians (n=417) in direct patient contact who were proficient in English were recruited from 10 international psychosocial oncology societies. Participants completed an online questionnaire, which included measures of demographic and work characteristics, EE and DP subscales of the Maslach Burnout Inventory-Human Services Survey, the Short Version ERI Questionnaire and the Work and Meaning Inventory. ResultsHigher effort and lower reward were both significantly associated with greater EE, although not DP. The interaction of higher effort and lower reward did not predict greater EE or DP. Overcommitment predicted both EE and DP but did not moderate the impact of effort and reward on burnout. Overall, the ERI model accounted for 33% of the variance in EE. Meaningful work significantly predicted both EE and DP but accounted for only 2% more of the variance in EE above and beyond the ERI model. ConclusionsThe ERI was only partially supported as a useful framework for investigating burnout in psychosocial oncology professionals. Meaningful work may be a viable extension of the ERI model. Burnout among health professionals may be reduced by interventions aimed at increasing self-efficacy and changes to the supportive work environment. Copyright (c) 2015 John Wiley & Sons, Ltd. C1 [Rasmussen, Victoria; Turnell, Adrienne; Butow, Phyllis; Juraskova, Ilona] Univ Sydney, Sch Psychol, Level 6 North,Lifehouse C39Z, Sydney, NSW 2006, Australia. [Butow, Phyllis; Juraskova, Ilona; Kirsten, Laura] Univ Sydney, Sch Psychol, Ctr Med Psychol & Evidence Based Decis Making CeM, Sydney, NSW 2006, Australia. [Butow, Phyllis] Univ Sydney, Psychooncol Cooperat Res Grp PoCoG, Sydney, NSW 2006, Australia. [Kirsten, Laura] Sydney West Canc Network, Nepean Canc Care Ctr, Westmead, NSW, Australia. [Wiener, Lori] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Patenaude, Andrea] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hoekstra-Weebers, Josette] Univ Groningen, Univ Med Ctr, Wenckebach Inst, Groningen, Netherlands. [Grassi, Luigi] Univ Ferrara, Inst Psychiat, Dept Biomed & Special Surg Sci, I-44100 Ferrara, Italy. RP Butow, P (reprint author), Univ Sydney, Sch Psychol, Level 6 North,Lifehouse C39Z, Sydney, NSW 2006, Australia. EM phyllis.butow@sydney.edu.au FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 2 Z9 2 U1 10 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD FEB PY 2016 VL 25 IS 2 BP 194 EP 202 DI 10.1002/pon.3902 PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA DD5RH UT WOS:000369981400010 PM 26239424 ER PT J AU Herbert, KM Sarkar, SK Mills, M De la Herran, HCD Neuman, KC Steitz, JA AF Herbert, Kristina M. Sarkar, Susanta K. Mills, Maria Delgado De la Herran, Hilda C. Neuman, Keir C. Steitz, Joan A. TI A heterotrimer model of the complete Microprocessor complex revealed by single-molecule subunit counting SO RNA LA English DT Article DE miRNA; Microprocessor complex; single-molecule; stoichiometry ID CRITICAL REGION 8; PRIMARY MICRORNAS; DROSHA-DGCR8 COMPLEX; PRIMARY TRANSCRIPTS; GEL-FILTRATION; DGCR8; PROTEIN; BINDING; HEME; DOMAIN AB During microRNA (miRNA) biogenesis, the Microprocessor complex (MC), composed minimally of Drosha, an RNaselll enzyme, and DGCR8, a double-stranded RNA-binding protein, cleaves the primary-miRNA (pri-miRNA) to release the pre-miRNA stem-loop structure. Size-exclusion chromatography of the MC, isolated from mammalian cells, suggested multiple copies of one or both proteins in the complex. However, the exact stoichiometry was unknown. Initial experiments suggested that DGCR8 bound pri-miRNA substrates specifically, and given that Drosha could not be bound or cross-linked to RNA, a sequential model for binding was established in which DGCR8 bound first and recruited Drosha. Therefore, many laboratories have studied DGCR8 binding to RNA in the absence of Drosha and have shown that deletion constructs of DGCR8 can multimerize in the presence of RNA. More recently, it was demonstrated that Drosha can bind pri-miRNA substrates in the absence of DGCR8, casting doubt on the sequential model of binding. In the same study, using a single-molecule photobleaching assay, fluorescent protein-tagged deletion constructs of DGCR8 and Drosha assembled into a heterotrimeric complex on RNA, comprising two DGCR8 molecules and one Drosha molecule. To determine the stoichiometry of Drosha and DGCR8 within the MC in the absence of added RNA, we also used a single-molecule photobleaching assay and confirmed the heterotrimeric model of the human MC. We demonstrate that a heterotrimeric complex is likely preformed in the absence of RNA and exists even when full-length proteins are expressed and purified from human cells, and when hAGT-derived tags are used rather than fluorescent proteins. C1 [Herbert, Kristina M.; Steitz, Joan A.] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biophys & Biochem, 333 Cedar St, New Haven, CT 06536 USA. [Herbert, Kristina M.; Delgado De la Herran, Hilda C.] Ctr Sci Res & Higher Educ Ensenada CICESE, Dept Microbiol, Ensenada 22860, Baja California, Mexico. [Sarkar, Susanta K.; Mills, Maria; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Sarkar, Susanta K.] Colorado Sch Mines, Dept Phys, Golden, CO 80401 USA. RP Herbert, KM; Steitz, JA (reprint author), Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biophys & Biochem, 333 Cedar St, New Haven, CT 06536 USA.; Herbert, KM (reprint author), Ctr Sci Res & Higher Educ Ensenada CICESE, Dept Microbiol, Ensenada 22860, Baja California, Mexico.; Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM kherbert@cicese.mx; neumankc@nhlbi.nih.gov; joan.steitz@yale.edu RI Neuman, Keir/F-7400-2011; Herbert, Kristina/A-3105-2010 OI Neuman, Keir/0000-0002-0863-5671; Herbert, Kristina/0000-0002-5288-3381 FU National Institute of General Medical Sciences (NIGMS, NIH) [GM026154]; Intramural Research Programs of the National Heart, Lung, and Blood Institute, National Institutes of Health; Burroughs Wellcome Fund Collaborative Research Travel Grant FX We are grateful to E. Abbondanzieri for initial discussions of labeling strategies, G. Piszczek of the NHLBI Biophysics core for help running SEC, A. Ditmore and Y. Seol of the Neuman laboratory for advice and software for fluorescent spot detection, N. Darricarrere of C. Crews' laboratory for the kind gift of the HEK293 Flp-In cells, and D. Liu and A. Miccinello of the Steitz laboratory for editorial help. J.A.S. is an investigator of the Howard Hughes Medical Institute. K.M.H. was an HHMI Fellow of the Damon Runyon Cancer Research Foundation. A Burroughs Wellcome Fund 2011 Collaborative Research Travel Grant was awarded to K.M.H. This work was supported by grant GM026154 from the National Institute of General Medical Sciences (NIGMS, NIH) to J.A.S. This research was supported in part by the Intramural Research Programs of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 30 TC 3 Z9 3 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 EI 1469-9001 J9 RNA JI RNA PD FEB PY 2016 VL 22 IS 2 BP 175 EP 183 DI 10.1261/rna.054684.115 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD2TP UT WOS:000369775400002 PM 26683315 ER PT J AU Bosselut, R AF Bosselut, Remy TI Pleiotropic Functions of H3K27Me3 Demethylases in Immune Cell Differentiation SO TRENDS IN IMMUNOLOGY LA English DT Review ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HISTONE LYSINE DEMETHYLASES; REPRESSIVE COMPLEX 2; RNA-POLYMERASE-II; GENE-EXPRESSION; TARGET GENES; T-CELLS; MOLECULAR-MECHANISMS; H3 METHYLATION; LINEAGE FATE AB The trimethylation of histone H3 lysine 27 (H3K27Me3) contributes to gene repression, notably through recruitment of Polycomb complexes, and has long been considered essential to maintain cell identity. Whereas H3K27Me3 was thought to be stable and not catalytically reversible, the discovery of the Utx and Jmjd3 demethylases changed this notion, raising new questions on the role of these enzymes in gene expression and cell differentiation. Recent studies have demonstrated critical roles for Utx and Jmjd3 in the development and function of immune cells, and revealed both demethylase and demethylase-independent activities of these enzymes. I review these finding here, and discuss the current understanding of the mechanisms that underlie the broad, yet highly cell- and gene-specific, impact of these enzymes in vivo. C1 [Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM remy@helix.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX I thank C. Bauge, J. Kim, S. Manna, and P. Love for discussions, and T. Gucci and M. Vecchio for discussions and critical reading of the manuscript, I apologize to colleagues whose work could not be cited because of space constraints. Research in the author's laboratory is supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 85 TC 4 Z9 4 U1 3 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 EI 1471-4981 J9 TRENDS IMMUNOL JI Trends Immunol. PD FEB PY 2016 VL 37 IS 2 BP 102 EP 113 DI 10.1016/j.it.2015.12.004 PG 12 WC Immunology SC Immunology GA DD7IG UT WOS:000370096300003 PM 26796037 ER PT J AU Resnik, DB Ariansen, JL Jamal, J Kissling, GE AF Resnik, David B. Ariansen, J. L. Jamal, Jaweria Kissling, Grace E. TI Institutional Conflict of Interest Policies at US Academic Research Institutions SO ACADEMIC MEDICINE LA English DT Article ID BIOMEDICAL-RESEARCH; NATIONAL-SURVEY AB Purpose Institutional conflicts of interest (ICOIs) occur when the institution or leaders with authority to act on behalf of the institution have conflicts of interest (COIs) that may threaten the objectivity, integrity, or trustworthiness of research because they could impact institutional decision making. The purpose of this study was to gather and analyze information about the ICOI policies of the top 100U.S. academic research institutions, ranked according to total research funding. Method From May-June 2014, the authors attempted to obtain ICOI policy information for the top 100U.S. academic research institutions from publicly available Web sites or via e-mail inquiry. If an ICOI policy was not found, the institutions' online COI policies were examined. Data on each institution's total research funding, national funding rank, public versus private status, and involvement in clinical research were collected. The authors developed a coding system for categorizing the ICOI policies and used it to code the policies for nine items. Interrater agreement and P values were assessed. Results Only 28/100 (28.0%) institutions had an ICOI policy. ICOI policies varied among the 28 institutions. Having an ICOI policy was positively associated with total research funding and national funding ranking but not with public versus private status or involvement in clinical research. Conclusions Although most U.S. medical schools have policies that address ICOIs, most of the top academic research institutions do not. Federal regulation and guidance may be necessary to encourage institutions to adopt ICOI policies and establish a standard form of ICOI review. C1 [Resnik, David B.; Kissling, Grace E.] NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. [Ariansen, J. L.] N Carolina Cent Univ, Durham, NC USA. RP Resnik, DB (reprint author), NIEHS, NIH, 111 Alexander Dr,Box 12233,Mail Drop E1-06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-07] NR 21 TC 1 Z9 1 U1 4 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD FEB PY 2016 VL 91 IS 2 BP 242 EP 246 DI 10.1097/ACM.0000000000000980 PG 5 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA DC5YP UT WOS:000369297000029 PM 26535868 ER PT J AU Deller, MC Kong, L Rupp, B AF Deller, Marc C. Kong, Leopold Rupp, Bernhard TI Protein stability: a crystallographer's perspective SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS LA English DT Article DE protein stability; protein crystallization; protein disorder; crystallizability ID IN-SITU PROTEOLYSIS; CRYSTALLIZATION PROPENSITY PREDICTION; MALTOSE-BINDING-PROTEIN; HIGH-LEVEL EXPRESSION; DIFFERENTIAL SCANNING CALORIMETRY; INTRINSICALLY DISORDERED PROTEINS; MACROMOLECULAR NMR-SPECTROSCOPY; NUCLEAR-MAGNETIC-RESONANCE; SURFACE ENTROPY REDUCTION; AMINO-ACID-SEQUENCE AB Protein stability is a topic of major interest for the biotechnology, pharmaceutical and food industries, in addition to being a daily consideration for academic researchers studying proteins. An understanding of protein stability is essential for optimizing the expression, purification, formulation, storage and structural studies of proteins. In this review, discussion will focus on factors affecting protein stability, on a somewhat practical level, particularly from the view of a protein crystallographer. The differences between protein conformational stability and protein compositional stability will be discussed, along with a brief introduction to key methods useful for analyzing protein stability. Finally, tactics for addressing protein-stability issues during protein expression, purification and crystallization will be discussed. C1 [Deller, Marc C.] Stanford Univ, Shriram Ctr, Macromol Struct Knowledge Ctr, Stanford ChEM H, 443 Via Ortega,Room 097,MC5082, Stanford, CA 94305 USA. [Kong, Leopold] NIDDK, Lab Cell & Mol Biol, NIH, Bldg 8,Room 1A03,8 Ctr Dr, Bethesda, MD 20814 USA. [Rupp, Bernhard] Kk Hofkristallamt, Dept Forens Crystallog, 91 Audrey Pl, Vista, CA 92084 USA. [Rupp, Bernhard] Med Univ Innsbruck, Dept Genet Epidemiol, Schopfstr 41, A-6020 Innsbruck, Austria. RP Deller, MC (reprint author), Stanford Univ, Shriram Ctr, Macromol Struct Knowledge Ctr, Stanford ChEM H, 443 Via Ortega,Room 097,MC5082, Stanford, CA 94305 USA. EM mdeller@stanford.edu FU k.-k. Hofkristallamt, Vista, California, USA; Austrian Science Fund (FWF) [P28395-B26] FX This work was sponsored in part by contributions from k.-k. Hofkristallamt, Vista, California, USA and Austrian Science Fund (FWF) project P28395-B26. We would like to thank members of the Joint Center for Structural Genomics for fruitful discussions and contribution of the Thermofluor and DXMS data. NR 258 TC 3 Z9 3 U1 13 U2 32 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 2053-230X J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Commun. PD FEB PY 2016 VL 72 BP 72 EP 95 DI 10.1107/S2053230X15024619 PN 2 PG 24 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA DC7FH UT WOS:000369384100001 PM 26841758 ER PT J AU Bao, W Chavarro, JE Tobias, DK Bowers, K Li, SS Hu, FB Zhang, CL AF Bao, Wei Chavarro, Jorge E. Tobias, Deirdre K. Bowers, Katherine Li, Shanshan Hu, Frank B. Zhang, Cuilin TI Long-term risk of type 2 diabetes in relation to habitual iron intake in women with a history of gestational diabetes: a prospective cohort study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE diet; gestational diabetes mellitus; iron; heme iron; type 2 diabetes mellitus ID BETA-CELL FUNCTION; GLUCOSE-INTOLERANCE; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; OXIDATIVE STRESS; HEART-DISEASE; MELLITUS; QUESTIONNAIRE; DETERMINANTS; STORES AB Background: An iron overload may induce pancreatic islet damage and increase risk of diabetes. Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM) after pregnancy. Objective: We aimed to examine the association of habitual iron intake with long-term risk of T2DM in this high-risk population. Design: We included 3976 women with a history of GDM from the Nurses' Health Study II cohort as part of the ongoing Diabetes & Women's Health Study. The women were followed up through 2009. Iron intake was assessed with the use of a validated food frequency questionnaire in 1991 and every 4 y thereafter. We used Cox proportional hazards models to estimate HRs and 95% CIs. Results: We documented 641 incident T2DM cases during 57,683 person-years of observation. Adjusted HRs for T2DM for the highest quartile compared with the lowest quartile were 1.64 (95% CI: 1.20, 2.25; P-trend = 0.02) for total iron intake and 1.80 (95% CI: 1.18, 2.74; P-trend = 0.005) for dietary heme iron intake. In addition, women who consumed >= 30.0 mg supplemental Fe/d, compared with nonusers, had an adjusted HR of 1.83 (95% CI: 1.25, 2.70; P-trend = 0.002). Conclusion: In women with a history of GDM, greater intakes of total iron, dietary heme iron, and supplemental iron were associated with higher risk of T2DM. C1 [Bao, Wei; Li, Shanshan; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. [Chavarro, Jorge E.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chavarro, Jorge E.; Tobias, Deirdre K.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chavarro, Jorge E.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Tobias, Deirdre K.] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Tobias, Deirdre K.] Harvard Univ, Sch Med, Boston, MA USA. [Bowers, Katherine] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Biostat & Epidemiol, Cincinnati, OH 45229 USA. RP Zhang, CL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, NIH, Rockville, MD USA. EM zhangcu@mail.nih.gov OI Bao, Wei/0000-0002-7301-5786 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH [HHSN275201000020C]; NIH [DK58845, CA50385, P30 DK46200, UM1 CA176726, 1K01DK103720-01]; American Diabetes Association [7-12-MN-34] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (contract HHSN275201000020C). The Nurses' Health Study II was funded by research grants DK58845, CA50385, P30 DK46200, and UM1 CA176726 from the NIH. DKT was supported by a mentored fellowship from the American Diabetes Association (7-12-MN-34) and a training grant from the NIH (1K01DK103720-01). NR 52 TC 1 Z9 1 U1 4 U2 9 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2016 VL 103 IS 2 BP 375 EP 381 DI 10.3945/ajcn.115.108712 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC8JJ UT WOS:000369465400012 PM 26762369 ER PT J AU Ma, YY Follis, JL Smith, CE Tanaka, T Manichaikul, AW Chu, AY Samieri, C Zhou, X Guan, WH Wang, L Biggs, ML Chen, YDI Hernandez, DG Borecki, I Chasman, DI Rich, SS Ferrucci, L Irvin, MR Aslibekyan, S Zhi, DG Tiwari, HK Claas, SA Sha, J Kabagambe, EK Lai, CQ Parnell, LD Lee, YC Amouyel, P Lambert, JC Psaty, BM King, IB Mozaffarian, D McKnight, B Bandinelli, S Tsai, MY Ridker, PM Ding, JZ Mstat, KL Liu, YM Sotoodehnia, N Barberger-Gateau, P Steffen, LM Siscovick, DS Absher, D Arnett, DK Ordovas, JM Lemaitre, RN AF Ma, Yiyi Follis, Jack L. Smith, Caren E. Tanaka, Toshiko Manichaikul, Ani W. Chu, Audrey Y. Samieri, Cecilia Zhou, Xia Guan, Weihua Wang, Lu Biggs, Mary L. Chen, Yii-Der I. Hernandez, Dena G. Borecki, Ingrid Chasman, Daniel I. Rich, Stephen S. Ferrucci, Luigi Irvin, Marguerite Ryan Aslibekyan, Stella Zhi, Degui Tiwari, Hemant K. Claas, Steven A. Sha, Jin Kabagambe, Edmond K. Lai, Chao-Qiang Parnell, Laurence D. Lee, Yu-Chi Amouyel, Philippe Lambert, Jean-Charles Psaty, Bruce M. King, Irena B. Mozaffarian, Dariush McKnight, Barbara Bandinelli, Stefania Tsai, Michael Y. Ridker, Paul M. Ding, Jingzhong Mstat, Kurt Lohmant Liu, Yongmei Sotoodehnia, Nona Barberger-Gateau, Pascale Steffen, Lyn M. Siscovick, David S. Absher, Devin Arnett, Donna K. Ordovas, Jose M. Lemaitre, Rozenn N. TI Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE DNA methylation; epidemiology; fatty acids; genetic variants; plasma lipids ID CORONARY-ARTERY-DISEASE; DNA METHYLATION; WIDE ASSOCIATION; TANGIER-DISEASE; CARDIOVASCULAR-DISEASE; LOWERING DRUGS; DIET NETWORK; BLOOD-LIPIDS; SINGLE CPG; LOCI AB Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (beta =-0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (beta = 3.87 mg/dL, P = 5.62 X 1021). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (beta = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (beta = 8.84%, P = 3.51 x 10(18)) and lower circulating EPA (p =-1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 =-2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r =-0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r =-0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation. C1 [Ma, Yiyi] Boston Univ, Dept Med, Biomed Genet, Boston, MA 02215 USA. [Ma, Yiyi; Smith, Caren E.; Lai, Chao-Qiang; Parnell, Laurence D.; Lee, Yu-Chi; Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Mozaffarian, Dariush] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Follis, Jack L.] Univ St Thomas, Dept Math Comp Sci & Cooperat Engn, Houston, TX 77006 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Bethesda, MD 20892 USA. [Hernandez, Dena G.] NIA, Lab Neurogenet, Bethesda, MD 20892 USA. [Manichaikul, Ani W.; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Chu, Audrey Y.; Wang, Lu; Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Samieri, Cecilia; Barberger-Gateau, Pascale] Univ Bordeaux, INSERM, U897, Bordeaux, France. [Samieri, Cecilia; Barberger-Gateau, Pascale] Univ Bordeaux, ISPED, Bordeaux, France. [Zhou, Xia; Steffen, Lyn M.] Univ Minnesota, Div Epidemiol & Community Hlth, Sch Publ Hlth, Minneapolis, MN USA. [Guan, Weihua] Univ Minnesota, Div Biostat, Sch Publ Hlth, Minneapolis, MN USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN USA. [Biggs, Mary L.; McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Biggs, Mary L.; Psaty, Bruce M.; McKnight, Barbara; Sotoodehnia, Nona; Lemaitre, Rozenn N.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Chen, Yii-Der I.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Chen, Yii-Der I.] Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Inst, Torrance, CA USA. [Borecki, Ingrid] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Irvin, Marguerite Ryan; Aslibekyan, Stella; Claas, Steven A.; Sha, Jin; Arnett, Donna K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Zhi, Degui; Tiwari, Hemant K.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Kabagambe, Edmond K.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Amouyel, Philippe; Lambert, Jean-Charles] INSERM, UMER1167, F-59045 Lille, France. [Amouyel, Philippe; Lambert, Jean-Charles] Univ Lille, Lille, France. [Amouyel, Philippe; Lambert, Jean-Charles] Inst Pasteur, Lille, France. [Amouyel, Philippe] Reg Univ Hosp Lille, Lille, France. [King, Irena B.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Mstat, Kurt Lohmant; Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol & Prevent Publ Hlth Sci, Winston Salem, NC USA. [Siscovick, David S.] New York Acad Med, New York, NY USA. [Absher, Devin] Hudson Alpha Inst Biotechnol, Huntsville, AL USA. [Ordovas, Jose M.] Cardiovasc Res Ctr, Dept Epidemiol & Populat Genet, Madrid, Spain. [Ordovas, Jose M.] IMDEA Food Inst, Madrid, Spain. RP Ma, YY (reprint author), Boston Univ, Dept Med, Biomed Genet, Boston, MA 02215 USA. EM yiyima@bu.edu RI Lambert, jean-charles/A-9553-2014; Samieri, Cecilia/E-3334-2014; OI Lambert, jean-charles/0000-0003-0829-7817; Samieri, Cecilia/0000-0001-9809-7506; Claas, Steven/0000-0001-9789-8395 FU NIH through the American Recovery and Reinvestment Act [5RC2HL102419]; National Heart, Lung, and Blood Institute (NHLBI) [U01HL07252A-04, 5R01HL1043135-04]; National Institute of Neurological Disorders and Stroke [T32NS054584]; NHLBI [HL092111, HL111089, HL116747, 1R01HL101250-01]; Laughlin Family; Alpha Phi Foundation; Locke Charitable Foundation FX Supported by the NIH through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419; to the "Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium"). The methylation analysis in the Genetics of Lipid Lowering Drugs and Diet Network was funded by the National Heart, Lung, and Blood Institute (NHLBI) (grants U01HL07252A-04 and 5R01HL1043135-04) and by the National Institute of Neurological Disorders and Stroke (grant T32NS054584). Methylation in the Cardiovascular Health Study was funded by the NHLBI (grants HL092111, HL111089, and HL116747) and by the Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. The methylation analysis the in Multi-Ethnic Study of Atherosclerosis was supported by the NHLBI (grant 1R01HL101250-01; to Wake Forest University Health Sciences). Study-specific sources of support and acknowledgments are listed in Supplemental Methods. NR 49 TC 0 Z9 0 U1 3 U2 8 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2016 VL 103 IS 2 BP 567 EP 578 DI 10.3945/ajcn.115.112987 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA DC8JJ UT WOS:000369465400033 PM 26791180 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Vaginal progesterone to prevent preterm birth in pregnant women with a sonographic short cervix: clinical and public health implications SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE biomarker; cervical length; cost-effectiveness; neonatal morbidity; pregnancy; prematurity; prevention; screening; singleton gestation; twin gestation; ultrasound ID PLACEBO-CONTROLLED TRIAL; COST-EFFECTIVENESS; DOUBLE-BLIND; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; TWIN GESTATIONS; UTERINE CERVIX; HIGH-RISK; LENGTH; DELIVERY; METAANALYSIS AB Vaginal progesterone administration to women with a sonographic short cervix is an efficacious and safe intervention used to prevent preterm birth and neonatal morbidity and mortality. The clinical and public health implications of this approach in the United States have been critically appraised and compared to other therapeutic interventions in obstetrics. Vaginal progesterone administration to women with a transvaginal sonographic cervical length (CL) <= 25 mm before 25 weeks of gestation is associated with a significant and substantial reduction of the risk for preterm birth from< 28 to< 35 weeks of gestation, respiratory distress syndrome, composite neonatal morbidity and mortality, admission to the neonatal intensive care unit, and mechanical ventilation. These beneficial effects have been achieved in women with a singleton gestation, with or without a history of spontaneous preterm birth, and did not differ significantly as a function of CL (< 10 mm, 10-20 mm, or 21-25 mm). The number of patients required for treatment to prevent 1 case of preterm birth or adverse neonatal outcomes ranges from 10-19 women. The number needed to screen for the prevention of 1 case of preterm birth before 34 weeks of gestation is 125 women, and 225 for the prevention of 1 case of major neonatal morbidity or neonatal mortality. Several cost-effectiveness and decision analyses have shown that the combination of universal transvaginal CL screening and vaginal progesterone administration to women with a short cervix is a cost-effective intervention that prevents preterm birth and associated perinatal morbidity and mortality. Universal assessment of CL and treatment with vaginal progesterone for singleton gestations in the United States would result in an annual reduction of approximately 30,000 preterm births before 34 weeks of gestation and of 17,500 cases of major neonatal morbidity or neonatal mortality. In summary, there is compelling evidence to recommend universal transvaginal CL screening at 18-24 weeks of gestation in women with a singleton gestation and to offer vaginal progesterone to those with a CL <= 25 mm, regardless of the history of spontaneous preterm birth, with the goal of preventing preterm birth and neonatal morbidity and mortality. C1 [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. [Conde-Agudelo, Agustin; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Detroit, MI USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD USA. EM romeror@mail.nih.gov FU Intramural NIH HHS NR 81 TC 8 Z9 8 U1 2 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2016 VL 214 IS 2 BP 235 EP 242 DI 10.1016/j.ajog.2015.09.102 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC9CJ UT WOS:000369518200010 PM 26450404 ER PT J AU Laurent, BS Cooke, M Krishnankutty, SM Asih, P Mueller, JD Kahindi, S Ayoma, E Oriango, RM Thumloup, J Drakeley, C Cox, J Collins, FH Lobo, NF Stevenson, JC AF Laurent, Brandyce St. Cooke, Mary Krishnankutty, Sindhu M. Asih, Puji Mueller, John D. Kahindi, Samuel Ayoma, Elizabeth Oriango, Robin M. Thumloup, Julie Drakeley, Chris Cox, Jonathan Collins, Frank H. Lobo, Neil F. Stevenson, Jennifer C. TI Molecular Characterization Reveals Diverse and Unknown Malaria Vectors in the Western Kenyan Highlands SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID POLYMERASE-CHAIN-REACTION; ANOPHELES-GAMBIAE COMPLEX; INSECTICIDE-TREATED NETS; PLASMODIUM-FALCIPARUM; SPATIAL-DISTRIBUTION; BITING BEHAVIOR; BED NETS; TRANSMISSION; ARABIENSIS; IDENTIFICATION AB The success of mosquito-based malaria control is dependent upon susceptible bionomic traits in local malaria vectors. It is crucial to have accurate and reliable methods to determine mosquito species composition in areas subject to malaria. An unexpectedly diverse set of Anopheles species was collected in the western Kenyan highlands, including unidentified and potentially new species carrying the malaria parasite Plasmodium falciparum. This study identified 2,340 anopheline specimens using both ribosomal DNA internal transcribed spacer region 2 and mitochondrial DNA cytochrome oxidase subunit 1 loci. Seventeen distinct sequence groups were identified. Of these, only eight could be molecularly identified through comparison to published and voucher sequences. Of the unidentified species, four were found to carry P. falciparum by circumsporozoite enzyme-linked immunosorbent assay and polymerase chain reaction, the most abundant of which had infection rates comparable to a primary vector in the area, Anopheles funestus. High-quality adult specimens of these unidentified species could not be matched to museum voucher specimens or conclusively identified using multiple keys, suggesting that they may have not been previously described. These unidentified vectors were captured outdoors. Diverse and unknown species have been incriminated in malaria transmission in the western Kenya highlands using molecular identification of unusual morphological variants of field specimens. This study demonstrates the value of using molecular methods to compliment vector identifications and highlights the need for accurate characterization of mosquito species and their associated behaviors for effective malaria control. C1 Univ Notre Dame, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England. Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Ctr Dis Control & Prevent, Kisumu, Kenya. Montana State Univ, Western Triangle Res Ctr, Conrad, MT USA. Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Malaria Res Inst, Baltimore, MD USA. RP Laurent, BS (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM brandyce.stlaurent@nih.gov OI St. Laurent, Brandyce/0000-0002-2957-5364 FU Bill & Melinda Gates Foundation under the Malaria Transmission Consortium grant [45114] FX This project was funded by the Bill & Melinda Gates Foundation under the Malaria Transmission Consortium grant no. 45114. This article has been approved by the Director of the Kenya Medical Research Institute. NR 59 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2016 VL 94 IS 2 BP 327 EP 335 DI 10.4269/ajtmh.15-0562 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA DC8JK UT WOS:000369465500014 ER PT J AU Vu, H Shulenin, S Grolla, A Audet, J He, SH Kobinger, G Unfer, RC Warfield, KL Aman, MJ Holtsberg, FW AF Vu, Hong Shulenin, Sergey Grolla, Allen Audet, Jonathan He, Shihua Kobinger, Gary Unfer, Robert C. Warfield, Kelly L. Aman, M. Javad Holtsberg, Frederick W. TI Quantitative serology assays for determination of antibody responses to Ebola virus glycoprotein and matrix protein in nonhuman primates and humans SO ANTIVIRAL RESEARCH LA English DT Article DE Ebola virus; Serology ELISA; Antibodies; Vaccine; Human; Nonhuman primate ID ZAIRE-EBOLAVIRUS; PARTICLES; MARBURG; VACCINES; IMMUNITY AB The West Africa Ebola virus disease (EVD) outbreak has reached unprecedented magnitude and caused worldwide concerns for the spread of this deadly virus. Recent findings in nonhuman primates (NHPs) demonstrate that antibodies can be protective against EVD. However, the role of antibody response in vaccine-mediated protection is not fully understood. To address these questions quantitative serology assays are needed for measurement of the antibody response to key Ebola virus (EBOV) proteins. Serology enzyme-linked immunosorbent assays (ELISA's), using a reference detection antibody, were developed in order to standardize the quantitation of antibody levels in vaccinated NHPs or in humans exposed to EBOV or immunized with an EBOV vaccine. Critical reagents were generated to support the development of the serology ELISAs. Recombinant EBOV matrix protein (VP40) was expressed in Escherichia coli and purified. Two variants of the glycoprotein (GP), the ectodomain lacking the trans membrane domain (GP Delta TM), and an engineered GP lacking the mucin-like domain (GP Delta muc) were expressed and purified from mammalian cell systems. Using these proteins, three ELISA methods were developed and optimized for reproducibility and robustness, including stability testing of critical reagents. The assay was used to determine the antibody response against VP40, GP Delta TM, and GP Delta muc in a NHP vaccine study using EBOV virus-like particles (VLP) vaccine expressing GP, VP40 and the nucleoprotein. Additionally, these ELISAs were used to successfully detect antibody responses to VP40, GP Delta TM and GP Delta muc in human sera from EBOV infected individuals. (C) 2015 Elsevier B.V. All rights reserved. C1 [Vu, Hong; Shulenin, Sergey; Unfer, Robert C.; Warfield, Kelly L.; Aman, M. Javad; Holtsberg, Frederick W.] Integrated BioTherapeut Inc, Gaithersburg, MD 20878 USA. [Grolla, Allen; Audet, Jonathan; He, Shihua; Kobinger, Gary] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Unfer, Robert C.] NIAID, AIDS Res Review Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Warfield, Kelly L.] Unither Virol LLC, Silver Spring, MD 20910 USA. RP Holtsberg, FW (reprint author), Integrated BioTherapeut Inc, Gaithersburg, MD 20878 USA. EM rick@integratedbiotherapeutics.com OI Audet, Jonathan/0000-0002-0743-7489 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800055C] FX This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800055C to MJA (IBT). The authors would like to thank R. Namdar for her technical assistance. NR 17 TC 1 Z9 1 U1 2 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2016 VL 126 BP 55 EP 61 DI 10.1016/j.antiviral.2015.11.012 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DD1KG UT WOS:000369680000007 PM 26681387 ER PT J AU Westover, JB Sefing, EJ Bailey, KW Van Wettere, AJ Jung, KH Dagley, A Wandersee, L Downs, B Smee, DF Furuta, Y Bray, M Gowen, BB AF Westover, Jonna B. Sefing, Eric J. Bailey, Kevin W. Van Wettere, Arnaud J. Jung, Kie-Hoon Dagley, Ashley Wandersee, Luci Downs, Brittney Smee, Donald F. Furuta, Yousuke Bray, Mike Gowen, Brian B. TI Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses SO ANTIVIRAL RESEARCH LA English DT Article DE Favipiravir; Ribavirin; Junin virus; Arenavirus; Viral hemorrhagic fever ID HANTAVIRUS PULMONARY SYNDROME; T-705 FAVIPIRAVIR; INFLUENZA-VIRUS; MOUSE MODEL; EFFICACY; INFECTION; DISEASE; ARENAVIRUS; TOLERANCE; THERAPY AB Favipiravir is approved in Japan to treat novel or re-emerging influenza viruses, and is active against a broad spectrum of RNA viruses, including Ebola. Ribavirin is the only other licensed drug with activity against multiple RNA viruses. Recent studies show that ribavirin and favipiravir act synergistically to inhibit bunyavirus infections in cultured cells and laboratory mice, likely due to their different mechanisms of action. Convalescent immune globulin is the only approved treatment for Argentine hemorrhagic fever caused by the rodent-borne Junin arenavirus. We previously reported that favipiravir is highly effective in a number of small animal models of Argentine hemorrhagic fever. We now report that addition of low dose of ribavirin synergistically potentiates the activity of favipiravir against Junin virus infection of guinea pigs and another arenavirus, Pichinde virus infection of hamsters. This suggests that the efficacy of favipiravir against hemorrhagic fever viruses can be further enhanced through the addition of low-dose ribavirin. (C) 2015 Elsevier B.V. All rights reserved. C1 [Westover, Jonna B.; Sefing, Eric J.; Bailey, Kevin W.; Van Wettere, Arnaud J.; Jung, Kie-Hoon; Dagley, Ashley; Wandersee, Luci; Downs, Brittney; Smee, Donald F.; Gowen, Brian B.] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA. [Van Wettere, Arnaud J.] Utah Vet Diagnost Lab, Logan, UT USA. [Furuta, Yousuke] Toyama Chem Co Ltd, Res Labs, Toyama, Japan. [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD USA. RP Gowen, BB (reprint author), 5600 Old Main Hill, Logan, UT 84322 USA. EM brian.gowen@usu.edu FU National Institute of Allergy and Infectious Diseases at the National Institutes of Health [U54 AI-065357, HHSN272201000039I] FX This work was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [U54 AI-065357 and HHSN272201000039I]. NR 23 TC 2 Z9 2 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2016 VL 126 BP 62 EP 68 DI 10.1016/j.antiviral.2015.12.006 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DD1KG UT WOS:000369680000008 PM 26711718 ER PT J AU Feelixge, HSD Stone, D Pietz, HL Roychoudhury, P Greninger, AL Schiffer, JT Aubert, M Jerome, KR AF Feelixge, Harshana S. De Silva Stone, Daniel Pietz, Harlan L. Roychoudhury, Pavitra Greninger, Alex L. Schiffer, Joshua T. Aubert, Martine Jerome, Keith R. TI Detection of treatment-resistant infectious HIV after genome-directed antiviral endonuclease therapy SO ANTIVIRAL RESEARCH LA English DT Article DE Zinc finger nuclease; Endonuclease; Resistance; Reverse transcriptase ID HEPATITIS-B-VIRUS; ZINC-FINGER-NUCLEASES; CERVICAL-CANCER CELLS; RNA-GUIDED ENDONUCLEASE; HUMAN T-CELLS; HUMAN-PAPILLOMAVIRUS; CRISPR/CAS9 SYSTEM; PROVIRAL DNA; DRUG-RESISTANCE; IN-VITRO AB Incurable chronic viral infections are a major cause of morbidity and mortality worldwide. One potential approach to cure persistent viral infections is via the use of targeted endonucleases. Nevertheless, a potential concern for endonuclease-based antiviral therapies is the emergence of treatment resistance. Here we detect for the first time an endonuclease-resistant infectious virus that is found with high frequency after antiviral endonuclease therapy. While testing the activity of HIV pol-specific zinc finger nucleases (ZFNs) alone or in combination with three prime repair exonuclease 2 (Trex2), we identified a treatment-resistant and infectious mutant virus that was derived from a ZFN-mediated disruption of reverse transcriptase (RT). Although gene disruption of HIV protease, RT and integrase could inhibit viral replication, a chance single amino acid insertion within the thumb domain of RT produced a virus that could actively replicate. The endonuclease-resistant virus could replicate in primary CD4(+) T cells, but remained susceptible to treatment with antiretroviral RT inhibitors. When secondary ZFN-derived mutations were introduced into the mutant virus's RT or integrase domains, replication could be abolished. Our observations suggest that caution should be exercised during endonuclease-based antiviral therapies; however, combination endonuclease therapies may prevent the emergence of resistance. (C) 2015 Elsevier B.V. All rights reserved. C1 [Feelixge, Harshana S. De Silva; Stone, Daniel; Pietz, Harlan L.; Roychoudhury, Pavitra; Schiffer, Joshua T.; Aubert, Martine; Jerome, Keith R.] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Greninger, Alex L.; Jerome, Keith R.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Pietz, Harlan L.; Jerome, Keith R.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Pietz, Harlan L.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Schiffer, Joshua T.] Univ Washington, Dept Med, Seattle, WA USA. [Pietz, Harlan L.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Jerome, KR (reprint author), Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. EM hdesilva@fredhutch.org; dstone2@fredhutch.org; harlan.pietz@nih.gov; proychou@fredhutch.org; agrening@uw.edu; jschiffe@fredhutch.org; maubert@fredhutch.org; kjerome@fredhutch.org OI Stone, Daniel/0000-0003-1619-7541 FU NIH [U19 AI 096111]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIAID) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NCI) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIMH) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIDA) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NICHD) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NHLBI) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIA) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIGMS) [P30 AI 027757]; University of Washington Center for AIDS Research (CFAR), an NIH under (NIDDK) [P30 AI 027757] FX This work was funded by NIH supported Martin Delaney Col laboratory grant U19 AI 096111 and in part by a developmental grant from the University of Washington Center for AIDS Research (CFAR), an NIH funded program under award number P30 AI 027757 which is supported by the following NIH Institutes and Centers (NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK). HLP was supported by a Research Scholarship from the Mary Gates Endowment for Students. NR 58 TC 9 Z9 9 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 EI 1872-9096 J9 ANTIVIR RES JI Antiviral Res. PD FEB PY 2016 VL 126 BP 90 EP 98 DI 10.1016/j.antiviral.2015.12.007 PG 9 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA DD1KG UT WOS:000369680000011 ER PT J AU Shearrer, GE O'Reilly, GA Belcher, BR Daniels, MJ Goran, MI Spruijt-Metz, D Davis, JN AF Shearrer, Grace E. O'Reilly, Gillian A. Belcher, Britini R. Daniels, Michael J. Goran, Michael I. Spruijt-Metz, Donna Davis, Jaimie N. TI The impact of sugar sweetened beverage intake on hunger and satiety in minority adolescents SO APPETITE LA English DT Article DE Satiety; Fullness; Ghrelin; Sugar sweetened beverage; Minority youth ID FRUCTOSE CORN SYRUP; FOOD-INTAKE; PHYSICAL-ACTIVITY; ENERGY-INTAKE; GHRELIN LEVELS; HUMAN OBESITY; CONSUMPTION; WEIGHT; FIBER; RESISTANCE AB Limited research has examined the effects of habitual SSB consumption on hunger/fullness ratings and gut hormones. This study hypothesized that high versus low intakes of habitual SSBs would result in greater hunger, decreased fullness, and a blunted gut hormone response, however the high versus low fiber group would exhibit decreased hunger and increased fullness. This was a randomized crossover feeding trial with 47 African American and Hispanic adolescents. The experiment included three 24-hour recalls to assess habitual dietary intake. During the test meal phase, subjects were served breakfast and lunch. During the ad libitum meal phase, subjects were fed an ad libitum dinner. During the test meal phase, blood was drawn every 30 minutes for 3 hours. During the ad libitum meal phase, hunger and fullness visual analogue scales were completed. For this analysis, subjects were grouped into the following habitual SSB categories: low SSB (<= 1 SSB serv/day), medium SSB (>1 - <2 serv/day), and high SSB (>= 2 sery/day). Fiber categories were created based on quartiles of intake. Mixed modeling was used to explore how SSB and fiber categories predicted ghrelin/PYY values and hunger/fullness ratings across time within and between test meals. The following a priori covariates included: sex, ethnicity, age, and obesity status. The low SSB group had higher fullness ratings over the ad libitum meal compared to the high SSB group (beta =-0.49, CI=(-0.89, -0.08), p=0.02) and higher ghrelin concentrations than the medium and high SSB group over the test meal phase (beta =-1.86, CI=(-2.81, -0.92), p<0.01). Habitual SSB intake appears to play a key role in moderating fullness responses possibly via ghrelin. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Shearrer, Grace E.; Davis, Jaimie N.] Univ Texas Austin, Dept Nutr, Austin, TX 78712 USA. [O'Reilly, Gillian A.; Spruijt-Metz, Donna] Univ So Calif, Ctr Econ & Social Res, Los Angeles, CA 90089 USA. [Belcher, Britini R.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Daniels, Michael J.] Univ Texas Austin, Dept Stat & Computat, Austin, TX 78712 USA. [Goran, Michael I.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Inst Prevent Res, Los Angeles, CA 90033 USA. RP Davis, JN (reprint author), Univ Texas Austin, Dept Nutr Sci, 103 West 24th St,A2703,TS Painter Hall,Room 3-24, Austin, TX 78712 USA. EM jaimie.davis@austin.utexas.edu FU National Institute for Minority Health and Health Disparities (NIMHD) as part of the USC Minority Health Center of Excellence [NCHMD P60 MD002254]; National Institutes of Cancer (NCI), NCI Centers for Transdisciplinary Research on Energetics and Cancer (TREC) as part of the USC Center for Transdisciplinary Research on Energetics and Cancer [U54 CA 116848] FX This work was supported by the National Institute for Minority Health and Health Disparities (NIMHD) as part of the USC Minority Health Center of Excellence (NCHMD P60 MD002254) and the National Institutes of Cancer (NCI), NCI Centers for Transdisciplinary Research on Energetics and Cancer (TREC, U54 CA 116848) as part of the USC Center for Transdisciplinary Research on Energetics and Cancer. NR 37 TC 1 Z9 1 U1 5 U2 23 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD FEB 1 PY 2016 VL 97 BP 43 EP 48 DI 10.1016/j.appet.2015.11.015 PG 6 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA DC4TQ UT WOS:000369213600006 PM 26606887 ER PT J AU Stewart, PE Carroll, JA Olano, LR Sturdevant, DE Rosa, PA AF Stewart, Philip E. Carroll, James A. Olano, L. Rennee Sturdevant, Daniel E. Rosa, Patricia A. TI Multiple Posttranslational Modifications of Leptospira biflexa Proteins as Revealed by Proteomic Analysis SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID INTERROGANS SEROVAR LAI; LYME-DISEASE SPIROCHETE; BORRELIA-BURGDORFERI; OUTER-MEMBRANE; RICKETTSIA-PROWAZEKII; BACTERIAL CHEMOTAXIS; ESCHERICHIA-COLI; GENE-EXPRESSION; VIRULENCE; GENOME AB The saprophyte Leptospira biflexa is an excellent model for studying the physiology of the medically important Leptospira genus, the pathogenic members of which are more recalcitrant to genetic manipulation and have significantly slower in vitro growth. However, relatively little is known regarding the proteome of L. biflexa, limiting its utility as a model for some studies. Therefore, we have generated a proteomic map of both soluble and membrane-associated proteins of L. biflexa during exponential growth and in stationary phase. Using these data, we identified abundantly produced proteins in each cellular fraction and quantified the transcript levels from a subset of these genes using quantitative reverse transcription-PCR (RT-PCR). These proteins should prove useful as cellular markers and as controls for gene expression studies. We also observed a significant number of L. biflexa membrane-associated proteins with multiple isoforms, each having unique isoelectric focusing points. L. biflexa cell lysates were examined for several posttranslational modifications suggested by the protein patterns. Methylation and acetylation of lysine residues were predominately observed in the proteins of the membrane-associated fraction, while phosphorylation was detected mainly among soluble proteins. These three posttranslational modification systems appear to be conserved between the free-living species L. biflexa and the pathogenic species Leptospira interrogans, suggesting an important physiological advantage despite the varied life cycles of the different species. C1 [Stewart, Philip E.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. [Carroll, James A.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Sturdevant, Daniel E.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. [Olano, L. Rennee] NIAID, Res Technol Branch, NIH, Twinbrook Facil, Rockville, MD USA. RP Stewart, PE (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. EM pestewart@niaid.nih.gov FU Intramural Research Program of the NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 63 TC 0 Z9 0 U1 5 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 EI 1098-5336 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 2016 VL 82 IS 4 BP 1183 EP 1195 DI 10.1128/AEM.03056-15 PG 13 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA DC7CJ UT WOS:000369375900021 ER PT J AU Johnson, KC Aragaki, AK Jackson, R Reiner, A Sandset, PM Rosing, J Dahm, AEA Rosendaal, F Manson, JE Martin, LW Liu, SM Kuller, LH Cushman, M Rossouw, JE AF Johnson, Karen C. Aragaki, Aaron K. Jackson, Rebecca Reiner, Alex Sandset, Per Morten Rosing, Jan Dahm, Anders E. A. Rosendaal, Frits Manson, JoAnn E. Martin, Lisa W. Liu, Simin Kuller, Lewis H. Cushman, Mary Rossouw, Jacques E. TI Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Coronary Heart Disease Due To Combined Estrogen Plus Progestin Therapy SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE activated protein C resistance; coronary disease; estrogens; hemostatics; progestins; tissue factor pathway inhibitor activity ID HORMONE REPLACEMENT THERAPY; HEALTHY POSTMENOPAUSAL WOMEN; FACTOR-V-LEIDEN; VENOUS THROMBOSIS; MYOCARDIAL-INFARCTION; PLASMINOGEN-ACTIVATOR; ORAL-CONTRACEPTIVES; CONTROLLED TRIAL; ISCHEMIC-STROKE; DOUBLE-BLIND AB Objective To examine whether tissue factor pathway inhibitor or acquired activated protein C (APC) resistance influences the increased risk of coronary heart disease (CHD) due to estrogen plus progestin therapy. Approach and Results Prospective nested case-control study of 205 cases of CHD and 481 matched controls in the Women's Health Initiative randomized trial of estrogen plus progestin therapy. After multivariable covariate adjustment, both baseline tissue factor pathway activity (P=0.01) and APC resistance (P=0.004) were associated positively with CHD risk. Baseline tissue factor pathway activity and APC resistance singly or jointly did not significantly modify the effect of estrogen plus progestin on CHD risk. Compared with placebo, estrogen plus progestin decreased tissue factor pathway inhibitor activity and increased APC resistance but these changes did not seem to modify or mediate the effect of estrogen plus progestin on CHD risk. Conclusions Tissue factor pathway inhibitor activity and APC resistance are related to CHD risk in women, but may not explain the increased CHD risk due to estrogen plus progestin therapy. The data from this study do not support the clinical use of measuring these hemostatic factors to help stratify risk before hormone therapy. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611. C1 [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, 66 N Pauline,Suite 633, Memphis, TN 38163 USA. [Aragaki, Aaron K.; Reiner, Alex] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Jackson, Rebecca] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Sandset, Per Morten; Dahm, Anders E. A.] Oslo Univ Hosp, Oslo, Norway. [Sandset, Per Morten; Dahm, Anders E. A.] Univ Oslo, Oslo, Norway. [Rosing, Jan] Maastrich Univ, Maastricht, Netherlands. [Rosendaal, Frits] Leiden Univ, Leiden, Netherlands. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. [Martin, Lisa W.] George Washington Univ, Washington, DC USA. [Liu, Simin] Brown Univ, Providence, RI 02912 USA. [Kuller, Lewis H.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Cushman, Mary] Univ Vermont, Burlington, VT USA. [Rossouw, Jacques E.] NHLBI, Bldg 10, Bethesda, MD 20892 USA. RP Johnson, KC (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, 66 N Pauline,Suite 633, Memphis, TN 38163 USA. EM kjohnson@uthsc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health, and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health, and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 31 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2016 VL 36 IS 2 BP 418 EP 424 DI 10.1161/ATVBAHA.115.306905 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DC8PX UT WOS:000369483200028 PM 26681757 ER PT J AU Szymczak, S Holzinger, E Dasgupta, A Malley, JD Molloy, AM Mills, JL Brody, LC Stambolian, D Bailey-Wilson, JE AF Szymczak, Silke Holzinger, Emily Dasgupta, Abhijit Malley, James D. Molloy, Anne M. Mills, James L. Brody, Lawrence C. Stambolian, Dwight Bailey-Wilson, Joan E. TI r2VIM: A new variable selection method for random forests in genome-wide association studies SO BIODATA MINING LA English DT Article DE Machine learning; Random forest; Variable selection; Variable importance; Genome-wide association study; Genetic; SNP ID PREDICTOR CORRELATION; REGRESSION TREES; REFRACTIVE ERROR; BILIRUBIN LEVELS; EYE DISEASE; METAANALYSIS; TRAITS; AREDS; PLINK AB Background: Machine learning methods and in particular random forests (RFs) are a promising alternative to standard single SNP analyses in genome-wide association studies (GWAS). RFs provide variable importance measures (VIMs) to rank SNPs according to their predictive power. However, in contrast to the established genome-wide significance threshold, no clear criteria exist to determine how many SNPs should be selected for downstream analyses. Results: We propose a new variable selection approach, recurrent relative variable importance measure (r2VIM). Importance values are calculated relative to an observed minimal importance score for several runs of RF and only SNPs with large relative VIMs in all of the runs are selected as important. Evaluations on simulated GWAS data show that the new method controls the number of false-positives under the null hypothesis. Under a simple alternative hypothesis with several independent main effects it is only slightly less powerful than logistic regression. In an experimental GWAS data set, the same strong signal is identified while the approach selects none of the SNPs in an underpowered GWAS. Conclusions: The novel variable selection method r2VIM is a promising extension to standard RF for objectively selecting relevant SNPs in GWAS while controlling the number of false-positive results. C1 [Szymczak, Silke; Holzinger, Emily; Bailey-Wilson, Joan E.] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. [Dasgupta, Abhijit] NIAMSD, Clin Trials & Outcomes Branch, NIH, 1 AMS Circle, Bethesda, MD 20892 USA. [Malley, James D.] NIH, Div Computat Biosci, Ctr Informat Technol, 12 South Dr, Bethesda, MD 20892 USA. [Molloy, Anne M.] Trinity Coll Dublin, Dept Clin Med, Sch Med, 152-160 Pearse St, Dublin 2, Ireland. [Mills, James L.] Eunice Shriver Natl Inst Child Hlth & Human Dev, Div Intramural Populat Hlth Res, NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. [Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Med Genom & Metab Genet Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, 422 Curie Blvd, Philadelphia, PA 19104 USA. [Szymczak, Silke] Univ Kiel, Inst Med Informat & Stat, Brunswiker Str 10, D-24105 Kiel, Germany. RP Szymczak, S (reprint author), NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA.; Szymczak, S (reprint author), Univ Kiel, Inst Med Informat & Stat, Brunswiker Str 10, D-24105 Kiel, Germany. EM szymczak@medinfo.uni-kiel.de FU National Human Genome Research Institute (NIH); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH); Center for Information Technology (NIH); National Institute of Child Health and Human Development grant [N01HD33348]; National Eye Institute grant [RO1EY020483]; Intramural Research Programs of the National Human Genome Research Institute; Eunice Shriver National Institute of Child Health and Development of the National Institutes of Health (NIH); Health Research Board, Dublin, Ireland FX This work was supported by the Intramural Research Programs of the National Human Genome Research Institute (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH) and Center for Information Technology (NIH) and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://hpc.nih.gov). AMM was funded by National Institute of Child Health and Human Development grant N01HD33348 and DS was funded by National Eye Institute grant RO1EY020483. The authors acknowledge the contributions made by the study participants in the Trinity Student Study (TSS). The TSS GWAS work was supported in part by the Intramural Research Programs of the National Human Genome Research Institute, the Eunice Shriver National Institute of Child Health and Development of the National Institutes of Health (NIH) and the Health Research Board, Dublin, Ireland. NR 39 TC 2 Z9 2 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-0381 J9 BIODATA MIN JI BioData Min. PD FEB 1 PY 2016 VL 9 AR 7 DI 10.1186/s13040-016-0087-3 PG 15 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA DD2XY UT WOS:000369786700001 PM 26839594 ER PT J AU Pasquini, MC Zhang, MJ Medeiros, BC Armand, P Hui, ZH Nishihori, T Aljurf, MD Akpek, G Cahn, JY Cairo, MS Cerny, J Copelan, EA Deol, A Freytes, CO Gale, RP Ganguly, S George, B Gupta, V Hale, GA Kamble, RT Klumpp, TR Lazarus, HM Luger, SM Liesveld, JL Litzow, MR Marks, DI Martino, R Norkin, M Olsson, RF Oran, B Pawarode, A Pulsipher, MA Ramanathan, M Reshef, R Saad, AA Saber, W Savani, BN Schouten, HC Ringden, O Tallman, MS Uy, GL Wood, WA Wirk, B Perez, WS Batiwalla, M Weisdorf, DJ AF Pasquini, Marcelo C. Zhang, Mei-Jie Medeiros, Bruno C. Armand, Philippe Hui, Zhen-Huan Nishihori, Taiga Aljurf, Mahmoud D. Akpek, Goerguen Cahn, Jean-Yves Cairo, Mitchell S. Cerny, Jan Copelan, Edward A. Deol, Abhinav Freytes, Cesar O. Gale, Robert Peter Ganguly, Siddhartha George, Biju Gupta, Vikas Hale, Gregory A. Kamble, Rammurti T. Klumpp, Thomas R. Lazarus, Hillard M. Luger, Selina M. Liesveld, Jane L. Litzow, Mark R. Marks, David I. Martino, Rodrigo Norkin, Maxim Olsson, Richard F. Oran, Betul Pawarode, Attaphol Pulsipher, Michael A. Ramanathan, Muthalagu Reshef, Ran Saad, Ayman A. Saber, Wael Savani, Bipin N. Schouten, Harry C. Ringden, Olle Tallman, Martin S. Uy, Geoffrey L. Wood, William A., Jr. Wirk, Baldeep Perez, Waleska S. Batiwalla, Minoo Weisdorf, Daniel J. TI Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Monosomal karyotype; Acute myeloid leukemia; Myelodysplastic syndrome; Allogeneic transplantation ID ACUTE MYELOGENOUS LEUKEMIA; MYELODYSPLASTIC SYNDROMES; REDUCED-INTENSITY; PROGNOSTIC VALUE; SCORING SYSTEM; ALLOGENEIC TRANSPLANTATION; CYTOGENETIC ABNORMALITIES; MARROW-TRANSPLANTATION; CONDITIONING REGIMEN; INTERNATIONAL BLOOD AB The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. (C) 2016 American Society for Blood and Marrow Transplantation. C1 [Pasquini, Marcelo C.; Zhang, Mei-Jie; Hui, Zhen-Huan; Saber, Wael; Perez, Waleska S.] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Medeiros, Bruno C.] Stanford Univ, Sch Med, Dept Hematol, Stanford, CA 94305 USA. [Armand, Philippe] Dana Farber Canc Inst, Dept Med Oncol Hematol Malignancies, Boston, MA 02115 USA. [Nishihori, Taiga] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh 11211, Saudi Arabia. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy Program, Gilbert, AZ USA. [Cahn, Jean-Yves] Univ Hosp, Dept Hematol, Grenoble, France. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Div Pediat Hematol Oncol & Stem Cell Transplantat, Valhalla, NY 10595 USA. [Cerny, Jan; Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Med, Worcester, MA USA. [Copelan, Edward A.] Carolinas HealthCare Syst, Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Charlotte, NC USA. [Deol, Abhinav] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Freytes, Cesar O.] S Texas Vet Hlth Care Syst, Div Hematol & Oncol, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Expt Med, Hematol Res Ctr, London, England. [Ganguly, Siddhartha] Univ Kansas, Med Ctr, Div Hematol & Oncol, Blood & Marrow Transplantat, Kansas City, KS 66103 USA. [George, Biju] Christian Med Coll & Hosp, Dept Haematol, Vellore, Tamil Nadu, India. [Gupta, Vikas] Univ Hlth Network, Princess Margaret Canc Ctr, Blood & Marrow Transplant Program, Toronto, ON, Canada. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL 33701 USA. [Kamble, Rammurti T.] Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA. [Klumpp, Thomas R.] Thomas Jefferson Univ Hosp, Dept Med Oncol, Philadelphia, PA 19107 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Luger, Selina M.; Reshef, Ran] Univ Penn, Med Ctr, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. [Liesveld, Jane L.] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Litzow, Mark R.] Mayo Clin, Div Hematol & Transplant Ctr, Rochester, MN USA. [Marks, David I.] Univ Hosp Bristol NHS Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England. [Martino, Rodrigo] Hosp Santa Creu & Sant Pau, Div Clin Hematol, Barcelona, Spain. [Norkin, Maxim] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Olsson, Richard F.; Ringden, Olle] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard F.] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Oran, Betul] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Div Canc Med, Houston, TX 77030 USA. [Pawarode, Attaphol] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Pulsipher, Michael A.] Univ So Calif, Keck Sch Med, Childrens Hosp Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA. [Saad, Ayman A.] Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA. [Savani, Bipin N.] Vanderbilt Univ, Dept Med, Div Hematol Oncol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Schouten, Harry C.] Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands. [Ringden, Olle] Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA. [Uy, Geoffrey L.] Washington Univ, Sch Med, Div Oncol, St Louis, MO USA. [Wood, William A., Jr.] Univ N Carolina, Dept Med, Div Hematol Oncol, Chapel Hill, NC USA. [Wirk, Baldeep] Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA. [Batiwalla, Minoo] NHLBI, NIH, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. [Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. RP Pasquini, MC (reprint author), 9200 W Wisconsin Ave, Milwaukee, WI 52336 USA. EM mpasquini@mcw.edu FU Public Health Service from the National Cancer Institute (NCI) [U24-CA076518]; Public Health Service from National Heart, Lung and Blood Institute (NHLBI) [U24-CA076518]; Public Health Service from National Institute of Allergy and Infectious Diseases (NIAID) [U24-CA076518]; NHLBI [5U10HL069294]; NCI [5U10HL069294]; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah; Wellpoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a grant/cooperative agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); 2 grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the United States Government. NR 44 TC 4 Z9 4 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2016 VL 22 IS 2 BP 248 EP 257 DI 10.1016/j.bbmt.2015.08.024 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA DC2JD UT WOS:000369042100010 PM 26327629 ER PT J AU Radin, RG Schisterman, EF AF Radin, R. G. Schisterman, E. F. TI Cardiovascular mortality in mothers following perinatal loss is a significant problem with an elusive cause SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Editorial Material C1 [Radin, R. G.; Schisterman, E. F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. RP Radin, RG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. OI Schisterman, Enrique/0000-0003-3757-641X 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 1470-0328 EI 1471-0528 J9 BJOG-INT J OBSTET GY JI BJOG PD FEB PY 2016 VL 123 IS 3 BP 399 EP 399 DI 10.1111/1471-0528.13320 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC1SV UT WOS:000368998000014 PM 25677248 ER PT J AU Colombo, RE Fiorentino, C Dodd, LE Hunsberger, S Haney, C Barrett, K Nabha, L Davey, RT Olivier, KN AF Colombo, Rhonda E. Fiorentino, Charles Dodd, Lori E. Hunsberger, Sally Haney, Carissa Barrett, Kevin Nabha, Linda Davey, Richard T., Jr. Olivier, Kenneth N. TI A phase 1 randomized, double-blind, placebo-controlled, crossover trial of DAS181 (Fludase (R)) in adult subjects with well-controlled asthma SO BMC INFECTIOUS DISEASES LA English DT Article DE Influenza; Asthma; Antiviral; DAS181 ID VIRUS-INFECTION AB Background: Influenza virus (IFV) infection is associated with increased morbidity and mortality in people with underlying lung disease. Treatment options for IFV are currently limited and antiviral resistance is a growing concern. DAS181, an inhaled antiviral with a unique mechanism of action, has shown promise in early clinical trials involving generally healthy human subjects. This study was undertaken to assess the safety and tolerability of DAS181 in individuals with underlying reactive airway disease. Methods: This was a randomized, double-blind, placebo-controlled, crossover phase 1 study of DAS181-F02. Dry particle inhaler administration of 10 mg was done on 3 consecutive days in ten adult volunteers with well-controlled asthma. The primary outcome was the frequency of adverse events (AEs), grade 1 or higher that occurred during each study period. Results: There were 280 AEs among ten evaluable subjects (56.8 % active; 43.2 % placebo); 90.7 % were grade 1. No grade 3 or higher AEs occurred. A statistically significant association between exposure to DAS181 and experiencing any AE, a grade 1 AE, or a grade 2 AE was not detected. Overall, the majority of AEs were classified as possibly related (35.7 %), unlikely related (38.9 %), or unrelated (15.4 %) to study drug administration. However, there was a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE. Respiratory effects, including dyspnea, dry cough, and chest discomfort related to respirations, accounted for all of the definitely related AEs and one of the most common probably related AEs. Conclusions: DAS181 was safe in this small study of otherwise healthy subjects with well-controlled asthma. However, the generalizability of these results is limited by the small sample size and generally mild nature of the subjects' asthma at baseline. The increased association of respiratory events classified as probably or definitely related to DAS181 administration suggests caution may need to be employed when administering DAS181 to individuals with less stable reactive airway disease. Further investigation in a controlled setting of the safety and efficacy of DAS181 in a larger population of asthmatic subjects with varying disease activity is warranted. C1 [Colombo, Rhonda E.] Georgia Regents Univ, Div Infect Dis, Augusta, GA USA. [Fiorentino, Charles; Barrett, Kevin; Nabha, Linda] NIAID, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Dodd, Lori E.; Hunsberger, Sally] NIAID, Biostat Res Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Haney, Carissa; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nabha, Linda] Georgetown Univ Hosp, Div Infect Dis & Travel Med, Washington, DC 20007 USA. [Davey, Richard T., Jr.] NIAID, Immunoregulat Lab, Bldg 10, Bethesda, MD 20892 USA. [Olivier, Kenneth N.] NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NIAID, Lab Clin Infect Dis, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Olivier, KN (reprint author), NHLBI, Cardiovasc & Pulm Branch, Bldg 10, Bethesda, MD 20892 USA. EM kenneth.olivier@nih.gov FU NIAID, NIH; NHLBI, NIH FX The study was funded in part by the Intramural Research Programs of the NIAID and NHLBI, NIH. Ansun Biopharma provided the DAS181-F02, placebo, and dry particle inhalers used in the study. NR 12 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD FEB 1 PY 2016 VL 16 AR 54 DI 10.1186/s12879-016-1358-9 PG 10 WC Infectious Diseases SC Infectious Diseases GA DC6XE UT WOS:000369362100001 PM 26830468 ER PT J AU Mukhopadhyay, P Baggelaar, M Erdelyi, K Cao, ZX Cinar, R Fezza, F Ignatowska-Janlowska, B Wilkerson, J van Gils, N Hansen, T Ruben, M Soethoudt, M Heitman, L Kunos, G Maccarrone, M Lichtman, A Pacher, P Van der Stelt, M AF Mukhopadhyay, Partha Baggelaar, Marc Erdelyi, Katalin Cao, Zongxian Cinar, Resat Fezza, Filomena Ignatowska-Janlowska, Bogna Wilkerson, Jenny van Gils, Noortje Hansen, Thomas Ruben, Marc Soethoudt, Marjolein Heitman, Laura Kunos, George Maccarrone, Mauro Lichtman, Aron Pacher, Pal Van der Stelt, Mario TI The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article ID ENDOCANNABINOID SYSTEM; DIABETIC-NEPHROPATHY; CONCISE GUIDE; IN-VIVO; INJURY; PHARMACOLOGY; BLOCKADE; DISEASE; BRAIN; INFLAMMATION AB Background and PurposeHere, we have characterized 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione hydrochloride (LEI-101) as a novel, peripherally restricted cannabinoid CB2 receptor agonist, using both in vitro and in vivo models. Experimental ApproachWe investigated the effects of LEI-101 on binding and functional activity. We assessed its in vitro and in vivo selectivity. Efficacy of LEI-101 was determined in a mouse model of cisplatin-induced nephrotoxicity. KEY RESULTS LEI-101 behaved as a partial agonist at CB2 receptors using beta- arrestin and GTP gamma S assays and was - 100- fold selective in CB2 / CB1 receptor- binding assays. It did not display any activity on endocannabinoid hydrolases and nor did it react with serine hydrolases in an activity- based protein profiling assay. In mice, LEI- 101 had excellent oral bioavailability reaching high concentrations in the kidney and liver with minimal penetration into the brain. LEI- 101 up to a dose of 60 mg center dot kg - 1 ( p. o.) did not exert any CNS- mediated effects in the tetrad assay, in mice. LEI- 101 ( p. o. or i. p.) at 3 or 10 mg center dot kg - 1 dose- dependently prevented kidney dysfunction and/ or morphological damage induced by cisplatin in mice. These protective effects were associated with improved renal histopathology, attenuated oxidative stress and inflammation in the kidney. These effects were absent in CB2 receptor knockout mice. Conclusion and ImplicationsThese results indicate that LEI-101 is a selective, largely peripherally restricted, orally available CB2 receptor agonist with therapeutic potential in diseases that are associated with inflammation and/or oxidative stress, including kidney disease. C1 [Mukhopadhyay, Partha; Erdelyi, Katalin; Cao, Zongxian; Cinar, Resat; Kunos, George; Pacher, Pal] NIH, Bldg 10, Bethesda, MD 20892 USA. [Baggelaar, Marc; Hansen, Thomas; Ruben, Marc; Soethoudt, Marjolein; Van der Stelt, Mario] Leiden Univ, Dept Bioorgan Synth, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. [Fezza, Filomena; Lichtman, Aron] Univ Roma Tor Vergata, Dept Expt Med & Surg, Rome, Italy. [Fezza, Filomena; Maccarrone, Mauro] Santa Lucia Fdn, European Ctr Brain Res, Rome, Italy. [Ignatowska-Janlowska, Bogna; Wilkerson, Jenny] Virginia Commonwealth Univ, Richmond, VA USA. [van Gils, Noortje; Heitman, Laura] Leiden Univ, Dept Med Chem, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. [Maccarrone, Mauro] Univ Rome, Dept Med, Campus Biomed, Rome, Italy. [Ruben, Marc] Mercachem Inc, Nijmegen, Netherlands. RP Pacher, P (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA.; Van der Stelt, M (reprint author), Leiden Univ, Dept Bioorgan Synth, Einsteinweg 55, NL-2333 CC Leiden, Netherlands.; Pacher, P (reprint author), NIAAA, NIH, 5625 Fishers Lane,MSC-9413, Bethesda, MD 20892 USA.; Van der Stelt, M (reprint author), Leiden Univ, Leiden Inst Chem, Bioorgan Chem, Einsteinweg 55, NL-2333 CC Leiden, Netherlands. EM pacher@mail.nih.gov; m.van.der.stelt@chem.leidenuniv.nl OI Ignatowska-Jankowska, Bogna/0000-0002-8427-1128; CINAR, RESAT/0000-0002-8597-7253 FU ECHO-STIP grant of the Dutch Research Council Chemical Sciences (NWO-CW); NIAAA/NIH; Ministero dell'Istruzione, dell'Universita e della Ricerca FX We thank Henk de Vries and Judy Harvey-White for excellent technical assistance. M.S. and M.v.d.S. are supported by ECHO-STIP grant of the Dutch Research Council Chemical Sciences (NWO-CW). P.P. and G.K. are supported by the Intramural Program of NIAAA/NIH. M.M. is supported by Ministero dell'Istruzione, dell'Universita e della Ricerca (PRIN 2010-2011 grant). NR 40 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD FEB PY 2016 VL 173 IS 3 BP 446 EP 458 DI 10.1111/bph.13338 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC3WM UT WOS:000369149600004 PM 26398481 ER PT J AU Hartman, RL Brown, TL Milavetz, G Spurgin, A Gorelick, DA Gaffney, GR Huestis, MA AF Hartman, Rebecca L. Brown, Timothy L. Milavetz, Gary Spurgin, Andrew Gorelick, David A. Gaffney, Gary R. Huestis, Marilyn A. TI Effect of Blood Collection Time on Measured Delta(9)-Tetrahydrocannabinol Concentrations: Implications for Driving Interpretation and Drug Policy SO CLINICAL CHEMISTRY LA English DT Article ID CONTROLLED SMOKED CANNABIS; MOTOR-VEHICLE CRASHES; WHOLE-BLOOD; ORAL FLUID; ALCOHOL; MARIJUANA; PLASMA; HEAVY; DRIVERS; USERS AB BACKGROUND: In driving-under-the-influence cases, blood typically is collected approximately 1.5-4 h after an incident, with unknown last intake time. This complicates blood Delta(9)-tetrahydrocannabinol (THC) interpretation, owing to rapidly decreasing concentrations immediately after inhalation. We evaluated how decreases in blood THC concentration before collection may affect interpretation of toxicological results. METHODS: Adult cannabis smokers (>= 1 X /3 months, <= 3 days/week) drank placebo or low-dose alcohol (approximately 0.065% peak breath alcohol concentration) 10 min before inhaling 500 mg placebo, 2.9%, or 6.7% vaporized THC (within-individuals), then took simulated drives 0.5-1.3 h postdose. Blood THC concentrations were determined before and up to 8.3 h postdose (limit of quantification 1 mu g/L). RESULTS: In 18 participants, observed C-max (at 0.17 h) for active (2.9 or 6.7% THC) cannabis were [median (range)] 38.2 mu/L (11.4-137) without alcohol and 47.9 ptg/L (13.0-210) with alcohol. THC C-max concentration decreased 73.5% (3.3%-89.5%) without alcohol and 75.1% (11.5%-85.4%) with alcohol in the first half-hour after active cannabis and 90.3% (76.1%-100%) and 91.3% (53.8%-97.0%), respectively, by 1.4 h postdose. When residual THC (from previous self administration) was present, concentrations rapidly decreased to preinhalation baselines and fluctuated around them. During-drive THC concentrations previously associated with impairment (>= 8.2 mu/L) decreased to median <5 mu/L by 3.3 h postdose and <2 p mu/L by 4.8 h postdose; only 1 participant had THC >= 5 mu/L after 3.3 h. CONCLUSIONS: Forensic blood THC co(n)centrations may be lower than common per se cutoffs despite greatly exceeding them while driving. Concentrations during driving cannot be back-extrapolated because of unknown time after intake and interindividual variability in rates of decrease. (C) 2015 American Association for Clinical Chemistry C1 [Hartman, Rebecca L.; Gorelick, David A.; Huestis, Marilyn A.] NIDA, Chem & Drug Metab, Intramural Res Program, NIH, Baltimore, MD USA. [Brown, Timothy L.] Univ Iowa, Natl Adv Driving Simulator, Iowa City, IA USA. [Milavetz, Gary; Spurgin, Andrew] Univ Iowa, Coll Pharm, Iowa City, IA 52242 USA. [Gorelick, David A.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Gaffney, Gary R.] Univ Iowa, Carver Coll Med, Iowa City, IA USA. RP Huestis, MA (reprint author), Biomed Res Ctr, Suite 200,Room 05A-721,251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH; US Office of National Drug Control Policy; National Institute on Drug Abuse; National Highway Traffic Safety Administration FX The Intramural Research Program, National Institute on Drug Abuse, NIH, and the US Office of National Drug Control Policy. T.L. Brown, National Institute on Drug Abuse, National Highway Traffic Safety Administration. NR 40 TC 6 Z9 6 U1 8 U2 19 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2016 VL 62 IS 2 BP 367 EP 377 DI 10.1373/clinchem.2015.248492 PG 11 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DC8KR UT WOS:000369468900012 PM 26823611 ER PT J AU Zhao, Z Sacks, DB AF Zhao, Zhen Sacks, David B. TI Detrimental Effects of Not Using International Reference Materials to Calibrate Cystatin C Assays SO CLINICAL CHEMISTRY LA English DT Letter C1 [Zhao, Zhen; Sacks, David B.] NIH, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. RP Zhao, Z (reprint author), Dept Lab Med, 10 Ctr Dr,Bldg 10,Room 2C306, Bethesda, MD 20892 USA. EM zhen.zhao@nih.gov FU Intramural NIH HHS NR 5 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2016 VL 62 IS 2 BP 410 EP 411 DI 10.1373/clinchem.2015.244988 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DC8KR UT WOS:000369468900018 PM 26553788 ER PT J AU Overby, CL Heale, B Aronson, S Cherry, JM Dwight, S Milosavljevic, A Nelson, T Niehaus, A Weaver, MA Ramos, EM Williams, MS AF Overby, C. L. Heale, B. Aronson, S. Cherry, J. M. Dwight, S. Milosavljevic, A. Nelson, T. Niehaus, A. Weaver, M. A. Ramos, E. M. Williams, M. S. TI Providing Access to Genomic Variant Knowledge in a Healthcare Setting: A Vision for the ClinGen Electronic Health Records Workgroup SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material AB The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH)-funded collaborative program that brings together a variety of projects designed to provide high-quality, curated information on clinically relevant genes and variants. ClinGen's EHR (Electronic Health Record) Workgroup aims to ensure that ClinGen is accessible to providers and patients through EHR and related systems. This article describes the current scope of these efforts and progress to date. The ClinGen public portal can be accessed at www.clinicalgenome.org. C1 [Overby, C. L.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Overby, C. L.] Univ Maryland, Sch Med, Ctr Hlth Related Informat & Bioimaging, Baltimore, MD 21201 USA. [Overby, C. L.; Nelson, T.; Williams, M. S.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Heale, B.] Univ Utah, Salt Lake City, UT USA. [Aronson, S.] Partners HealthCare Personalized Med, Cambridge, MA USA. [Cherry, J. M.; Dwight, S.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Milosavljevic, A.] Baylor Coll Med, Houston, TX 77030 USA. [Niehaus, A.; Ramos, E. M.] NHGRI, NIH, Rockville, MD USA. [Weaver, M. A.] Amer Coll Med Genet & Genom, Bethesda, MD USA. RP Overby, CL (reprint author), Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA.; Overby, CL (reprint author), Univ Maryland, Sch Med, Ctr Hlth Related Informat & Bioimaging, Baltimore, MD 21201 USA.; Overby, CL (reprint author), Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. EM coverby@medicine.umaryland.edu OI Overby, Casey/0000-0001-9302-5968 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; NHGRI NIH HHS [U01 HG007437, 1U41HG006834-01A1, U01 HG007436, 1U01HG007436-01, 1U01HG007437-01, U41 HG006834]; NLM NIH HHS [T15LM007124]; PHS HHS [HHSN261200800001E] NR 10 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 157 EP 160 DI 10.1002/cpt.270 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100015 PM 26418054 ER PT J AU Kalman, LV Agundez, JAG Appell, ML Black, JL Bell, GC Boukouvala, S Bruckner, C Bruford, E Caudle, K Coulthard, SA Daly, AK Del Tredici, AL den Dunnen, JT Drozda, K Everts, RE Flockhart, D Freimuth, RR Gaedigk, A Hachad, H Hartshorne, T Ingelman-Sundberg, M Klein, TE Lauschke, VM Maglott, DR McLeod, HL McMillin, GA Meyer, UA Muller, DJ Nickerson, DA Oetting, WS Pacanowski, M Pratt, VM Relling, MV Roberts, A Rubinstein, WS Sangkuhl, K Schwab, M Scott, SA Sim, SC Thirumaran, RK Toji, LH Tyndale, RF van Schaik, RHN Whirl-Carrillo, M Yeo, KTJ Zanger, UM AF Kalman, L. V. Agundez, J. A. G. Appell, M. Lindqvist Black, J. L. Bell, G. C. Boukouvala, S. Bruckner, C. Bruford, E. Caudle, K. Coulthard, S. A. Daly, A. K. Del Tredici, A. L. den Dunnen, J. T. Drozda, K. Everts, R. E. Flockhart, D. Freimuth, R. R. Gaedigk, A. Hachad, H. Hartshorne, T. Ingelman-Sundberg, M. Klein, T. E. Lauschke, V. M. Maglott, D. R. McLeod, H. L. McMillin, G. A. Meyer, U. A. Mueller, D. J. Nickerson, D. A. Oetting, W. S. Pacanowski, M. Pratt, V. M. Relling, M. V. Roberts, A. Rubinstein, W. S. Sangkuhl, K. Schwab, M. Scott, S. A. Sim, S. C. Thirumaran, R. K. Toji, L. H. Tyndale, R. F. van Schaik, R. H. N. Whirl-Carrillo, M. Yeo, K. T. J. Zanger, U. M. TI Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID PERSONALIZED MEDICINE; IMPLEMENTATION CONSORTIUM; MOLECULAR-PATHOLOGY; VKORC1 HAPLOTYPES; CLINICAL-PRACTICE; DRUG DEVELOPMENT; INFORMATION; PERSPECTIVE; ASSOCIATION; TRANSPORTER AB This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward. C1 [Kalman, L. V.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Agundez, J. A. G.] Univ Extremadura, Dept Pharmacol, Caceres, Spain. [Appell, M. Lindqvist] Linkoping Univ, Fac Med & Hlth Sci, Dept Med & Hlth Sci, Div Drug Res, Linkoping, Sweden. [Black, J. L.; Freimuth, R. R.] Mayo Clin, Rochester, MN USA. [Bell, G. C.; McLeod, H. L.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Boukouvala, S.] Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis, Greece. [Bruckner, C.] Affymetrix, Santa Clara, CA USA. [Bruford, E.] European Mol Biol Lab, EMBL EBI, HUGO Gene Nomenclature Comm, Wellcome Genome Campus, Hinxton, England. [Caudle, K.; Relling, M. V.] St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. [Coulthard, S. A.; Daly, A. K.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Del Tredici, A. L.] Millennium Hlth LLC, San Diego, CA USA. [den Dunnen, J. T.] Leiden Univ, Med Ctr, Dept Human Genet & Clin Genet, Leiden, Netherlands. [Drozda, K.; Pacanowski, M.] US FDA, Silver Spring, MD USA. [Everts, R. E.] Agena Biosci, San Diego, CA USA. [Flockhart, D.; Pratt, V. M.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Gaedigk, A.] Univ Missouri, Childrens Mercy Kansas City, Div Clin Pharmacol & Therapeut Innovat, Kansas City, MO 64110 USA. [Gaedigk, A.] Univ Missouri, Sch Med, Kansas City, MO 64108 USA. [Hachad, H.] Translat Software, Bellevue, WA USA. [Hartshorne, T.] Thermo Fisher Sci, Dept Genet Anal, San Francisco, CA USA. [Ingelman-Sundberg, M.; Lauschke, V. M.; Sim, S. C.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Klein, T. E.; Sangkuhl, K.; Whirl-Carrillo, M.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Maglott, D. R.; Rubinstein, W. S.] Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD USA. [McMillin, G. A.] Univ Utah, Salt Lake City, UT USA. [McMillin, G. A.] ARUP Labs, Salt Lake City, UT USA. [Meyer, U. A.] Univ Basel, Basel, Switzerland. [Mueller, D. J.] Univ Toronto, Dept Psychiat, CAMH, Toronto, ON, Canada. [Nickerson, D. A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Oetting, W. S.] Univ Minnesota, Dept Expt & Clin Pharmacol, Minneapolis, MN USA. [Roberts, A.] Aegis Sci Corp, Nashville, TN USA. [Schwab, M.; Zanger, U. M.] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany. [Schwab, M.; Zanger, U. M.] Univ Hosp, Dept Clin Pharmacol, Tubingen, Germany. [Scott, S. A.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Thirumaran, R. K.] Genelex Corp, Seattle, WA USA. [Toji, L. H.] Coriell Inst Med Res, Camden, NJ USA. [Tyndale, R. F.] Univ Toronto, CAMH, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Tyndale, R. F.] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada. [van Schaik, R. H. N.] Erasmus MC, Dept Clin Chem, Int Federat Clin Chem IFCC Task Force Pharmacogen, Rotterdam, Netherlands. [Yeo, K. T. J.] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. RP Kalman, LV (reprint author), Ctr Dis Control & Prevent, Atlanta, GA USA. EM LKalman@cdc.gov RI Agundez, Jose/A-5503-2008; Mueller, Daniel/L-4159-2016; Zanger, Ulrich/A-9364-2012; Daly, Ann/H-3144-2011; OI Mueller, Daniel/0000-0003-4978-4400; Zanger, Ulrich/0000-0002-5276-2002; Daly, Ann/0000-0002-7321-0629; Agundez, Jose/0000-0001-6895-9160; Bruford, Elspeth/0000-0002-8380-5247; Lauschke, Volker/0000-0002-1140-6204 FU Intramural CDC HHS [CC999999]; NCI NIH HHS [P30 CA021765]; NHGRI NIH HHS [U01 HG007762, U01HG007762, U41 HG003345, U41HG003345]; NIDA NIH HHS [R01 DA035736]; NIGMS NIH HHS [U19 GM61388, 2 R01 GM088076-05, K23 GM104401, R01 GM088076, R24 GM061374, R24 GM115264, R24 GM61374, R24GM115264, U19 GM061388]; Wellcome Trust [099129/Z/12/Z] NR 54 TC 8 Z9 9 U1 5 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 IS 2 BP 172 EP 185 DI 10.1002/cpt.280 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC9HW UT WOS:000369533100020 PM 26479518 ER PT J AU Moody, TW Nuche-Berenguer, B Jensen, RT AF Moody, Terry W. Nuche-Berenguer, Bernardo Jensen, Robert T. TI Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE cancer; glial tumors; lung cancer; neuroblastoma; PACAP; VIP ID HUMAN PROSTATE-CANCER; HUMAN NEUROBLASTOMA-CELLS; HORMONE-RELEASING HORMONE; HUMAN BRAIN-TUMORS; BREAST-CANCER; PEPTIDE VIP; LUNG-CANCER; COLON-CANCER; NEUROENDOCRINE TUMORS; PAC1 RECEPTOR AB Purpose of reviewTo summarize the roles of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase activating polypeptide (PACAP) and their receptors (VPAC1, VPAC2, PAC1) in human tumors as well as their role in potential novel treatments.Recent findingsConsiderable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially in the role of transactivation of the epidermal growth factor family. The overexpression of VPAC1/2 and PAC1 on a number of common neoplasms (breast, lung, prostate, central nervous system and neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues.SummaryVIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery are all suggesting possible novel tumor treatments. C1 [Moody, Terry W.] NCI, Dept Hlth & Human Serv, Ctr Canc Res, Off Director, Bethesda, MD 20892 USA. [Nuche-Berenguer, Bernardo; Jensen, Robert T.] NIDDK, NIH, Digest Dis Branch, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIH, Bldg 10,Rm 9C-103, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU NCI; NIDDK of the NIH FX This research was supported by the intramural program on NCI and NIDDK of the NIH. NR 172 TC 2 Z9 3 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2016 VL 23 IS 1 BP 38 EP 47 DI 10.1097/MED.0000000000000218 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD1BW UT WOS:000369657100007 PM 26702849 ER PT J AU Lodish, MB Trivellin, G Stratakis, CA AF Lodish, Maya B. Trivellin, Giampaolo Stratakis, Constantine A. TI Pituitary gigantism: update on molecular biology and management SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE gigantism; G-protein coupled receptor 101; pituitary adenoma; X chromosome; X-linked acrogigantism syndrome ID MCCUNE-ALBRIGHT-SYNDROME; ENDOCRINE NEOPLASIA TYPE-1; MESSENGER-RNA EXPRESSION; GROWTH-HORMONE EXCESS; THERAPEUTIC RESPONSES; CARNEY COMPLEX; ADENOMAS; HYPERPLASIA; MUTATIONS; MECHANISM AB Purpose of reviewTo provide an update on the mechanisms leading to pituitary gigantism, as well as to familiarize the practitioner with the implication of these genetic findings on treatment decisions.Recent findingsPrior studies have identified gigantism as a feature of a number of monogenic disorders, including mutations in the aryl hydrocarbon receptor interacting protein gene, multiple endocrine neoplasia types 1 and 4, McCune Albright syndrome, Carney complex, and the paraganglioma, pheochromocytoma, and pituitary adenoma association because of succinate dehydrogenase defects. We recently described a previously uncharacterized form of early-onset pediatric gigantism caused by microduplications on chromosome Xq26.3 and we termed it X-LAG (X-linked acrogigantism). The age of onset of increased growth in X-LAG is significantly younger than other pituitary gigantism cases, and control of growth hormone excess is particularly challenging.SummaryKnowledge of the molecular defects that underlie pituitary tumorigenesis is crucial for patient care as they guide early intervention, screening for associated conditions, genetic counseling, surgical approach, and choice of medical management. Recently described microduplications of Xq26.3 account for more than 80% of the cases of early-onset pediatric gigantism. Early recognition of X-LAG may improve outcomes, as successful control of growth hormone excess requires extensive anterior pituitary resection and are difficult to manage with medical therapy alone. C1 [Lodish, Maya B.; Trivellin, Giampaolo; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Lodish, MB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov RI Trivellin, Giampaolo/J-6583-2016 OI Trivellin, Giampaolo/0000-0003-2384-4153 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX The 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 50 TC 3 Z9 3 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2016 VL 23 IS 1 BP 72 EP 80 DI 10.1097/MED.0000000000000212 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DD1BW UT WOS:000369657100012 PM 26574647 ER PT J AU de Bree, GJ Lynch, RM AF de Bree, Godelieve J. Lynch, Rebecca M. TI B cells in HIV pathogenesis SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE B cell; HIV; neutralizing antibody; T-follicular helper cell; vaccine ID IMMUNODEFICIENCY-VIRUS-INFECTION; T FOLLICULAR HELPER; BROADLY NEUTRALIZING ANTIBODIES; ANTIRETROVIRAL THERAPY; VIREMIC INDIVIDUALS; IMMUNE ACTIVATION; SHIV CHALLENGE; RHESUS-MONKEYS; EFFICACY TRIAL; PLASMA-CELLS AB Purpose of reviewThe induction of a virus-clearing humoral immune response in natural HIV infection is impaired. Insights into early events in HIV infection that affect B-cell responses and antibody development are addressed and related to strategies for the design of an HIV vaccine.Recent findingsBroadly neutralizing antibody responses do not develop early in HIV-1 infection, and recent reports highlight the role of preexisting suboptimal B-cell populations that can dominate the early antibody response. Furthermore, from the earliest phases of infection, virus replication is a driving force behind alterations in the B cell and T-follicular helper cell (T-FH) compartments. Paradoxically, the factors that drive these abnormalities, such as high virus load, duration of infection, and increased viral diversity, are likely necessary for the development of both T-FH and broadly neutralizing antibodies.SummaryThese data provide new insights into prerequisites for an effective HIV vaccine. First, a vaccine should induce specific B-cell lineages so that preexisting cross-reactivity is avoided and, additionally, it must mimic high levels of diverse antigen in the absence of chronic virus replication within immune cells to activate high levels of quality of T-FH and stimulate antibody maturation. C1 [de Bree, Godelieve J.] Univ Amsterdam, Acad Med Ctr, Dept Internal Med, Amsterdam Inst Global Hlth & Dev, NL-1012 WX Amsterdam, Netherlands. [Lynch, Rebecca M.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP de Bree, GJ (reprint author), Univ Amsterdam, Acad Med Ctr, Amsterdam Inst Global Hlth & Dev, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM g.j.debree@amc.uva.nl NR 57 TC 3 Z9 3 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0951-7375 EI 1473-6527 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD FEB PY 2016 VL 29 IS 1 BP 23 EP 30 DI 10.1097/QCO.0000000000000225 PG 8 WC Infectious Diseases SC Infectious Diseases GA DC9NZ UT WOS:000369549600003 PM 26658653 ER PT J AU Chen, SH Oyarzabal, EA Hong, JS AF Chen, Shih-Heng Oyarzabal, Esteban A. Hong, Jau-Shyong TI Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration SO CURRENT OPINION IN PHARMACOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TOLL-LIKE RECEPTORS; NADPH OXIDASE; ALZHEIMERS-DISEASE; DOPAMINERGIC NEURODEGENERATION; PARKINSONS-DISEASE; IMMUNE ACTIVATION; OXIDATIVE STRESS; ALPHA-SYNUCLEIN; AMYLOID-BETA AB As average life expectancy rises throughout the world, neurodegenerative diseases have emerged as one of the greatest global public heath challenges in modern times. Substantial efforts have been made in researching neurodegenerative diseases over the last few decades, yet their predominantly sporadic nature has made uncovering their etiologies challenging. Mounting evidence has suggested that factors like damage-associated molecular patterns (DAMPs) released by stressed and dying neurons are likely involved in disease pathology and in stimulating chronic activation of microglia that contributes to neuronal oxidative stress and degeneration. This review focuses on how the microglial integrin receptor Mac1 and its downstream effector NADPH oxidase (NOX2) contribute to maintaining chronic neuroinflammation and are crucial in inflammation-driven neurotoxicity in neurodegenerative diseases. Our hope is to provide new insights on novel targets and therapies that could slow or even halt neurodegeneration. C1 [Chen, Shih-Heng; Oyarzabal, Esteban A.; Hong, Jau-Shyong] NIEHS, NIH, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. [Oyarzabal, Esteban A.] Univ N Carolina, Neurobiol Curriculum, Chapel Hill, NC USA. RP Chen, SH (reprint author), NIEHS, NIH, Neurobiol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM chens3@niehs.nih.gov FU Intramural Research Program of the 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 58 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 EI 1471-4973 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD FEB PY 2016 VL 26 BP 54 EP 60 DI 10.1016/j.coph.2015.10.001 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC4RP UT WOS:000369208300009 PM 26498406 ER PT J AU Vaupel, DB Schindler, CW Chefer, S Belcher, AM Ahmet, I Scheidweiler, KB Huestis, MA Stein, EA AF Vaupel, D. B. Schindler, C. W. Chefer, S. Belcher, A. M. Ahmet, I. Scheidweiler, K. B. Huestis, M. A. Stein, E. A. TI Delayed emergence of methamphetamine's enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Methamphetamine; Abstinence; Blood pressure; Heart rate; Rhesus monkey ID CONSCIOUS SQUIRREL-MONKEYS; RHESUS-MONKEYS; COCAINE; SENSITIZATION; RATS; METHYLPHENIDATE; AMPHETAMINE; MECHANISMS; TOLERANCE; RESPONSES AB Background: Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use. Methods: Eight male rhesus monkeys with long histories of intravenous methamphetamine self administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naive monkeys. Cardiovascular responses to methamphetamine were followed for 2.5 h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals. Results: No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence. Conclusions: Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events. Published by Elsevier Ireland Ltd. C1 [Vaupel, D. B.; Chefer, S.; Belcher, A. M.; Stein, E. A.] NIDA, Neuroimaging Res Branch, Baltimore, MD USA. [Schindler, C. W.] NIDA, Preclin Pharmacol Sect, Baltimore, MD USA. [Scheidweiler, K. B.; Huestis, M. A.] NIDA, Chem & Drug Metab Sect, Baltimore, MD USA. [Ahmet, I.] NIA, NIH, Baltimore, MD 21224 USA. RP Schindler, CW (reprint author), NIDA, Preclin Pharmacol Sect, NIH, 251 Bayview Blvd,Suite 200,Room 05A717, Baltimore, MD 21224 USA. EM cschind@helix.nih.gov FU National Institute on Drug Abuse; National Institute on Aging, NIH FX This work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Aging, NIH. NR 32 TC 1 Z9 1 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2016 VL 159 BP 181 EP 189 DI 10.1016/j.drugalcdep.2015.12.008 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DC8LX UT WOS:000369472200024 PM 26775284 ER PT J AU Pilkonis, PA Yu, L Dodds, NE Johnston, KL Lawrence, SM Hilton, TF Daley, DC Patkar, AA McCarty, D AF Pilkonis, Paul A. Yu, Lan Dodds, Nathan E. Johnston, Kelly L. Lawrence, Suzanne M. Hilton, Thomas F. Daley, Dennis C. Patkar, Ashwin A. McCarty, Dennis TI Item banks for substance use from the Patient-Reported Outcomes Measurement Information System (PROMIS (R)): Severity of use and positive appeal of use (vol 156, pg 184, 2015) SO DRUG AND ALCOHOL DEPENDENCE LA English DT Correction C1 [Pilkonis, Paul A.; Yu, Lan; Dodds, Nathan E.; Johnston, Kelly L.; Lawrence, Suzanne M.; Daley, Dennis C.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Yu, Lan] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Hilton, Thomas F.] NIDA, Indian Harbor Beach, FL 32937 USA. [Patkar, Ashwin A.] Duke Univ, Sch Med, Dept Psychiat, Durham, NC 27705 USA. [Patkar, Ashwin A.] Duke Univ, Sch Med, Dept Community & Family Med, Durham, NC 27705 USA. [McCarty, Dennis] Oregon Hlth & Sci Univ, Publ Hlth & Prevent Med, Portland, OR 97239 USA. RP Pilkonis, PA (reprint author), Western Psychiat Inst & Clin, 3811 OHara St, Pittsburgh, PA 15213 USA. EM pilkonispa@upmc.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 1 PY 2016 VL 159 BP 285 EP 286 DI 10.1016/j.drugalcdep.2015.12.003 PG 2 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA DC8LX UT WOS:000369472200039 ER PT J AU O'Brien, KM Upson, K Cook, NR Weinberg, CR AF O'Brien, Katie M. Upson, Kristen Cook, Nancy R. Weinberg, Clarice R. TI Environmental Chemicals in Urine and Blood: Improving Methods for Creatinine and Lipid Adjustment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article ID ORGANOCHLORINE LEVELS; POPULATION; SERUM AB BACKGROUND: Investigators measuring exposure biomarkers in urine typically adjust for-creatinine to account for dilution-dependent sample variation in urine concentrations. Similarly, it is standard to adjust for serum lipids when measuring lipophilic chemicals in serum. However, there is controversy regarding the best approach, and existing methods may not effectively correct for measurement error. OBJECTIVES: We compared adjustment methods, including novel approaches, using simulated case-control data. METHODS: Using a directed acyclic graph framework, we defined six causal scenarios for -epidemiologic studies of environmental chemicals measured in urine or serum. The scenarios include variables known to influence creatinine (e.g., age and hydration) or serum lipid levels (e.g., body mass index and recent fat intake). Over a range of true effect sizes, we analyzed each scenario using seven adjustment approaches and estimated the corresponding bias and confidence interval coverage across 1,000 simulated studies. RESULTS: For urinary biomarker measurements, our novel method, which incorporates both covariate-adjusted standardization and the inclusion of creatinine as a covariate in the regression model, had low bias and possessed 95% confidence interval coverage of nearly 95% for most simulated scenarios. For serum biomarker measurements, a similar approach involving standardization plus serum lipid level adjustment generally performed well. CONCLUSIONS: To control measurement error bias caused by variations in serum lipids or by urinary diluteness, we recommend improved methods for standardizing exposure concentrations across individuals. C1 [O'Brien, Katie M.; Weinberg, Clarice R.] NIEHS, Biostat & Computat Biol Branch, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Upson, Kristen] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Cook, Nancy R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. RP Weinberg, CR (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov RI Upson, Kristen/D-4504-2017; OI Upson, Kristen/0000-0001-9598-8776; O'Brien, Katie/0000-0002-1931-1349 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES049003-23] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (grant Z01ES049003-23). NR 14 TC 13 Z9 14 U1 2 U2 13 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2016 VL 124 IS 2 BP 220 EP 227 DI 10.1289/ehp.1509693 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DC6NX UT WOS:000369337900015 PM 26219104 ER PT J AU Uchida, N Green, R Ballantine, J Skala, LP Hsieh, MM Tisdale, JF AF Uchida, Naoya Green, Rashidah Ballantine, Josiah Skala, Luke P. Hsieh, Matthew M. Tisdale, John F. TI Kinetics of lentiviral vector transduction in human CD34(+) cells SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID HEMATOPOIETIC REPOPULATING CELLS; MURINE BETA-THALASSEMIA; VIRUS TYPE-1 INFECTION; CENTRAL DNA FLAP; GENE-THERAPY; IN-VIVO; EFFICIENT TRANSDUCTION; PHENOTYPIC CORRECTION; NUCLEAR IMPORT; COPY NUMBER AB Unlike cell lines, human hematopoietic stem cells (HSCs) are less efficiently transduced with HIV-1 vectors, potentially limiting this approach. To investigate which step (internalization, reverse transcription, nuclear transport, and integration) limits lentiviral transduction, we evaluated the kinetics of lentiviral transduction in human CD34(+) cells. We transduced HeLa and CD34(+) cells with self-inactivating HIV-1 vector at low and tenfold higher multiplicity of infection (MOI) and evaluated vector amounts at various time points based on the rationale that if a given step was not limiting, tenfold greater vector amounts would be obtained at the tenfold higher MOI. We observed slower internalization ( > 60 min), a peak in reverse transcription at 24 hours, and completion of integration at 3 days in CD34(+) cells. In HeLa cells, there were approximately tenfold greater amounts at high MOI at all time points. When compared with HeLa cells, CD34(+) cells exhibited larger differences in vector amounts between high and low MOIs at 2-6 hours and a smaller difference at 12 hours to 10 days, revealing a limitation in human CD34(+) cell transduction around 12 hours, which corresponds to reverse transcription. In serial measurements of reverse transcription at 24 hours, vector amounts did not decrease once detected among CD34(+) cells. When using an HSC expansion medium, we observed less limitation for starting reverse transcription and more efficient transduction among CD34(+) cells in vitro and in xenografted mice. These data suggest that it is the initiation of reverse transcription that limits lentiviral transduction of human CD34(+) cells. Our findings provide an avenue for optimizing human CD34(+) cell transduction. Published by Elsevier Inc. on behalf of ISEH - International Society for Experimental Hematology. C1 [Uchida, Naoya; Green, Rashidah; Ballantine, Josiah; Skala, Luke P.; Hsieh, Matthew M.; Tisdale, John F.] NIDDK, Mol & Clin Hematol Branch, NHLBI, NIH, Bethesda, MD 20892 USA. RP Uchida, N (reprint author), Mol & Clin Hematol Branch, 9000 Rockville Pike,Bldg 10,9N112, Bethesda, MD 20892 USA. EM uchidan@nhlbi.nih.gov OI Ballantine, Josiah/0000-0001-9534-9392; Hsieh, Matthew/0000-0002-3706-6615 FU intramural research program of National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at National Institutes of Health (NIH) FX This work was supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). We thank Molly E. Evans for editing the article. We thank Kayo Uchida for statistical analysis. We thank Lydia Raines and Anna Shvygin for help in performing experiments. NR 39 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2016 VL 44 IS 2 BP 106 EP 115 DI 10.1016/j.exphem.2015.10.003 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA DC8KY UT WOS:000369469700004 PM 26499040 ER PT J AU Pawlyk, BS Bulgakov, OV Sun, X Adamian, M Shu, X Smith, AJ Berson, EL Ali, RR Khani, S Wright, AF Sandberg, MA Li, T AF Pawlyk, B. S. Bulgakov, O. V. Sun, X. Adamian, M. Shu, X. Smith, A. J. Berson, E. L. Ali, R. R. Khani, S. Wright, A. F. Sandberg, M. A. Li, T. TI Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa SO GENE THERAPY LA English DT Article ID LEBER CONGENITAL AMAUROSIS; RETINAL DEGENERATION; EXON ORF15; REPLACEMENT THERAPY; CANINE MODEL; MOUSE MODELS; MUTATIONS; CONE; ROD; RP2 AB The X-linked RP3 gene codes for the ciliary protein RPGR and accounts for over 10% of inherited retinal degenerations. The critical RPGR-ORF15 splice variant contains a highly repetitive purine-rich linker region that renders it unstable and difficult to adapt for gene therapy. To test the hypothesis that the precise length of the linker region is not critical for function, we evaluated whether adeno-associated virus-mediated replacement gene therapy with a human ORF15 variant containing in-frame shortening of the linker region could reconstitute RPGR function in vivo. We delivered human RPGR-ORF15 replacement genes with deletion of most (314 codons, 'short form') or 1/3 (126 codons, 'long form') of the linker region to Rpgr null mice. Human RPGR-ORF15 expression was detected post treatment with both forms of ORF15 transgenes. However, only the long form correctly localized to the connecting cilia and led to significant functional and morphological rescue of rods and cones. Thus the highly repetitive region of RPGR is functionally important but that moderate shortening of its length, which confers the advantage of added stability, preserves its function. These findings provide a theoretical basis for optimizing replacement gene design in clinical trials for X-linked RP3. C1 [Pawlyk, B. S.; Adamian, M.; Berson, E. L.; Sandberg, M. A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Sch Med, Boston, MA USA. [Bulgakov, O. V.; Sun, X.; Li, T.] NEI, 6 Ctr Dr, Bethesda, MD 20892 USA. [Shu, X.; Wright, A. F.] Univ Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland. [Shu, X.] Glasgow Caledonian Univ, Dept Life Sci, Glasgow G4 0BA, Lanark, Scotland. [Smith, A. J.; Ali, R. R.] UCL, Inst Ophthalmol, Dept Genet, London, England. [Khani, S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Sch Med, Boston, MA USA. RP Li, T (reprint author), NEI, 6 Ctr Dr, Bethesda, MD 20892 USA.; Pawlyk, BS (reprint author), Massachusetts Eye & Ear Infirm, Berman Gund Lab, 243 Charles St, Boston, MA 02114 USA. EM Basil_Pawlyk@meei.harvard.edu; tiansen.li@nih.gov FU National Eye Institute [EY10581]; NEI [5P30EY14104]; Foundation Fighting Blindness; Foundation for Retina Research; Massachusetts Lions Eye Research Fund; European Union (AAVEYE); UK Department of Health, National Institute of Health Research BMRC for Ophthalmology; UK Fight for Sight FX We thank Dr Jeng-Shin Lee at the Research Vector Core at Harvard Medical School for AAV vector packaging, and Drs Peter Colosi and Zhijian Wu at the National Eye Institute for helpful discussions. This work was supported by National Eye Institute grant EY10581, NEI core grant for Vision Research (5P30EY14104), the Foundation Fighting Blindness, the Foundation for Retina Research, the Massachusetts Lions Eye Research Fund and by grants from the European Union (AAVEYE), the UK Department of Health, National Institute of Health Research BMRC for Ophthalmology and UK Fight for Sight. NR 47 TC 4 Z9 4 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 EI 1476-5462 J9 GENE THER JI Gene Ther. PD FEB PY 2016 VL 23 IS 2 BP 196 EP 204 DI 10.1038/gt.2015.93 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA DC9NY UT WOS:000369549500010 PM 26348595 ER PT J AU Smagulova, F Brick, K Pu, YM Camerini-Otero, RD Petukhova, GV AF Smagulova, Fatima Brick, Kevin Pu, Yongmei Camerini-Otero, R. Daniel Petukhova, Galina V. TI The evolutionary turnover of recombination hot spots contributes to speciation in mice SO GENES & DEVELOPMENT LA English DT Article DE homologous recombination; meiosis; Prdm9; recombination hot spots; DSB hot spots; hybrid sterility; speciation ID MISMATCH REPAIR SYSTEM; IMPRINTED CHROMOSOMAL REGIONS; HISTONE H3 METHYLTRANSFERASE; DNA-BINDING SPECIFICITIES; ZINC-FINGER PROTEINS; IN-HOUSE MICE; MEIOTIC RECOMBINATION; HUMAN GENOME; ESCHERICHIA-COLI; CHIP-SEQ AB Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. In most mammals, theDNAdouble-strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci (hot spots) by sequence-specific binding of the PRDM9 protein. Rapid evolution of the DNA-binding specificity of PRDM9 and gradual erosion of PRDM9-binding sites by gene conversion will alter the recombination landscape over time. To better understand the evolutionary turnover of recombination hot spots and its consequences, we mapped DSB hot spots in four major subspecies of Mus musculus with different Prdm9 alleles and in their F1 hybrids. We found that hot spot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hot spots that become active in the hybrids. As crossovers are disfavored at such hot spots, we propose that sequence divergence generated by hot spot turnover may create an impediment for recombination in hybrids, potentially leading to reduced fertility and, eventually, speciation. C1 [Smagulova, Fatima; Pu, Yongmei; Petukhova, Galina V.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Brick, Kevin; Camerini-Otero, R. Daniel] NIDDK, NIH, Bethesda, MD 20814 USA. [Smagulova, Fatima] INSERM, Irset UMR1085, F-35042 Rennes, France. RP Petukhova, GV (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA.; Camerini-Otero, RD (reprint author), NIDDK, NIH, Bethesda, MD 20814 USA. EM rdcamerini@mail.nih.gov; galina.petukhova@usuhs.edu RI Smagulova, Fatima/K-5459-2015 OI Smagulova, Fatima/0000-0001-6883-1968 FU National Institutes of Health from the National Institute of General Medical Sciences [1R01GM084104]; March of Dimes Foundation [1-FY13-506]; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX We thank M. Lichten and P. Hsieh for critical feedback on the manuscript, and Florencia Pratto for many helpful discussions and suggestions. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http://biowulf.nih.gov). This research was supported by National Institutes of Health grant 1R01GM084104 from the National Institute of General Medical Sciences (G.V.P.), March of Dimes Foundation grant 1-FY13-506 (G.V.P.), and the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (R.D.C.-O.). NR 65 TC 7 Z9 7 U1 2 U2 16 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD FEB 1 PY 2016 VL 30 IS 3 BP 266 EP 280 DI 10.1101/gad.270009.115 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA DC6PV UT WOS:000369343000004 PM 26833728 ER PT J AU Qiu, HF Chereji, RV Hu, CH Cole, HA Rawal, Y Clark, DJ Hinnebusch, AG AF Qiu, Hongfang Chereji, Razvan V. Hu, Cuihua Cole, Hope A. Rawal, Yashpal Clark, David J. Hinnebusch, Alan G. TI Genome-wide cooperation by HAT Gcn5, remodeler SWI/SNF, and chaperone Ydj1 in promoter nucleosome eviction and transcriptional activation SO GENOME RESEARCH LA English DT Article ID RNA-POLYMERASE-II; CHROMATIN-MODIFYING COMPLEXES; TATA-BINDING PROTEIN; AAA-ATPASE YTA7; IN-VIVO; PHO5 PROMOTER; POL-II; HISTONE EVICTION; YEAST PHO5; COACTIVATOR COMPLEX AB Chaperones, nucleosome remodeling complexes, and histone acetyltransferases have been implicated in nucleosome disassembly at promoters of particular yeast genes, but whether these cofactors function ubiquitously, as well as the impact of nucleosome eviction on transcription genome-wide, is poorly understood. We used chromatin immunoprecipitation of histone H3 and RNA polymerase II (Pol II) in mutants lacking single or multiple cofactors to address these issues for about 200 genes belonging to the Gcn4 transcriptome, of which about 70 exhibit marked reductions in H3 promoter occupancy on induction by amino acid starvation. Examining four target genes in a panel of mutants indicated that SWI/SNF, Gcn5, the Hsp70 cochaperone Ydj1, and chromatin-associated factor Yta7 are required downstream from Gcn4 binding, whereas Asf1/Rtt109, Nap1, RSC, and H2AZ are dispensable for robust H3 eviction in otherwise wild-type cells. Using ChIP-seq to interrogate all 70 exemplar genes in single, double, and triple mutants implicated Gcn5, Snf2, and Ydj1 in H3 eviction at most, but not all, Gcn4 target promoters, with Gcn5 generally playing the greatest role and Ydj1 the least. Remarkably, these three cofactors cooperate similarly in H3 eviction at virtually all yeast promoters. Defective H3 eviction in cofactor mutants was coupled with reduced Pol II occupancies for the Gcn4 transcriptome and the most highly expressed uninduced genes, but the relative Pol II levels at most genes were unaffected or even elevated. These findings indicate that nucleosome eviction is crucial for robust transcription of highly expressed genes but that other steps in gene activation are more rate-limiting for most other yeast genes. C1 [Qiu, Hongfang; Hu, Cuihua; Rawal, Yashpal; Hinnebusch, Alan G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Chereji, Razvan V.; Cole, Hope A.; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA.; Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov; ahinnebusch@nih.gov OI Chereji, Razvan/0000-0002-0572-6412 FU Intramural Research Program of the National Institutes of Health (NIH) FX We thank Krishnamurthy Natarajan for sharing expression micro-array data on SM-induced WT cells, James Iben for valuable assistance with bioinformatics, and Chhabi Govind and members of our laboratories for helpful suggestions. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) and utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov). NR 73 TC 2 Z9 2 U1 3 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD FEB PY 2016 VL 26 IS 2 BP 211 EP 225 DI 10.1101/gr.196337.115 PG 15 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA DC6PK UT WOS:000369341900007 PM 26602697 ER PT J AU Nandy, K Chellappa, R Kumar, A Lockett, SJ AF Nandy, Kaustav Chellappa, Rama Kumar, Amit Lockett, Stephen J. TI Segmentation of Nuclei From 3D Microscopy Images of Tissue via Graphcut Optimization SO IEEE JOURNAL OF SELECTED TOPICS IN SIGNAL PROCESSING LA English DT Article DE 3D nuclear segmentation; graph cuts; optical microscopy; seed detection ID INTERACTIVE SEGMENTATION; CONFOCAL MICROSCOPY; CELL SEGMENTATION; CUT; SECTIONS; DYNAMICS; EMBRYOS; 2D AB Nuclear segmentation in 3D microscopic tissue images remains a challenge due to tight packing of the cells, low contrast and poor depth resolution. To address this problem, we developed a robust and accurate nuclear segmentation algorithm suited for tissue samples of higher organisms such as mice and humans. The study was inspired by previous works in graphcut-based segmentation in areas other than optical microscopy. We propose a novel seed detection method for nuclei in 3D tissue images that uses a robust model-based 2D slice by slice segmentation followed by a non-maximal suppression like algorithm for selection of the most prospective set of seeds. After seed detection, for each target nucleus the method transformed the microscopic volume to a geometric volume in spherical space with respect to the respective seed point and found the globally optimal surface in that geometric volume which separated the target cell nucleus from the rest of the volume using a graphcut-based algorithm. Comparing the automatic segmentation maps obtained by the proposed method to those obtained from a number of state-of-the art methods demonstrate superior robustness and accuracy of the proposed method in terms of three evaluation metrics. Along with the automatic method, we also present an interactive version of the algorithm. C1 [Nandy, Kaustav; Lockett, Stephen J.] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Ft Detrick, MD 21702 USA. [Chellappa, Rama] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. [Kumar, Amit] NCI, Canc & Dev Biol Lab, NIH, Ft Detrick, MD 21702 USA. RP Nandy, K; Lockett, SJ (reprint author), Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Ft Detrick, MD 21702 USA.; Chellappa, R (reprint author), Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA.; Kumar, A (reprint author), NCI, Canc & Dev Biol Lab, NIH, Ft Detrick, MD 21702 USA. EM nandyk@mail.nih.gov; rama@umiacs.umd.edu; kumara@mail.nih.gov; locketts@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The Office of Human Subjects Research (OHSR) at the National Institutes of Health, USA determined on January 2 2008 that federal regulations for the protection of human subjects do not apply to this research project. The human material used in this study had been de-identified before any of the authors received it. The guest editor coordinating the review of this manuscript and approving it for publication was Dr. Charles Kervrann. NR 47 TC 2 Z9 2 U1 3 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1932-4553 EI 1941-0484 J9 IEEE J-STSP JI IEEE J. Sel. Top. Signal Process. PD FEB PY 2016 VL 10 IS 1 BP 140 EP 150 DI 10.1109/JSTSP.2015.2505148 PG 11 WC Engineering, Electrical & Electronic SC Engineering GA DC8UT UT WOS:000369495900012 ER PT J AU Yang, Q Ge, MQ Kokalari, B Redai, IG Wang, XX Kemeny, DM Bhandoola, A Haczku, A AF Yang, Qi Ge, Moyar Q. Kokalari, Blerina Redai, Imre G. Wang, Xinxin Kemeny, David M. Bhandoola, Avinash Haczku, Angela TI Group 2 innate lymphoid cells mediate ozone-induced airway inflammation and hyperresponsiveness in mice SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Ozone; group 2 innate lymphoid cells; airway hyperresponsiveness ID PUBLIC-HEALTH BENEFITS; NATURAL HELPER-CELLS; TYPE-2 IMMUNITY; ADAPTIVE IMMUNITY; POLLUTION CONTROL; ASTHMA; HYPERREACTIVITY; LUNG; EOSINOPHILS; EXPRESSION AB Background: Asthmatic patients are highly susceptible to air pollution and in particular to the effects of ozone (O-3) inhalation, but the underlying mechanisms remain unclear. Objective: Using mouse models of O-3-induced airway inflammation and airway hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2s). Methods: C57BL/6 and BALB/c mice were exposed to Aspergillus fumigatus, O-3, or both (3 ppm for 2 hours). ILC2s were isolated by means of fluorescence-activated cell sorting and studied for Il5 and Il13 mRNA expression. ILC2s were depleted with anti-Thy1.2 mAb and replaced by means of intratracheal transfer of ex vivo expanded Thy1.1 ILC2s. Cytokine levels (ELISA and quantitative PCR), inflammatory cell profile, and AHR (flexiVent) were assessed in the mice. Results: In addition to neutrophil influx, O-3 inhalation elicited the appearance of eosinophils and IL-5 in the airways of BALB/c but not C57BL/6 mice. Although O-3-induced expression of IL-33, a known activator of ILC2s, in the lung was similar between these strains, isolated pulmonary ILC2s from O-3-exposed BALB/c mice had significantly greater Il5 and Il13 mRNA expression than C57BL/6 mice. This suggested that an altered ILC2 function in BALB/c mice might mediate the increased O-3 responsiveness. Indeed, anti-Thy1.2 treatment abolished but ILC2s added back dramatically enhanced O-3-induced AHR. Conclusions: O-3-induced activation of pulmonary ILC2s was necessary and sufficient to mediate asthma-like changes in BALB/c mice. This previously unrecognized role of ILC2s might help explain the heightened susceptibility of human asthmatic airways to O-3 exposure. C1 [Yang, Qi; Wang, Xinxin; Bhandoola, Avinash] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Yang, Qi; Bhandoola, Avinash] NCI, T Cell Biol & Dev Sect, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Ge, Moyar Q.; Kokalari, Blerina; Redai, Imre G.; Haczku, Angela] Univ Penn, Dept Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA. [Ge, Moyar Q.; Haczku, Angela] Univ Calif Davis, Translat Lung Biol Ctr, Pulm Crit Care & Sleep Med, One Shields Ave, Davis, CA 95616 USA. [Ge, Moyar Q.; Kemeny, David M.] Natl Univ Singapore, Dept Microbiol, Singapore 117548, Singapore. RP Haczku, A (reprint author), Univ Calif Davis, Translat Lung Biol Ctr, Pulm Crit Care & Sleep Med, One Shields Ave, Davis, CA 95616 USA.; Bhandoola, A (reprint author), NCI, T Cell Biol & Dev Sect, Lab Genome Integr, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM avinash.bhandoola@nih.gov; haczku@ucdavis.edu RI Ge, Qing/N-5855-2016; OI Ge, Qing/0000-0002-5407-342X FU [R01AI072197]; [RC1ES018505]; [P30ES013508]; [R21 AI059621]; [AI098428] FX Supported by grant R01AI072197 (to A.H.), RC1ES018505 (to A.H.), P30ES013508 (to A.H.), R21 AI059621 (to A.B. and A.H.), and AI098428 (to A.B.). NR 37 TC 2 Z9 2 U1 2 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 BP 571 EP 578 DI 10.1016/j.jaci.2015.06.037 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA DC5BN UT WOS:000369235500027 PM 26282284 ER PT J AU Lawrence, MG Leiding, JW Lyons, JJ Hsu, AP Nelson, CC Jones, N Fitzgerald, A Chien, WW Workman, L Platts-Mills, TA Brewer, C Gafni, RI Stone, KD Milner, JD Holland, SM AF Lawrence, Monica G. Leiding, Jennifer W. Lyons, Jonathan J. Hsu, Amy P. Nelson, Celeste C. Jones, Nina Fitzgerald, Alan Chien, Wade W. Workman, Lisa Platts-Mills, Thomas A. Brewer, Carmen Gafni, Rachel I. Stone, Kelly D. Milner, Joshua D. Holland, Steven M. TI GATA3 haploinsufficiency does not block allergic sensitization or atopic disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID TRANSCRIPTION FACTOR; HDR SYNDROME; ABNORMALITIES; GENE C1 [Lawrence, Monica G.; Workman, Lisa; Platts-Mills, Thomas A.; Stone, Kelly D.] Univ Virginia Hlth Syst, Asthma & Allerg Dis Ctr, Charlottesville, VA USA. [Leiding, Jennifer W.; Hsu, Amy P.; Fitzgerald, Alan; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lyons, Jonathan J.; Nelson, Celeste C.; Milner, Joshua D.] NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Leiding, Jennifer W.] Univ S Florida, Dept Pediat, Div Allergy Immunol & Rheumatol, St Petersburg, FL 33701 USA. [Jones, Nina] Natl Lab Canc Res, Leidos Biomed Res Inc, Clin Res Directorate CMRP, Frederick, MD USA. [Chien, Wade W.; Brewer, Carmen] Natl Inst Deafness & Other Commun Disorders, Div Intramural Res, NIH, Bethesda, MD USA. [Chien, Wade W.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Gafni, Rachel I.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smh@nih.gov OI Lyons, Jonathan/0000-0002-2346-8189 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS [Z01 AI000647-16]; NCI NIH HHS [HHSN261200800001E] NR 9 TC 0 Z9 0 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 BP 627 EP + DI 10.1016/j.jaci.2015.06.041 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA DC5BN UT WOS:000369235500038 PM 26282285 ER PT J AU Spinner, MA Ker, JP Stoudenmire, CJ Fadare, O Mace, EM Orange, JS Hsu, AP Holland, SM AF Spinner, Michael A. Ker, Jennifer P. Stoudenmire, Charles J. Fadare, Oluwole Mace, Emily M. Orange, Jordan S. Hsu, Amy P. Holland, Steven M. TI GATA2 deficiency underlying severe blastomycosis and fatal herpes simplex virus-associated hemophagocytic lymphohistiocytosis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID HISTOPLASMOSIS; MUTATIONS C1 [Spinner, Michael A.] Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. [Ker, Jennifer P.] Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, 221 Kirkland Hall, Nashville, TN 37235 USA. [Stoudenmire, Charles J.; Fadare, Oluwole] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA. [Mace, Emily M.; Orange, Jordan S.] Texas Childrens Hosp, Baylor Coll Med, Ctr Human Immunobiol, Houston, TX 77030 USA. [Hsu, Amy P.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural NIH HHS [Z01 AI000646-16]; NIAID NIH HHS [Z01-AI-00647-25] NR 9 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2016 VL 137 IS 2 BP 638 EP + DI 10.1016/j.jaci.2015.07.043 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA DC5BN UT WOS:000369235500043 PM 26395816 ER PT J AU Taieb, D Barlier, A Yang, CZ Pertuit, M Tchoghandjian, A Rochette, C Zattara-Canoni, H Figarella-Branger, D Zhuang, ZP Pacak, K Metellus, P AF Taieb, David Barlier, Anne Yang, Chunzhang Pertuit, Morgane Tchoghandjian, Aurelie Rochette, Claire Zattara-Canoni, Helene Figarella-Branger, Dominique Zhuang, Zhengping Pacak, Karel Metellus, Philippe TI Somatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Hypoxia-inducible factor 2 alpha; Hemangioblastoma; Von Hippel-Lindau syndrome ID HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR GENE; CEREBELLAR HEMANGIOBLASTOMAS; VHL GENE; CAPILLARY HEMANGIOBLASTOMAS; GERMLINE MUTATION; IN-VIVO; PARAGANGLIOMA; POLYCYTHEMIA; PHEOCHROMOCYTOMA AB Central nervous system hemangioblastomas (CNS-HBs) occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. CNS-HBs share some molecular similarities with pheochromocytomas/paragangliomas (PPGLs) and renal cell carcinomas (RCCs). Recently, hypoxia-inducible factors, particularly somatic HIF2A mutations, have been found to play an important role in the pathogenesis of PPGLs. Somatic mutations in HIF2A have been reported in PPGLs associated with polycythemia, which have been reported to also be present in patients with RCCs and HBs. However, whether CNS-HBs is associated with the presence of a HIF2A mutation is currently uknown. We analyzed somatic HIF2A and VHL mutations in a series of 28 sporadic CNS-HBs. We also investigated the expression of HIF target proteins and hypoxia-associated factor (HAF). Two sporadic CNS-HBs were found to have somatic HIF2A mutations. One tumor had 2 HIF2A missense mutations, one of which was previously described in a PPGL (c.1121 T > A, F374Y). The second patient had coexistence of somatic truncated mutations (c.1669 C > T, Q557*) in HIF2A together with a VHL mutation. Neither of the two patients had polycythemia at the time of diagnosis. We demonstrate that the novel truncated mutation in HIF2A (Q557*) affects HIF-2 alpha prolyl hydroxylation with its reduced ubiquitination but intact transcriptional activity, resulting in an activating effect. Both CNS-HB samples showed positive expression of VEGFR2/CA9/Glut1 and HAF. Our data support the unique central role of the VHL/HIF-2 alpha signaling pathway in the molecular pathogenesis of CNS-HBs and show for the first time the presence of HIF2A mutations in sporadic HB. C1 [Taieb, David] La Timone Univ Hosp, Dept Nucl Med, 264 RUE St Pierre, F-13385 Marseille, France. [Taieb, David] CERIMED, 264 RUE St Pierre, F-13385 Marseille, France. [Taieb, David] Aix Marseille Univ, Inst J Paoli I Calmettes, Marseille Cancerol Res Ctr, Inserm UMR1068, 264 RUE St Pierre, F-13385 Marseille, France. [Barlier, Anne; Pertuit, Morgane] Aix Marseille Univ, Concept Hosp, Mol Biol Lab, F-13385 Marseille, France. [Barlier, Anne; Pertuit, Morgane] Aix Marseille Univ, CNRS, UMR CRN2M 7286, F-13385 Marseille, France. [Yang, Chunzhang; Zhuang, Zhengping] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Tchoghandjian, Aurelie; Figarella-Branger, Dominique] Aix Marseille Univ, La Timone Univ Hosp, Dept Neuropathol, F-13385 Marseille, France. [Rochette, Claire] Aix Marseille Univ, La Timone Univ Hosp, Dept Endocrinol, F-13385 Marseille, France. [Zattara-Canoni, Helene] Aix Marseille Univ, La Timone Univ Hosp, Dept Genet, F-13385 Marseille, France. [Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Metellus, Philippe] Aix Marseille Univ, La Timone Univ Hosp, Dept Neurosurg, F-13385 Marseille, France. RP Taieb, D (reprint author), La Timone Univ Hosp, Dept Nucl Med, 264 RUE St Pierre, F-13385 Marseille, France.; Taieb, D (reprint author), CERIMED, 264 RUE St Pierre, F-13385 Marseille, France.; Taieb, D (reprint author), Aix Marseille Univ, Inst J Paoli I Calmettes, Marseille Cancerol Res Ctr, Inserm UMR1068, 264 RUE St Pierre, F-13385 Marseille, France. EM david.taieb@ap-hm.fr OI Barlier, Anne/0000-0002-3740-6173 NR 37 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD FEB PY 2016 VL 126 IS 3 BP 473 EP 481 DI 10.1007/s11060-015-1983-y PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA DC7TX UT WOS:000369424400013 PM 26514359 ER PT J AU Janssen, I Chen, CC Taieb, D Patronas, NJ Millo, CM Adams, KT Nambuba, J Herscovitch, P Sadowski, SM Fojo, AT Buchmann, I Kebebew, E Pacak, K AF Janssen, Ingo Chen, Clara C. Taieb, David Patronas, Nicholas J. Millo, Corina M. Adams, Karen T. Nambuba, Joan Herscovitch, Peter Sadowski, Samira M. Fojo, Antonio T. Buchmann, Inga Kebebew, Electron Pacak, Karel TI Ga-68-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE Ga-68-DOTATATE; F-18-FDOPA; head and neck paraganglioma ID POSITRON-EMISSION-TOMOGRAPHY; RECEPTOR RADIONUCLIDE THERAPY; METASTATIC PHEOCHROMOCYTOMA; IN-111-PENTETREOTIDE SCINTIGRAPHY; GERMLINE MUTATIONS; GLOMUS TUMORS; SDHB; I-123-METAIODOBENZYLGUANIDINE; SUPERIORITY; EXPRESSION AB Pheochromocytornas/paragangliomas overexpress somatostatin receptors, and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogehase complex, subunit B, mutation-related metastatic pheochromocytomas/paragangliomas using Ga-68-DOTATATE PET/CT. Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared with anatomic imaging with CT/MRI and other functional imaging modalities, including F-18-fluorohydroyphenylalanine (F-18-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. Methods: Ga-68-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent F-18-FDOPA PET/CT, F-18-FDG PET/CT, and CT/MRI, with 18 patients also undergoing F-18-fluorodopamine (F-18-FDA) PET/CT. F-18-FDOPA PET/CT and CT/MRI served as the imaging comparators. Results: Thirty-eight lesions in 20 patients were detected, with F-18-FDOPA PET/CT identifying 37 of 38 and CT/MRI identifying 23 of 38 lesions (P < 0.01). All 38 and an additional 7 lesions (P = 0.016) were detected on Ga-68-DOTATATE PET/CT. Significantly fewer lesions were identified by F-18-FDG PET/CT (24/38, P < 0.01) and F-18-FDA PET/CT (10/34, P < 0.01). Conclusion: Ga-68-DOTATATE PET/CT identified more lesions than other imaging modalities. With the results of the present study, and the increasing availability and use of DOTA analogs in the therapy of neuroendocrine tumors, we expect that Ga-68-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future. C1 [Janssen, Ingo; Adams, Karen T.; Nambuba, Joan; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Adult & Reprod Endocrinol, NIH, Bethesda, MD USA. [Janssen, Ingo; Buchmann, Inga] Univ Hosp Schleswig Holstein, Dept Radiol & Nucl Med, Nucl Med Sect, Lubeck, Germany. [Chen, Clara C.] NIH, Nucl Med Div, Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Taieb, David] Aix Marseille Univ, CERIMED, La Timone Univ Hosp, Dept Nucl Med, Marseille, France. [Patronas, Nicholas J.] NIH, Sect Neuroradiol Radiol & Imaging Sci, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Millo, Corina M.; Herscovitch, Peter] NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sadowski, Samira M.; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. [Fojo, Antonio T.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), Eunice Kennedy Shriver NICHD, Sect Med Neuroendocrinol, NIH, CRC, Bldg 10,Rm 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported, in part, by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. No other potential conflict of interest relevant to this article was reported. NR 37 TC 10 Z9 10 U1 0 U2 3 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 FEB PY 2016 VL 57 IS 2 BP 186 EP 191 DI 10.2967/jnumed.115.161018 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DC6UG UT WOS:000369354500031 PM 26564322 ER PT J AU Zanotti-Fregonara, P Xu, R Zoghbi, SS Liow, JS Fujita, M Veronese, M Gladding, RL Rallis-Frutos, D Hong, J Pike, VW Innis, RB AF Zanotti-Fregonara, Paolo Xu, Rong Zoghbi, Sami S. Liow, Jeih-San Fujita, Masahiro Veronese, Mattia Gladding, Robert L. Rallis-Frutos, Denise Hong, Jinsoo Pike, Victor W. Innis, Robert B. TI The PET Radioligand F-18-FIMX Images and Quantifies Metabotropic Glutamate Receptor 1 in Proportion to the Regional Density of Its Gene Transcript in Human Brain SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE mGluRl; F-18-FIMX; PET; gene transcripts ID IN-VIVO; GRAPHICAL ANALYSIS; SPECTRAL-ANALYSIS; DYNAMIC PET; MGLUR1; BINDING; MONKEY; MODEL; VITRO AB A recent study from our laboratory found that F-18-FIMX is an excellent PET radioligand for quantifying metabotropic glutamate receptor 1 (mGluR1) in monkey brain. This study evaluated the ability of F-18-FIMX to quantify mGluR1 in humans. A second goal was to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific uptake and nondisplaceable uptake (V-ND) in each brain region. Methods: After injection of 189 +/- 3 MBq of F-18-FIMX, 12 healthy volunteers underwent a dynamic PET scarf over 120 min: For 6 volunteers, images were acquired until 210 min. A metabolite corrected arterial input function was measured from the radial artery. Four other subjects underwent whole-body scanning to estimate radiation exposure. Results: F-18-FIMX uptake into the human brain was high (SUV = 4-6 in the cerebellum), peaked at about 10 min, and washed out rapidly. An unconstrained 2-tissue-compartment model fitted the data well, and distribution volume (V-T) (mL.cm(-3)) values ranged from 1.5 in the caudate to 11 in the cerebellum. A 120-min scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 min was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that VND of F-18-FIMX was quite low (0.5 mL.cm(-3)). This measure of VND in humans was similar to that from a receptor blocking study in monkeys, after correcting for differences in plasma protein binding. Similar to other F-18-labeled ligands, the effective dose was about 23 mu Sv/MBq. Conclusion: F-18-FIMX can quantify mGluR1 in the human brain with a 120- to 170-min scan. Correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacologic doses of a blocking agent. C1 [Zanotti-Fregonara, Paolo; Xu, Rong; Zoghbi, Sami S.; Liow, Jeih-San; Fujita, Masahiro; Gladding, Robert L.; Rallis-Frutos, Denise; Hong, Jinsoo; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Zanotti-Fregonara, Paolo] Univ Bordeaux, INCIA UMR CNRS 5287, Pl Amelie Raba Leon, F-33076 Bordeaux, France. [Veronese, Mattia] Kings Coll London, IoPPN, Dept Neuroimaging, London WC2R 2LS, England. RP Zanotti-Fregonara, P (reprint author), Univ Bordeaux, INCIA UMR CNRS 5287, Pl Amelie Raba Leon, F-33076 Bordeaux, France. EM paolo.zanotti-fregonara@chu-bordeaux.fr RI Veronese, Mattia/A-6012-2013 OI Veronese, Mattia/0000-0003-3562-0683 FU Intramural Research Program of the National Institute of Mental Health [ZIAMH002852]; National Institutes of Health (IRP-NIMH-NIH) FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by the Intramural Research Program of the National Institute of Mental Health (project no. ZIAMH002852, under clinicaltrials.gov identifier NCT02230592), National Institutes of Health (IRP-NIMH-NIH). No other potential conflict of interest relevant to this article was reported. NR 28 TC 4 Z9 4 U1 0 U2 6 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 FEB PY 2016 VL 57 IS 2 BP 242 EP 247 DI 10.2967/jnumed.115.162461 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DC6UG UT WOS:000369354500041 PM 26514176 ER PT J AU Garvey, M Avenevoli, S Anderson, K AF Garvey, Marjorie Avenevoli, Shelli Anderson, Kathleen TI The National Institute of Mental Health Research Domain Criteria and Clinical Research in Child and Adolescent Psychiatry SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE Research Domain Criteria; RDoC; clinical research; child and adolescent psychiatry; National Institute of Mental Health ID SIBLINGS RESEARCH CONSORTIUM; COMPUTERIZED NEUROCOGNITIVE BATTERY; AUTISM SPECTRUM DISORDER; HIGH BLOOD-PRESSURE; DEVELOPMENTAL PSYCHOPATHOLOGY; ALZHEIMERS-DISEASE; RDOC FRAMEWORK; 7TH REPORT; NEUROSCIENCE; COMORBIDITY AB Objective: This review discusses the relevance of the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) to clinical research in child and adolescent psychiatry. Method: We summarize the characteristics of the NIMH RDoC project and then provide examples of RDoC designs that are of relevance to clinical investigators in child and adolescent psychiatry. The final section addresses questions regarding the impact of RDoC on clinical care. Results: RDoC encourages investigators to investigate psychopathology dimensionally: greater or lesser degrees of healthy/adapted functioning of neurobiological, cognitive, and behavioral processes (constructs) that cut across current diagnostic categories. Elucidation of the developmental components of RDoC constructs is needed to ensure they are fully validated. Integrating RDoC approaches into clinical research of child and adolescent psychopathology is contributing to our understanding of development as an aspect of the heterogeneity within DSM disorders and commonalities across seemingly disparate disorders. Continued efforts promise to also explain the processes that lead to mental illness in at-risk populations. Conclusion: Incorporating an RDoC approach in clinical research in child and adolescent psychiatry promises to be a fruitful avenue of research into the root causes and manifestations of mental illness, which will eventually lead to more precise treatments. Although the long-term aspiration of RDoC is to help reduce the burden of suffering for those with mental illnesses, it is not intended to be used for practical clinical purposes at this early stage. C1 [Garvey, Marjorie; Avenevoli, Shelli; Anderson, Kathleen] NIMH, Div Translat Res, Bethesda, MD 20892 USA. RP Garvey, M (reprint author), 6001 Execut Blvd, Bethesda, MD 20852 USA. EM marjorie.garvey@nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 39 TC 6 Z9 6 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2016 VL 55 IS 2 BP 93 EP 98 DI 10.1016/j.jaac.2015.11.002 PG 6 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DC6TQ UT WOS:000369352900003 PM 26802775 ER PT J AU Sylvester, CM Barch, DM Harms, MP Belden, AC Oakberg, TJ Gold, AL White, LK Benson, BE Troller-Renfree, S Degnan, KA Henderson, HA Luby, JL Fox, NA Pine, DS AF Sylvester, Chad M. Barch, Deanna M. Harms, Michael P. Belden, Andy C. Oakberg, Timothy J. Gold, Andrea L. White, Lauren K. Benson, Brenda E. Troller-Renfree, Sonya Degnan, Kathryn A. Henderson, Heather A. Luby, Joan L. Fox, Nathan A. Pine, Daniel S. TI Early Childhood Behavioral Inhibition Predicts Cortical Thickness in Adulthood SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE behavioral inhibition; anxiety; cortical thickness; structural MRI; cingulate ID GENERALIZED ANXIETY DISORDER; HUMAN CEREBRAL-CORTEX; VOXEL-BASED MORPHOMETRY; PEDIATRIC ANXIETY; SURFACE RECONSTRUCTION; ATTENTION NETWORK; COGNITIVE CONTROL; TEMPERAMENT; CHILDREN; ASSOCIATIONS AB Objective: Behavioral inhibition (BI) during early childhood predicts risk for anxiety disorders and altered cognitive control in adolescence. Although BI has been linked to variation in brain function through adulthood, few studies have examined relations between early childhood BI and adult brain structure. Method: The relation between early childhood BI and cortical thickness in adulthood was examined in a cohort of individuals followed since early childhood (N = 53, mean age 20.5 years). Analyses tested whether anxiety and/or cognitive control during adolescence moderated relations between BI and cortical thickness. Cognitive control was measured with the Eriksen Flanker Task. Initial analyses examined cortical thickness in regions of interest previously implicated in BI, anxiety disorders, and cognitive control: dorsal anterior cingulate (dACC), anterior insula (aI), and subgenual anterior cingulate (sgACC); and volumes of the amygdala and hippocampus. Exploratory analyses examined relations across the prefrontal cortex. Results: BI during early childhood related to thinner dACC in adulthood. Neither anxiety nor cognitive control moderated this relation. A stronger congruency effect on the Eriksen Flanker Task during adolescence independently related to thinner dACC in adulthood. Higher anxiety during adolescence related to thicker cortex in the right ventrolateral prefrontal cortex (VLPFC) in adulthood among those with low BI as children. Conclusion: Temperament in early childhood and the interaction between temperament and later anxiety relate to adult brain structure. These results are consistent with prior work associating BI and anxiety with functional brain variability in the dACC and VLPFC. C1 [Sylvester, Chad M.; Barch, Deanna M.; Harms, Michael P.; Belden, Andy C.; Luby, Joan L.] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Oakberg, Timothy J.] Univ Colorado Denver, Denver, CO USA. [Gold, Andrea L.; White, Lauren K.; Benson, Brenda E.; Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Troller-Renfree, Sonya; Degnan, Kathryn A.; Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Henderson, Heather A.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. RP Sylvester, CM (reprint author), Washington Univ, Sch Med, Psychiat, 4444 Forest Pk,Suite 2500, St Louis, MO 63110 USA. EM sylvestc@psychiatry.wustl.edu RI Belden, Andy/I-1830-2012; OI Belden, Andy/0000-0002-3294-9232; Harms, Michael/0000-0001-7945-036X; Gold, Andrea/0000-0003-4447-776X FU National Institutes of Health [T32MH100019, R01MH090786, R37HD017899, U01MH093349, R01MH074454]; Parker Fund; Taylor Institute; NIMH Intramural Research Program FX This research was supported by National Institutes of Health grants T32MH100019 (C.S.), R01MH090786 (D.B. and J.L.), R37HD017899 (N.F.), U01MH093349 (N F), R01MH074454 (N.F.); the Parker Fund (C.S.); the Taylor Institute (C.S); and the NIMH Intramural Research Program (D.P.). NR 60 TC 2 Z9 2 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2016 VL 55 IS 2 BP 122 EP 129 DI 10.1016/j.jaac.2015.11.007 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DC6TQ UT WOS:000369352900007 PM 26802779 ER PT J AU Watsky, RE Pollard, KL Greenstein, D Shora, L Dillard-Broadnax, D Gochman, P Clasen, LS Berman, RA Rapoport, JL Gogtay, N Ordonez, AE AF Watsky, Rebecca E. Pollard, Katharine Ludovici Greenstein, Deanna Shora, Lorie Dillard-Broadnax, Diane Gochman, Peter Clasen, Liv S. Berman, Rebecca A. Rapoport, Judith L. Gogtay, Nitin Ordonez, Anna E. TI Severity of Cortical Thinning Correlates With Schizophrenia Spectrum Symptoms SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE schizophrenia spectrum; cortical thinning; childhood-onset schizophrenia; psychosis; schizotypal personality disorder ID CHILDHOOD-ONSET SCHIZOPHRENIA; SCHIZOTYPAL PERSONALITY-DISORDER; GRAY-MATTER DEFICITS; NONPSYCHOTIC SIBLINGS; BRAIN-DEVELOPMENT; PSYCHOSIS; FAMILY; RISK; ABNORMALITIES; FEATURES AB Objective: This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS). Method: A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings. Results: Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers. Conclusion: The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype. C1 [Watsky, Rebecca E.; Pollard, Katharine Ludovici; Greenstein, Deanna; Shora, Lorie; Dillard-Broadnax, Diane; Gochman, Peter; Clasen, Liv S.; Berman, Rebecca A.; Rapoport, Judith L.; Gogtay, Nitin; Ordonez, Anna E.] NIMH, Child Psychiat Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Watsky, RE (reprint author), NIMH, Child Psychiat Branch, Room 4N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM rebecca.watsky@nih.gov FU National Institute of Mental Health [84-M-0050] FX This research was supported by the Intramural Research Program of the National Institute of Mental Health; Protocol ID 84-M-0050. NR 43 TC 0 Z9 1 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD FEB PY 2016 VL 55 IS 2 BP 130 EP 136 DI 10.1016/j.jaac.2015.11.008 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA DC6TQ UT WOS:000369352900008 PM 26802780 ER PT J AU Rabel, A Leitman, SF Miller, JL AF Rabel, Antoinette Leitman, Susan F. Miller, Jeffery L. TI Ask about ice, then consider iron SO JOURNAL OF THE AMERICAN ASSOCIATION OF NURSE PRACTITIONERS LA English DT Review DE Pica; iron deficiency; pagophagia; review; menstruation; pregnancy; hemorrhage ID DEFICIENCY ANEMIA; BLOOD-DONORS; PICA; PAGOPHAGIA; PREGNANCY; WOMEN; MANAGEMENT; GEOPHAGIA; THERAPY; HISTORY AB Background and purposeThe study aims to review a condition defined by the desire to consume ice in order to satisfy an addictive-like compulsion, rather than for purposes of hydration or pain relief. This condition is called ice pica, or pagophagia. Associations between ice pica and iron deficiency, suggestions for clinical screening of at risk populations, and recommendations for treatment and follow-up care are provided. Data SourcesAn extensive literature review of original research articles, reviews, clinical practice manuscripts, and scientific publications on pica and pagophagia. ConclusionsA compulsion or craving for the consumption of ice is often overlooked in clinical practice. It is therefore important for clinicians to include ice pica as part of the review of systems for certain patient populations. Ice pica is frequently associated with iron deficiency, and iron supplementation is an effective therapy in most cases. Implications for practiceKnowledge gained from screening for ice pica can generate valuable patient information and lead to the diagnosis and treatment of iron deficiency. The populations at risk include young women and blood donors of either sex. C1 [Rabel, Antoinette; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. [Leitman, Susan F.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, 10 Ctr Dr,Bldg 10,Room 9N311, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU Intramural Research Program of the NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 41 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2327-6886 EI 2327-6924 J9 J AM ASSOC NURSE PRA JI J. Am. Assoc. Nurs. Pract. PD FEB PY 2016 VL 28 IS 2 BP 116 EP 120 DI 10.1002/2327-6924.12268 PG 5 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA DC3ZO UT WOS:000369159500010 PM 25943566 ER PT J AU Eicher, JD Xue, LT Ben-Shlomo, Y Beswick, AD Johnson, AD AF Eicher, John D. Xue, Luting Ben-Shlomo, Yoav Beswick, Andrew D. Johnson, Andrew D. TI Replication and hematological characterization of human platelet reactivity genetic associations in men from the Caerphilly Prospective Study (CaPS) SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Platelet aggregation; SNPs; Thrombin; Blood platelets; Platelet count ID ISCHEMIC-HEART-DISEASE; GENOME-WIDE ASSOCIATION; VON-WILLEBRAND-FACTOR; FIBRIN D-DIMER; WHOLE-BLOOD; AGGREGATION; PEAR1; ACTIVATION; RISK; MEGAKARYOPOIESIS AB Platelet reactivity, an important factor in hemostasis and chronic disease, has widespread inter-individual variability with a substantial genetic contribution. Previously, our group performed a genome-wide association study of platelet reactivity identifying single nucleotide polymorphisms (SNPs) associated with ADP- and epinephrine- induced aggregation, including SNPs in MRVI1, PIK3CG, JMJD1C, and PEAR1, among others. Here, we assessed the association of these previously identified SNPs with ADP-, thrombin-, and shear- induced platelet aggregation. Additionally, we sought to expand the association of these SNPs with blood cell counts and hemostatic factors. To accomplish this, we examined the association of 12 SNPs with seven platelet reactivity and various hematological measures in 1300 middle-aged men in the Caerphilly Prospective Study. Nine of the examined SNPs showed at least suggestive association with platelet reactivity. The strongest associations were with rs12566888 in PEAR1 to ADP-induced (p = 1.51 x 10(-7)) and thrombin-induced (p = 1.91 x 10(-6)) reactivity in platelet rich plasma. Our results indicate PEAR1 functions in a relatively agonist independent manner, possibly through subsequent intracellular propagation of platelet activation. rs10761741 in JMJD1C showed suggestive association with ADP-induced reactivity (p = 1.35 x 10(-3)), but its strongest associations were with platelet-related cell counts (p = 1.30 x 10(-9)). These associations indicate variation in JMJD1C influences pathways that modulate platelet development as well as those that affect reactivity. Associations with other blood cell counts and hemostatic factors were generally weaker among the tested SNPs, indicating a specificity of these SNPs' function to platelets. Future genome-wide analyses will further assess association of these genes and identify new genes important to platelet biology. C1 [Eicher, John D.; Xue, Luting; Johnson, Andrew D.] Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Xue, Luting] Boston Univ, Biostat Program, Boston, MA 02215 USA. [Ben-Shlomo, Yoav] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Beswick, Andrew D.] Univ Bristol, Sch Clin Sci, Bristol, Avon, England. RP Johnson, AD (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA.; Johnson, AD (reprint author), NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. EM johnsonad2@nhlbi.nih.gov RI Johnson, Andrew/G-6520-2013 FU National Heart, Lung and Blood Institute; Medical Research Council of the United Kingdom; MRC Grant [G9824960] FX The authors wish to acknowledge the subjects who volunteered their time and effort as well as the National Heart, Lung and Blood Institute Intramural Research Program funding to Dr. Chris J. O'Donnell for the support of SNP genotyping. The Caerphilly Prospective Study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The Caerphilly DNA Bank was established by an MRC Grant (G9824960). NR 36 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD FEB PY 2016 VL 41 IS 2 SI SI BP 343 EP 350 DI 10.1007/s11239-015-1290-7 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA DC6OH UT WOS:000369338900015 PM 26519038 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from USDA and OLAW SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 EI 1548-4475 J9 LAB ANIMAL JI Lab Anim. PD FEB PY 2016 VL 45 IS 2 BP 59 EP 59 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA DC6TI UT WOS:000369352100017 PM 26814350 ER PT J AU Florea, AD Townsley, DM Dumitriu, B Winkler, T Valdez, J Bolan, C Dunbar, C Young, N Braylan, RC Calvo, KR AF Florea, Alina Dulau Townsley, Danielle M. Dumitriu, Bogdan Winkler, Thomas Valdez, Janet Bolan, Charles Dunbar, Cynthia Young, Neal Braylan, Raul C. Calvo, Katherine R. TI Multilineage Bone Marrow Response to Eltrombopag in Aplastic Anemia SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 [Florea, Alina Dulau; Townsley, Danielle M.; Dumitriu, Bogdan; Winkler, Thomas; Valdez, Janet; Bolan, Charles; Dunbar, Cynthia; Young, Neal; Braylan, Raul C.; Calvo, Katherine R.] NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1357 BP 342A EP 342A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702098 ER PT J AU Florea, AD Young, N Maric, I Braylan, RC AF Florea, Alina Dulau Young, Neal Maric, Irina Braylan, Raul C. TI Expression of Glycosylphosphatidylinositol (GPI) Anchor Protein (AP) in Bone Marrows of Normal Subjects and Aplastic Anemia Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Clones, as Determined by Fluorescent Aerolysin (FLAER) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. NHLBI, Bldg 10, 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1356 BP 342A EP 342A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702097 ER PT J AU Gong, SY Ganapathi, KA McCall, CM Crane, GM Xi, LQ Raffeld, M Pittaluga, S Duffield, AS Jaffe, ES AF Gong, Shunyou Ganapathi, Karthik A. McCall, Chad M. Crane, Genevieve M. Xi, Liqiang Raffeld, Mark Pittaluga, Stefania Duffield, Amy S. Jaffe, Elaine S. TI EBV plus Marginal Zone Lymphoma in Immunocompromised Patients: Report of Five Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1376 BP 347A EP 347A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702117 ER PT J AU Kallen, ME Townsley, DM Dumitriu, B Hsu, AP Ganapathi, KA Wang, WX Bolan, C Holland, SM Young, NS Calvo, KR AF Kallen, Michael E. Townsley, Danielle M. Dumitriu, Bogdan Hsu, Amy P. Ganapathi, Karthik A. Wang, Weixin Bolan, Charles Holland, Steven M. Young, Neal S. Calvo, Katherine R. TI Bone Marrow Failure in Telomere Disease in Comparison to Aplastic Anemia and GATA2 Deficiency SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Bldg 10, Bethesda, MD 20892 USA. 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1405 BP 355A EP 355A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702146 ER PT J AU Schmidt, J Salaverria, I Gong, SY Pittaluga, S Gonzalez, B Balague, O Marafioti, T Mozos, A Cabecadas, JM Bonzheim, I Fend, F Campo, E Jaffe, ES Quintanilla-Fend, L AF Schmidt, Janine Salaverria, Itziar Gong, Shunyou Pittaluga, Stefania Gonzalez, Blanca Balague, Olga Marafioti, Theresa Mozos, Anna Cabecadas, Jose M. Bonzheim, Irina Fend, Falko Campo, Elias Jaffe, Elaine S. Quintanilla-Fend, Leticia TI The Genetic Landscape in Follicular Lymphoma, Pediatric Type SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Univ Hosp, Tubingen, Germany. IDIBAPS, Hosp Clin, Barcelona, Spain. NCI, Bethesda, MD 20892 USA. Barts & London NHS Trust, London, England. Hosp Santa Creu & Sant Pau, Barcelona, Spain. Inst Portugues Oncol Francisco Gentil, Lisbon, Portugal. NR 0 TC 0 Z9 0 U1 5 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1483 BP 376A EP 376A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702223 ER PT J AU Wake, LM Ahn, I Farooqui, M Hahn, J Tian, X Stetler-Stevenson, M Marti, G Wiestner, A Maric, I AF Wake, Laura M. Ahn, Inhye Farooqui, Mohammed Hahn, Jamie Tian, Xin Stetler-Stevenson, Maryalice Marti, Gerald Wiestner, Adrian Maric, Irina TI Dual Antibody Immunohistochemistry: A Cost-Efficient and Sensitive New Tool for the Detection of Minimal Residual CLL SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NIH, CC, DLM, Bldg 10, Bethesda, MD 20892 USA. US FDA, CDRH, Bethesda, MD 20014 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1507 BP 382A EP 382A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702246 ER PT J AU Xiao, WB Sanchez, GM Marrero, B de Jesus, AA Miniti, C Gong, SY Schafernak, KT Goldbach-Mansky, R Calvo, KR AF Xiao, Wenbin Sanchez, Gina Montealegre Marrero, Bernadette de Jesus, Adriana Almeida Miniti, Caterina Gong, Shunyou Schafernak, Kristian T. Goldbach-Mansky, Raphaela Calvo, Katherine R. TI Spectrum of Bone Marrow Features in CANDLE Syndrome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, CC, Bldg 10, Bethesda, MD 20892 USA. NIAMS, NIH, Bethesda, MD USA. NHLBI, Bldg 10, Bethesda, MD 20892 USA. Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA. Phoenix Childrens Hosp, Phoenix, AZ 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1520 BP 385A EP 385A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702259 ER PT J AU Xiao, WB Kuang, FL Sharma, S Hahn, J Stetler-Stevenson, M Raffeld, M Klion, A Maric, I AF Xiao, Wenbin Kuang, Fei Li Sharma, Sachein Hahn, Jamie Stetler-Stevenson, Maryalice Raffeld, Mark Klion, Amy Maric, Irina TI Hypereosinophilic Syndrome with Clonal T-cell Receptor Gene Rearrangement: A Retrospective Study of 51 Patients SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NCI, 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1519 BP 385A EP 385A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702258 ER PT J AU McCarthy, A Moreno, V Xu, NZ Kennedy, S Merino, MJ AF McCarthy, Aoife Moreno, Vanessa Xu Naizhen Kennedy, Susan Merino, Maria J. TI PD-L1 Expression in Intraocular Malignant Melanomas. Correlation with Morphologic Patterns and Outcome SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Royal Victoria Eye & Ear Hosp, Dublin, Ireland. 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1718 BP 433A EP 434A PG 2 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702456 ER PT J AU McCarthy, A Moreno, V Xu, NZ Kennedy, S Merino, MJ AF McCarthy, Aoife Moreno, Vanessa Xu Naizhen Kennedy, Susan Merino, Maria J. TI Intraocular Malignant Melanoma: Correlation of Morphological and Molecular Findings with Outcome in an Irish Cohort SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Royal Victoria Eye & Ear Hosp, Dublin, Ireland. NCI, 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1717 BP 433A EP 433A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702455 ER PT J AU Pineda, I Edwards, N Goldstein, D Ray-Chaudhury, A AF Pineda, Itzel Edwards, Nancy Goldstein, David Ray-Chaudhury, Abhik TI Expression of Nuclear Receptor NR4A3 in Multiple System Atrophy and Dementia With Lewy Bodies SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 [Pineda, Itzel; Edwards, Nancy; Goldstein, David; Ray-Chaudhury, Abhik] NINDS, NIH, Bldg 36,Rm 4D04, 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1726 BP 435A EP 435A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702464 ER PT J AU Adsay, V Roa, JC Basturk, O Torres, J Mucientes, F Del Pozo, M Villaseca, MA Aguayo, G Bellolio, ER Araya, JC Endo, I Lee, K Jang, KT Jang, JY Ohike, N Shimizu, M Hirabayashi, K Terris, B Zamboni, G Reid, M Xue, Y Bedolla, G Quigley, B Krasinskas, A Akkas, G Memis, B Klimstra, D Hruban, RH Zhu, B Van Dyke, AL Koshiol, J AF Adsay, Volkan Roa, Juan Carlos Basturk, Olca Torres, Javiera Mucientes, Francisco Del Pozo, Maeva Villaseca, Miguel A. Aguayo, Gloria Bellolio, Enrique R. Araya, Juan Carlos Endo, Itaru Lee, KyoungBun Jang, Kee-Taek Jang, Jin-Young Ohike, Nobu Shimizu, Michio Hirabayashi, Kenichi Terris, Benoit Zamboni, Giuseppe Reid, Michelle Xue, Yue Bedolla, Gabriela Quigley, Brian Krasinskas, Alyssa Akkas, Gizem Memis, Bahar Klimstra, David Hruban, Ralph H. Zhu, Bin Van Dyke, Alison L. Koshiol, Jill TI Epithelial Atypia in the Gallbladder: Diagnosis and Classification in an International Consensus Study SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Emory, Atlanta, GA USA. Pontificia Univ Catolica Chile, Alameda 340, Santiago, Chile. MSKCC, New York, NY USA. Yokohama City Univ, Yokohama, Kanagawa 232, Japan. SNU, Seoul, South Korea. SMC, Seoul, South Korea. Showa, Tokyo, Japan. Hakujikai Hosp, Tokyo, Japan. Hosp Cochin, Paris, France. Univ Verona, I-37100 Verona, Italy. JHU, Baltimore, MD USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1738 BP 438A EP 439A PG 3 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702476 ER PT J AU Roa, JC Basturk, O Torres, J Mucientes, F Del Pozo, M Villaseca, MA Aguayo, G Bellolio, ER Araya, JC Endo, I Jang, KT Lee, K Jang, JY Ohike, N Shimizu, M Hirabayashi, K Terris, B Zamboni, G Reid, M Xue, Y Bedolla, G Quigley, B Krasinskas, AM Akkas, G Memis, B Klimstra, D Hruban, RH Zhu, B Van Dyke, AL Koshiol, J Adsay, V AF Roa, Juan Carlos Basturk, Olca Torres, Javiera Mucientes, Francisco Del Pozo, Maeva Villaseca, Miguel A. Aguayo, Gloria Bellolio, Enrique R. Araya, Juan Carlos Endo, Itaru Jang, Kee-Taek Lee, KyoungBun Jang, Jin-Young Ohike, Nobu Shimizu, Michio Hirabayashi, Kenichi Terris, Benoit Zamboni, Giuseppe Reid, Michelle Xue, Yue Bedolla, Gabriela Quigley, Brian Krasinskas, Alyssa M. Akkas, Gizem Memis, Bahar Klimstra, David Hruban, Ralph H. Zhu, Bin Van Dyke, Alison L. Koshiol, Jill Adsay, Volkan TI Marked Geographic Differences in the Pathologic Diagnosis of Non-Invasive (Tis) vs Minimally Invasive (T1) Gallbladder Cancer: Santiago Consensus Conference Highlights the Need for the Unifying Category "Early Gallbladder Cancer" (EGBC) SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Pontificia Univ Catolica Chile, Alameda 340, Santiago, Chile. MSKCC, New York, NY USA. Yokohama City Univ, Yokohama, Kanagawa 232, Japan. SMC, Seoul, South Korea. SNU, Seoul, South Korea. Showa, Tokyo, Japan. Hakujikai Hosp, Tokyo, Japan. Tokai Univ, Tokyo 151, Japan. Hop Cochin, 27 Rue Faubourg St Jacques, F-75674 Paris, France. Univ Verona, I-37100 Verona, Italy. Emory Univ, Atlanta, GA 30322 USA. JHU, Baltimore, MD USA. NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1772 BP 447A EP 447A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702510 ER PT J AU Killian, J Arcila, ME Batlevi, C Ladanyi, M Meltzer, P Ptashkin, R Younes, A AF Killian, Jonathan Arcila, Maria E. Batlevi, Connie Ladanyi, Marc Meltzer, Paul Ptashkin, Ryan Younes, Anas TI Utility of Oral Fluid (Saliva) for Molecular Profiling in Hematologic Malignancy SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1803 BP 455A EP 455A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270702541 ER PT J AU Felisiak-Golabek, A Wasag, B Wang, ZF Czapiewski, P Biernat, W Lasota, J Miettinen, M AF Felisiak-Golabek, Anna Wasag, Bartosz Wang, Zengfeng Czapiewski, Piotr Biernat, Wojciech Lasota, Jerzy Miettinen, Markku TI Inactivation of BRCA1 Associated Protein-1 (BAP1) in Mesothelioma. Immunohistochemical and Molecular Genetic Study of 94 Cases SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 NCI, Bethesda, MD 20892 USA. Med Univ Gdansk, Gdansk, Poland. 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 1862 BP 470A EP 470A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270703014 ER PT J AU Varma, H Faust, PL Nagy, PL Iglesias, AD Lagana, SM Wou, K Hirano, M Mansukhani, M Hoff, KE Copeland, WC Naini, AB AF Varma, Hemant Faust, Phyllis L. Nagy, Peter L. Iglesias, Alejandro D. Lagana, Stephen M. Wou, Karen Hirano, Michio Mansukhani, Mahesh Hoff, Kirsten E. Copeland, William C. Naini, Ali B. TI Whole-Exome Sequencing Identifies a Homozygous POLG2 Missense Variant in an Infant with Fulminant Hepatic Failure and Mitochondrial DNA Depletion SO LABORATORY INVESTIGATION LA English DT Meeting Abstract CT 105th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 12-18, 2016 CL Seattle, WA SP US & Canadian Acad Pathol C1 Columbia Univ, Med Ctr, New York, NY USA. New York Presbyterian Hosp, New York, NY USA. NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 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 0023-6837 EI 1530-0307 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2016 VL 96 SU 1 MA 2079 BP 523A EP 523A PG 1 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA DC5OQ UT WOS:000369270703231 ER PT J AU Mattijssen, S Maraia, RJ AF Mattijssen, Sandy Maraia, Richard J. TI LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; MESSENGER-RNA DECAY; GENE-EXPRESSION; LA; BINDING; SEQUENCE; TTP; MECHANISMS; STABILITY; CELLS AB LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3' un-translated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of beta-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-alpha), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-alpha-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-alpha-TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. C1 [Mattijssen, Sandy; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA. [Maraia, Richard J.] US PHS, Commissioned Corps, Washington, DC USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA.; Maraia, RJ (reprint author), US PHS, Commissioned Corps, Washington, DC USA. EM maraiar@mail.nih.gov FU HHS \ NIH \ National Institute of Child Health and Human Development (NICHD) [HD000412-23] FX HHS vertical bar NIH vertical bar National Institute of Child Health and Human Development (NICHD) provided funding to Richard J. Maraia under grant number HD000412-23. NR 38 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2016 VL 36 IS 4 BP 574 EP 584 DI 10.1128/MCB.00804-15 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DC5YF UT WOS:000369295900004 ER PT J AU Zakharov, AV Varlamova, EV Lagunin, AA Dmitriev, AV Muratov, EN Fourches, D Kuz'min, VE Poroikov, VV Tropsha, A Nicklaus, MC AF Zakharov, Alexey V. Varlamova, Ekaterina V. Lagunin, Alexey A. Dmitriev, Alexander V. Muratov, Eugene N. Fourches, Denis Kuz'min, Victor E. Poroikov, Vladimir V. Tropsha, Alexander Nicklaus, Marc C. TI QSAR Modeling and Prediction of Drug-Drug Interactions SO MOLECULAR PHARMACEUTICS LA English DT Article DE drug-drug interactions; QSAR modeling; simplex descriptors; GUSAR; QNA; DDI; toxicity; adverse drug reactions; mixtures ID TETRAHYMENA-PYRIFORMIS; MOLECULAR-STRUCTURE; SIMILARITY; CYTOCHROME-P450; COMBINATIONS; STRATEGIES; TOXICITY; POINT; PASS; TIME AB Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100 000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27 966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database. C1 [Zakharov, Alexey V.; Nicklaus, Marc C.] NCI, Comp Aided Drug Design Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS, 376 Boyles St, Frederick, MD 21702 USA. [Varlamova, Ekaterina V.; Kuz'min, Victor E.] Natl Acad Sci Ukraine, AV Bogatsky Phys Chem Inst, Dept Mol Struct & Cheminformat, Lustdorfskaya Doroga 86, UA-65080 Odessa, Ukraine. [Varlamova, Ekaterina V.] Odessa Natl Polytech Univ, Dept Chem Technol, 1 Shevchenko Ave, UA-65000 Odessa, Ukraine. [Lagunin, Alexey A.; Dmitriev, Alexander V.; Poroikov, Vladimir V.] Inst Biochem Chem, 10-8 Pogodinskaya St, Moscow 119121, Russia. [Lagunin, Alexey A.] Pirogov Russian Natl Res Med Univ, Medicobiol Dept, Ostrovitianov Str 1, Moscow 117997, Russia. [Muratov, Eugene N.; Tropsha, Alexander] Univ N Carolina, Lab Mol Modeling, Div Chem Biol & Med Chem, UNC Eshelman Sch Pharm, Beard Hall 301,CB 7568, Chapel Hill, NC 27599 USA. [Fourches, Denis] N Carolina State Univ, Dept Chem, Bioinformat Res Ctr, Raleigh, NC 27695 USA. RP Nicklaus, MC (reprint author), NCI, Comp Aided Drug Design Grp, Biol Chem Lab, Ctr Canc Res,NIH,DHHS, 376 Boyles St, Frederick, MD 21702 USA. EM mn1@helix.nih.gov RI Muratov, Eugene/C-4454-2014; Lagunin, Alexey/G-3745-2010; Dmitriev, Alexander/R-9165-2016 OI Muratov, Eugene/0000-0003-4616-7036; Lagunin, Alexey/0000-0003-1757-8004; FU Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]; Russian Scientific Foundation [14-15-00449, 14-43-00024]; NIH [GM66940, GM096967]; FAPEG [201310267001095]; STCU [P407] FX This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Creation of the data sets of drugs made by A.A.L., A.V.D., and V.V.P. was partly supported by the Russian Scientific Foundation grant 14-15-00449. E.N.M., D.F., and A.T. acknowledge partial support by NIH (grants GM66940 and GM096967) and FAPEG (grant 201310267001095). A.T. acknowledges partial support from the Russian Scientific Foundation (project 14-43-00024). E.V.V., E.N.M., and V.E.K. acknowledge partial support from STCU (Grant P407). We thank Neil B. Sandson for useful discussions. NR 48 TC 3 Z9 3 U1 8 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD FEB PY 2016 VL 13 IS 2 BP 545 EP 556 DI 10.1021/acs.molpharmaceut.5b00762 PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA DC6VE UT WOS:000369356900022 PM 26669717 ER PT J AU Gillet, JP Andersen, JB Madigan, JP Varma, S Bagni, RK Powell, K Burgan, WE Wu, CP Calcagno, AM Ambudkar, SV Thorgeirsson, SS Gottesman, MM AF Gillet, Jean-Pierre Andersen, Jesper B. Madigan, James P. Varma, Sudhir Bagni, Rachel K. Powell, Katie Burgan, William E. Wu, Chung-Pu Calcagno, Anna Maria Ambudkar, Suresh V. Thorgeirsson, Snorri S. Gottesman, Michael M. TI A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy SO MOLECULAR PHARMACOLOGY LA English DT Article ID CANCER RESISTANCE PROTEIN; MEMBRANE TRANSPORTERS; MULTIDRUG-RESISTANCE; BRAIN ACCUMULATION; CONNECTIVITY MAP; CHEMORESISTANCE; SORAFENIB; CELLS; CHEMOSENSITIVITY; CLASSIFICATION AB Despite improvements in the management of liver cancer, the survival rate for patients with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role. Here, we analyzed the expression of 377 multidrug resistance (MDR)-associated genes in two independent cohorts of patients with advanced HCC, with the aim of finding ways to improve survival in this poor-prognosis cancer. Taqman-based quantitative polymerase chain reaction revealed a 45-gene signature that predicts overall survival (OS) in patients with HCC. Using the Connectivity Map Tool, we were able to identify drugs that converted the gene expression profiles of HCC cell lines from ones matching patients with poor OS to profiles associated with good OS. We found three compounds that convert the gene expression profiles of three HCC cell lines to gene expression profiles associated with good OS. These compounds increase histone acetylation, which correlates with the synergistic sensitization of those MDR tumor cells to conventional chemotherapeutic agents, including cisplatin, sorafenib, and 5-fluorouracil. Our results indicate that it is possible to modulate gene expression profiles in HCC cell lines to those associated with better outcome. This approach also increases sensitization of HCC cells toward conventional chemotherapeutic agents. This work suggests new treatment strategies for a disease for which few therapeutic options exist. C1 [Gillet, Jean-Pierre; Madigan, James P.; Wu, Chung-Pu; Calcagno, Anna Maria; Ambudkar, Suresh V.; Gottesman, Michael M.] NIH, Cell Biol Lab, Bldg 10, Bethesda, MD 20892 USA. [Andersen, Jesper B.; Thorgeirsson, Snorri S.] NIH, Expt Carcinogenesis Lab, Bldg 10, Bethesda, MD 20892 USA. [Varma, Sudhir] NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Varma, Sudhir] NIAID, NIH, Off Sci Management & Operat, Off Cyber Infrastructure & Computat Biol,Bioinfor, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bagni, Rachel K.; Powell, Katie; Burgan, William E.] NIH, Frederick Natl Lab Canc Res, Prot Express Lab, Viral Technol Grp, Frederick, MD USA. [Bagni, Rachel K.; Powell, Katie; Burgan, William E.] NIH, Frederick Natl Lab Canc Res, Prot Express Lab, Mol Detect Grp, Frederick, MD USA. [Gillet, Jean-Pierre] Univ Namur, Fac Med, Namur Res Inst Life Sci NARILIS, Lab Mol Canc Biol,Mol Physiol Res Unit URPhyM, Namur, Belgium. [Andersen, Jesper B.] Univ Copenhagen, Biotech Res & Innovat Ctr, Ole Maaloes Vej 5, DK-2200 Copenhagen N, Denmark. RP Gottesman, MM (reprint author), Cell Biol Lab, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottes-man@nih.gov FU Intramural Research Program of the National Institutes of Health (NIH); federal funds from the National Cancer Institute NIH [HHSN2612008000001E] FX This research was funded by the Intramural Research Program of the National Institutes of Health (NIH). The project was funded in part with federal funds from the National Cancer Institute NIH [Contract HHSN2612008000001E]. 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 42 TC 2 Z9 2 U1 2 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2016 VL 89 IS 2 BP 263 EP 272 DI 10.1124/mol.115.101360 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC6BV UT WOS:000369305700006 PM 26668215 ER PT J AU Fritsche, LG Igl, W Bailey, JNC Grassmann, F Sengupta, S Bragg-Gresham, JL Burdon, KP Hebbring, SJ Wen, C Gorski, M Kim, IK Cho, D Zack, D Souied, E Scholl, HPN Bala, E Lee, KE Hunter, DJ Sardell, RJ Mitchell, P Merriam, JE Cipriani, V Hoffman, JD Schick, T Lechanteur, YTE Guymer, RH Johnson, MP Jiang, YD Stanton, CM Buitendijk, GHS Zhan, XW Kwong, AM Boleda, A Brooks, M Gieser, L Ratnapriya, R Branham, KE Foerster, JR Heckenlively, JR Othman, MI Vote, BJ Liang, HH Souzeau, E McAllister, IL Isaacs, T Hall, J Lake, S Mackey, DA Constable, IJ Craig, JE Kitchner, TE Yang, ZL Su, ZG Luo, HR Chen, D Hong, OY Flagg, K Lin, D Mao, GP Ferreyra, H Starke, K von Strachwitz, CN Wolf, A Brandl, C Rudolph, G Olden, M Morrison, MA Morgan, DJ Schu, M Ahn, J Silvestri, G Tsironi, EE Park, KH Farrer, LA Orlin, A Brucker, A Li, MY Curcio, CA Mohand-Said, S Sahel, JM Audo, I Benchaboune, M Cree, AJ Rennie, CA Goverdhan, SV Grunin, M Hagbi-Levi, S Campochiaro, P Katsanis, N Holz, FG Blond, F Blanche, H Deleuze, JF Igo, RP Truitt, B Peachey, NS Meuer, SM Myers, CE Moore, EL Klein, R Hauser, MA Postel, EA Courtenay, MD Schwartz, SG Kovach, JL Scott, WK Liew, G Tan, AG Gopinath, B Merriam, JC Smith, RT Khan, JC Shahid, H Moore, AT McGrath, JA Laux, R Brantley, MA Agarwal, A Ersoy, L Caramoy, A Langmann, T Saksens, NTM de Jong, EK Hoyng, CB Cain, MS Richardson, AJ Martin, TM Blangero, J Weeks, DE Dhillon, B van Duijn, CM Doheny, KF Romm, J Klaver, CCW Hayward, C Gorin, MB Klein, ML Baird, PN den Hollander, AI Fauser, S Yates, JRW Allikmets, R Wang, JJ Schaumberg, DA Klein, BEK Hagstrom, SA Chowers, I Lotery, AJ Leveillard, T Zhang, K Brilliant, MH Hewitt, AW Swaroop, A Chew, EY Pericak-Vance, MA DeAngelis, M Stambolian, D Haines, JL Iyengar, SK Weber, BHF Abecasis, GR Heid, IM AF Fritsche, Lars G. Igl, Wilmar Bailey, Jessica N. Cooke Grassmann, Felix Sengupta, Sebanti Bragg-Gresham, Jennifer L. Burdon, Kathryn P. Hebbring, Scott J. Wen, Cindy Gorski, Mathias Kim, Ivana K. Cho, David Zack, Donald Souied, Eric Scholl, Hendrik P. N. Bala, Elisa Lee, Kristine E. Hunter, David J. Sardell, Rebecca J. Mitchell, Paul Merriam, Joanna E. Cipriani, Valentina Hoffman, Joshua D. Schick, Tina Lechanteur, Yara T. E. Guymer, Robyn H. Johnson, Matthew P. Jiang, Yingda Stanton, Chloe M. Buitendijk, Gabrielle H. S. Zhan, Xiaowei Kwong, Alan M. Boleda, Alexis Brooks, Matthew Gieser, Linn Ratnapriya, Rinki Branham, Kari E. Foerster, Johanna R. Heckenlively, John R. Othman, Mohammad I. Vote, Brendan J. Liang, Helena Hai Souzeau, Emmanuelle McAllister, Ian L. Isaacs, Timothy Hall, Janette Lake, Stewart Mackey, David A. Constable, Ian J. Craig, Jamie E. Kitchner, Terrie E. Yang, Zhenglin Su, Zhiguang Luo, Hongrong Chen, Daniel Hong Ouyang Flagg, Ken Lin, Danni Mao, Guanping Ferreyra, Henry Starke, Klaus von Strachwitz, Claudia N. Wolf, Armin Brandl, Caroline Rudolph, Guenther Olden, Matthias Morrison, Margaux A. Morgan, Denise J. Schu, Matthew Ahn, Jeeyun Silvestri, Giuliana Tsironi, Evangelia E. Park, Kyu Hyung Farrer, Lindsay A. Orlin, Anton Brucker, Alexander Li, Mingyao Curcio, Christine A. Mohand-Said, Saddek Sahel, Jose-Main Audo, Isabelle Benchaboune, Mustapha Cree, Angela J. Rennie, Christina A. Goverdhan, Srinivas V. Grunin, Michelle Hagbi-Levi, Shira Campochiaro, Peter Katsanis, Nicholas Holz, Frank G. Blond, Frederic Blanche, Helene Deleuze, Jean-Francois Igo, Robert P., Jr. Truitt, Barbara Peachey, Neal S. Meuer, Stacy M. Myers, Chelsea E. Moore, Emily L. Klein, Ronald Hauser, Michael A. Postel, Eric A. Courtenay, Monique D. Schwartz, Stephen G. Kovach, Jaclyn L. Scott, William K. Liew, Gerald Tan, Ava G. Gopinath, Bamini Merriam, John C. Smith, R. Theodore Khan, Jane C. Shahid, Humma Moore, Anthony T. McGrath, J. Allie Laux, Renee Brantley, Milam A., Jr. Agarwal, Anita Ersoy, Lebriz Caramoy, Albert Langmann, Thomas Saksens, Nicole T. M. de Jong, Eiko K. Hoyng, Carel B. Cain, Melinda S. Richardson, Andrea J. Martin, Tammy M. Blangero, John Weeks, Daniel E. Dhillon, Bal van Duijn, Cornelia M. Doheny, Kimberly F. Romm, Jane Klaver, Caroline C. W. Hayward, Caroline Gorin, Michael B. Klein, Michael L. Baird, Paul N. den Hollander, Anneke I. Fauser, Sascha Yates, John R. W. Allikmets, Rando Wang, Jie Jin Schaumberg, Debra A. Klein, Barbara E. K. Hagstrom, Stephanie A. Chowers, Itay Lotery, Andrew J. Leveillard, Thierry Zhang, Kang Brilliant, Murray H. Hewitt, Alex W. Swaroop, Anand Chew, Emily Y. Pericak-Vance, Margaret A. DeAngelis, Margaret Stambolian, Dwight Haines, Jonathan L. Iyengar, Sudha K. Weber, Bernhard H. F. Abecasis, Goncalo R. Heid, Iris M. TI A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants SO NATURE GENETICS LA English DT Article ID SEQUENCING IDENTIFIES RARE; BODY-MASS INDEX; HIGH-RISK; SUSCEPTIBILITY LOCI; DISEASE; GENE; MUTATION; BIOLOGY; OSTEOARTHRITIS; METAANALYSIS AB Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 x 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 x 10(-10)). Very rare coding variants (frequency <0.1 %) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes. C1 [Fritsche, Lars G.; Sengupta, Sebanti; Bragg-Gresham, Jennifer L.; Zhan, Xiaowei; Kwong, Alan M.; Foerster, Johanna R.; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Igl, Wilmar; Gorski, Mathias; Starke, Klaus; Brandl, Caroline; Olden, Matthias; Heid, Iris M.] Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany. [Bailey, Jessica N. Cooke; Igo, Robert P., Jr.; Truitt, Barbara; Laux, Renee; Haines, Jonathan L.; Iyengar, Sudha K.] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Grassmann, Felix; Brandl, Caroline; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Bragg-Gresham, Jennifer L.] Univ Michigan, Dept Internal Med Nephrol, Kidney Epidemiol & Cost Ctr, Ann Arbor, MI 48109 USA. [Burdon, Kathryn P.; Vote, Brendan J.; Mackey, David A.; Hewitt, Alex W.] Univ Tasmania, Menzies Res Inst Tasmania, Sch Med, Hobart, Tas, Australia. [Hebbring, Scott J.; Kitchner, Terrie E.; Brilliant, Murray H.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Wen, Cindy; Chen, Daniel; Lin, Danni; Mao, Guanping] Univ Calif San Diego, Dept Ophthalmol, San Diego, CA 92103 USA. [Wen, Cindy; Luo, Hongrong; Chen, Daniel; Hong Ouyang; Flagg, Ken; Lin, Danni; Mao, Guanping; Ferreyra, Henry; Zhang, Kang] Vet Affairs San Diego Hlth Syst, La Jolla, CA USA. [Kim, Ivana K.] Harvard Univ, Sch Med, Dept Ophthalmol, Retina Serv,Massachusetts Eye & Ear, Boston, MA USA. [Cho, David; Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zack, Donald; Scholl, Hendrik P. N.; Campochiaro, Peter] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Zack, Donald] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Zack, Donald; Campochiaro, Peter] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Zack, Donald] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD USA. [Zack, Donald] Univ Paris 06, Inst Vis, Paris, France. [Souied, Eric] Univ Paris Est Creteil, Hop Henri Mondor, Hop Intercommunal Creteil, Creteil, France. [Scholl, Hendrik P. N.; Holz, Frank G.] Univ Bonn, Dept Ophthalmol, Bonn, Germany. [Bala, Elisa; Peachey, Neal S.] Louis Stokes Cleveland Vet Affairs Med Ctr, Cleveland, OH USA. [Lee, Kristine E.; Meuer, Stacy M.; Myers, Chelsea E.; Moore, Emily L.; Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Hunter, David J.; Schaumberg, Debra A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sardell, Rebecca J.; Courtenay, Monique D.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Mitchell, Paul; Liew, Gerald; Tan, Ava G.; Gopinath, Bamini; Wang, Jie Jin] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia. [Merriam, Joanna E.; Merriam, John C.; Smith, R. Theodore; Allikmets, Rando] CUNY, Dept Ophthalmol, New York, NY 10021 USA. [Cipriani, Valentina; Sahel, Jose-Main; Moore, Anthony T.; Yates, John R. W.] UCL, Inst Ophthalmol, London, England. [Cipriani, Valentina; Moore, Anthony T.; Yates, John R. W.] Moorfields Eye Hosp, London, England. [Hoffman, Joshua D.; McGrath, J. Allie] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Schick, Tina; Ersoy, Lebriz; Caramoy, Albert; Langmann, Thomas; Fauser, Sascha] Univ Hosp Cologne, Dept Ophthalmol, Cologne, Germany. [Lechanteur, Yara T. E.; Saksens, Nicole T. M.; de Jong, Eiko K.; Hoyng, Carel B.; den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands. [Guymer, Robyn H.; Liang, Helena Hai; Mackey, David A.; Cain, Melinda S.; Richardson, Andrea J.; Baird, Paul N.; Hewitt, Alex W.] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Johnson, Matthew P.; Blangero, John] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX USA. [Jiang, Yingda; Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Stanton, Chloe M.; Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland. [Buitendijk, Gabrielle H. S.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; van Duijn, Cornelia M.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Zhan, Xiaowei] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA. [Zhan, Xiaowei] Univ Texas SW Med Ctr Dallas, Ctr Genet Host Def, Dallas, TX 75390 USA. [Boleda, Alexis; Brooks, Matthew; Gieser, Linn; Ratnapriya, Rinki; Swaroop, Anand] NEI, N NRL, US Natl Inst Hlth, Bethesda, MD USA. [Branham, Kari E.; Heckenlively, John R.; Othman, Mohammad I.] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Souzeau, Emmanuelle; Hall, Janette; Lake, Stewart; Craig, Jamie E.] Flinders Univ S Australia, Flinders Med Ctr, Dept Ophthalmol, Adelaide, SA 5001, Australia. [McAllister, Ian L.; Isaacs, Timothy; Mackey, David A.; Constable, Ian J.; Khan, Jane C.; Hewitt, Alex W.] Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Yang, Zhenglin] Hosp Univ Elect Sci & Technol China, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu, Peoples R China. [Yang, Zhenglin] Sichuan Prov Peoples Hosp, Chengdu, Peoples R China. [Yang, Zhenglin] Chinese Acad Sci, Sichuan Translat Med Hosp, Chengdu, Peoples R China. [Su, Zhiguang; Zhang, Kang] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Mol Med Res Ctr, Chengdu 610064, Peoples R China. [von Strachwitz, Claudia N.] EyeCte Southwest, Stuttgart, Germany. [Wolf, Armin; Rudolph, Guenther] Univ Munich, Univ Eye Clin, Munich, Germany. [Brandl, Caroline] Univ Hosp Regensburg, Dept Ophthalmol, Regensburg, Germany. [Morrison, Margaux A.; Morgan, Denise J.; DeAngelis, Margaret] Univ Utah, Dept Ophthalmol & Visual Sci, Salt Lake City, UT USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Med Biomed Genet, Boston, MA USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Schu, Matthew; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Ahn, Jeeyun] Seoul Natl Univ, Boramae Med Ctr, Seoul Metropolitan Govt, Dept Ophthalmol, Seoul, South Korea. [Silvestri, Giuliana] Queens Univ, Ctr Expt Med, Belfast, Antrim, North Ireland. [Tsironi, Evangelia E.] Univ Thessaly, Sch Med, Dept Ophthalmol, Larisa, Greece. [Park, Kyu Hyung] Seoul Natl Univ, Bundang Hosp, Dept Ophthalmol, Songnam, South Korea. [Orlin, Anton] Weill Cornell Med Coll, Dept Ophthalmol, New York, NY USA. [Brucker, Alexander] Univ Penn, Dept Ophthalmol, Perelman Sch Med, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Li, Mingyao] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Curcio, Christine A.] Univ Alabama Birmingham, Dept Ophthalmol, Birmingham, AL 35294 USA. [Mohand-Said, Saddek; Sahel, Jose-Main; Audo, Isabelle; Blond, Frederic; Leveillard, Thierry] INSERM, Paris, France. [Mohand-Said, Saddek; Sahel, Jose-Main; Audo, Isabelle; Blond, Frederic; Leveillard, Thierry] Inst Vis, Dept Genet, Paris, France. [Mohand-Said, Saddek; Sahel, Jose-Main; Audo, Isabelle; Blond, Frederic; Leveillard, Thierry] CNRS, Paris, France. [Mohand-Said, Saddek; Sahel, Jose-Main; Benchaboune, Mustapha] Ctr Hosp Natl Ophtalmol Quinze Vingts, Paris, France. [Sahel, Jose-Main] Fdn Ophtalmol Adolphe Rothschild, Paris, France. [Sahel, Jose-Main] Acad Sci, Inst France, Paris, France. [Audo, Isabelle] Inst Ophthalmol, Dept Mol Genet, London, England. [Cree, Angela J.; Goverdhan, Srinivas V.; Lotery, Andrew J.] Univ Southampton, Fac Med, Clin & Expt Sci, Southampton SO9 5NH, Hants, England. [Rennie, Christina A.] Univ Hosp Southampton, Southampton, Hants, England. [Grunin, Michelle; Hagbi-Levi, Shira; Chowers, Itay] Hadassah Hebrew Univ, Med Ctr, Dept Ophthalmol, Jerusalem, Israel. [Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA. [Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC USA. [Katsanis, Nicholas] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Blanche, Helene; Deleuze, Jean-Francois] Fdn Jean Dausset, CEPH, Paris, France. [Deleuze, Jean-Francois] Commissariat Energie Atom & Energies Alternat CEA, Ctr Natl Genotypage, Inst Genom, Evry, France. [Peachey, Neal S.; Hagstrom, Stephanie A.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Hauser, Michael A.; Postel, Eric A.] Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Hauser, Michael A.] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC USA. [Schwartz, Stephen G.; Kovach, Jaclyn L.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Naples, FL USA. [Smith, R. Theodore] NYU, Sch Med, Dept Ophthalmol, New York, NY USA. [Khan, Jane C.] Royal Perth Hosp, Dept Ophthalmol, Perth, WA 6001, Australia. [Khan, Jane C.; Shahid, Humma; Yates, John R. W.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Shahid, Humma] Cambridge Univ Hosp Natl Hlth Serv NHS Fdn Trust, Dept Ophthalmol, Cambridge, England. [Moore, Anthony T.] Univ Calif San Francisco, Sch Med, Dept Ophthalmol, San Francisco, CA USA. [Brantley, Milam A., Jr.; Agarwal, Anita] Vanderbilt Univ, Dept Ophthalmol & Visual Sci, 221 Kirkland Hall, Nashville, TN 37235 USA. [Martin, Tammy M.; Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Dhillon, Bal] Univ Edinburgh, Sch Clin Sci, Edinburgh, Midlothian, Scotland. [Doheny, Kimberly F.; Romm, Jane] Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD USA. [Gorin, Michael B.] Univ Calif Los Angeles, Jules Stein Eye Inst, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90024 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Schaumberg, Debra A.] Univ Utah, Sch Med, Moran Eye Ctr, Ctr Translat Med, Salt Lake City, UT USA. [Schaumberg, Debra A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Haines, Jonathan L.] Case Western Reserve Univ, Sch Med, Inst Computat Biol, Cleveland, OH 44106 USA. RP Abecasis, GR (reprint author), Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA.; Heid, IM (reprint author), Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany.; Iyengar, SK (reprint author), Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM ski@case.edu; goncalo@umich.edu; iris.heid@klinik.uni-regensburg.de RI Hewitt, Alex/D-1936-2013; Mitchell, Paul/P-1498-2014; de Jong, Eiko/P-3407-2015; Wang, Jie Jin/P-1499-2014; Cipriani, Valentina/A-8549-2012; Mackey, David/H-5340-2014; Sahel, Jose-Alain/F-3172-2017 OI Hewitt, Alex/0000-0002-5123-5999; de Jong, Eiko/0000-0001-6520-0407; Wang, Jie Jin/0000-0001-9491-4898; Cipriani, Valentina/0000-0002-0839-9955; Mackey, David/0000-0001-7914-4709; Cooke Bailey, Jessica/0000-0002-4001-8702; smith, theodore/0000-0002-1693-943X; Weeks, Daniel/0000-0001-9410-7228; FU Center for Inherited Diseases Research (CIDR) Program [HHSN268201200008I]; [1X01HG006934-01]; [R01 EY022310] FX We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H. NR 51 TC 51 Z9 51 U1 15 U2 46 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD FEB PY 2016 VL 48 IS 2 BP 134 EP 143 DI 10.1038/ng.3448 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DC2JV UT WOS:000369043900010 PM 26691988 ER PT J AU Lood, C Blanco, LP Purmalek, MM Carmona-Rivera, C De Ravin, SS Smith, CK Malech, HL Ledbetter, JA Elkon, KB Kaplan, MJ AF Lood, Christian Blanco, Luz P. Purmalek, Monica M. Carmona-Rivera, Carmelo De Ravin, Suk S. Smith, Carolyne K. Malech, Harry L. Ledbetter, Jeffrey A. Elkon, Keith B. Kaplan, Mariana J. TI Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease SO NATURE MEDICINE LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; PEPTIDYLARGININE DEIMINASE INHIBITION; NADPH OXIDASE; NLRP3 INFLAMMASOME; OXIDATIVE DAMAGE; CELL-DEATH; ERYTHEMATOSUS; ATHEROSCLEROSIS; MACROPHAGES; ACTIVATION AB Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondria! reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondria! ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulornatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondria! DNA in autoimmune diseases. C1 [Lood, Christian; Elkon, Keith B.] Univ Washington, Div Rheumatol, Seattle, WA 98195 USA. [Blanco, Luz P.; Purmalek, Monica M.; Carmona-Rivera, Carmelo; Smith, Carolyne K.; Kaplan, Mariana J.] NIAMSD, System Autoimmun Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [De Ravin, Suk S.; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Ledbetter, Jeffrey A.; Elkon, Keith B.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. RP Elkon, KB (reprint author), Univ Washington, Div Rheumatol, Seattle, WA 98195 USA.; Kaplan, MJ (reprint author), NIAMSD, System Autoimmun Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.; Elkon, KB (reprint author), Univ Washington, Dept Immunol, Seattle, WA 98195 USA. EM elkon@uw.edu; mariana.kaplan@nih.gov OI Malech, Harry/0000-0001-5874-5775; Purmalek, Monica/0000-0003-2756-161X FU Washington Research Foundation, Leap for Lupus; Wenner-Gren Foundation; foundation BLANCEFLOR Boncompagni-Ludovisi nee Bildt; Intramural Research Program at NIAMS/NIH FX We thank X. Sun, L. Tanaka (both at University of Washington), and E. Moore (National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIAMS) for technical assistance; W. Wang (University of Washington) for providing mouse mitochondria isolated from hearts; D. Kuhns (NIAID) for scientific input, and R. Siegel (NIAMS) for critical review of the manuscript. We also thank H.-W. Sun, M. Ward (both at NIAMS) and C. Spiekerman (University of Washington) for expert statistical advice. We also thank M. Gale for providing Tmem173-knockout mice. The study was supported by grants from the Washington Research Foundation, Leap for Lupus (K.B.E.), the Wenner-Gren Foundation, the foundation BLANCEFLOR Boncompagni-Ludovisi nee Bildt (C.L.), and the Intramural Research Program at NIAMS/NIH (L.P.B., M.P., C.K.S., C.C.-R. and M.J.K.). The funding bodies had no part in the study design; the collection, analysis and interpretation of the data; the writing of the manuscript or the submission. NR 53 TC 59 Z9 60 U1 18 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD FEB PY 2016 VL 22 IS 2 BP 146 EP 153 DI 10.1038/nm.4027 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DC8JX UT WOS:000369466800008 PM 26779811 ER PT J AU Cloonan, SM Glass, K Laucho-Contreras, ME Bhashyam, AR Cervo, M Pabon, MA Konrad, C Polverino, F Siempos, II Perez, E Mizumura, K Ghosh, MC Parameswaran, H Williams, NC Rooney, KT Chen, ZH Goldklang, MP Yuan, GC Moore, SC Demeo, DL Rouault, TA D'Armiento, JM Schon, EA Manfredi, G Quackenbush, J Mahmood, A Silverman, EK Owen, CA Choi, AMK AF Cloonan, Suzanne M. Glass, Kimberly Laucho-Contreras, Maria E. Bhashyam, Abhiram R. Cervo, Morgan Pabon, Maria A. Konrad, Csaba Polverino, Francesca Siempos, Ilias I. Perez, Elizabeth Mizumura, Kenji Ghosh, Manik C. Parameswaran, Harikrishnan Williams, Niamh C. Rooney, Kristen T. Chen, Zhi-Hua Goldklang, Monica P. Yuan, Guo-Cheng Moore, Stephen C. Demeo, Dawn L. Rouault, Tracey A. D'Armiento, Jeanine M. Schon, Eric A. Manfredi, Giovanni Quackenbush, John Mahmood, Ashfaq Silverman, Edwin K. Owen, Caroline A. Choi, Augustine M. K. TI Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice SO NATURE MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; CYTOCHROME-C-OXIDASE; GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; REGULATORY PROTEIN-2; TARGETED DELETION; LUNG-CANCER; COPD; DEFICIENCY; ANEMIA AB Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice. Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice, which had higher mitochondria! iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondria! iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD. C1 [Cloonan, Suzanne M.; Pabon, Maria A.; Siempos, Ilias I.; Perez, Elizabeth; Mizumura, Kenji; Williams, Niamh C.; Rooney, Kristen T.; Choi, Augustine M. K.] New York Presbyterian Hosp, Weill Cornell Med Coll, Joan & Sanford I Weill Dept Med, New York, NY USA. [Cloonan, Suzanne M.; Laucho-Contreras, Maria E.; Bhashyam, Abhiram R.; Polverino, Francesca; Mizumura, Kenji; Chen, Zhi-Hua; Demeo, Dawn L.; Silverman, Edwin K.; Owen, Caroline A.; Choi, Augustine M. K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Glass, Kimberly; Yuan, Guo-Cheng; Quackenbush, John] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Glass, Kimberly; Yuan, Guo-Cheng; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Glass, Kimberly; Demeo, Dawn L.; Quackenbush, John; Silverman, Edwin K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Cervo, Morgan; Moore, Stephen C.; Mahmood, Ashfaq] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Konrad, Csaba; Manfredi, Giovanni] Weill Cornell Med Coll, Brain & Mind Res Inst, New York, NY USA. [Polverino, Francesca; Owen, Caroline A.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Polverino, Francesca] Univ Parma, Dept Pulm, I-43100 Parma, Italy. [Siempos, Ilias I.] Univ Athens, Sch Med, Evangelismos Hosp, Dept Crit Care Med & Pulm Serv 1, Athens, Greece. [Ghosh, Manik C.; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Parameswaran, Harikrishnan] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Chen, Zhi-Hua] Zhejiang Univ, Sch Med, Dept Resp & Crit Care Med, Hosp 2, Hangzhou, Zhejiang, Peoples R China. [Goldklang, Monica P.; D'Armiento, Jeanine M.] Columbia Univ, Dept Anesthesiol, New York, NY USA. [Goldklang, Monica P.; D'Armiento, Jeanine M.] Columbia Univ, Dept Med, New York, NY USA. [D'Armiento, Jeanine M.] Columbia Univ, Dept Physiol & Cellular Biophys, New York, NY USA. [Schon, Eric A.] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Schon, Eric A.] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY USA. RP Choi, AMK (reprint author), New York Presbyterian Hosp, Weill Cornell Med Coll, Joan & Sanford I Weill Dept Med, New York, NY USA.; Choi, AMK (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. EM amc2056@med.cornell.edu RI Polverino, Francesca/F-3816-2017; OI Polverino, Francesca/0000-0001-9686-5698; Rooney, Kristen T/0000-0002-7495-1437 FU US National Institutes of Health (NIH) [P01-HL114501, R01-HL055330, R01-HL079904, R01-A1111475-01, R01-HL86814, R21-HL111835, HL122513, R01-HL086936, P01-HD080642]; NIH-National Heart, Lung and Blood Institute [K99-HL125899]; American Lung Association Biomedical Research [RG-348928]; Flight Attendants Medical Research Institute (FAMRI) clinical innovator award; clinical innovator FAMRI [CIA 123046]; FAMRI Young Clinical Scientist a [YFEL141004, YFEL103236]; US Department of Defense [W911F-15-1-0169]; NIH [P01-HL114501, P01-HL105339, R01-HL111759, R21-ES025379-01, R01-GM088999]; Brigham and Women's Hospital-Lovelace Respiratory Research institute Research Consortium; intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; Muscular Dystrophy Association; J. Willard and Alice S. Marriott Foundation FX The authors thank J.S. Moon, H.C. Lam, K. Taylor and B. Ding for technical assistance. The authors also acknowledge S. Chan (Harvard Medical School) for the cyto-GRX2 and mito-GRX2 plasmids, Y. Hua (Columbia University) for the breeding of the Sco2ki/ki and Sco2ki/ko mice and J. Connelly (ApoPharma Inc.) for providing Ferriprox. The authors also thank R. Rubio for assistance with RNA-seq, Y. Shao for assistance with the microarray study and M. Ericsson for assistance with transmission electron microscopy. The authors also acknowledge discussion and input from S.W. Ryter, C.A. MacRae and P.Y. Sips. This work was supported by US National Institutes of Health (NIH) grants P01-HL114501 (A.M.K.C.), R01-HL055330 (A.M.K.C.), R01-HL079904 (A.M.K.C.), R01-A1111475-01 (C.A.O.), R01-HL86814 (C.A.O.), R21-HL111835 (C.A.O.), HL122513 (H.P.), R01-HL086936 (to J.M.D'A.) and P01-HD080642 (Project 2 to E.A.S.), NIH-National Heart, Lung and Blood Institute grant K99-HL125899 (S.M.C.), American Lung Association Biomedical Research grant RG-348928 (S.M.C.), a Flight Attendants Medical Research Institute (FAMRI) clinical innovator award (A.M.K.C.), clinical innovator FAMRI grant CIA#123046 (C.A.O.), FAMRI Young Clinical Scientist awards YFEL141004 (F.P.) and YFEL103236 (M.P.G.), and US Department of Defense grant W911F-15-1-0169 (E.A.S.). S.M.C., A.M.K.C., J.Q. and E.K.S. were also supported by NIH grant P01-HL105339 (to E.K.S.). K.G. was supported by NIH grant R01-HL111759 (to J.Q., G.C.Y. and E.K.S.). C.A.O. was also supported by NIH grants R21-ES025379-01 (to A. Fedulov), P01-HL105339 (to E.K.S.) and P01-HL114501 (to A.M.K.C.) and by Brigham and Women's Hospital-Lovelace Respiratory Research institute Research Consortium grants. G.M. and C.K. were supported by NIH grant R01-GM088999 (to G.M.). M.C.G. and T.A.R. acknowledge support from the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. Additional support was provided by the Muscular Dystrophy Association (E.A.S.) and the J. Willard and Alice S. Marriott Foundation (E.A.S.). NR 60 TC 9 Z9 9 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD FEB PY 2016 VL 22 IS 2 BP 163 EP 174 DI 10.1038/nm.4021 PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA DC8JX UT WOS:000369466800010 PM 26752519 ER PT J AU Stuber, GD Wise, RA AF Stuber, Garret D. Wise, Roy A. TI Lateral hypothalamic circuits for feeding and reward SO NATURE NEUROSCIENCE LA English DT Review ID MELANIN-CONCENTRATING HORMONE; BRAIN-STIMULATION REWARD; MEDIAL FOREBRAIN-BUNDLE; PIMOZIDE-INDUCED EXTINCTION; MESOLIMBIC DOPAMINE SYSTEM; CONDITIONED TASTE-AVERSION; NUCLEUS-ACCUMBENS SHELL; VENTRAL TEGMENTAL AREA; ELECTRICAL-STIMULATION; SELF-STIMULATION AB In experiments conducted over 60 years ago, the lateral hypothalamic area (LHA) was identified as a critical neuroanatomical substrate for motivated behavior. Electrical stimulation of the LHA induces voracious feeding even in well-fed animals. In the absence of food, animals will work tirelessly, often lever-pressing thousands of times per hour, for electrical stimulation at the same site that provokes feeding, drinking and other species-typical motivated behaviors. Here we review the classic findings from electrical stimulation studies and integrate them with more recent work that has used contemporary circuit-based approaches to study the LHA. We identify specific anatomically and molecularly defined LHA elements that integrate diverse information arising from cortical, extended amygdala and basal forebrain networks to ultimately generate a highly specified and invigorated behavioral state conveyed via LHA projections to downstream reward and feeding-specific circuits. C1 [Stuber, Garret D.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Stuber, Garret D.] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC USA. [Stuber, Garret D.] Univ N Carolina, Neurosci Ctr, Chapel Hill, NC USA. [Wise, Roy A.] NIDA, Intramural Res Program, US Natl Inst Hlth, Dept Hlth & Human Serv, Baltimore, MD USA. RP Stuber, GD (reprint author), Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA.; Stuber, GD (reprint author), Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC USA.; Stuber, GD (reprint author), Univ N Carolina, Neurosci Ctr, Chapel Hill, NC USA. EM gstuber@med.unc.edu RI Stuber, Garret/E-1160-2011 FU Klarman Family Foundation; Brain and Behavior Research Foundation; Foundation for Prader-Willi Research; Foundation of Hope; National Institute on Drug Abuse [DA032750, DA038168]; Department of Psychiatry at UNC Chapel Hill; Intramural Research Program at the National Institute on Drug Abuse FX We thank J. Jennings for input on the manuscript and members of the Stuber laboratory for helpful discussion. This work was supported by the Klarman Family Foundation, the Brain and Behavior Research Foundation, the Foundation for Prader-Willi Research, the Foundation of Hope, the National Institute on Drug Abuse (DA032750 and DA038168), and the Department of Psychiatry at UNC Chapel Hill (G.D.S.). R.A.W. was supported by the Intramural Research Program at the National Institute on Drug Abuse. NR 148 TC 18 Z9 18 U1 8 U2 23 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2016 VL 19 IS 2 BP 198 EP 205 DI 10.1038/nn.4220 PG 8 WC Neurosciences SC Neurosciences & Neurology GA DC4EG UT WOS:000369172600007 PM 26814589 ER PT J AU Krashes, MJ Lowell, BB Garfield, AS AF Krashes, Michael J. Lowell, Bradford B. Garfield, Alastair S. TI Melanocortin-4 receptor-regulated energy homeostasis SO NATURE NEUROSCIENCE LA English DT Review ID AGOUTI-RELATED PROTEIN; CENTRAL-NERVOUS-SYSTEM; BROWN ADIPOSE-TISSUE; HYPOTHALAMIC PROOPIOMELANOCORTIN NEURONS; MITOGEN-ACTIVATED PROTEIN; GASTRIC BYPASS-SURGERY; INCREASED DIETARY-FAT; EARLY-ONSET OBESITY; PARAVENTRICULAR NUCLEUS; AGRP NEURONS AB The melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components-two antagonistically acting ligands and two cognate receptors-this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the melanocortin-4 receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis. C1 [Krashes, Michael J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Krashes, Michael J.] NIDA, NIH, Baltimore, MD USA. [Lowell, Bradford B.; Garfield, Alastair S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Dept Med,Med Sch, Boston, MA 02215 USA. [Garfield, Alastair S.] Univ Edinburgh, Ctr Integrat Physiol, Edinburgh, Midlothian, Scotland. RP Krashes, MJ (reprint author), NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA.; Krashes, MJ (reprint author), NIDA, NIH, Baltimore, MD USA. EM michael.krashes@nih.gov; agarfiel@staffmail.ed.ac.uk FU University of Edinburgh; US National Institutes of Health [R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, P30 DK046200, P30 DK057521, DK075087, DK075090] FX This work was supported by a University of Edinburgh Chancellor's Fellowship (A.S.G.) and US National Institutes of Health grants to B.B.L. (R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, R37 DK053477, BNORC Transgenic Core P30 DK046200, BADERC Transgenic Core P30 DK057521) and to M.J.K. (Intramural Research Program, NIDDK; DK075087, DK075090). NR 140 TC 14 Z9 15 U1 8 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 EI 1546-1726 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2016 VL 19 IS 2 BP 206 EP 219 DI 10.1038/nn.4202 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DC4EG UT WOS:000369172600008 PM 26814590 ER PT J AU Rehermann, B AF Rehermann, Barbara TI Advances in hepatitis C research and treatment SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material ID VIRUS; INFECTION C1 [Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr, Bethesda, MD 20892 USA. EM rehermann@nih.gov NR 10 TC 3 Z9 3 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5045 EI 1759-5053 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD FEB PY 2016 VL 13 IS 2 BP 70 EP 71 DI 10.1038/nrgastro.2015.227 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DC6EW UT WOS:000369313600004 PM 26790365 ER PT J AU Dudek, SM Alexander, GM Farris, S AF Dudek, Serena M. Alexander, Georgia M. Farris, Shannon TI Rediscovering area CA2: unique properties and functions SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID HIPPOCAMPAL PYRAMIDAL CELLS; CALCIUM-BINDING PROTEINS; VASOPRESSIN 1B RECEPTOR; CENTRAL-NERVOUS-SYSTEM; ADULT-RAT HIPPOCAMPUS; SULFATE PROTEOGLYCAN IMMUNOREACTIVITY; FIBROBLAST GROWTH-FACTOR; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; SUBSTANCE-P AB Hippocampal area CA2 has several features that distinguish it from CA1 and CA3, including a unique gene expression profile, failure to display long-term potentiation and relative resistance to cell death. A recent increase in interest in the CA2 region, combined with the development of new methods to define and manipulate its neurons, has led to some exciting new discoveries on the properties of CA2 neurons and their role in behaviour. Here, we review these findings and call attention to the idea that the definition of area CA2 ought to be revised in light of gene expression data. C1 [Dudek, Serena M.; Alexander, Georgia M.; Farris, Shannon] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Farris, Shannon/0000-0003-4473-1684 FU Intramural Research Program of National Institute of Environmental Health Sciences, US National Institutes of Health [Z01 ES100221] FX The authors thank D. Lustberg and other members of the Dudek laboratory for comments on the manuscript. This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, US National Institutes of Health (Z01 ES100221). NR 176 TC 10 Z9 10 U1 3 U2 16 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 FEB PY 2016 VL 17 IS 2 BP 89 EP 102 DI 10.1038/nrn.2015.22 PG 14 WC Neurosciences SC Neurosciences & Neurology GA DC4GU UT WOS:000369179700007 PM 26806628 ER PT J AU Meffert, H Hwang, S Nolan, ZT Chen, G Blair, JR AF Meffert, Harma Hwang, Soonjo Nolan, Zachary T. Chen, Gang Blair, James R. TI Segregating attention from response control when performing a motor inhibition task Segregating attention from response control SO NEUROIMAGE LA English DT Article DE Cognitive control; Go/No-go; fMRI; Generalized psychophysiological interactions ID INFERIOR FRONTAL-CORTEX; STOP-SIGNAL INHIBITION; EVENT-RELATED FMRI; GO/NO-GO TASKS; FUNCTIONAL CONNECTIVITY; PREFRONTAL CORTEX; COGNITIVE CONTROL; PSYCHOPHYSIOLOGICAL INTERACTIONS; GENDER-DIFFERENCES; NEURAL MECHANISMS AB Considerable work has demonstrated that inferior frontal gyrus (IFG), anterior insula cortex (AIC) and the supplementary motor area (SMA) are responsive during inhibitory control tasks. However, there is disagreement as to whether this relates to response selection/inhibition or attentional processing. The current study investigates this by using a Go/No-go task with a factorial design. We observed that both left IFG and dorsal pre-SMA were responsive to no-go cues irrespective of cue frequency. This suggests a role for both in the inhibition of motor responses. Generalized psychophysiological interaction (gPPI) analyses suggest that inferior frontal gyrus may implement this function through interaction with basal ganglia and by suppressing the visual representation of cues associated with no-go responses. Anterior insula cortex and a more ventral portion of pre-SMA showed greater responsiveness to low frequency relative to higher frequency stimuli, irrespective of response type. This may reflect the hypothesized role of anterior insula cortex in marking low frequency items for additional processing (cf. Menon and Uddin, 2010). Consistent with this, the gPPI analysis revealed significantly greater anterior insula cortex connectivity with visual cortex in response to low relative to high frequency cues. Published by Elsevier Inc. C1 [Meffert, Harma; Hwang, Soonjo; Nolan, Zachary T.; Blair, James R.] NIH, Sect Affect & Cognit Neurosci, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Chen, Gang] NIH, Sci & Stat Comp Core, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Meffert, H (reprint author), NIMH, NIH, Sect Affect & Cognit Neurosci, 9000 Rockville Pike,Bldg 15k,Room 300-E,MSC 2670, Bethesda, MD 20814 USA. EM harma.meffert@nih.gov OI Meffert, Harma/0000-0002-7298-7276 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health [1-ZIA-MH002860-08] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (1-ZIA-MH002860-08). NR 80 TC 2 Z9 2 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2016 VL 126 BP 27 EP 38 DI 10.1016/j.neuroimage.2015.11.029 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DC5VX UT WOS:000369289800003 PM 26584863 ER PT J AU Koay, CG Yeh, PH Ollinger, JM Irfanoglu, MO Pierpaoli, C Basser, PJ Oakes, TR Riedy, G AF Koay, Cheng Guan Yeh, Ping-Hong Ollinger, John M. Irfanoglu, M. Okan Pierpaoli, Carlo Basser, Peter J. Oakes, Terrence R. Riedy, Gerard TI Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI): A framework for single-subject analysis in diffusion tensor imaging SO NEUROIMAGE LA English DT Article DE Elliptical cone of uncertainty; DTI; FDR; FNR; Exact Wilcoxon-Mann-Whitney p-value computation ID FALSE DISCOVERY RATE; BRAIN WHITE-MATTER; DT-MRI DATA; MAGNETIC-RESONANCE; PHYSIOLOGICAL NOISE; SPATIAL STATISTICS; FIBER ORIENTATION; ROBUST ESTIMATION; UNCERTAINTY; SIGNAL AB The purpose of this work is to develop a framework for single-subject analysis of diffusion tensor imaging (DTI) data. This framework is termed Tract Orientation and Angular Dispersion Deviation Indicator (TOADDI) because it is capable of testing whether an individual tract as represented by the major eigenvector of the diffusion tensor and its corresponding angular dispersion are significantly different from a group of tracts on a voxel-by-voxel basis. This work develops two complementary statistical tests based on the elliptical cone of uncertainty, which is a model of uncertainty or dispersion of the major eigenvector of the diffusion tensor. The orientation deviation test examines whether the major eigenvector from a single subject is within the average elliptical cone of uncertainty formed by a collection of elliptical cones of uncertainty. The shape deviation test is based on the two-tailed Wilcoxon-Mann-Whitney two-sample test between the normalized shape measures (area and circumference) of the elliptical cones of uncertainty of the single subject against a group of controls. The False Discovery Rate (FDR) and False Non-discovery Rate (FNR) were incorporated in the orientation deviation test. The shape deviation test uses FDR only. TOADDI was found to be numerically accurate and statistically effective. Clinical data from two Traumatic Brain Injury (TBI) patients and one non-TBI subject were tested against the data obtained from a group of 45 non-TBI controls to illustrate the application of the proposed framework in single-subject analysis. The frontal portion of the superior longitudinal fasciculus seemed to be implicated in both tests (orientation and shape) as significantly different from that of the control group. The TBI patients and the single non-TBI subject were well separated under the shape deviation test at the chosen FDR level of 0.0005. TOADDI is a simple but novel geometrically based statistical framework for analyzing DTI data. TOADDI may be found useful in single-subject, graph-theoretic and group analyses of DTI data or DTI-based tractography techniques. Published by Elsevier Inc. C1 [Koay, Cheng Guan; Yeh, Ping-Hong; Ollinger, John M.; Oakes, Terrence R.; Riedy, Gerard] Natl Intrepid Ctr Excellence NICoE, Bethesda, MD USA. [Yeh, Ping-Hong; Irfanoglu, M. Okan] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Koay, Cheng Guan; Irfanoglu, M. Okan; Pierpaoli, Carlo; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD USA. [Koay, Cheng Guan] NorthTide Grp LLC, Dulles, VA USA. [Riedy, Gerard] Natl Capital Neuroimaging Consortium, Bethesda, MD USA. RP Koay, CG (reprint author), Walter Reed Natl Mil Med Ctr, Natl Intrepid Ctr Excellence, Bethesda, MD USA. EM guankoac@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX C.G. Koay dedicates this work to the memory of Madam Oh Soo See. The authors would like to thank Drs Connie Duncan and Louis French for sharing TBI patients' imaging data. The authors would also like to thank Ms. Elyssa Sham for coordinating the recruitment of patients and volunteers, Mr. John A. Morissette for acquiring the clinical data, Mr. Justin S. Senseney for managing the clinical data. Appendix E contains an abridged and concise version of the first part of the author's unpublished lecture note prepared for the occasion of the Mathematics/Computer Science Annual Alumni Lecture at Berea College on November 9, 2012. The current implementation of the proposed framework was built upon the HI-SPEED software packets of which C.G. Koay is the principal developer. HI-SPEED software packets are available for research use at URL:http://sites.google.com/site/hispeedpackets/. P.J. Basser and C. Pierpaoli are supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Mathematica (R) implementation of the two versions of the Wilcoxon-Mann-Whitney U tests, one with tied ranks and the other one without tied ranks, will be available as online supplementary materials on the publisher website. NR 90 TC 0 Z9 0 U1 3 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2016 VL 126 BP 151 EP 163 DI 10.1016/j.neuroimage.2015.11.046 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DC5VX UT WOS:000369289800014 PM 26638985 ER PT J AU Schliep, KC Mitchell, EM Mumford, SL Radin, RG Zarek, SM Sjaarda, L Schisterman, EF AF Schliep, Karen C. Mitchell, Emily M. Mumford, Sunni L. Radin, Rose G. Zarek, Shvetha M. Sjaarda, Lindsey Schisterman, Enrique F. TI Trying to Conceive After an Early Pregnancy Loss An Assessment on How Long Couples Should Wait SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID LOW-DOSE ASPIRIN; INTERPREGNANCY INTERVAL; PERINATAL OUTCOMES; RANDOMIZED-TRIAL; SPONTANEOUS-ABORTION; MISCARRIAGE; RISK; GESTATION; WOMEN; TIME AB OBJECTIVE:To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date.METHODS:In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18-40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy.RESULTS:Couples with a 0-3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30-2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates.CONCLUSION:Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Bethesda, MD USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. Univ Utah, Div Publ Hlth, Dept Family & Prevent Med, Salt Lake City, UT USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland [HHSN267200603423, HHSN267200603424, HHSN267200603426] FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract Nos. HHSN267200603423, HHSN267200603424, HHSN267200603426). NR 28 TC 3 Z9 3 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2016 VL 127 IS 2 BP 204 EP 212 DI 10.1097/AOG.0000000000001159 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DC5IS UT WOS:000369255300004 PM 26942344 ER PT J AU Jupp, B Murray, JE Jordan, ER Xia, J Fluharty, M Shrestha, S Robbins, TW Dalley, JW AF Jupp, Bianca Murray, Jennifer E. Jordan, Emily R. Xia, Jing Fluharty, Meg Shrestha, Saurav Robbins, Trevor W. Dalley, Jeffrey W. TI Social dominance in rats: effects on cocaine self-administration, novelty reactivity and dopamine receptor binding and content in the striatum SO PSYCHOPHARMACOLOGY LA English DT Article DE Social status; Psychostimulants; High responder; Anxiety; Impulsivity; Resource competition ID FEMALE CYNOMOLGUS MONKEYS; REACTION-TIME-TASK; DEFEAT STRESS; INDIVIDUAL-DIFFERENCES; PREFRONTAL CORTEX; ANIMAL BEHAVIOR; SEEKING TRAITS; IMPULSIVITY; AVAILABILITY; AMPHETAMINE AB Studies in human and non-human primates demonstrate that social status is an important determinant of cocaine reinforcement. However, it is unclear whether social rank is associated with other traits that also predispose to addiction and whether social status similarly predicts cocaine self-administration in rats. The objective of this study is to investigate whether social ranking assessed using a resource competition task affects (i) the acquisition, maintenance and reinstatement of cocaine self-administration; (ii) the dopaminergic markers in the striatum; and (iii) the expression of ancillary traits for addiction. Social ranking was determined in group-housed rats based upon drinking times during competition for a highly palatable liquid. Rats were then evaluated for cocaine self-administration and cue-induced drug reinstatement or individual levels of impulsivity, anxiety and novelty-induced locomotor activity. Finally, dopamine content, dopamine transporter (DAT) and dopamine D-2/D-3 (D-2/3) receptor binding were measured postmortem in the dorsal and ventral striatum. Rats deemed socially dominant showed enhanced novelty reactivity but were neither more impulsive nor anxious compared with subordinate rats. Dominant rats additionally maintained higher rates of cocaine self-administration but showed no differences in the acquisition, extinction and reinstatement of this behaviour. D-2/3 binding was elevated in the nucleus accumbens shell and dorsal striatum of dominant rats when compared to subordinate rats, and was accompanied by elevated DAT and reduced dopamine content in the nucleus accumbens shell. These findings show that social hierarchy influences the rate of self-administered cocaine but not anxiety or impulsivity in rats. Similar to non-human primates, these effects may be mediated by striatal dopaminergic systems. C1 [Jupp, Bianca; Murray, Jennifer E.; Jordan, Emily R.; Xia, Jing; Fluharty, Meg; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England. [Jupp, Bianca; Murray, Jennifer E.; Jordan, Emily R.; Xia, Jing; Fluharty, Meg; Robbins, Trevor W.; Dalley, Jeffrey W.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England. [Shrestha, Saurav] NIMH, Mol Imagine Branch, NIH, Bethesda, MD 20892 USA. [Dalley, Jeffrey W.] Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. RP Dalley, JW (reprint author), Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.; Dalley, JW (reprint author), Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England.; Dalley, JW (reprint author), Univ Cambridge, Dept Psychiat, Cambridge CB2 2QQ, England. EM jwd20@cam.ac.uk FU Medical Research Council (MRC) [G0701500]; MRC [G1000183]; Wellcome Trust of the Behavioural and Clinical Neuroscience Institute [093875/Z/10/Z]; MRC Imperial College-Cambridge University-Manchester University (ICCAM) strategic addiction cluster; AXA Research Fund; Gates Foundation FX This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and by a joint award from the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience Institute. The authors acknowledge additional funding from the MRC Imperial College-Cambridge University-Manchester University (ICCAM) strategic addiction cluster. BJ was supported by a Fellowship from the AXA Research Fund. ERJ was the recipient of a studentship from the Gates Foundation. NR 56 TC 6 Z9 6 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2016 VL 233 IS 4 BP 579 EP 589 DI 10.1007/s00213-015-4122-8 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DC5FE UT WOS:000369246100003 PM 26554388 ER PT J AU Kuo, CC Shen, H Harvey, BK Yu, SJ Kopajtic, T Hinkle, JJ Kyrkanides, S Katz, JL Wang, Y AF Kuo, Chi-Chung Shen, Hui Harvey, Brandon K. Yu, Seong-Jin Kopajtic, Theresa Hinkle, Josh. J. Kyrkanides, Stephanos Katz, Jonathan L. Wang, Yun TI Differential modulation of methamphetamine-mediated behavioral sensitization by overexpression of Mu opioid receptors in nucleus accumbens and ventral tegmental area SO PSYCHOPHARMACOLOGY LA English DT Article DE Methamphetamine; Mu opioid receptor; Sensitization; AAV ID DOPAMINE OVERFLOW; MESSENGER-RNA; MICE; EXPRESSION; NEURONS; ANTAGONISTS; INDUCTION; COCAINE; MK-801; BRAIN AB Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions. The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system. We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined. Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection. Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity. C1 [Yu, Seong-Jin; Kopajtic, Theresa; Wang, Yun] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan. [Kuo, Chi-Chung; Shen, Hui; Harvey, Brandon K.; Yu, Seong-Jin; Hinkle, Josh. J.; Katz, Jonathan L.; Wang, Yun] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Kyrkanides, Stephanos] SUNY Stony Brook, Hlth Sci Ctr, Dept Childrens Dent, Stony Brook, NY 11794 USA. RP Wang, Y (reprint author), Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan.; Wang, Y (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov FU NIDA Intramural Research Program, USA; NHRI, Taiwan FX Funding for this study was provided by the NIDA Intramural Research Program, USA, and the NHRI, Taiwan. NR 52 TC 0 Z9 0 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD FEB PY 2016 VL 233 IS 4 BP 661 EP 672 DI 10.1007/s00213-015-4134-4 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DC5FE UT WOS:000369246100010 PM 26554386 ER PT J AU Kitahara, CM McCullough, ML Franceschi, S Rinaldi, S Wolk, A Neta, G Adami, HO Anderson, K Andreotti, G Freeman, LEB Bernstein, L Buring, JE Clavel-Chapelon, F De Roo, LA Gao, YT Gaziano, JM Giles, GG Hakansson, N Horn-Ross, PL Kirsh, VA Linet, MS Maclnnis, RJ Orsini, N Park, Y Patel, AV Purdue, MP Riboli, E Robien, K Rohan, T Sandler, DP Schairer, C Schneider, AB Sesso, HD Shu, XO Singh, PN van den Brandt, PA Ward, E Weiderpass, E White, E Xiang, YB Zeleniuch-Jacquotte, A Zheng, W Hartge, P de Gonzalez, AB AF Kitahara, Cari M. McCullough, Marjorie L. Franceschi, Silvia Rinaldi, Sabina Wolk, Alicja Neta, Gila Adami, Hans Olov Anderson, Kristin Andreotti, Gabriella Freeman, Laura E. Beane Bernstein, Leslie Buring, Julie E. Clavel-Chapelon, Francoise De Roo, Lisa A. Gao, Yu-Tang Gaziano, J. Michael Giles, Graham G. Hakansson, Niclas Horn-Ross, Pamela L. Kirsh, Vicki A. Linet, Martha S. Maclnnis, Robert J. Orsini, Nicola Park, Yikyung Patel, Alpa V. Purdue, Mark P. Riboli, Elio Robien, Kimberly Rohan, Thomas Sandler, Dale P. Schairer, Catherine Schneider, Arthur B. Sesso, Howard D. Shu, Xiao-Ou Singh, Pramil N. van den Brandt, Piet A. Ward, Elizabeth Weiderpass, Elisabete White, Emily Xiang, Yong-Bing Zeleniuch-Jacquotte, Anne Zheng, Wei Hartge, Patricia de Gonzalez, Amy Berrington TI Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype: Pooled Analysis of 22 Prospective Studies SO THYROID LA English DT Article ID BASE-LINE CHARACTERISTICS; BODY-MASS INDEX; NIH-AARP DIET; UNITED-STATES; BREAST-CANCER; LARGE COHORT; POSTMENOPAUSAL WOMEN; PHYSICAL-ACTIVITY; FAT DISTRIBUTION; LIFE-STYLE AB Background: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. Methods: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. Results: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5cm)=1.07 [1.04-1.10], BMI (per 5kg/m(2))=1.06 [1.02-1.10], waist circumference (per 5cm)=1.03 [1.01-1.05], young-adult BMI (per 5kg/m(2))=1.13 [1.02-1.25], and adulthood BMI gain (per 5kg/m(2))=1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p=0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. Conclusion: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies. C1 [Kitahara, Cari M.; Andreotti, Gabriella; Freeman, Laura E. Beane; Linet, Martha S.; Schairer, Catherine; Hartge, Patricia; de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [McCullough, Marjorie L.; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Franceschi, Silvia; Rinaldi, Sabina] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France. [Wolk, Alicja; Hakansson, Niclas; Orsini, Nicola] Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-10401 Stockholm, Sweden. [Neta, Gila] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Adami, Hans Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Adami, Hans Olov; Buring, Julie E.; Sesso, Howard D.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Anderson, Kristin] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Anderson, Kristin] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Buring, Julie E.; Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA. [Clavel-Chapelon, Francoise] Ctr Res Epidemiol & Populat Hlth CESP, INSERM, U1018, Villejuif, France. [Clavel-Chapelon, Francoise] France Paris South Univ, INSERM, UMRS 1018, Team 9, Villejuif, France. [De Roo, Lisa A.] Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway. [De Roo, Lisa A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Gao, Yu-Tang] Shanghai Jiao Tong Univ, Sch Med, Dept Epidemiol, Shanghai Canc Inst,Renji Hosp, Shanghai, Peoples R China. [Gaziano, J. Michael; Sesso, Howard D.] Brigham & Womens Hosp, Div Aging, 75 Francis St, Boston, MA 02115 USA. [Gaziano, J. Michael] Massachusetts Vet Epidemiol Res & Informat Ctr, Geriatric Res Educ & Clin Ctr, VA Boston Healthcare Syst, Boston, MA USA. [Giles, Graham G.; Maclnnis, Robert J.] Canc Epidemiol Ctr, Canc Council Victoria, Melbourne, Vic, Australia. [Giles, Graham G.; Maclnnis, Robert J.] Univ Melbourne, Ctr Biostat & Epidemiol, Melbourne Sch Populat & Global Hlth, Carlton, Vic 3053, Australia. [Horn-Ross, Pamela L.] Canc Prevent Inst Calif, Fremont, CA USA. [Kirsh, Vicki A.] Canc Care Ontario, Prevent & Canc Control, Toronto, ON, Canada. [Kirsh, Vicki A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Park, Yikyung] Washington Univ, Div Publ Hlth Sci, Sch Med, St Louis, MO USA. [Purdue, Mark P.] Ontario Inst Canc Res, Toronto, ON, Canada. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Imperial Sch Publ Hlth, London, England. [Robien, Kimberly] George Washington Univ, Milken Inst Sch Publ Hlth, Dept Exercise & Nutr Sci, Washington, DC USA. [Rohan, Thomas] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Schneider, Arthur B.] Univ Illinois, Sect Endocrinol Diabet & Metab, Chicago, IL USA. [Shu, Xiao-Ou] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr,Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Singh, Pramil N.] Loma Linda Univ, Sch Publ Hlth, Ctr Hlth Res, Loma Linda, CA 92350 USA. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands. [Ward, Elizabeth] Amer Canc Soc, Intramural Res, Atlanta, GA 30329 USA. [Weiderpass, Elisabete] Univ Tromso, Dept Community Med, Fac Hlth Sci, Arctic Univ Norway, Tromso, Norway. [Weiderpass, Elisabete] Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, Oslo, Norway. [Weiderpass, Elisabete] Folkalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland. [White, Emily] Fred Hutchinson Canc Res Ctr, Publ Hlth Serv Div, 1124 Columbia St, Seattle, WA 98104 USA. [White, Emily] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Div Epidemiol, Dept Populat Hlth, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Inst Canc, New York, NY USA. RP Kitahara, CM (reprint author), Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Rm 7E 536, Bethesda, MD 20892 USA. EM kitaharac@mail.nih.gov RI Purdue, Mark/C-9228-2016; Weiderpass, Elisabete/M-4029-2016; CLAVEL, Christine/P-6333-2016; Zheng, Wei/O-3351-2013; Beane Freeman, Laura/C-4468-2015; Kitahara, Cari/R-8267-2016; OI Purdue, Mark/0000-0003-1177-3108; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Weiderpass, Elisabete/0000-0003-2237-0128; Zheng, Wei/0000-0003-1226-070X; Beane Freeman, Laura/0000-0003-1294-4124; Robien, Kim/0000-0002-2120-2280; Sandler, Dale/0000-0002-6776-0018 FU Swedish Research Council; Swedish Cancer Foundation; Karolinska Institutet, Stockholm, Sweden; American Cancer Society; National Cancer Institute [R01 CA77398, R01 CA39742, CA-34933, CA-40360, CA-097193, R37 CA070867, UM1 CA182910, R01 CA082729, UM1 CA173640, K05-CA154337]; California Department of Public Health (CDPH) [103885]; NCI's SEER program [HHSN261201000140C, HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's (CDCP) National Program of Cancer Registries [U58DP003862-01]; World Cancer Research Fund [2009/92]; European Commission (DG-SANCO); International Agency for Research on Cancer; Danish Cancer Society, Denmark; Ligue Contre le Cancer, France; Institut Gustave Roussy, France; Mutuelle Generale de l'Education Nationale, France; Institut National de la Sante et de la Recherche Medicale, France; Deutsche Krebshilfe, Germany; Deutsches Krebsforschungszentrum; Federal Ministry of Education and Research, Germany; Hellenic Health Foundation, Greece; Italian Association for Research on Cancer; National Research Council, Italy; Dutch Ministry of Public Health, Welfare and Sports, the Netherlands; Netherlands Cancer Registry, the Netherlands; LK Research Funds, the Netherlands; Dutch Prevention Funds, the Netherlands; Dutch ZON (Zorg Onderzoek Nederland), the Netherlands; World Cancer Research Fund, London, UK; Statistics Netherlands, the Netherlands; European Research Council, Norway; Health Research Fund; Regional Government of Andalucia [6236]; Regional Government of Asturias [6236]; Regional Government of Basque Country [6236]; Regional Government of Murcia [6236]; Navarra, ISCIII RETIC, Spain [RD06/0020/0091]; Swedish Cancer Society, Sweden; Swedish Scientific Council, Sweden; Regional Government of Skane; Vasterbotten, Sweden; Cancer Research United Kingdom; Medical Research Council, United Kingdom; Stroke Association, United Kingdom; British Heart Foundation, United Kingdom; Department of Health, Food Standards Agency, United Kingdom; Wellcome Trust; French National Cancer Institute (L'Institut National du Cancer; INCA) [2009-139]; Ligue contre le Cancer (France); Institut Gustave Roussy (France); Mutuelle Generale de l'Education Nationale (France); Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid; German Cancer Research Center (DKFZ); German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC) [DR06/0020/0091]; regional government from Asturias; regional government from Andalucia; regional government from Murcia; regional government from Navarra; regional government from Vasco Country; Catalan Institute of Oncology of Spain; Cancer Research UK; Medical Research Council, UK; Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; Wellcome Trust, UK; Hellenic Health Foundation; Compagnia San Paolo, Italy; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Nordforsk-Centre of Excellence programme; National Health and Medical Research Council of Australia [209057, 251533]; National Heart, Lung, and Blood Institute [HL-26490, HL-34595]; National Institutes of Health, Bethesda, MD; NIH, National Institute of Environmental Health Sciences [ZO1-ES-044005]; Office of Dietary Supplements [K05-CA154337] FX COSM and SMC: These cohorts are supported by the Swedish Research Council, the Swedish Cancer Foundation, and by Strategic Funds from Karolinska Institutet, Stockholm, Sweden.; CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort.; CTS: The CTS is supported by grant R01 CA77398 from the National Cancer Institute. The collection of cancer incidence data used in the CTS is supported by the California Department of Public Health (CDPH) as part of the state-wide cancer reporting program mandated by California Health and Safety Code Section 103885; the NCI's SEER program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's (CDCP) National Program of Cancer Registries, under agreement U58DP003862-01 awarded to the CDPH. The ideas and opinions expressed herein are those of the author(s) and endorsement by the CDPH, NCI, and CDCP or their contractors and subcontractors is not intended nor should be inferred.; EPIC: The authors are grateful to the support of the World Cancer Research Fund (2009/92). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society, Denmark; Ligue Contre le Cancer, France; Institut Gustave Roussy, France; Mutuelle Generale de l'Education Nationale, France; Institut National de la Sante et de la Recherche Medicale, France; Deutsche Krebshilfe, Germany, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research, Germany; Hellenic Health Foundation, Greece; Italian Association for Research on Cancer; National Research Council, Italy; Dutch Ministry of Public Health, Welfare and Sports, the Netherlands; Netherlands Cancer Registry, the Netherlands; LK Research Funds, the Netherlands; Dutch Prevention Funds, the Netherlands; Dutch ZON (Zorg Onderzoek Nederland), the Netherlands; World Cancer Research Fund, London, UK; Statistics Netherlands, the Netherlands; European Research Council, Norway; Health Research Fund, Regional Governments of Andalucia, Asturias, Basque Country, Murcia (project no. 6236) and Navarra, ISCIII RETIC (RD06/0020/0091), Spain; Swedish Cancer Society, Sweden; Swedish Scientific Council, Sweden; Regional Government of Skane and Vasterbotten, Sweden; Cancer Research United Kingdom; Medical Research Council, United Kingdom; Stroke Association, United Kingdom, British Heart Foundation, United Kingdom; Department of Health, Food Standards Agency, United Kingdom; and Wellcome Trust; United Kingdom. We thank Bertrand Hemon for his precious help with the EPIC database. The principle investigators and funders corresponding to each of the EPIC centers that contributed cases were Kim Overvad, Anne Tjonneland (Denmark); Francoise Clavel-Chapelon (France); Heiner Boeing, Rudolf Kaaks (Germany); Antonia Trichopoulou (Greece); Vittorio Krogh, Domenico Palli, Paolo Vineis, Salvatore Panico, Rosario Tumino (Italy); Eiliv Lund (Norway); Antonio Agudo, Maria Jose Sanchez, J. Ramon Quiros, Carmen Navarro, Aurelio Barricarte, Miren Dorronsoro (Spain); Mattias Johansson, Jonas Manjer (Sweden); H. Bas Bueno-de-Mesquita, Petra H. Peeters (The Netherlands); Timothy Key, Nick Wareham (UK); The coordination of European Prospective Investigation into Cancer and Nutrition is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer.; The national cohorts are supported by the French National Cancer Institute (L'Institut National du Cancer; INCA); Grant Number: 2009-139; Ligue contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid; German Cancer Research Center (DKFZ); German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health (RTICC (DR06/0020/0091); the participating regional governments from Asturias, Andalucia, Murcia, Navarra and Vasco Country and the Catalan Institute of Oncology of Spain; Cancer Research UK; Medical Research Council, UK; the Stroke Association, UK; British Heart Foundation; Department of Health, UK; Food Standards Agency, UK; the Wellcome Trust, UK; the Hellenic Health Foundation; Italian Association for Research on Cancer; Compagnia San Paolo, Italy; Dutch Ministry of Public Health, Welfare and Sports; Dutch Ministry of Health; Dutch Prevention Funds; LK Research Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Nordforsk-Centre of Excellence programme.; IWHS: The authors thank the study participants. IWHS is funded by a grant from the National Cancer Institute (R01 CA39742).; Melbourne Collaborative Cohort Study: This study was made possible by the contribution of many people, including the original investigators and the diligent team who recruited the participants and who continue working on follow-up. We would also like to express our gratitude to the many thousands of Melbourne residents who continue to participate in the study. This work was supported by infrastructure from Cancer Council Victoria and grants from the National Health and Medical Research Council of Australia 209057 and 251533.; PHS: This study is supported by grants from the National Cancer Institute (CA-34933, CA-40360, and CA-097193) and from the National Heart, Lung, and Blood Institute (HL-26490 and HL-34595), National Institutes of Health, Bethesda, MD.; The Sister Study is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZO1-ES-044005). Support for data collection and study and data management are provided by Social & Scientific Systems, Inc., and Westat, Inc., Durham, NC. Aimee D'Aloisio, Sandra Halverson, Dan Scharf, and David Shore helped prepare the data for this analysis.; The SWHS and SMHS are supported in part by research grants from the National Cancer Institute (R37 CA070867, UM1 CA182910, R01 CA082729, and UM1 CA173640). The authors thank participants and research staff members of the studies for their contribution.; USRT: The authors thank the study participants and Jerry Reid of the American Registry of Radiologic Technologists for their continued support of this study; Diane Kampa and Allison Iwan of the University of Minnesota for study management and data collection; and Jeremy Miller at Information Management Services, Inc., for biomedical computing support.; VITAL: Emily White was supported by the grant K05-CA154337 (National Cancer Institute and Office of Dietary Supplements). NR 63 TC 3 Z9 3 U1 2 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD FEB 1 PY 2016 VL 26 IS 2 BP 306 EP 318 DI 10.1089/thy.2015.0319 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC8YO UT WOS:000369506700016 PM 26756356 ER PT J AU Bridge, H Leopold, DA Bourne, JA AF Bridge, Holly Leopold, David A. Bourne, James A. TI Adaptive Pulvinar Circuitry Supports Visual Cognition SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID LATERAL GENICULATE-NUCLEUS; RETINAL GANGLION-CELLS; CORTICAL AREA MT; MIDDLE TEMPORAL AREA; MACAQUE MONKEY; SUPERIOR COLLICULUS; INFERIOR PULVINAR; MEDIAL PULVINAR; FUNCTIONAL-ORGANIZATION; RHESUS-MONKEY AB The pulvinar is the largest thalamic nucleus in primates and one of the most mysterious. Endeavors to understand its role in vision have focused on its abundant connections with the visual cortex. While its connectivity mapping in the cortex displays a broad topographic organization, its projections are also marked by considerable convergence and divergence. As a result, the pulvinar is often regarded as a central forebrain hub. Moreover, new evidence suggests that its comparatively modest input from structures such as the retina and superior colliculus may critically shape the functional organization of the visual cortex, particularly during early development. Here we review recent studies that cast fresh light on how the many convergent pathways through the pulvinar contribute to visual cognition. C1 [Bridge, Holly] John Radcliffe Hosp, FMRIB Ctr, Oxford OX3 9DU, England. [Leopold, David A.] NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA. [Bourne, James A.] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. RP Bourne, JA (reprint author), Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. EM James.Bourne@monash.edu OI Bourne, James/0000-0002-0902-3108; Leopold, David/0000-0002-1345-6360 FU National Health and Medical Research Senior Research Fellowship [APP1077677, APP1042893]; Intramural Research Program of the National Institute of Mental Health; Royal Society International Exchange Grant FX The authors thank Phil Owen for assistance with the figures and Mary Baldwin, Aldan Murphy, and Jude Mitchell for their insightful comments on earlier versions. J.A.B is supported by a National Health and Medical Research Senior Research Fellowship (APP1077677) and project grants (APP1042893) H.B, Is a Royal Society University Research Fellow. This work was supported, in part, by the Intramural Research Program of the National Institute of Mental Health (D.A.L) and a Royal Society International Exchange Grant to H.B. and J.A.B. NR 86 TC 6 Z9 6 U1 6 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD FEB PY 2016 VL 20 IS 2 BP 146 EP 157 DI 10.1016/j.tics.2015.10.003 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA DC8MJ UT WOS:000369473400012 PM 26553222 ER PT J AU De Flora, S Ganchev, G Iltcheva, M La Maestra, S Micale, RT Steele, VE Balansky, R AF De Flora, Silvio Ganchev, Gancho Iltcheva, Marietta La Maestra, Sebastiano Micale, Rosanna T. Steele, Vernon E. Balansky, Roumen TI Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CANCER CHEMOPREVENTIVE AGENTS; ACTIVATED RECEPTOR-GAMMA; STRAIN A/J MICE; CIGARETTE-SMOKE; N-ACETYLCYSTEINE; TOBACCO-SMOKE; MOUSE LUNG; ESTROGEN METABOLISM; DIABETIC-PATIENTS AB Many drugs in common use possess pleiotropic properties that make them capable of interfering with carcinogenesis mechanisms. We discuss here the ability of pharmacological agents to mitigate the pulmonary carcinogenicity of mainstream cigarette smoke. The evaluated agents include anti-inflammatory drugs (budesonide, celecoxib, aspirin, naproxen, licofelone), antidiabetic drugs (metformin, pioglitazone), antineoplastic agents (lapatinib, bexarotene, vorinostat), and other drugs and supplements (phenethyl isothiocyanate, myo-inositol, N-acetylcysteine, ascorbic acid, berry extracts). These drugs have been evaluated in mouse models mimicking interventions either in current smokers or in ex-smokers, or in prenatal chemoprevention. They display a broad spectrum of activities by attenuating either smoke-induced preneoplastic lesions or benign tumors and/or malignant tumors. Together with epidemiological data, these findings provide useful information to predict the potential effects of pharmacological agents in smokers. C1 [De Flora, Silvio; La Maestra, Sebastiano; Micale, Rosanna T.; Balansky, Roumen] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Ganchev, Gancho; Iltcheva, Marietta; Balansky, Roumen] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Steele, Vernon E.] NCI, Div Canc Prevent, Rockville, MD 20892 USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. EM sdf@unige.it FU National Institutes of Health (National Cancer Institute) [HHSN-261200533001C, HHSN-261200433000C, HHSN-2612012000151]; Bulgarian Ministry of Education, Youth, and Science (National Research Fund) FX These studies were supported by grants from the National Institutes of Health (National Cancer Institute, contracts HHSN-261200533001C, HHSN-261200433000C, and HHSN-2612012000151) and by the Bulgarian Ministry of Education, Youth, and Science (National Research Fund). NR 144 TC 4 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD FEB PY 2016 VL 37 IS 2 BP 120 EP 142 DI 10.1016/j.tips.2015.11.003 PG 23 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DC8ID UT WOS:000369462200005 PM 26726119 ER PT J AU Pursnani, A Celeng, C Schlett, CL Maythofer, T Zakroysky, P Lee, H Ferencik, M Fleg, JL Bamberg, F Wiviott, SD Truong, QA Udelson, JE Nagurney, JT Hoffmann, U AF Pursnani, Amit Celeng, Csilla Schlett, Christopher L. Maythofer, Thomas Zakroysky, Pearl Lee, Hang Ferencik, Maros Fleg, Jerome L. Bamberg, Fabian Wiviott, Stephen D. Truong, Quynh A. Udelson, James E. Nagurney, John T. Hoffmann, Udo TI Use of Coronary Computed Tomographic Angiography Findings to Modify Statin and Aspirin Prescription in Patients With Acute Chest Pain SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID INTERNATIONAL MULTICENTER REGISTRY; ARTERY-DISEASE; PROGNOSTIC VALUE; CT ANGIOGRAPHY; EMERGENCY-DEPARTMENT; SYMPTOMATIC PATIENTS; CLINICAL-OUTCOMES; RISK-FACTORS; ATHEROSCLEROSIS; METAANALYSIS AB Coronary CT angiography (CCTA) is used in patients with low-intermediate chest pain presenting to the emergency department for its reliability in excluding acute coronary syndrome (ACS). However, its influence on medication modification in this setting is unclear. We sought to determine whether knowledge of CCTA-based coronary artery disease (CAD) was associated with change in statin and aspirin prescription. We used the CCTA arm of the Rule Out Myocardial Infarction using Computed Angiographic Tomography II multicenter, randomized control trial (R-II) and comparison cohort from the observational Rule Out Myocardial Infarction using Computed Angiographic Tomography I cohort (R-I). In R-II, subjects were randomly assigned to CCTA to guide decision making, whereas in R-I patients underwent CCTA with results blinded to caregivers and managed according to standard care. Our final cohort consisted of 277 subjects from R-I and 370 from R-II. ACS rate was similar (6.9% vs 6.2% respectively, p = 0.75). For subjects with CCTA-detected obstructive CAD without ACS, initiation of statin was significantly greater after disclosure of CCTA results (0% in R-I vs 20% in R-II, p = 0.009). Conversely, for subjects without CCTA-detected. CAD, aspirin prescription was lower with disclosure of CCTA results (16% in R-I vs 4.8% in R-II, p = 0.001). However, only 68% of subjects in R-II with obstructive CAD were discharged on statin and 65% on aspirin. In conclusion, physician knowledge of CCTA results leads to improved alignment of aspirin and statin with the presence and severity of CAD although still many patients with CCTA-detected CAD are not discharged on aspirin or statin. Our findings suggest opportunity for practice improvement when CCTA is performed in the emergency department. (C) 2016 Elsevier Inc. All rights reserved. C1 [Pursnani, Amit; Celeng, Csilla; Maythofer, Thomas; Ferencik, Maros; Truong, Quynh A.; Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Div Cardiol,Cardiac Magnet Resonance Positron Emi, Boston, MA 02115 USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Emergency Med, Boston, MA USA. [Schlett, Christopher L.] Univ Heidelberg Hosp, Dept Diagnost & Intervent Radiol, Heidelberg, Germany. [Zakroysky, Pearl; Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Bamberg, Fabian] Univ Munich, Klinikum Grosshadern, Dept Clin Radiol, D-80539 Munich, Germany. [Wiviott, Stephen D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. RP Pursnani, A (reprint author), Harvard Univ, Sch Med, Dept Radiol, Div Cardiol,Cardiac Magnet Resonance Positron Emi, Boston, MA 02115 USA. EM amit.pursnani@gmail.com FU National Institutes of Health/ National Heart Lung Blood Institute (Bethesda, Maryland) [U01HL092040, U01HL092022, 5K24HL113128] FX The study was supported by the grants U01HL092040, U01HL092022 and 5K24HL113128 from National Institutes of Health/ National Heart Lung Blood Institute (Bethesda, Maryland). NR 16 TC 2 Z9 2 U1 2 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 1 PY 2016 VL 117 IS 3 BP 319 EP 324 DI 10.1016/j.amjcard.2015.10.052 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DC4ME UT WOS:000369194200001 PM 26762723 ER PT J AU Whitman, MC Andrews, C Chan, WM Tischfield, MA Stasheff, SF Brancati, F Ortiz-Gonzalez, X Nuovo, S Garaci, F MacKinnon, SE Hunter, DG Grant, PE Engle, EC AF Whitman, Mary C. Andrews, Caroline Chan, Wai-Man Tischfield, Max A. Stasheff, Steven F. Brancati, Francesco Ortiz-Gonzalez, Xilma Nuovo, Sara Garaci, Francesco MacKinnon, Sarah E. Hunter, David G. Grant, P. Ellen Engle, Elizabeth C. TI Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE tubulin; congenital fibrosis of extraocular muscles; tubulinopathy; cortical development; TUBB3 ID ALPHA-BETA-TUBULIN; CONGENITAL FIBROSIS; EXTRAOCULAR-MUSCLES; KIF21A; RESOLUTION AB One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both. (c) 2015 Wiley Periodicals, Inc. C1 [Whitman, Mary C.; MacKinnon, Sarah E.; Hunter, David G.; Engle, Elizabeth C.] Boston Childrens Hosp, Dept Ophthalmol, Boston, MA 02115 USA. [Whitman, Mary C.; Hunter, David G.; Engle, Elizabeth C.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Whitman, Mary C.; Andrews, Caroline; Chan, Wai-Man; Tischfield, Max A.; Engle, Elizabeth C.] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Andrews, Caroline; Chan, Wai-Man; Tischfield, Max A.; Engle, Elizabeth C.] Boston Childrens Hosp, Dept Neurol, CLS 14075,300 Longwood Ave, Boston, MA 02115 USA. [Andrews, Caroline; Chan, Wai-Man; Tischfield, Max A.; Engle, Elizabeth C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Andrews, Caroline; Chan, Wai-Man; Engle, Elizabeth C.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Chan, Wai-Man; Engle, Elizabeth C.] Boston Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Stasheff, Steven F.] Univ Iowa, Dept Pediat Neurol, Iowa City, IA USA. [Stasheff, Steven F.] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. [Stasheff, Steven F.] Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA. [Stasheff, Steven F.] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Brancati, Francesco] Gabriele dAnnunzio Univ, Dept Med Oral & Biotechnol Sci, Chieti, Italy. [Ortiz-Gonzalez, Xilma] Childrens Hosp Philadelphia, Dept Neurol, Philadelphia, PA 19104 USA. [Nuovo, Sara] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy. [Garaci, Francesco] Univ Roma Tor Vergata, Dept Diagnost Imaging Mol Imaging Intervent Radio, Rome, Italy. [Grant, P. Ellen] Harvard Univ, Sch Med, Dept Radiol, Boston Childrens Hosp, Boston, MA 02115 USA. [Engle, Elizabeth C.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Engle, Elizabeth C.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Engle, Elizabeth C.] Boston Childrens Hosp, Dept Med Genet, Boston, MA 02115 USA. [Stasheff, Steven F.] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. RP Engle, EC (reprint author), Boston Childrens Hosp, Dept Neurol, CLS 14075,300 Longwood Ave, Boston, MA 02115 USA. EM Elizabeth.engle@childrens.harvard.edu FU National Eye Institute of the National Institutes of Health [R01EY12498]; Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [HD018655]; Harvard-Vision Clinical Scientist Development Program Research [5K12EY016335]; Knights Templar Eye Foundation; Children's Hospital Ophthalmology Foundation; National Institute of Neurological Disorders and Stroke [5K12NS049453-09] FX Grant sponsor: National Eye Institute of the National Institutes of Health; Grant number: R01EY12498; Grant sponsor: Boston Children's Hospital Intellectual and Developmental Disabilities Research Center; Grant number: HD018655; Grant sponsor: Harvard-Vision Clinical Scientist Development Program Research; Grant number: 5K12EY016335; Grant sponsor: Knights Templar Eye Foundation; Grant sponsor: Children's Hospital Ophthalmology Foundation; Grant sponsor: National Institute of Neurological Disorders and Stroke; Grant number: 5K12NS049453-09. NR 14 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2016 VL 170 IS 2 BP 297 EP 305 DI 10.1002/ajmg.a.37362 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA DB9BR UT WOS:000368811500003 PM 26639658 ER PT J AU Savage, SA Ballew, BJ Giri, N Chandrasekharappa, SC Ameziane, N de Winter, J Alter, BP AF Savage, Sharon A. Ballew, Bari J. Giri, Neelam Chandrasekharappa, Settara C. Ameziane, Najim de Winter, Johan Alter, Blanche P. CA NCI DCEG Canc Genomics Res Lab NCI DCEG Canc Sequencing Working G TI Novel FANCI mutations in Fanconi anemia with VACTERL association SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Fanconi anemia; FANCI; VACTERL association ID BONE-MARROW FAILURE; DNA-REPAIR; CHROMOSOME BREAKAGE; PROTEIN; IDENTIFICATION; PATHWAY; GENE AB Fanconi anemia (FA) is an inherited bone marrow failure syndrome caused by mutations in DNA repair genes; some of these patients may have features of the VACTERL association. Autosomal recessive mutations in FANCI are a rare cause of FA. We identified FANCI mutations by next generation sequencing in three patients in our FA cohort among several whose mutated gene was unknown. Four of the six mutations are novel and all mutations are likely deleterious to protein function. There are now 16 reported cases of FA due to FANCI of whom 7 have at least 3 features of the VACTERL association (44%). This suggests that the VACTERL association in patients with FA may be seen in patients with FANCI mutations more often than previously recognized. (c) 2015 Wiley Periodicals, Inc. C1 [Savage, Sharon A.; Ballew, Bari J.; Giri, Neelam; Alter, Blanche P.; NCI DCEG Canc Sequencing Working G] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [NCI DCEG Canc Genomics Res Lab] NCI Frederick, Canc Genom Res Lab, Leidos Biomed Res, Rockville, MD USA. [Chandrasekharappa, Settara C.] NHGRI, Canc Genet & Comparat Genom Branch, Bethesda, MD 20892 USA. [Ameziane, Najim; de Winter, Johan] Vrije Univ Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E454, Bethesda, MD 20850 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015; Tobias, Geoffrey/M-4135-2016; OI Savage, Sharon/0000-0001-6006-0740; Tobias, Geoffrey/0000-0002-2878-8253; Dagnall, Casey/0000-0001-7334-4718 FU Intramural Research Program; National Cancer Institute; NIH FX Grant sponsor: Intramural Research Program; Grant sponsor: National Cancer Institute; Grant sponsor: NIH. NR 22 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB PY 2016 VL 170 IS 2 BP 386 EP 391 DI 10.1002/ajmg.a.37461 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DB9BR UT WOS:000368811500013 PM 26590883 ER PT J AU McMillin, M Frampton, G Quinn, M Ashfaq, S de los Santos, M Grant, S DeMorrow, S AF McMillin, Matthew Frampton, Gabriel Quinn, Matthew Ashfaq, Samir de los Santos, Mario, III Grant, Stephanie DeMorrow, Sharon TI Bile Acid Signaling Is Involved in the Neurological Decline in a Murine Model of Acute Liver Failure SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID BLOOD-BRAIN-BARRIER; FULMINANT HEPATIC-FAILURE; DUCT-LIGATED RATS; CHOLANGIOCARCINOMA GROWTH; BILIARY OBSTRUCTION; OPPOSING ACTIONS; GENE-EXPRESSION; MOUSE MODEL; CELL-DEATH; ENCEPHALOPATHY AB Hepatic encephalopathy is a serious neurological complication of liver failure. Serum bile acids are elevated after Liver damage and may disrupt the blood-brain barrier and enter the brain. Our aim was to assess the role of serum bile acids in the neurological complications after acute liver failure. C57Bl/6 or cytochrome p450 7A1 knockout (Cyp7A1(-/-)) mice were fed a control, cholestyramine-containing, or bile acid-containing diet before azoxymethane (AOM)-induced acute Liver failure. In parallel, mice were given an intracerebroventricular infusion of farnesoid X receptor (FXR) Vivo-morpholino before AOM injection. Liver damage, neurological decline, and molecular analyses of bile acid signaling were performed. Total bile acid Levels were increased in the cortex of AOM-treated mice. Reducing serum bile acids via cholestyramine feeding or using Cyp7A1(-/-) mice reduced bile acid Levels and delayed AOM-induced neurological decline, whereas cholic acid or deoxycholic acid feeding worsened AOM-induced neurological decline. The expression of bile acid signaling machinery apical sodium-dependent bile acid transporter, FXR, and small heterodimer partner increased in the frontal cortex, and blocking FXR signaling delayed AOM-induced neurological decline. In conclusion, circulating bile acids may play a pathological role during hepatic encephalopathy, although precisely how they dysregulate normal brain function is unknown. Strategies to minimize serum bile acid concentrations may reduce the severity of neurological complications associated with liver failure. C1 [McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Grant, Stephanie; DeMorrow, Sharon] Texas A&M Hlth Sci Ctr, Dept Internal Med, Coll Med, Temple, TX 76504 USA. [McMillin, Matthew; Frampton, Gabriel; Ashfaq, Samir; de los Santos, Mario, III; Grant, Stephanie; DeMorrow, Sharon] Baylor Scott & White Hlth, Digest Dis Res Ctr, Temple, TX USA. [McMillin, Matthew; Frampton, Gabriel; Grant, Stephanie; DeMorrow, Sharon] Cent Texas Vet Healthcare Syst, 1901 S 1st St,Bldg 205, Temple, TX 76504 USA. [Quinn, Matthew] NIEHS, Lab Signal Transduct, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. RP DeMorrow, S (reprint author), Cent Texas Vet Healthcare Syst, 1901 S 1st St,Bldg 205, Temple, TX 76504 USA.; DeMorrow, S (reprint author), Texas A&M Hlth Sci Ctr, Dept Internal Med, Baylor Scott & White Hlth, 1901 S 1st St,Bldg 205, Temple, TX 76504 USA. EM demorrow@medicine.tamhsc.edu OI McMillin, Matthew/0000-0002-5980-0921 FU NIH R01 award [DK082435]; NIH K01 award [DK078532]; Scott & White Intramural grant [050339]; US Department of Veterans Affairs Biomedical Laboratory Research and Development Service VA merit award [BX002638-01] FX Supported by an NIH R01 award DK082435, an NIH K01 award DK078532, a Scott & White Intramural grant award 050339, and a US Department of Veterans Affairs Biomedical Laboratory Research and Development Service VA merit award BX002638-01 (all to S.D.). NR 58 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2016 VL 186 IS 2 BP 312 EP 323 DI 10.1016/j.ajpath.2015.10.005 PG 12 WC Pathology SC Pathology GA DC1IL UT WOS:000368969900010 PM 26683664 ER PT J AU Nilubol, N Weinstein, LS Simonds, WF Jensen, RT Marx, SJ Kebebew, E AF Nilubol, Naris Weinstein, Lee S. Simonds, William F. Jensen, Robert T. Marx, Stephen J. Kebebew, Electron TI Limited Parathyroidectomy in Multiple Endocrine Neoplasia Type 1-Associated Primary Hyperparathyroidism: A Setup for Failure SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PREOPERATIVE IMAGING TESTS; SESTAMIBI SCAN; REOPERATION; MEN1; MANIFESTATIONS; ULTRASOUND; MANAGEMENT; OPERATION; ADENOMAS; SURGERY AB Recently, some surgeons have suggested that minimally invasive parathyroidectomy guided by preoperative localizing studies of patients with multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) provides an acceptable outcome while minimizing the risk of hypoparathyroidism. This study aimed to evaluate the outcome for MEN1 patients who underwent limited parathyroidectomy compared with subtotal parathyroidectomy. The authors performed a retrospective analysis of 99 patients with MEN1-associated pHPT who underwent at least one parathyroid operation at their institution. Preoperative imaging studies, intraoperative findings, and clinical outcomes for patients were compared. A total of 99 patients underwent 146 operations. Persistent pHPT was significantly higher in patients whose initial operations involved removal of 1 or 2 glands (69 %) or 2.5 to 3 glands (20 %) compared with those who had 3.5 or more glands removed (6 %) (P < 0.01). Persistent pHPT occurred in 5 % of all operations that cumulatively removed 3.5 or more parathyroid glands compared with 40 % of operations that removed 3 or fewer glands (P < 0.01). The single largest parathyroid gland was correctly identified preoperatively in 69 % (22/32) of the patients. However, preoperative localizing studies missed enlarged contralateral parathyroid glands in 86 % (19/22) of these patients. Preoperative localizing studies missed the largest contralateral parathyroid gland in 16 % (5/32) of the patients. Limited parathyroidectomy in MEN1 is associated with a high failure rate and should not be performed. Preoperative identification of a single enlarged parathyroid gland in MEN1 is not reliable enough to justify unilateral neck exploration because additional enlarged contralateral parathyroid glands are frequently missed. C1 [Nilubol, Naris; Kebebew, Electron] NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weinstein, Lee S.; Simonds, William F.; Marx, Stephen J.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Nilubol, N (reprint author), NCI, Endocrine Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM niluboln@mail.nih.gov OI Weinstein, Lee/0000-0002-1899-5152 FU Intramural NIH HHS NR 36 TC 2 Z9 2 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2016 VL 23 IS 2 BP 416 EP 423 DI 10.1245/s10434-015-4865-9 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA DB7UH UT WOS:000368721400011 PM 26542588 ER PT J AU Ward, MM Deodhar, A Akl, EA Lui, A Ermann, J Gensler, LS Smith, JA Borenstein, D Hiratzka, J Weiss, PF Inman, RD Majithia, V Haroon, N Maksymowych, WP Joyce, J Clark, BM Colbert, RA Figgie, MP Hallegua, DS Prete, PE Rosenbaum, JT Stebulis, JA Van Den Bosch, F Yu, DTY Miller, AS Reveille, JD Caplan, L AF Ward, Michael M. Deodhar, Atul Akl, Elie A. Lui, Andrew Ermann, Joerg Gensler, Lianne S. Smith, Judith A. Borenstein, David Hiratzka, Jayme Weiss, Pamela F. Inman, Robert D. Majithia, Vikas Haroon, Nigil Maksymowych, Walter P. Joyce, Janet Clark, Bruce M. Colbert, Robert A. Figgie, Mark P. Hallegua, David S. Prete, Pamela E. Rosenbaum, James T. Stebulis, Judith A. Van Den Bosch, Filip Yu, David T. Y. Miller, Amy S. Reveille, John D. Caplan, Liron TI American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CLASSIFICATION CRITERIA; PSORIATIC-ARTHRITIS; MANAGEMENT; EFFICACY; SAFETY; INJECTIONS; THERAPY; DRUGS; GRADE AB ObjectiveTo provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). MethodsA core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. ResultsIn patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. ConclusionThese recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas. C1 [Ward, Michael M.; Colbert, Robert A.] NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. [Deodhar, Atul; Hiratzka, Jayme; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Akl, Elie A.] Amer Univ Beirut, Beirut, Lebanon. [Akl, Elie A.] McMaster Univ, Hamilton, ON, Canada. [Lui, Andrew; Gensler, Lianne S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ermann, Joerg] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Smith, Judith A.] Univ Wisconsin, Madison, WI 53706 USA. [Borenstein, David] Arthrit & Rheumatism Assoc, Washington, DC USA. [Weiss, Pamela F.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Weiss, Pamela F.] Univ Penn, Philadelphia, PA 19104 USA. [Inman, Robert D.; Haroon, Nigil] Univ Toronto, Toronto, ON, Canada. [Majithia, Vikas] Univ Mississippi, Med Ctr, Jackson, MS USA. [Maksymowych, Walter P.] Univ Alberta, Edmonton, AB, Canada. [Joyce, Janet; Miller, Amy S.] Amer Coll Rheumatol, 60 Execut Pk S,Suite 150, Atlanta, GA 30329 USA. [Clark, Bruce M.] RPT, Vancouver, BC, Canada. [Figgie, Mark P.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [Hallegua, David S.] Cedars Sinai Med Ctr, Beverly Hills, CA USA. [Prete, Pamela E.] VA Long Beach Med Ctr, Long Beach, CA USA. [Prete, Pamela E.] Univ Calif Irvine, Irvine, CA USA. [Rosenbaum, James T.] Legacy Devers Eye Inst, Portland, OR USA. [Stebulis, Judith A.] Univ Massachusetts, Worcester, MA 01605 USA. [Van Den Bosch, Filip] Univ Ghent, B-9000 Ghent, Belgium. [Yu, David T. Y.] Univ Calif Los Angeles, Los Angeles, CA USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Caplan, Liron] Denver VA Med Ctr, Denver, CO USA. [Caplan, Liron] Univ Colorado, Aurora, CO USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU American College of Rheumatology; Spondylitis Association of America FX This work was supported by the American College of Rheumatology and the Spondylitis Association of America. We thank our patient representative for adding valuable perspectives. We thank Laurie Savage and Charlotte Howard of the Spondylitis Association of America for their partnership on this project. We thank Regina Parker for administrative assistance and Tamara Rader, who with Janet Joyce, developed and reviewed the literature search strategies. We appreciate the contributions of Drs. Robert Hart, Siba Raychaudhuri, and James Witter to the literature review. NR 29 TC 3 Z9 3 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD FEB PY 2016 VL 68 IS 2 BP 151 EP 166 DI 10.1002/acr.22708 PG 16 WC Rheumatology SC Rheumatology GA DB9RT UT WOS:000368855100001 PM 26401907 ER PT J AU Ward, MM Deodhar, A Akl, EA Lui, A Ermann, J Gensler, LS Smith, JA Borenstein, D Hiratzka, J Weiss, PF Inman, RD Majithia, V Haroon, N Maksymowych, WP Joyce, J Clark, BM Colbert, RA Figgie, MP Hallegua, DS Prete, PE Rosenbaum, JT Stebulis, JA van den Bosch, F Yu, DTY Miller, AS Reveille, JD Caplan, L AF Ward, Michael M. Deodhar, Atul Akl, Elie A. Lui, Andrew Ermann, Joerg Gensler, Lianne S. Smith, Judith A. Borenstein, David Hiratzka, Jayme Weiss, Pamela F. Inman, Robert D. Majithia, Vikas Haroon, Nigil Maksymowych, Walter P. Joyce, Janet Clark, Bruce M. Colbert, Robert A. Figgie, Mark P. Hallegua, David S. Prete, Pamela E. Rosenbaum, James T. Stebulis, Judith A. van den Bosch, Filip Yu, David T. Y. Miller, Amy S. Reveille, John D. Caplan, Liron TI American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; CLASSIFICATION CRITERIA; PSORIATIC-ARTHRITIS; MANAGEMENT; EFFICACY; SAFETY; INJECTIONS; THERAPY; DRUGS; GRADE AB Objective. To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods. A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. Results. In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. Conclusion. These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas. C1 [Ward, Michael M.; Colbert, Robert A.] NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. [Deodhar, Atul; Hiratzka, Jayme; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Akl, Elie A.] Amer Univ Beirut, Beirut, Lebanon. [Akl, Elie A.] McMaster Univ, Hamilton, ON, Canada. [Lui, Andrew; Gensler, Lianne S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ermann, Joerg] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Smith, Judith A.] Univ Wisconsin, Madison, WI 53706 USA. [Borenstein, David] Arthrit & Rheumatism Associates, Washington, DC USA. [Weiss, Pamela F.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Weiss, Pamela F.] Univ Penn, Philadelphia, PA 19104 USA. [Inman, Robert D.; Haroon, Nigil] Univ Toronto, Toronto, ON, Canada. [Majithia, Vikas] Univ Mississippi, Med Ctr, Jackson, MS USA. [Maksymowych, Walter P.] Univ Alberta, Edmonton, AB, Canada. [Joyce, Janet; Miller, Amy S.] Amer Coll Rheumatol, 60 Execut Pk S,Suite 150, Atlanta, GA 30329 USA. [Clark, Bruce M.] RPT, Vancouver, BC, Canada. [Figgie, Mark P.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [Hallegua, David S.] Cedars Sinai Med Ctr, Beverly Hills, CA USA. [Prete, Pamela E.] VA Long Beach Med Ctr, Long Beach, CA USA. [Prete, Pamela E.] Univ Calif Irvine, Irvine, CA USA. [Rosenbaum, James T.] Legacy Devers Eye Inst, Portland, OR USA. [Stebulis, Judith A.] Univ Massachusetts, Worcester, MA 01605 USA. [van den Bosch, Filip] Univ Ghent, B-9000 Ghent, Belgium. [Yu, David T. Y.] Univ Calif Los Angeles, Los Angeles, CA USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Caplan, Liron] Denver VA Med Ctr, Denver, CO USA. [Caplan, Liron] Univ Colorado, Aurora, CO USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; Abbott; Amgen; Pfizer; Novartis; AbbVie; UCB; Johnson Johnson; Celgene; Iroko; Janssen; Amgen/Pfizer; GlaxoSmithKline; Janssen/Johnson & Johnson/Centocor/Ortho Biotech Products; Janssen Biotech; Augurex; Bristol-Myers Squibb; Medtronic; Ethicon; Q-Med AB; Centocor; IDEC; Xoma; Roche; Isis; Pharmacia; La Jolla Pharma; Genentech; Proctor Gamble; Genelabs; MedImmune; Human Genome Sciences; Array Biopharma; Cipher; Regeneron; Lux Biosciences; Elan; Allergan; Santen; Teva; Sanofi; Janssen/Johnson Johnson FX Drs. Ward and Colbert's work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH.; Dr. Deodhar has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Pfizer, and Novartis (less than $10,000 each) and from AbbVie and UCB (more than $10,000 each), and research grants from Novartis, UCB, Johnson & Johnson, and Amgen. Dr. Ermann has received honoraria from AbbVie (less than $10,000) for Advisory Board service. Dr. Gensler has received consulting fees, speaking fees, and/or honoraria from AbbVie, UCB, and Amgen (less than $10,000 each) and research grants from Celgene and AbbVie. Dr. Borenstein has received consulting fees, speaking fees, and/or honoraria from Iroko and Abbott (less than $10,000 each) and honoraria from Clinical Care Options (more than $10,000). Dr. Inman has received consulting fees, speaking fees, and/or honoraria from AbbVie, Abbott, Janssen, Amgen/Pfizer, UCB, Novartis, and Celgene (less than $10,000 each). Dr. Majithia has received consulting fees, speaking fees, and/or honoraria from GlaxoSmithKline (less than $10,000). Dr. Haroon has received consulting fees, speaking fees, and/or honoraria from AbbVie, Abbott, Amgen, Janssen/Johnson & Johnson/Centocor/Ortho Biotech Products, Janssen Biotech, Celgene, UCB, and Pfizer (less than $10,000 each). Dr. Maksymowych has received consulting fees, speaking fees, and/or honoraria from AbbVie, UCB, Pfizer, Amgen, Janssen, and Augurex (less than $10,000 each) and receives licensing fees and royalties from Augurex for the 14-3-3 biomarker. Mr. Clark has received consulting fees, speaking fees, and/or honoraria from AbbVie, Abbott, Amgen, Janssen, and Bristol-Myers Squibb (less than $10,000 each). Dr. Figgie has received consulting fees, speaking fees, and/or honoraria from Medtronic and Ethicon (less than $10,000 each). Dr. Hallegua has received consulting fees, speaking fees, and/or honoraria from AbbVie, Q-Med AB, UCB, Bristol-Myers Squibb, Centocor, Amgen, IDEC, Xoma, Novartis, Roche, Isis, Pharmacia, La Jolla Pharma, Genentech, Proctor & Gamble, Genelabs, MedImmune, Human Genome Sciences, Array Biopharma, and Cipher (less than $10,000 each). Dr. Prete has received consulting fees, speaking fees, and/or honoraria from Abbott (less than $10,000). Dr. Rosenbaum has received consulting fees, speaking fees, and/or honoraria from UCB, Regeneron, Xoma, Lux Biosciences, Elan, Allergan, Santen, Teva, Novartis, Sanofi, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, and Genentech (less than $10,000 each) and is a contributor to UpToDate. Dr. van den Bosch has received consulting fees, speaking fees, and/or honoraria from AbbVie, Bristol-Myers Squibb, Celgene, Janssen/Johnson & Johnson, Pfizer, and UCB (less than $10,000 each). Dr. Reveille has received consulting fees, speaking fees, and/or honoraria from Abbott and UCB (less than $10,000 each). NR 29 TC 24 Z9 27 U1 3 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD FEB PY 2016 VL 68 IS 2 BP 282 EP 298 DI 10.1002/art.39298 PG 17 WC Rheumatology SC Rheumatology GA DC0XY UT WOS:000368942500005 PM 26401991 ER PT J AU Gencer, B Auer, R de Rekeneire, N Butler, J Kalogeropoulos, A Bauer, DC Kritchevsky, SB Miljkovic, I Vittinghoff, E Harris, T Rodondi, N AF Gencer, Baris Auer, Reto de Rekeneire, Nathalie Butler, Javed Kalogeropoulos, Andreas Bauer, Douglas C. Kritchevsky, Stephen B. Miljkovic, Iva Vittinghoff, Eric Harris, Tamara Rodondi, Nicolas TI Association between resistin levels and cardiovascular disease events in older adults: The health, aging and body composition study SO ATHEROSCLEROSIS LA English DT Article DE Cardiovascular prevention; Biomarkers; Inflammation; Insulin resistance; Cohort studies ID CORONARY-HEART-DISEASE; INSULIN-RESISTANCE; ARTERY-DISEASE; ATHEROSCLEROSIS; INFLAMMATION; EXPRESSION; OBESITY; HUMANS; RISK; ADIPONECTIN AB Objective: Prospective data on the association between resistin levels and cardiovascular disease (CVD) events are sparse with conflicting results. Methods: We studied 3044 aged 70-79 years from the Health, Aging, and Body Composition Study. CVD events were defined as coronary heart disease (CHD) or stroke events. "Hard" CHD events were defined as CHD death or myocardial infarction. We estimated hazard ratio (HR) and 95% confidence intervals (CI) according to the quartiles of serum resistin concentrations and adjusted for clinical variables, and then further adjusted for metabolic disease (body mass index, fasting plasma glucose, abdominal visceral and subcutaneous adipose tissue, leptin, adiponectin, insulin) and inflammation (C-reactive protein, interleukin-6, tumor necrosis factors-alpha). Results: During a median follow-up of 10.1 years, 559 patients had "hard" CHD events, 884 CHD events and 1106 CVD Events. Unadjusted incidence rate for CVD events was 36.6 (95% CI 32.1-41.1) per 1000 persons-year in the lowest quartile and 54.0 per 1000 persons-year in the highest quartile (95% CI 48.2 -59.8, P for trend < 0.001). In the multivariate models adjusted for clinical variables, HRs for the highest vs. lowest quartile of resistin was 1.52 (95% CI 1.20-1.93, P < 0.001) for "Hard" CHD events, 1.41 (95% CI 1.16-1.70, P = 0.001) for CHD events and 1.35 (95% CI 1.14-1.59, P = 0.002) for CVD events. Further adjustment for metabolic disease slightly reduced the associations while adjustment for inflammation markedly reduced the associations. Conclusions: In older adults, higher resistin levels are associated with CVD events independently of clinical risk factors and metabolic disease markers, but markedly attenuated by inflammation. (C) 2015 Elsevier Ireland Ltd. All rights reserved. C1 [Gencer, Baris] Univ Hosp Geneva, Dept Med, Div Cardiol, Geneva, Switzerland. [Auer, Reto] Univ Lausanne Hosp, Dept Ambulatory & Community Med, Lausanne, Switzerland. [de Rekeneire, Nathalie] Yale Univ, Dept Internal Med, Geriatr Sect, New Haven, CT USA. [Butler, Javed] SUNY Stony Brook, Div Cardiol, Long Isl City, NY USA. [Kalogeropoulos, Andreas] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Bauer, Douglas C.; Vittinghoff, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kritchevsky, Stephen B.] Wake Forrest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Miljkovic, Iva] Univ Pittsburgh, Ctr Aging & Populat Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Harris, Tamara] NIA, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. [Rodondi, Nicolas] Univ Hosp Bern, Dept Gen Internal Med, Bern, Switzerland. RP Rodondi, N (reprint author), Univ Hosp Bern, Dept Gen Internal Med, Bern, Switzerland. EM Nicolas.Rodondi@insel.ch OI Miljkovic, Iva/0000-0002-3155-9777 FU Swiss National Science Foundation [SNSF SPUM33CM30-140336, SNSF 320030-150025]; Swiss Heart Foundation; Geneva University Hospitals; Foundation Schmidheiny; Foundation Gerbex-Bourget; De Reuter Foundation; National Institutes of Health (NIH). National Institute on Aging (NIA), Bethesda Md; NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR01259]; NIA FX Dr Gencer's research on cardiovascular prevention is supported by a grant from the Swiss National Science Foundation (SNSF SPUM33CM30-140336, Inflammation and acute coronary syndromes (ACS) - Novel strategies for prevention and clinical management, Swiss Heart Foundation, Geneva University Hospitals, Foundation Schmidheiny, Foundation Gerbex-Bourget and De Reuter Foundation. Prof Rodondi's research is supported by a grant from the Swiss National Science Foundation (SNSF 320030-150025) and the Swiss Heart Foundation. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH). National Institute on Aging (NIA), Bethesda Md. This research was supported by NIA Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR01259. The NIA funded the Health ABC Study, reviewed the manuscript, and approved its publication. The authors are solely responsible for the design and conduct of this analysis, all study analyses and drafting end editing of the paper. NR 29 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD FEB PY 2016 VL 245 BP 181 EP 186 DI 10.1016/j.atherosclerosis.2015.12.004 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC1NG UT WOS:000368982400047 PM 26724528 ER PT J AU Vargas, JD Manichaikul, A Wang, XQ Rich, SS Rotter, JI Post, WS Polak, JF Budoff, MJ Bluemke, DA AF Vargas, Jose D. Manichaikul, Ani Wang, Xin-Qun Rich, Stephen S. Rotter, Jerome I. Post, Wendy S. Polak, Joseph F. Budoff, Matthew J. Bluemke, David A. TI Common genetic variants and subclinical atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) SO ATHEROSCLEROSIS LA English DT Article DE Genetics; Coronary calcium; Single nucleotide polymorphism; Intima-medial thickness ID CORONARY-ARTERY-DISEASE; GENOME-WIDE ASSOCIATION; AMERICAN-HEART-ASSOCIATION; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; CHROMOSOME 9P21; COMPUTED-TOMOGRAPHY; SUSCEPTIBILITY LOCI; AFRICAN-AMERICANS; CALCIFICATION AB Background and aims: Subclinical atherosclerosis (sCVD), measured by coronary artery calcium (CAC) and carotid intima media thickness (CIMT) is associated with cardiovascular disease (CVD). Genome-Wide Association Studies (GWAS) of sCVD and CVD have focused primarily on Caucasian populations. We hypothesized that these associations may differ in populations from distinct genetic backgrounds. Methods: The associations between sCVD and 66 single nucleotide polymorphisms (SNPs) from published GWAS of sCVD and CVD were tested in 8224 Multi-Ethnic Study of Atherosclerosis (MESA) and MESA Family participants [2329 Caucasians (EUA), 691 Chinese (CHN), 2482 African Americans (AFA), and 2012 Hispanic (HIS)] using an additive model adjusting for CVD risk factors, with SNP significance defined by a Bonferroni-corrected p < 7.6 x 10(-4) (0.05/66). Results: In EUA there were significant associations for CAC with SNPs in 9p21 (rs1333049, P = 2 x 10(-9); rs4977574, P = 4 x 10(-9)), COL4A1 (rs9515203, P = 9 x 10(-6)), and PHACTR1 (rs9349379, P = 4 x 10(-4)). In HIS, CAC was associated with SNPs in 9p21 (rs1333049, P = 8 x 10(-5); rs4977574, P = 5 x 10(-5)), APOA5 (rs964184, P = 2 x 10(-4)), and ADAMTS7 (rs7173743, P = 4 x 10(-4)). There were no associations between CAC and 9p21 SNPs for AFA and CHN. Fine mapping of the 9p21 region revealed SNPs with robust associations with CAC in EUA and HIS but no significant associations in AFA and CHN. Conclusion: Our results suggest some shared genetic architecture for sCVD across ethnic groups, while also underscoring the possibility of novel variants and/or pathways in risk of CVD in ethnically diverse populations. Published by Elsevier Ireland Ltd. C1 [Vargas, Jose D.] Georgetown Univ Hosp, MedStar Hlth Res Inst, Washington, DC 20007 USA. [Manichaikul, Ani; Wang, Xin-Qun] Univ Virginia, Biostat Sect, Dept Publ Hlth Sci, Charlottesville, VA USA. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth & Genom, Dept Publ Hlth Sci, Charlottesville, VA USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90509 USA. [Post, Wendy S.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Polak, Joseph F.] Tufts Univ, Sch Med, Dept Radiol, Boston, MA 02111 USA. [Budoff, Matthew J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Vargas, Jose D.; Bluemke, David A.] NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Radiol & Imaging Sci, Ctr Clin, 10 Ctr Dr,Bldg 10-1c351, Bethesda, MD 20892 USA. EM bluemked@cc.nih.gov OI Manichaikul, Ani/0000-0002-5998-795X; Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040]; NHLBI [N02-HL-6-4278]; National Center for Advancing Translational Sciences, CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL071258]; [R01HL071259]; [M01-RR00425]; [UL1RR033176] FX MESA and the MESA SHARe project are conducted and supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079 and UL1-TR-000040 from the National Heart, Lung, and Blood Institute (NHLBI, http://www.nhlbi.nih.gov). MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, M01-RR00425, UL1RR033176, and UL1TR000124. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The MESA study was approved by the institutional review boards of the participating institutions and participants provided informed consent prior to study participation. This manuscript was approved for submission by the Presentations and Publications Committee. NR 50 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD FEB PY 2016 VL 245 BP 230 EP 236 DI 10.1016/j.atherosclerosis.2015.11.034 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC1NG UT WOS:000368982400054 PM 26789557 ER PT J AU Park, J Park, SY Kim, JH AF Park, JaeIn Park, Soo Young Kim, Jae-Hong TI Leukotriene B-4 receptor-2 contributes to chemoresistance of SK-OV-3 ovarian cancer cells through activation of signal transducer and activator of transcription-3-linked cascade SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE SK-OV-3 cells; Ovarian cancer; Cisplatin; Chemoresistance; BLT2; STAT-3 ID PANCREATIC-CANCER; BREAST-CANCER; DRUG-RESISTANCE; PATHWAY; PROLIFERATION; INTERLEUKIN-6; METASTASIS; INVASION; CISPLATIN; APOPTOSIS AB Inflammation and inflammatory mediators are intimately linked with chemoresistance through complex pathways in the tumor microenvironment However, the mechanism by which inflammatory mediators (e.g., eicosanoids) contribute to chemoresistance remains elusive. In this study, we found that the low-affinity leukotriene B-4 receptor-2 (BLT2) and its ligand leukotriene B4 were highly up-regulated in cisplatin-resistant SK-OV-3 ovarian cancer cells and play critical roles in mediating the chemoresistance through the activation of signal transducer and activator of transcription-3 (STAT-3) and the subsequent up-regulation of interleukin-6 (IL-6). BLT2 depletion with siRNA clearly abolished the chemoresistance to cisplatin in SK-OV-3 ovarian cancer cells and further increased cell sensitivity to cisplatin chemotherapy by down-regulating the 'STAT-3-IL-6' cascade. Enlarged tumor formation due to the cisplatin resistance of SK-OV-3 cells in cisplatin-treated athymic mice was also substantially reduced by co-treatment with the BLT2 inhibitor in vivo. Our study demonstrates that BLT2 is a novel contributor to cisplatin resistance in SK-OV-3 ovarian cancer cells and thus may be a potential therapeutic target for the treatment of cisplatin-resistant ovarian cancer. (C) 2015 Elsevier B.V. All rights reserved. C1 [Park, JaeIn; Kim, Jae-Hong] Korea Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 136701, South Korea. [Park, Soo Young] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Kim, JH (reprint author), Korea Univ, Coll Life Sci & Biotechnol, Dept Biotechnol, Seoul 136701, South Korea. EM jhongldm@korea.ac.kr RI Kim, Jae-Hong/B-2530-2009 FU Bio & Medical Technology Development Program Grant through the National Research Foundation (NRF) - Ministry of Science, Information and Communication Technologies (ICT) and Future Planning, Republic of Korea [2012M3A9C5048709, 2012M3A9C1053532]; Basic Science Research Program through NRF funded by the Ministry of Education [2015R1D1A1A01057757]; Korea University Grant; BK21 Plus Program (School of Life Sciences and Biotechnology, Korea University) FX This work was supported by Bio & Medical Technology Development Program Grant (2012M3A9C5048709, 2012M3A9C1053532) through the National Research Foundation (NRF) funded by the Ministry of Science, Information and Communication Technologies (ICT) and Future Planning, Republic of Korea. Also, this work was supported by Basic Science Research Program (2015R1D1A1A01057757) through NRF funded by the Ministry of Education. This work was also supported by a Korea University Grant and BK21 Plus Program (School of Life Sciences and Biotechnology, Korea University). NR 41 TC 3 Z9 3 U1 2 U2 3 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 FEB PY 2016 VL 1863 IS 2 BP 236 EP 243 DI 10.1016/j.bbamcr.2015.11.011 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DC1CT UT WOS:000368955100007 PM 26597704 ER PT J AU Karim, ZA Alshbool, FZ Vemana, HP Conlon, C Druey, KM Khasawneh, FT AF Karim, Zubair A. Alshbool, Fatima Z. Vemana, Hari Priya Conlon, Christine Druey, Kirk M. Khasawneh, Fadi T. TI CXCL12 regulates platelet activation via the regulator of G-protein signaling 16 SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Platelets; Signal transduction; Regulators of G-protein signaling; Regulator of G-protein signaling 16; Stromal cell-derived factor; CXCL12 ID HETEROTRIMERIC G-PROTEINS; PROGENITOR CELLS; RGS PROTEINS; KINASE-C; RECEPTOR; EXPRESSION; GROWTH; PHOSPHORYLATION; CHEMOATTRACTANT; AGGREGATION AB The regulators of G protein signaling (RGS) protein superfamily negatively controls G protein-coupled receptor signal transduction pathways. One of the members of this family, RGS16, is highly expressed in megakaryocytes and platelets. Studies of its function in platelet and megakaryocyte biology have been limited, in part, due to lack of pharmacological inhibitors. For example, RGS16 overexpression inhibited CXC chemokine receptor 4 (O(CR4)mediated megakaryocyte migration. More recent studies showed that the chemokine stromal cell-derived factor (SDF1 alpha or CXCL12) regulates platelet function via CXCR4. Based on these considerations, the present study investigated the capacity of RGS16 to regulate CXCL12-dependent platelet function, using the RGS16 knockout mouse model (Rgs16(-/-)). RGS16-deficient platelets had increased protease activated receptor 4 and collagen-induced aggregation, as well as increased CXCL12-dependent agonist-induced aggregation, dense and alpha granule secretion, integrin alpha IIb beta 3 activation and phosphatidylserine exposure compared to those from WT littermates. CXCL12 alone did not stimulate aggregation or secretion in either RGS16-deficient or WT platelets. Furthermore, platelets from Rgs16(-/-) mice displayed enhanced phosphorylation of ERK and Akt following CXCL12 stimulation relative to controls. Finally, we also found that PKCS is involved in regulating CXCL12-dependent activation of ERK and Akt, in the Rgs16-deficient platelets. Collectively, our findings provide the first evidence that RGS16 plays an important role in platelet function by modulating CXCL12-dependent platelet activation. (C) 2015 Elsevier B.V. All rights reserved. C1 [Karim, Zubair A.; Vemana, Hari Priya; Conlon, Christine; Khasawneh, Fadi T.] Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, 309 E Second St, Pomona, CA 91766 USA. [Alshbool, Fatima Z.] Loma Linda Univ, Dept Pharmacol, Loma Linda, CA 92354 USA. [Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 50 South Dr Room 4154, Bethesda, MD 20892 USA. RP Khasawneh, FT (reprint author), Western Univ Hlth Sci, Coll Pharm, Dept Pharmaceut Sci, 309 E Second St, Pomona, CA 91766 USA. EM fkhasawneh@westernu.edu FU College of Pharmacy, Western University of Health Sciences, Pomona, CA FX This work was supported by funds from the College of Pharmacy, Western University of Health Sciences, Pomona, CA (to F.T.K). NR 45 TC 1 Z9 1 U1 0 U2 4 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 FEB PY 2016 VL 1863 IS 2 BP 314 EP 321 DI 10.1016/j.bbamcr2015.11.028 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DC1CT UT WOS:000368955100015 PM 26628381 ER PT J AU Xia, YQ Tian, J Chen, XY AF Xia, Yuqiong Tian, Jie Chen, Xiaoyuan TI Effect of surface properties on liposomal siRNA delivery SO BIOMATERIALS LA English DT Review DE siRNA delivery; Liposomes; Surface charge; PEGylation; Ligand modification ID SMALL INTERFERING RNA; ACCELERATED BLOOD CLEARANCE; CALCIUM-PHOSPHATE NANOPARTICLES; LIPID-LIKE MATERIALS; PEG IGM PRODUCTION; IN-VIVO; GENE DELIVERY; CANCER-CELLS; POLY(ETHYLENE GLYCOL); CATIONIC LIPOSOMES AB Liposomes are one of the most widely investigated carriers for siRNA delivery. The surface properties of liposomal carriers, including the surface charge, PEGylation, and ligand modification can significantly affect the gene silencing efficiency. Three barriers of systemic siRNA delivery (long blood circulation, efficient tumor penetration and efficient cellular uptake/endosomal escape) are analyzed on liposomal carriers with different surface charges, PEGylations and ligand modifications. Cationic formulations dominate siRNA delivery and neutral formulations also have good performance while anionic formulations are generally not proper for siRNA delivery. The PEG dilemma (prolonged blood circulation vs. reduced cellular uptake/endosomal escape) and the side effect of repeated PEGylated formulation (accelerated blood clearance) were discussed. Effects of ligand modification on cationic and neutral formulations were analyzed. Finally, we summarized the achievements in liposomal siRNA delivery, outlined existing problems and provided some future perspectives. Published by Elsevier Ltd. C1 [Xia, Yuqiong; Tian, Jie] Xidian Univ, Sch Life Sci & Technol, Xian 710071, Shaanxi, Peoples R China. [Tian, Jie] Chinese Acad Sci, Inst Automat, Beijing 100190, Peoples R China. [Chen, Xiaoyuan] NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. RP Tian, J (reprint author), Xidian Univ, Sch Life Sci & Technol, Xian 710071, Shaanxi, Peoples R China.; Chen, XY (reprint author), NIBIB, LOMIN, NIH, Bethesda, MD 20892 USA. EM tian@ieee.org; shawn.chen@nih.gov RI Song, Jiangdian/L-6992-2016; Tian, Jie/H-1190-2011 OI Song, Jiangdian/0000-0002-3355-9930; Tian, Jie/0000-0003-0498-0432 FU program of China Scholarships Council [1408260074]; Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health FX This work is supported by the program of China Scholarships Council (1408260074) and the Intramural Research Program, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. NR 104 TC 16 Z9 16 U1 32 U2 91 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 EI 1878-5905 J9 BIOMATERIALS JI Biomaterials PD FEB PY 2016 VL 79 BP 56 EP 68 DI 10.1016/j.biomaterials.2015.11.056 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA DB9WM UT WOS:000368868400006 PM 26695117 ER PT J AU Li, MH Kales, SC Ma, K Shoemaker, BA Crespo-Barreto, J Cangelosi, AL Lipkowitz, S Panchenko, AR AF Li, Minghui Kales, Stephen C. Ma, Ke Shoemaker, Benjamin A. Crespo-Barreto, Juan Cangelosi, Andrew L. Lipkowitz, Stanley Panchenko, Anna R. TI Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation SO CANCER RESEARCH LA English DT Article ID MOLECULAR-DYNAMICS; MISSENSE MUTATIONS; SOMATIC MUTATIONS; BINDING-AFFINITY; TYROSINE KINASES; STRUCTURAL BASIS; C-CBL; IMPACT; PREDICTION; COMPLEXES AB Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved, depicting the protein at different stages of its activation cycle and thus providing mechanistic insight underlying how stability-activity tradeoffs in cancer-related proteins-may influence disease onset and progression. In this study, we computationally modeled the effects of missense cancer mutations on structures representing four stages of the CBL activation cycle to identify driver mutations that affect CBL stability, binding, and activity. We found that recurrent, homozygous, and leukemia-specific mutations had greater destabilizing effects on CBL states than random noncancer mutations. We further tested the ability of these computational models, assessing the changes in CBL stability and its binding to ubiquitin-conjugating enzyme E2, by performing blind CBL-mediated EGFR ubiquitination assays in cells. Experimental CBL ubiquitin ligase activity was in agreement with the predicted changes in CBL stability and, to a lesser extent, with CBL-E2 binding affinity. Two thirds of all experimentally tested mutations affected the ubiquitin ligase activity by either destabilizing CBL or disrupting CBL-E2 binding, whereas about one-third of tested mutations were found to be neutral. Collectively, our findings demonstrate that computational methods incorporating multiple protein conformations and stability and binding affinity evaluations can successfully predict the functional consequences of cancer mutations on protein activity, and provide a proof of concept for mutations in CBL. (C)2015 AACR. C1 [Li, Minghui; Shoemaker, Benjamin A.; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike,Bldg 38A,Room 8S814, Bethesda, MD 20894 USA. [Kales, Stephen C.; Ma, Ke; Crespo-Barreto, Juan; Cangelosi, Andrew L.; Lipkowitz, Stanley] NCI, Womens Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike,Bldg 38A,Room 8S814, Bethesda, MD 20894 USA.; Lipkowitz, S (reprint author), NCI, Womens Malignancies Branch, NIH, Bldg 10,Room 4B54, Bethesda, MD 20892 USA. EM lipkowis@mail.nih.gov; panch@ncbi.nlm.nih.gov RI Li, Minghui/E-4339-2016 FU Intramural Research Program of the National Library of Medicine at the U.S. NIH; Intramural Research Program of the NCI, Center for Cancer Research at the U.S. NIH FX M. Li, B.A. Shoemaker and A.R. Panchenko were supported by the Intramural Research Program of the National Library of Medicine at the U.S. NIH. S.C. Kales, K. Ma, J. Crespo-Barreto, A.L. Cangelosi, and S. Lipkowitz were supported by the Intramural Research Program of the NCI, Center for Cancer Research at the U.S. NIH. NR 49 TC 2 Z9 2 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2016 VL 76 IS 3 BP 561 EP 571 DI 10.1158/0008-5472.CAN-14-3812 PG 11 WC Oncology SC Oncology GA DC2YL UT WOS:000369084600008 PM 26676746 ER PT J AU Li, ZJ Chen, P Su, R Hu, C Li, YY Elkahloun, AG Zuo, ZX Gurbuxani, S Arnovitz, S Weng, HY Wang, YG Li, SL Huang, H Neilly, MB Wang, GG Jiang, X Liu, PP Jin, J Chen, JJ AF Li, Zejuan Chen, Ping Su, Rui Hu, Chao Li, Yuanyuan Elkahloun, Abdel G. Zuo, Zhixiang Gurbuxani, Sandeep Arnovitz, Stephen Weng, Hengyou Wang, Yungui Li, Shenglai Huang, Hao Neilly, Mary Beth Wang, Gang Greg Jiang, Xi Liu, Paul P. Jin, Jie Chen, Jianjun TI PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease SO CANCER RESEARCH LA English DT Article ID MIXED-LINEAGE LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION PROFILE; MOLECULAR SIGNATURES; H3K79 METHYLATION; NPM1 MUTATIONS; HOXA9; LEUKEMOGENESIS; TRANSLOCATIONS; TRANSFORMATION AB Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion-mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1-mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes. (C) 2016 AACR. C1 [Li, Zejuan; Chen, Ping; Hu, Chao; Li, Yuanyuan; Zuo, Zhixiang; Arnovitz, Stephen; Weng, Hengyou; Wang, Yungui; Li, Shenglai; Huang, Hao; Neilly, Mary Beth; Jiang, Xi; Chen, Jianjun] Univ Chicago, Dept Med, Hematol Oncol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Su, Rui; Hu, Chao; Zuo, Zhixiang; Weng, Hengyou; Wang, Yungui; Jiang, Xi; Chen, Jianjun] Univ Cincinnati, Coll Med, Dept Canc Biol, 3125 Eden Ave,Room 3316, Cincinnati, OH USA. [Hu, Chao; Wang, Yungui; Jin, Jie] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Inst Hematol, Hangzhou 310003, Zhejiang, Peoples R China. [Elkahloun, Abdel G.; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Gurbuxani, Sandeep] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Wang, Gang Greg] Univ N Carolina, Sch Med, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Li, Zejuan] Univ Chicago, Dept Human Genet, 5841 South Maryland,Room G701-MC0077, Chicago, IL 60637 USA. RP Chen, JJ (reprint author), Univ Cincinnati, Coll Med, Dept Canc Biol, 3125 Eden Ave,Room 3316, Cincinnati, OH USA.; Li, ZJ (reprint author), Univ Chicago, Dept Human Genet, 5841 South Maryland,Room G701-MC0077, Chicago, IL 60637 USA. EM zli7@bsd.uchicago.edu; chen3jj@uc.edu RI Zuo, Zhixiang/M-4441-2016; OI Zuo, Zhixiang/0000-0002-2492-2689; Wang, G Greg/0000-0002-7210-9940 FU NIH [CA178454, CA182528, CA127277]; Leukemia & Lymphoma Society (LLS); LLS Translational Research Grant; American Cancer Society (ACS) Research Scholar grant; ACS-IL Research Scholar grant; Gabrielle's Angel Foundation for Cancer Research; Intramural Research Program of National Human Genome Research Institute, NIH FX This work was supported in part by the NIH R01 grants CA178454, CA182528, and CA127277 (J. Chen), Leukemia & Lymphoma Society (LLS) Special Fellowship (Z. Li), LLS Translational Research Grant (J. Chen), American Cancer Society (ACS) Research Scholar grant (J. Chen), ACS-IL Research Scholar grant (Z. Li), Gabrielle's Angel Foundation for Cancer Research (J. Chen, Z. Li, X. Jiang, and H. Huang), and Intramural Research Program of National Human Genome Research Institute, NIH (A.G. Elkahloun and P.P. Liu). NR 49 TC 1 Z9 1 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2016 VL 76 IS 3 BP 619 EP 629 DI 10.1158/0008-5472.CAN-15-1566 PG 11 WC Oncology SC Oncology GA DC2YL UT WOS:000369084600013 PM 26747896 ER PT J AU Finnberg, NK Gokare, P Navaraj, A Kuhs, KAL Cerniglia, G Yagita, H Takeda, K Motoyama, N El-Deiry, WS AF Finnberg, Niklas K. Gokare, Prashanth Navaraj, Arunasalam Kuhs, Krystle A. Lang Cerniglia, George Yagita, Hideo Takeda, Kazuyoshi Motoyama, Noboru El-Deiry, Wafik S. TI Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity SO CANCER RESEARCH LA English DT Article ID METASTATIC COLORECTAL-CANCER; ANTI-DR5 ANTIBODY THERAPY; INDUCED APOPTOSIS; MICE; CONATUMUMAB; KINASE; LIGAND; APO2L/TRAIL; HEPATOCYTES; DEFICIENCY AB The combination of TRAIL death receptor agonists and radio-chemotherapy to treat advanced cancers continues to be investigated in clinical trials. We previously showed that normal cells with a functional DNA damage response (DDR) upregulate the expression of death-inducing receptor DR5/TRAILR2/TNFRSF10B in a p53-dependent manner that sensitizes them to treatment with DR5 agonists. However, it is unclear if targeting DR5 selectively sensitizes cancer cells to agonist treatment following exposure to DNA-damaging chemotherapy, and to what extent normal tissues are targeted. Here, we show that the combined administration of the DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wild-type mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5(+) crypt base columnar stem cells in a p53-and DR5-dependent manner. Furthermore, we confirmed that normal human epithelial cells treated with the human DR5-agonistic mAb and chemotherapeutic agents were also greatly sensitized to cell death. Interestingly, our data also indicated that genetic or pharmacologic targeting of Chk2 may counteract GIT without negatively affecting the antitumor responses of combined DR5 agonist/chemotherapy treatment, further linking the DDR to TRAIL death receptor signaling in normal cells. In conclusion, the combination of DR5-targeting agonistic mAbs with DNA damaging chemotherapy may pose a risk of developing toxicity-induced conditions, and the effects of mAb-based strategies on the dose-limiting toxicity of chemotherapy must be considered when establishing new combination therapies. (C)2015 AACR. C1 [Finnberg, Niklas K.; Gokare, Prashanth; El-Deiry, Wafik S.] Fox Chase Canc Ctr, Dept Med Oncol, Lab Translat Oncol & Expt Canc Therapeut, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Finnberg, Niklas K.; Gokare, Prashanth; El-Deiry, Wafik S.] Fox Chase Canc Ctr, Mol Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Finnberg, Niklas K.; Gokare, Prashanth; Navaraj, Arunasalam; El-Deiry, Wafik S.] Penn State Hershey Canc Inst, Div Hematol Oncol, Hershey, PA USA. [Kuhs, Krystle A. Lang] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Infect, Bethesda, MD 20892 USA. [Cerniglia, George] Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Yagita, Hideo; Takeda, Kazuyoshi] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. [Motoyama, Noboru] Natl Ctr Geriatr & Gerontol, Dept Cognit Brain Sci, Res Inst, Nagoya, Aichi, Japan. RP El-Deiry, WS (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave,Room P2035, Philadelphia, PA 19111 USA. EM wafik.eldeiry@gmail.com FU NCI NIH HHS [R01 CA173453] NR 35 TC 0 Z9 0 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2016 VL 76 IS 3 BP 700 EP 712 DI 10.1158/0008-5472.CAN-15-2759 PG 13 WC Oncology SC Oncology GA DC2YL UT WOS:000369084600020 PM 26609054 ER PT J AU Jones, K Wockner, L Brennan, RM Keane, C Chattopadhyay, PK Roederer, M Price, DA Cole, DK Hassan, B Beck, K Gottlieb, D Ritchie, DS Seymour, JF Vari, F Crooks, P Burrows, SR Gandhi, MK AF Jones, K. Wockner, L. Brennan, R. M. Keane, C. Chattopadhyay, P. K. Roederer, M. Price, D. A. Cole, D. K. Hassan, B. Beck, K. Gottlieb, D. Ritchie, D. S. Seymour, J. F. Vari, F. Crooks, P. Burrows, S. R. Gandhi, M. K. TI The impact of HLA class I and EBV latency-II antigen-specific CD8(+) T cells on the pathogenesis of EBV+ Hodgkin lymphoma SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE classical Hodgkin lymphoma; Epstein-Barr virus; genetic associations; HLA class I; T cell immunity ID EPSTEIN-BARR-VIRUS; GENOME-WIDE ASSOCIATION; COMPLEX CLASS-I; LYMPHOPROLIFERATIVE DISEASE; INFECTIOUS-MONONUCLEOSIS; NASOPHARYNGEAL CARCINOMA; COMPLETE RESPONSES; INTERFERON-GAMMA; IMMUNE-RESPONSE; B-CELLS AB In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein-Barr virus (EBV) latency-II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV(+)cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA-A*02 is protective in EBV(+)cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA-A*02(-)versus HLA-A*02(+) EBV(+)cHL patients, suggesting that LMP2A-specific CD8(+) T cell anti-tumoral immunity may be relatively ineffective in HLA-A*02(-) EBV(+)cHL. To ascertain the impact of HLA class I on EBV latency antigen-specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV(+)cHL, the magnitude of ex-vivo LMP1/2A-specific CD8(+) T cell responses was elevated in HLA-A*02(+) patients. Furthermore, in a controlled in-vitro assay, LMP2A-specific CD8(+) T cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA class I-restricted immunity, immunodominant EBNA3A/3B/3C-specific CD8(+) T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A-specific responses were confined largely to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8(+) T cell response than non-HLA-A*02 alleles, an effect confined to EBV latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV(+)cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency-II antigen-specific CD8(+) T cell hierarchies. C1 [Jones, K.; Keane, C.; Vari, F.; Crooks, P.; Gandhi, M. K.] Univ Queensland, Translat Res Inst, Diamantina Inst, Blood Canc Res, Level 5 East,Diamantina Rd West, Brisbane, Qld 4102, Australia. [Jones, K.; Keane, C.; Gandhi, M. K.] QIMR Berghofer Med Res Inst, Clin Immunohaematol Lab, Brisbane, Qld, Australia. [Wockner, L.] QIMR Berghofer Med Res Inst, Stat Unit, Brisbane, Qld, Australia. [Brennan, R. M.; Burrows, S. R.] QIMR Berghofer Med Res Inst, Cellular Immunol Lab, Brisbane, Qld, Australia. [Keane, C.; Gandhi, M. K.] Princess Alexandra Hosp, Dept Haematol, Brisbane, Qld 4102, Australia. [Chattopadhyay, P. K.; Roederer, M.] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Price, D. A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Price, D. A.; Cole, D. K.; Hassan, B.] Cardiff Univ, Sch Med, Inst Infect & Immun, Cardiff CF10 3AX, S Glam, Wales. [Beck, K.] Cardiff Univ, Sch Dent, Tissue Engn & Reparat Dent, Cardiff CF10 3AX, S Glam, Wales. [Gottlieb, D.] Westmead Hosp, Blood & Marrow Transplant Serv, Sydney, NSW, Australia. [Ritchie, D. S.] Peter MacCallum Canc Ctr, Dept Haematol, Melbourne, Vic, Australia. [Ritchie, D. S.; Seymour, J. F.] Univ Melbourne, Melbourne, Vic, Australia. RP Gandhi, MK (reprint author), Univ Queensland, Translat Res Inst, Diamantina Inst, Blood Canc Res, Level 5 East,Diamantina Rd West, Brisbane, Qld 4102, Australia. EM M.Gandhi@uq.edu.au RI Price, David/C-7876-2013; Gandhi, Maher/C-6991-2012; OI Price, David/0000-0001-9416-2737; Cole, David/0000-0003-0028-9396; Wockner, Leesa/0000-0002-8921-9265; Chattopadhyay, Pratip/0000-0002-5457-9666 FU Leukaemia Foundation (Australia); Leukaemia Foundation of Queensland FX This study was conducted under the auspices of the Australasian Leukaemia and Lymphoma Group. K. J. and C. K. were supported by the Leukaemia Foundation (Australia). M. K. G. is supported by the Leukaemia Foundation of Queensland. D. A. P. is a Wellcome Trust Senior Investigator. S. R. B is an NHMRC Principal Research Fellow (APP1021452). NR 65 TC 3 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9104 EI 1365-2249 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD FEB PY 2016 VL 183 IS 2 BP 206 EP 220 DI 10.1111/cei.12716 PG 15 WC Immunology SC Immunology GA DC0SP UT WOS:000368928300006 PM 26422112 ER PT J AU Sampson, ML Gounden, V van Deventer, HE Remaley, AT AF Sampson, Maureen L. Gounden, Verena van Deventer, Hendrik E. Remaley, Alan T. TI CUSUM-Logistic Regression analysis for the rapid detection of errors in clinical laboratory test results SO CLINICAL BIOCHEMISTRY LA English DT Article DE Average of normals; Logistic regression; Quality control; Laboratory test errors ID QUALITY-CONTROL; NORMALS METHOD; AVERAGE AB Objective: The main drawback of the periodic analysis of quality control (QC) material is that test performance is not monitored in time periods between QC analyses, potentially leading to the reporting of faulty test results. The objective of this study was to develop a patient based QC procedure for the more timely detection of test errors. Method: Results from a Chem-14 panel measured on the Beckman LX20 analyzer were used to develop the model. Each test result was predicted from the other 13 members of the panel by multiple regression, which resulted in correlation coefficients between the predicted and measured result of >0.7 for 8 of the 14 tests. A logistic regression model, which utilized the measured test result, the predicted test result, the day of the week and time of day, was then developed for predicting test errors. The output of the logistic regression was tallied by a daily CUSUM approach and used to predict test errors, with a fixed specificity of 90%. Results: The mean average run length (ARL) before error detection by CUSUM-Logistic Regression (CSLR) was 20 with a mean sensitivity of 97%, which was considerably shorter than the mean ARL of 53 (sensitivity 87.5%) for a simple prediction model that only used the measured result for error detection. Conclusion: A CUSUM-Logistic Regression analysis of patient laboratory data can be an effective approach for the rapid and sensitive detection of clinical laboratory errors. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Sampson, Maureen L.; Gounden, Verena; van Deventer, Hendrik E.; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bldg 10,Room 2C-407,9000 Rockville Pike, Bethesda, MD 20892 USA. [Gounden, Verena] Univ KwaZulu Natal, Dept Chem Pathol, Durban, South Africa. [Gounden, Verena] Inkosi Albert Luthuli Cent Hosp, Natl Hlth Lab Serv, Durban, South Africa. [van Deventer, Hendrik E.] Lancet Labs, Johannesburg, South Africa. RP Remaley, AT (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 10,Room 2C-407,9000 Rockville Pike, Bethesda, MD 20892 USA. EM msampson@cc.nih.gov; verena.gounden@nhls.ac.za; manuel.vandeventer@gmail.com; aremaley1@nhlbi.nih.gov FU NIH Clinical Center FX This research was supported by intramural research funds of the NIH Clinical Center. NR 11 TC 1 Z9 1 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD FEB PY 2016 VL 49 IS 3 BP 201 EP 207 DI 10.1016/j.clinbiochem.2015.10.019 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DC3XN UT WOS:000369153100002 PM 26523981 ER PT J AU Cho, YE Kim, HS Lai, C Stanfill, A Cashion, A AF Cho, Young-Eun Kim, Hyung-Suk Lai, Chen Stanfill, Ansley Cashion, Ann TI Oxidative stress is associated with weight gain in recipients at 12-months following kidney transplantation SO CLINICAL BIOCHEMISTRY LA English DT Article DE Kidney transplantation; Oxidative stress; Weight gain ID RENAL-TRANSPLANTATION; LIPID-PEROXIDATION; METABOLIC SYNDROME; OBESITY; IMPACT; CYCLOSPORINE; PREVALENCE; BIOMARKERS; SURVIVAL; THERAPY AB Objective: Weight gain after kidney transplantation (Tx) is considered a risk factor for poor outcomes. Increased oxidative stress is associated with not only chronic renal disease and Tx, but also obesity and cardiovascular disease. The aim of this pilot study was to test whether oxidative stress is related to weight gain at 12-months after kidney Tx and to obtain preliminary insight into potential mechanisms involved. Design & methods: Recipients (n = 33) were classified into two groups; weight loss and weight gain, based on their weight changes at 12-months post-transplant. Total antioxidant capacity (TAOC) and lipid peroxidation (TBARS) were measured to evaluate oxidative stress from plasma at baseline and 12-months. A secondary data analysis was conducted to identify potential gene regulation. Results: Seventeen recipients lost (-6.63 +/- 5.52 kg), and sixteen recipients gained weight (8.94 +/- 6.18 kg). TAOC was significantly decreased at 12-months compared to baseline for the total group, however, there was no significant difference between groups at either time point. TBARS was higher in weight gain group, at both time points, and it was significantly higher at 12-months (p = 0.012). Gene expression profiling analysis showed that 7 transcripts annotated to reactive oxygen species related genes in adipose tissue were expressed significantly lower in weight gain group at baseline, which might be a negative feedback mechanism to reduce oxidative stress. Conclusion: These results may indicate that elevated oxidative stress (TBARS) is associated with weight gain after kidney Tx and that incorporating early clinical prevention strategies known to decrease oxidative stress could be recommended. (C) 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. C1 [Cho, Young-Eun; Kim, Hyung-Suk; Lai, Chen; Cashion, Ann] NINR, NIH, 3 Ctr Dr,Bldg 3,Room 5E26, Bethesda, MD 20892 USA. [Stanfill, Ansley] Univ Pittsburgh, 440 Victoria Bldg,3500 Victoria St, Pittsburgh, PA 15261 USA. RP Cashion, A (reprint author), NINR, NIH, 3 Ctr Dr,Bldg 3,Room 5E26, Bethesda, MD 20892 USA. EM young-eun.cho@nih.gov; kimhy@mail.nih.gov; laichi@mail.nih.gov; stanfill@pitt.edu; ann.cashion@nih.gov FU National Institute of Nursing Research of the National Institutes of Health [R01NR009270]; National Institute of Nursing Research intramural funding FX The authors would like to thank colleagues at the University of Tennessee Health Science Center, Memphis, Tennessee for the help in patient recruitment, plasma sample collection and genomic data management. Research reported in this study was supported by the National Institute of Nursing Research of the National Institutes of Health under award number R01NR009270, and the National Institute of Nursing Research intramural funding. NR 39 TC 0 Z9 0 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 EI 1873-2933 J9 CLIN BIOCHEM JI Clin. Biochem. PD FEB PY 2016 VL 49 IS 3 BP 237 EP 242 DI 10.1016/j.clinbiochem.2015.11.002 PG 6 WC Medical Laboratory Technology SC Medical Laboratory Technology GA DC3XN UT WOS:000369153100008 PM 26545907 ER PT J AU Eaton, A Iasonos, A Gounder, MM Pamer, EG Drilon, A Vulih, D Smith, GL Ivy, SP Spriggs, DR Hyman, DM AF Eaton, Anne Iasonos, Alexia Gounder, Mrinal M. Pamer, Erika G. Drilon, Alexander Vulih, Diana Smith, Gary L. Ivy, S. Percy Spriggs, David R. Hyman, David M. TI Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER AB Purpose: Phase I studies rely on investigators to accurately attribute adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Attribution in the phase I setting has not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution. Experimental Design: Individual patient records from 38 phase I studies activated between 2000 and 2010 were used. Dose was defined as a percentage of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All P values were two-sided. Results: 11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (P = 0.0920 for grade >3, P = 0.4194 for grade >1), whereas related toxicity increased with dose (P < 0.0001, both grade >= 3 and >= 1). Similar results were observed across toxicity categories. In the five-tier system, toxicities attributed as "possibly," " probably," or "definitely" related were associated with dose (all P < 0.0001), whereas toxicities attributed as "unlikely" or "unrelated" were not (all P > 0.1). Conclusions: Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association that could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a two-tier system by collapsing "possibly," "probably," and "definitely" related. (C) 2015 AACR. C1 [Eaton, Anne; Iasonos, Alexia] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Iasonos, Alexia; Gounder, Mrinal M.; Drilon, Alexander; Spriggs, David R.; Hyman, David M.] Weill Cornell Med Coll, New York, NY USA. [Gounder, Mrinal M.; Pamer, Erika G.; Drilon, Alexander; Spriggs, David R.; Hyman, David M.] Mem Sloan Kettering Canc Ctr, Dept Med, Dev Therapeut, 1275 York Ave, New York, NY 10021 USA. [Vulih, Diana] Theradex Syst Inc, Princeton, NJ USA. [Smith, Gary L.; Ivy, S. Percy] NCI, Bethesda, MD 20892 USA. RP Hyman, DM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10065 USA. EM hymand@mskcc.org FU Cancer Center core grant [P30 CA008748]; Translational and Integrative Medicine Research Fund at Memorial Sloan Kettering Cancer Center, New York, NY FX This work was supported in part by the Cancer Center core grant P30 CA008748. The core grant provides funding to institutional cores such as Biostatistics, which was used in this study. A. Iasonos was partially funded by The Translational and Integrative Medicine Research Fund at Memorial Sloan Kettering Cancer Center, New York, NY. NR 15 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2016 VL 22 IS 3 BP 553 EP 559 DI 10.1158/1078-0432.CCR-15-0339 PG 7 WC Oncology SC Oncology GA DC2XY UT WOS:000369083300006 PM 26324741 ER PT J AU Xu, L Ziegelbauer, J Wang, R Wu, WW Shen, RF Juhl, H Zhang, YQ Rosenberg, A AF Xu, Lai Ziegelbauer, Joseph Wang, Rong Wu, Wells W. Shen, Rong-Fong Juhl, Hartmut Zhang, Yaqin Rosenberg, Amy TI Distinct Profiles for Mitochondrial t-RNAs and Small Nucleolar RNAs in Locally Invasive and Metastatic Colorectal Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; RECTAL-CANCER; COLON-CANCER; EXPRESSION; HYPOXIA; GENES; MICRORNA; PROLIFERATION; METABOLISM; BIOMARKERS AB Purpose: To gain insight into factors involved in tumor progression and metastasis, we examined the role of noncoding RNAs in the biologic characteristics of colorectal carcinoma, in paired samples of tumor together with normal mucosa from the same colorectal carcinoma patient. The tumor and healthy tissue samples were collected and stored under stringent conditions, thereby minimizing warm ischemic time. Experimental Design: We focused particularly on distinctions among high-stage tumors and tumors with known metastases, performing RNA-Seq analysis that quantifies transcript abundance and identifies novel transcripts. Results: In comparing 35 colorectal carcinomas, including 9 metastatic tumors (metastases to lymph nodes and lymphatic vessels), with their matched healthy control mucosa, we found a distinct signature of mitochondrial transfer RNAs (MT-tRNA) and small nucleolar RNAs (snoRNA) for metastatic and high-stage colorectal carcinoma. We also found the following: (i) MT-TF (phenylalanine) and snord12B expression correlated with a substantial number of miRNAs and mRNAs in 14 colorectal carcinomas examined; (ii) an miRNA signature of oxidative stress, hypoxia, and a shift to glycolytic metabolism in 14 colorectal carcinomas, regardless of grade and stage; and (iii) heterogeneous MT-tRNA/snoRNA fingerprints for 35 pairs. Conclusions: These findings could potentially assist in more accurate and predictive staging of colorectal carcinoma, including identification of those colorectal carcinomas likely to metastasize. (C)2015 AACR. C1 [Xu, Lai; Wang, Rong; Zhang, Yaqin; Rosenberg, Amy] FDA, OBP DBRR 3, CDER, Silver Spring, MD USA. [Ziegelbauer, Joseph] NCI, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. [Wu, Wells W.; Shen, Rong-Fong] FDA, Facil Biotechnol Resources, CBER, Silver Spring, MD USA. [Juhl, Hartmut] Indivumed GMBH, Hamburg, Germany. RP Rosenberg, A (reprint author), FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA. EM amy.rosenberg@fda.hhs.gov OI Ziegelbauer, Joseph/0000-0001-6464-6941 FU Intramural NIH HHS [Z99 OD999999] NR 34 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2016 VL 22 IS 3 BP 773 EP 784 DI 10.1158/1078-0432.CCR-15-0737 PG 12 WC Oncology SC Oncology GA DC2XY UT WOS:000369083300027 PM 26384739 ER PT J AU Galipeau, J Krampera, M Barrett, J Dazzi, F Deans, RJ Debruijn, J Dominici, M Fibbe, WE Gee, AP Gimble, JM Hematti, P Koh, MBC Leblanc, K Martin, I McNiece, IK Mendicino, M Oh, S Ortiz, L Phinney, DG Planat, V Shi, YF Stroncek, DF Viswanathan, S Weiss, DJ Sensebe, L AF Galipeau, Jacques Krampera, Mauro Barrett, John Dazzi, Francesco Deans, Robert J. Debruijn, Joost Dominici, Massimo Fibbe, Willem E. Gee, Adrian P. Gimble, Jeffery M. Hematti, Peiman Koh, Mickey B. C. Leblanc, Katarina Martin, Ivan McNiece, Ian K. Mendicino, Michael Oh, Steve Ortiz, Luis Phinney, Donald G. Planat, Valerie Shi, Yufang Stroncek, David F. Viswanathan, Sowmya Weiss, Daniel J. Sensebe, Luc TI International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials SO CYTOTHERAPY LA English DT Article DE Mesenchymal Stromal cells; potency assays; release assays; matrix assays; immune functional testing; clinical trials; ISCT ID HUMAN BONE-MARROW; STEM-CELLS; CHEMOKINE RECEPTORS; IFN-GAMMA; SUPPRESSION; EXPRESSION; MSC; ACTIVATION; STIMULATION; INHIBITOR AB Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum of early- to late-phase clinical trials in both industry and academic sponsored studies. There is a broad consensus that despite different tissue sourcing and varied culture expansion protocols, human MSC-like cell products likely share fundamental mechanisms of action mediating their anti-inflammatory and tissue repair functionalities. Identification of functional markers of potency and reduction to practice of standardized, easily deployable methods of measurements of such would benefit the field. This would satisfy both mechanistic research as well as development of release potency assays to meet Regulatory Authority requirements for conduct of advanced clinical studies and their eventual registration. In response to this unmet need, the International Society for CellularTherapy (ISCT) addressed the issue at an international workshop in May 2015 as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was focused on discussing potency assays germane to immunomodulation by MSC-like products in clinical indications targeting immune disorders.We here provide consensus perspective arising from this forum. We propose that focused analysis of selected MSC markers robustly deployed by in vitro licensing and metricized with a matrix of assays should be responsive to requirements from Regulatory Authorities.Workshop participants identified three preferred analytic methods that could inform a matrix assay approach: quantitative RNA analysis of selected gene products; flow cytometry analysis of functionally relevant surface markers and protein based assay of secretome. We also advocate that potency assays acceptable to the Regulatory Authorities be rendered publicly accessible in an "open-access" manner, such as through publication or database collection. C1 [Galipeau, Jacques] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA USA. [Galipeau, Jacques] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Krampera, Mauro] Univ Verona, Dept Med, Stem Cell Res Lab & Cell Factory, Sect Hematol, I-37100 Verona, Italy. [Barrett, John] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Dazzi, Francesco] Kings Coll London, Regenerat & Heamatol Med, London WC2R 2LS, England. [Deans, Robert J.] Athersys Inc, Regenerat Med, Cleveland, OH USA. [Debruijn, Joost] Queen Mary Univ London, Sch Engn & Mat Sci, London, England. [Dominici, Massimo] Univ Hosp Modena & Reggio Emilia, Dept Med & Surg Sci Children & Adults, Div Oncol, Modena, Italy. [Fibbe, Willem E.] Leiden Univ, Med Ctr, Dept Immunohematol & Bloodtransfus, Leiden, Netherlands. [Gee, Adrian P.] Texas Childrens Hosp, Houston Methodist Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Gimble, Jeffery M.] Tulane Univ, Sch Med, Dept Med, Ctr Stem Cell Res & Regenerat Med, New Orleans, LA 70112 USA. [Gimble, Jeffery M.] Tulane Univ, Sch Med, Dept Surg, New Orleans, LA 70112 USA. [Hematti, Peiman] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI USA. [Hematti, Peiman] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Koh, Mickey B. C.] St George Hosp, Dept Haematol, London, England. [Koh, Mickey B. C.] Sch Med, London,