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, England. [Leblanc, Katarina] Karolinska Inst, Div Clin Immunol & Transfus Med, Stockholm, Sweden. [Martin, Ivan] Univ Basel Hosp, Dept Med, CH-4031 Basel, Switzerland. [McNiece, Ian K.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Mendicino, Michael] Mesoblast Inc, New York, NY USA. [Oh, Steve] ASTAR, Bioproc Technol Inst, Stem Cell Grp, Singapore, Singapore. [Ortiz, Luis] Univ Pittsburgh, Grad Sch Publ Hlth, Div Occupat & Environm Hlth, Pittsburgh, PA USA. [Phinney, Donald G.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. [Planat, Valerie] IFR150 STROMALab UMR 5273 UPS CNRS EFS INSERM U10, Toulouse, France. [Shi, Yufang] Chinese Acad Sci, Inst Hlth Sci, Shanghai, Peoples R China. [Stroncek, David F.] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Viswanathan, Sowmya] Univ Hlth Network, Cell Therapy Program, Toronto, ON, Canada. [Weiss, Daniel J.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Sensebe, Luc] UMR5273 STROMALab CNRS EFS UPS INSERM U1031, Toulouse, France. [Koh, Mickey B. C.] Hlth Sci Author, Blood Serv Grp, Singapore, Singapore. [Shi, Yufang] Soochow Univ, Affiliated Hosp 1, Inst Translat Med, Suzhou, Peoples R China. RP Galipeau, J (reprint author), Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA USA.; Galipeau, J (reprint author), Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA.; Galipeau, J (reprint author), Winship Canc Inst, 1365B Clifton Rd, Atlanta, GA 30322 USA. EM jgalipe@emory.edu RI ortiz, luis/H-9851-2013; OI ortiz, luis/0000-0003-4510-7066 FU International Society for Cell Therapy (ISCT) FX The workshop on potency release assays was sponsored by an unrestricted grant from the International Society for Cell Therapy (ISCT) as part of the 21st ISCT annual meeting held in Las Vegas, Nevada, in May 2015. This ISCT guidance article is not necessarily the position/perspective of the authors' respective companies or institutions. NR 55 TC 22 Z9 22 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1465-3249 EI 1477-2566 J9 CYTOTHERAPY JI Cytotherapy PD FEB PY 2016 VL 18 IS 2 BP 151 EP 159 DI 10.1016/j.jcyt.2015.11.008 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA DC3NB UT WOS:000369124900001 PM 26724220 ER PT J AU Riddle, MA Maher, BS Wang, Y Grados, M Bienvenu, OJ Goes, FS Cullen, B Murphy, DL Rauch, SL Greenberg, BD Knowles, JA McCracken, JT Pinto, A Piacentini, J Pauls, DL Rasmussen, SA Shugart, YY Nestadt, G Samuels, J AF Riddle, Mark A. Maher, Brion S. Wang, Ying Grados, Marco Bienvenu, O. Joseph Goes, Fernando S. Cullen, Bernadette Murphy, Dennis L. Rauch, Scott L. Greenberg, Benjamin D. Knowles, James A. McCracken, James T. Pinto, Anthony Piacentini, John Pauls, David L. Rasmussen, Steven A. Shugart, Yin Yao Nestadt, Gerald Samuels, Jack TI OBSESSIVE-COMPULSIVE PERSONALITY DISORDER: EVIDENCE FOR TWO DIMENSIONS SO DEPRESSION AND ANXIETY LA English DT Article DE obsessive-compulsive disorder; personality disorder; genetic; assessment and diagnosis; hoarding ID OCD COLLABORATIVE GENETICS; GENOTYPING ERRORS; COMMUNITY SAMPLE; DSM-IV; PREVALENCE; IDENTIFICATION; ASSOCIATION; RATIONALE; FAMILY AB BackgroundTo determine possible dimensions that underlie obsessive-compulsive personality disorder (OCPD) and to investigate their clinical correlates, familiality, and genetic linkage. MethodsParticipants were selected from 844 adults assessed with the Structured Instrument for the Diagnosis of DSM-IV Personality Disorders (SIDP) in the OCD Collaborative Genetics Study (OCGS) that targeted families with obsessive-compulsive disorder (OCD) affected sibling pairs. We conducted an exploratory factor analysis, which included the eight SIDP-derived DSM-IV OCPD traits and the indecision trait from the DSM-III, assessed clinical correlates, and estimated sib-sib correlations to evaluate familiality of the factors. Using MERLIN and MINX, we performed genome-wide quantitative trait locus (QTL) linkage analysis to test for allele sharing among individuals. ResultsTwo factors were identified: Factor 1: order/control (perfectionism, excessive devotion to work, overconscientiousness, reluctance to delegate, and rigidity); and Factor 2: hoarding/indecision (inability to discard and indecisiveness). Factor 1 score was associated with poor insight, whereas Factor 2 score was associated with task incompletion. A significant sib-sib correlation was found for Factor 2 (rICC = .354, P < .0001) but not Factor 1 (rICC = .129, P = .084). The linkage findings were different for the two factors. When Factor 2 was analyzed as a quantitative trait, a strong signal was detected on chromosome 10 at marker d10s1221: KAC LOD = 2.83, P = .0002; and marker d10s1225: KAC LOD = 1.35, P = .006. ConclusionsThe results indicate two factors of OCPD, order/control and hoarding/indecision. The hoarding/indecision factor is familial and shows modest linkage to a region on chromosome 10. C1 [Riddle, Mark A.; Wang, Ying; Grados, Marco; Bienvenu, O. Joseph; Goes, Fernando S.; Cullen, Bernadette; Nestadt, Gerald; Samuels, Jack] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway,Suite 203, Baltimore, MD 21205 USA. [Maher, Brion S.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, 550 N Broadway,Suite 203, Baltimore, MD 21205 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. [Rauch, Scott L.] Harvard Univ, Sch Med, Dept Psychiat, McLean Hosp, Boston, MA 02115 USA. [Greenberg, Benjamin D.; Rasmussen, Steven A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, James A.] Univ So Calif, Sch Med, Dept Psychiat, Los Angeles, CA USA. [McCracken, James T.; Piacentini, John] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Pinto, Anthony] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY 10032 USA. [Pauls, David L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Psychiat & Neurodev Genet Unit, Boston, MA USA. [Shugart, Yin Yao] NIMH, Unit Stat Genom, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Riddle, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 550 N Broadway,Suite 203, Baltimore, MD 21205 USA.; Riddle, MA (reprint author), Johns Hopkins Univ, Sch Med, 550 N Broadway,Suite 203, Baltimore, MD 21205 USA. EM mriddle1@jhmi.edu RI Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU National Institute of Mental Health; NIH; NARSAD; Seaside Therapeutics; Roche; Shire; Dart Neuroscience [R01MH50214, MH071507, MH079489, MH079487, MH079488, MH079494] FX Contract grant sponsor: National Institute of Mental Health; Contract grant sponsor: NIH; Contract grant sponsor: NARSAD; Contract grant sponsor: Seaside Therapeutics; Contract grant sponsor: Roche; Contract grant sponsor: Shire Contract grant sponsor: Dart Neuroscience; Contract grant numbers: R01MH50214, MH071507, MH079489, MH079487, MH079488, and MH079494. NR 42 TC 1 Z9 1 U1 6 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD FEB PY 2016 VL 33 IS 2 BP 128 EP 135 DI 10.1002/da.22452 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DC2SE UT WOS:000369065800004 PM 26594839 ER PT J AU Nelson, EE Jarcho, JM Guyer, AE AF Nelson, Eric E. Jarcho, Johanna M. Guyer, Amanda E. TI Social re-orientation and brain development: An expanded and updated view SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Review DE Motivation; Sensitive periods; Learning; Attention ID MEDIAL PREFRONTAL CORTEX; ANTICIPATED PEER EVALUATION; ADOLESCENT RISK-TAKING; ULTRASONIC VOCALIZATION RESPONSES; INFERIOR TEMPORAL CORTEX; MATERNAL-DEPRIVATION; AMYGDALA RESPONSE; SENSITIVE PERIODS; NEURAL ACTIVATION; COGNITIVE CONTROL AB Social development has been the focus of a great deal of neuroscience based research over the past decade. In this review, we focus on providing a framework for understanding how changes in facets of social development may correspond with changes in brain function. We argue that (1) distinct phases of social behavior emerge based on whether the organizing social force is the mother, peer play, peer integration, or romantic intimacy; (2) each phase is marked by a high degree of affect-driven motivation that elicits a distinct response in subcortical structures; (3) activity generated by these structures interacts with circuits in prefrontal cortex that guide executive functions, and occipital and temporal lobe circuits, which generate specific sensory and perceptual social representations. We propose that the direction, magnitude and duration of interaction among these affective, executive, and perceptual systems may relate to distinct sensitive periods across development that contribute to establishing long-term patterns of brain function and behavior. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). C1 [Nelson, Eric E.; Jarcho, Johanna M.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Guyer, Amanda E.] Univ Calif Davis, Ctr Mind & Brain, Dept Human Ecol, Davis, CA 95618 USA. RP Nelson, EE (reprint author), NIMH, Bldg 15K,9000 Rockville Pike, Bethesda, MD 20892 USA. EM nelson@mail.nih.gov OI Jarcho, Johanna/0000-0001-9075-6968 FU Intramural Research Program of NIMH; NIH [R01-MH098370, R01-MH093605]; William T. Grant Scholars Award FX This research was supported by the Intramural Research Program of NIMH (EEN & JMJ), NIH grants R01-MH098370, R01-MH093605 (AEG), and a William T. Grant Scholars Award (AEG). NR 187 TC 10 Z9 10 U1 4 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 EI 1878-9307 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD FEB PY 2016 VL 17 BP 118 EP 127 DI 10.1016/j.dcn.2015.12.008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DB8IO UT WOS:000368760600015 PM 26777136 ER PT J AU Fradkin, JE Wallace, JA Akolkar, B Rodgers, GP AF Fradkin, Judith E. Wallace, Julie A. Akolkar, Beena Rodgers, Griffin P. TI Type 1 Diabetes-Reaping the Rewards of a Targeted Research Investment SO DIABETES LA English DT Article ID ISLET TRANSPLANTATION; INTENSIVE TREATMENT; CONTROLLED-TRIAL; MELLITUS; INSULIN; COMPLICATIONS; ASSOCIATION; MODULATION; ABATACEPT; PANCREAS AB The Diabetes Control and Complications Trial (DCCT) precipitated a major research effort to develop new approaches to achieve near-normal glycemic control in real-world settings in people with type 1 diabetes. Toward that end, a unique funding stream from the U.S. Congress the Special Statutory Funding Program for Type 1 Diabetes Research has provided nearly $2.5 billion for research into the prevention, cure, and treatment of type 1 diabetes since 1998. This funding generated a targeted, sustained investment in type 1 diabetes research with six specific goals: identifying new therapeutic targets through the understanding of disease etiology and pathogenesis, preventing or reversing the disease, developing cell replacement therapy, improving management and care, preventing or reducing the complications, and attracting new talent and applying new technologies to type 1 diabetes research. This Perspective describes exciting results that have emerged from the investment and further advances on the horizon, including artificial pancreas technologies, new therapies for diabetic retinopathy, and breakthroughs in laboratory production of beta-cells. The recent program extension enables us to build on this foundation and pursue key new initiatives to harness emerging technologies and develop the next generation of type 1 diabetes researchers. C1 [Fradkin, Judith E.; Akolkar, Beena] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Wallace, Julie A.] NIDDK, Off Sci Program & Policy Anal, NIH, Bethesda, MD 20892 USA. [Rodgers, Griffin P.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. EM fradkinj@mail.nih.gov NR 28 TC 1 Z9 1 U1 3 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2016 VL 65 IS 2 BP 307 EP 313 DI 10.2337/db15-1030 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC1HS UT WOS:000368968000001 PM 26798117 ER PT J AU Traurig, M Hanson, RL Marinelarena, A Kobes, S Piaggi, P Cole, S Curran, JE Blangero, J Goring, H Kumar, S Nelson, RG Howard, BV Knowler, WC Baier, LJ Bogardus, C AF Traurig, Michael Hanson, Robert L. Marinelarena, Alejandra Kobes, Sayuko Piaggi, Paolo Cole, Shelley Curran, Joanne E. Blangero, John Goering, Harald Kumar, Satish Nelson, Robert G. Howard, Barbara V. Knowler, William C. Baier, Leslie J. Bogardus, Clifton TI Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression SO DIABETES LA English DT Article ID PIMA-INDIANS; INSULIN-RESISTANCE; MELLITUS; CLASSIFICATION; PREVALENCE; DISCOVERY; DIAGNOSIS; DISEASE; DESIGN AB Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 x 10-7) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 x 10-15) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes. C1 [Traurig, Michael; Hanson, Robert L.; Marinelarena, Alejandra; Kobes, Sayuko; Piaggi, Paolo; Nelson, Robert G.; Knowler, William C.; Baier, Leslie J.; Bogardus, Clifton] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Cole, Shelley] Texas Biomed Res Inst, San Antonio, TX USA. [Curran, Joanne E.; Blangero, John; Goering, Harald; Kumar, Satish] Univ Texas Brownsville, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX 78520 USA. [Howard, Barbara V.] MedStar Hlth Res Inst, Hyattsville, MD USA. [Howard, Barbara V.] Georgetown Howard Univ, Ctr Clin & Translat Sci, Washington, DC USA. RP Bogardus, C (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM cbogardu@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Heart, Lung, and Blood Institute [U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65520, U01-HL65521] FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. The SHS was supported by cooperative agreement grants U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65520, and U01-HL65521 from the National Heart, Lung, and Blood Institute. This study utilized the computational resources of the Biowulf system at the National Institutes of Health, Bethesda, MD (for a description, see https://helix.nih.gov/). NR 27 TC 0 Z9 0 U1 1 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2016 VL 65 IS 2 BP 510 EP 519 DI 10.2337/db15-0571 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC1HS UT WOS:000368968000022 PM 26487785 ER PT J AU Hivert, MF Christophi, CA Franks, PW Jablonski, KA Ehrmann, DA Kahn, SE Horton, ES Pollin, TI Mather, KJ Perreault, L Barrett-Connor, E Knowler, WC Florez, JC AF Hivert, Marie-France Christophi, Costas A. Franks, Paul W. Jablonski, Kathleen A. Ehrmann, David A. Kahn, Steven E. Horton, Edward S. Pollin, Toni I. Mather, Kieren J. Perreault, Leigh Barrett-Connor, Elizabeth Knowler, William C. Florez, Jose C. CA Diabetes Prevention Program Res TI Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants SO DIABETES LA English DT Article ID BETA-CELL DYSFUNCTION; RELATIVE CONTRIBUTIONS; GLUCOSE-TOLERANCE; GLYCEMIC TRAITS; INTERVENTION; HOMEOSTASIS; SECRETION AB Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (beta= -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (beta = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants. C1 [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02115 USA. [Hivert, Marie-France; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [Christophi, Costas A.; Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Franks, Paul W.] Lund Univ, Dept Clin Sci, Ctr Diabet, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. [Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Div Med, Umea, Sweden. [Ehrmann, David A.] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Horton, Edward S.] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, Boston, MA 02215 USA. [Horton, Edward S.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Pollin, Toni I.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Pollin, Toni I.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Pollin, Toni I.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Mather, Kieren J.] Indiana Univ Sch Med, Dept Med, Div Endocrinol, Indianapolis, IN 46202 USA. [Perreault, Leigh] Univ Colorado, Dept Med, Div Endocrinol Metab & Diabet, Anschutz Med Campus, Aurora, CO USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family Med & Publ Hlth, Div Epidemiol, La Jolla, CA 92093 USA. [Knowler, William C.] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA.; Florez, JC (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.; Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Florez, JC (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. EM dppmail@bsc.gwu.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [DK-48489]; NIDDK; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart, Lung, and Blood Institute; Office of Research on Women's Health; National Institute on Minority Health and Health Disparities; Centers for Disease Control and Prevention; American Diabetes Association FX During the DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding (grant DK-48489) to the clinical centers and the Coordinating Center for the design and conduct of the study, and The collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding was also provided by the National Institute of Child Health and Human Development; the National Institute on Aging; the National Eye Institute; the National Heart, Lung, and Blood Institute; the Office of Research on Women's Health; the National Institute on Minority Health and Health Disparities; the Centers for Disease Control and Prevention; and the American Diabetes Association. Lipha (Merck-Sante) provided medication, and LifeScan, Inc. donated materials during the DPP and DPPOS. NR 20 TC 4 Z9 4 U1 2 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD FEB PY 2016 VL 65 IS 2 BP 520 EP 526 DI 10.2337/db15-0950 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC1HS UT WOS:000368968000023 PM 26525880 ER PT J AU Nyenswah, TG Kateh, F Bawo, L Massaquoi, M Gbanyan, M Fallah, M Nagbe, TK Karsor, KK Wesseh, CS Sieh, S Gasasira, A Graaff, P Hensley, L Rosling, H Lo, T Pillai, SK Gupta, N Montgomery, JM Ransom, RL Williams, D Laney, AS Lindblade, KA Slutsker, L Telfer, JL Christie, A Mahoney, F De Cock, KM AF Nyenswah, Tolbert G. Kateh, Francis Bawo, Luke Massaquoi, Moses Gbanyan, Miatta Fallah, Mosoka Nagbe, Thomas K. Karsor, Kollie K. Wesseh, C. Sanford Sieh, Sonpon Gasasira, Alex Graaff, Peter Hensley, Lisa Rosling, Hans Lo, Terence Pillai, Satish K. Gupta, Neal Montgomery, Joel M. Ransom, Ray L. Williams, Desmond Laney, A. Scott Lindblade, Kim A. Slutsker, Laurence Telfer, Jana L. Christie, Athalia Mahoney, Frank De Cock, Kevin M. TI Ebola and Its Control in Liberia, 2014-2015 SO EMERGING INFECTIOUS DISEASES LA English DT Article ID JANUARY-FEBRUARY 2015; HEALTH-CARE WORKERS; VIRUS DISEASE; COUNTY; TRANSMISSION; AUGUST; VILLAGE; CLUSTER; OCTOBER; MANAGEMENT AB The severe epidemic Of Ebola virus disease in Liberia started in March 2014. On May 9, 2015, the World Health Organization declared Liberia free of Ebola, 42 days after safe burial of the last known case-patient. However, another 6 cases occurred during June July; on September 3, 2015, the country was again declared free of Ebola. Liberia had by then reported 10,672 cases of Ebola and 4,808 deaths, 37.0% and 42.6%, respectively, of the 28,103 cases and 11,290 deaths reported from the 3 countries that were heavily affected at that time. Essential components of the response included government leadership and sense of urgency, coordinated international assistance, sound technical work, flexibility guided by epidemiologic data, transparency and effective communication, and efforts by communities themselves. Priorities after the epidemic include surveillance in case of resurgence, restoration of health services, infection control in healthcare settings, and strengthening of basic public health systems. C1 [Nyenswah, Tolbert G.; Kateh, Francis; Bawo, Luke; Massaquoi, Moses; Gbanyan, Miatta; Fallah, Mosoka; Nagbe, Thomas K.; Karsor, Kollie K.; Wesseh, C. Sanford; Sieh, Sonpon; Rosling, Hans] Minist Hlth & Social Welf, Monrovia, Liberia. [Gasasira, Alex] World Hlth Org, Monrovia, Liberia. [Graaff, Peter] United Nations Mission Emergency Ebola Response, Monrovia, Liberia. [Hensley, Lisa] NIH, Bldg 10, Bethesda, MD 20892 USA. [Rosling, Hans] Karolinska Inst, Stockholm, Sweden. [Lo, Terence; Pillai, Satish K.; Gupta, Neal; Montgomery, Joel M.; Ransom, Ray L.; Williams, Desmond; Laney, A. Scott; Lindblade, Kim A.; Slutsker, Laurence; Telfer, Jana L.; Christie, Athalia; Mahoney, Frank; De Cock, Kevin M.] Ctr Dis Control & Prevent, 1600 Clifton Rd,NE,Mailstop D69, Atlanta, GA 30329 USA. RP De Cock, KM (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,NE,Mailstop D69, Atlanta, GA 30329 USA. EM kmd2@cdc.gov NR 36 TC 3 Z9 3 U1 4 U2 35 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2016 VL 22 IS 2 BP 169 EP 177 DI 10.3201/eid2202.151456 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC1HX UT WOS:000368968500001 PM 26811980 ER PT J AU Fischer, RJ Judson, S Miazgowicz, K Bushmaker, T Munster, VJ AF Fischer, Robert J. Judson, Seth Miazgowicz, Kerri Bushmaker, Trent Munster, Vincent J. TI Ebola Virus Persistence in Semen Ex Vivo SO EMERGING INFECTIOUS DISEASES LA English DT Article ID DISEASE; TRANSMISSION; STABILITY; OUTBREAK; KIKWIT; FLUIDS; CONGO AB On March 20, 2015, a case of Ebola virus disease was identified in Liberia that most likely was transmitted through sexual contact. We assessed the efficiency of detecting Ebola virus in semen samples by molecular diagnostics and the stability of Ebola virus in ex vivo semen under simulated tropical conditions. C1 [Fischer, Robert J.; Judson, Seth; Miazgowicz, Kerri; Bushmaker, Trent; Munster, Vincent J.] NIH, 903 S 4th St, Hamilton, MT 59840 USA. RP Munster, VJ (reprint author), NIH, 903 S 4th St, Hamilton, MT 59840 USA.; Munster, VJ (reprint author), NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI Munster, Vincent/0000-0002-2288-3196 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 15 TC 5 Z9 5 U1 0 U2 14 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2016 VL 22 IS 2 BP 289 EP 291 DI 10.3201/eid2202.151278 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC1HX UT WOS:000368968500019 PM 26811984 ER PT J AU de Wit, E Falzarano, D Onyango, C Rosenke, K Marzi, A Ochieng, M Juma, B Fischer, RJ Prescott, JB Safronetz, D Omballa, V Owuor, C Hoenen, T Groseth, A van Doremalen, N Zemtsova, G Self, J Bushmaker, T McNally, K Rowe, T Emery, SL Feldmann, F Williamson, B Nyenswah, TG Grolla, A Strong, JE Kobinger, G Stroeher, U Rayfield, M Bolay, FK Zoon, KC Stassijns, J Tampellini, L de Smet, M Nichol, ST Fields, B Sprecher, A Feldmann, H Massaquoi, M Munster, VJ AF de Wit, Emmie Falzarano, Darryl Onyango, Clayton Rosenke, Kyle Marzi, Andrea Ochieng, Melvin Juma, Bonventure Fischer, Robert J. Prescott, Joseph B. Safronetz, David Omballa, Victor Owuor, Collins Hoenen, Thomas Groseth, Allison van Doremalen, Neeltje Zemtsova, Galina Self, Joshua Bushmaker, Trenton McNally, Kristin Rowe, Thomas Emery, Shannon L. Feldmann, Friederike Williamson, Brandi Nyenswah, Tolbert G. Grolla, Allen Strong, James E. Kobinger, Gary Stroeher, Ute Rayfield, Mark Bolay, Fatorma K. Zoon, Kathryn C. Stassijns, Jorgen Tampellini, Livia de Smet, Martin Nichol, Stuart T. Fields, Barry Sprecher, Armand Feldmann, Heinz Massaquoi, Moses Munster, Vincent J. TI The Merits of Malaria Diagnostics during an Ebola Virus Disease Outbreak SO EMERGING INFECTIOUS DISEASES LA English DT Article ID INFECTIONS; RISK; PCR AB Malaria is a major public health concern in the countries affected by the Ebola virus disease epidemic in West Africa. We determined the feasibility of using molecular malaria diagnostics during an Ebola virus disease outbreak and report the incidence of Plasmodium spp. parasitemia in persons with suspected Ebola virus infection. C1 [de Wit, Emmie; Falzarano, Darryl; Rosenke, Kyle; Marzi, Andrea; Fischer, Robert J.; Prescott, Joseph B.; Safronetz, David; Hoenen, Thomas; Groseth, Allison; van Doremalen, Neeltje; Bushmaker, Trenton; McNally, Kristin; Feldmann, Friederike; Williamson, Brandi; Feldmann, Heinz; Munster, Vincent J.] NIH, Hamilton, MT USA. [Onyango, Clayton; Juma, Bonventure; Fields, Barry] Ctr Dis Control & Prevent, Nairobi, Kenya. [Ochieng, Melvin; Omballa, Victor; Owuor, Collins] Kenya Govt Med Res Ctr, Nairobi, Kenya. [Zemtsova, Galina; Self, Joshua; Rowe, Thomas; Emery, Shannon L.; Stroeher, Ute; Rayfield, Mark; Nichol, Stuart T.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Nyenswah, Tolbert G.; Massaquoi, Moses] Minist Hlth & Social Welf, Monrovia, Liberia. [Safronetz, David; Grolla, Allen; Strong, James E.; Kobinger, Gary] Publ Hlth Agcy Canada, Winnipeg, MB, Canada. [Bolay, Fatorma K.] Liberian Inst Biomed Res, Charlesville, Liberia. [Zoon, Kathryn C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Stassijns, Jorgen; Tampellini, Livia; de Smet, Martin; Sprecher, Armand] Med Sans Frontieres, Brussels, Belgium. [Falzarano, Darryl] Univ Saskatchewan, Saskatoon, SK, Canada. [Hoenen, Thomas; Groseth, Allison] Friedrich Loeffler Inst, Greifswald, Germany. RP Munster, VJ (reprint author), NIH, Virol Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM vincent.munster@nih.gov OI Hoenen, Thomas/0000-0002-5829-6305; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH FX This work was funded in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 14 TC 4 Z9 4 U1 1 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2016 VL 22 IS 2 BP 323 EP 326 DI 10.3201/eid2202.151656 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC1HX UT WOS:000368968500030 PM 26814608 ER PT J AU Hoenen, T Groseth, A Rosenke, K Fischer, RJ Hoenen, A Judson, SD Martellaro, C Falzarano, D Marzi, A Squires, RB Wollenberg, KR de Wit, E Prescott, J Safronetz, D van Doremalen, N Bushmaker, T Feldmann, F McNally, K Bolay, FK Fields, B Sealy, T Rayfield, M Nichol, ST Zoon, KC Massaquoi, M Munster, VJ Feldmann, H AF Hoenen, Thomas Groseth, Allison Rosenke, Kyle Fischer, Robert J. Hoenen, Andreas Judson, Seth D. Martellaro, Cynthia Falzarano, Darryl Marzi, Andrea Squires, R. Burke Wollenberg, Kurt R. de Wit, Emmie Prescott, Joseph Safronetz, David van Doremalen, Neeltje Bushmaker, Trenton Feldmann, Friederike McNally, Kristin Bolay, Fatorma K. Fields, Barry Sealy, Tara Rayfield, Mark Nichol, Stuart T. Zoon, Kathryn C. Massaquoi, Moses Munster, Vincent J. Feldmann, Heinz TI Nanopore Sequencing as a Rapidly Deployable Ebola Outbreak Tool SO EMERGING INFECTIOUS DISEASES LA English DT Article ID VIRUS; TRANSMISSION; LIBERIA AB Rapid sequencing of RNA/DNA from pathogen samples obtained during disease outbreaks provides critical scientific and public health information. However, challenges exist for exporting samples to laboratories or establishing conventional sequencers in remote outbreak regions. We successfully used a novel, pocket-sized nanopore sequencer at a field diagnostic laboratory in Liberia during the current Ebola virus outbreak. C1 [Hoenen, Thomas; Groseth, Allison] Friedrich Loeffler Inst, Sudufer 10, D-17493 Greifswald, Germany. [Hoenen, Thomas; Groseth, Allison; Rosenke, Kyle; Fischer, Robert J.; Judson, Seth D.; Martellaro, Cynthia; Falzarano, Darryl; Marzi, Andrea; de Wit, Emmie; Prescott, Joseph; Safronetz, David; van Doremalen, Neeltje; Bushmaker, Trenton; Feldmann, Friederike; McNally, Kristin; Munster, Vincent J.; Feldmann, Heinz] NIH, Hamilton, MT USA. [Falzarano, Darryl] Univ Saskatchewan, Saskatoon, SK, Canada. [Squires, R. Burke; Wollenberg, Kurt R.; Zoon, Kathryn C.] NIH, Bldg 10, Bethesda, MD 20892 USA. [Bolay, Fatorma K.] Liberian Inst Biomed Res, Charles Ville, Liberia. [Fields, Barry; Sealy, Tara; Rayfield, Mark; Nichol, Stuart T.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Massaquoi, Moses] Minist Hlth & Social Welf, Monrovia, Liberia. RP Hoenen, T (reprint author), Friedrich Loeffler Inst, Sudufer 10, D-17493 Greifswald, Germany. EM thomas.hoenen@fli.bund.de OI Hoenen, Thomas/0000-0002-5829-6305; de Wit, Emmie/0000-0002-9763-7758; Munster, Vincent/0000-0002-2288-3196; Squires, R Burke/0000-0001-9666-6285 FU Intramural Research Program of NIH, National Institute of Allergy and Infectious Diseases FX This work was supported in part by the Intramural Research Program of NIH, National Institute of Allergy and Infectious Diseases, and used the high-performance computational capabilities of the Biowulf Linux cluster at NIH (http://biowulf.nih.gov). The complete genome sequences reported in this manuscript were deposited in GenBank under the accession numbers KR074996.1-KR075003.1 and the nearly complete sequences under accession numbers KU042954 and KU042955. NR 15 TC 11 Z9 12 U1 2 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2016 VL 22 IS 2 BP 331 EP 334 DI 10.3201/eid2202.151796 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC1HX UT WOS:000368968500032 PM 26812583 ER PT J AU Safronetz, D Sacko, M Sogoba, N Rosenke, K Martellaro, C Traore, S Cisse, I Maiga, O Boisen, M Nelson, D Oottamasathien, D Millett, M Garry, RF Branco, LM Doumbia, S Feldmann, H Traore, MS AF Safronetz, David Sacko, Moussa Sogoba, Nafomon Rosenke, Kyle Martellaro, Cynthia Traore, Sekou Cisse, Issa Maiga, Ousmane Boisen, Matt Nelson, Diana Oottamasathien, Darin Millett, Molly Garry, Robert F. Branco, Luis M. Doumbia, Seydou Feldmann, Heinz Traore, Mamadou S. TI Vectorborne Infections, Mali SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID SIERRA-LEONE; VIRUS; PERSISTENCE C1 [Safronetz, David; Rosenke, Kyle; Martellaro, Cynthia; Feldmann, Heinz] NIH, Hamilton, MT USA. Inst Natl Rech Sante Publ, Bamako, Mali. [Sogoba, Nafomon; Maiga, Ousmane; Doumbia, Seydou] Univ Sci Tech & Technol Bamako, Bamako, Mali. [Boisen, Matt; Nelson, Diana; Oottamasathien, Darin; Millett, Molly; Feldmann, Heinz] Corgenix Med Corp Inc, Broomfield, CO USA. [Garry, Robert F.] Tulane Sch Med, New Orleans, LA USA. [Branco, Luis M.] Zalgen Labs LLC, Germantown, MD USA. [Safronetz, David] Publ Hlth Agcy Canada, Natl Microbiol Lab, Zoonot Dis & Special Pathogens, Winnipeg, MB, Canada. RP Feldmann, H (reprint author), NIH, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM feldmannh@niaid.nih.gov OI Branco, Luis/0000-0001-8161-0182 FU Intramural NIH HHS NR 6 TC 0 Z9 0 U1 0 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 EI 1080-6059 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2016 VL 22 IS 2 BP 340 EP 342 DI 10.3201/eid2202.150688 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC1HX UT WOS:000368968500036 PM 26812625 ER PT J AU Prasad, V Oseran, A Fakhrejahani, F AF Prasad, Vinay Oseran, Andrew Fakhrejahani, Farhad TI The use of gene expression profiling and mutation analysis increases the cost of care for patients with carcinoma of unknown primary; does it also improve survival? SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material C1 [Prasad, Vinay; Fakhrejahani, Farhad] NCI, Med Oncol Serv, NIH, 10 Ctr Dr 10-12N226, Bethesda, MD 20892 USA. [Oseran, Andrew] Georgetown Med Sch, Washington, DC USA. RP Prasad, V (reprint author), Oregon Hlth & Sci Univ, Div Hematol Oncol, Knight Canc Inst, Dept Publ Hlth,Ctr Hlth Care Eth, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM prasad@ohsu.edu NR 17 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 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD FEB PY 2016 VL 54 BP 159 EP 162 DI 10.1016/j.ejca.2015.09.006 PG 4 WC Oncology SC Oncology GA DC3WQ UT WOS:000369150000020 PM 26608119 ER PT J AU Kennedy, DA Kurath, G Brito, IL Purcell, MK Read, AF Winton, JR Wargo, AR AF Kennedy, David A. Kurath, Gael Brito, Ilana L. Purcell, Maureen K. Read, Andrew F. Winton, James R. Wargo, Andrew R. TI Potential drivers of virulence evolution in aquaculture SO EVOLUTIONARY APPLICATIONS LA English DT Article DE aquaculture; evolution of virulence; infectious diseases ID HEMATOPOIETIC-NECROSIS-VIRUS; SPOT-SYNDROME-VIRUS; HEMORRHAGIC SEPTICEMIA VIRUS; TROUT ONCORHYNCHUS-MYKISS; MAREKS-DISEASE VIRUS; GYRODACTYLUS-SALARIS MALMBERG; PENAEUS LITOPENAEUS VANNAMEI; BACTERIAL KIDNEY-DISEASE; EMERGING VIRAL DISEASES; WILD ATLANTIC SALMON AB Infectious diseases are economically detrimental to aquaculture, and with continued expansion and intensification of aquaculture, the importance of managing infectious diseases will likely increase in the future. Here, we use evolution of virulence theory, along with examples, to identify aquaculture practices that might lead to the evolution of increased pathogen virulence. We identify eight practices common in aquaculture that theory predicts may favor evolution toward higher pathogen virulence. Four are related to intensive aquaculture operations, and four others are related specifically to infectious disease control. Our intention is to make aquaculture managers aware of these risks, such that with increased vigilance, they might be able to detect and prevent the emergence and spread of increasingly troublesome pathogen strains in the future. C1 [Kennedy, David A.; Read, Andrew F.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, W-245A Millennium Sci Bldg, University Pk, PA 16802 USA. [Kennedy, David A.; Read, Andrew F.] Penn State Univ, Dept Entomol, W-245A Millennium Sci Bldg, University Pk, PA 16802 USA. [Kennedy, David A.; Read, Andrew F.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Kurath, Gael; Purcell, Maureen K.; Winton, James R.] US Geol Survey, Western Fisheries Res Ctr, Seattle, WA USA. [Brito, Ilana L.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Wargo, Andrew R.] Virginia Inst Marine Sci, Coll William & Mary, Gloucester Point, VA 23062 USA. RP Kennedy, DA (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, W-245A Millennium Sci Bldg, University Pk, PA 16802 USA.; Kennedy, DA (reprint author), Penn State Univ, Dept Entomol, W-245A Millennium Sci Bldg, University Pk, PA 16802 USA. EM dak30@psu.edu OI Purcell, Maureen/0000-0003-0154-8433 FU RAPIDD Program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health; Institute of General Medical Sciences [R01GM105244]; National Institutes of Health as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases Program FX DAK was funded by the RAPIDD Program of the Science and Technology Directorate, Department of Homeland Security and Fogarty International Center, National Institutes of Health, and by the Institute of General Medical Sciences (R01GM105244), National Institutes of Health as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Tiffany Bogich, Mike Boots, Rachel Breyta, Marine Brieuc, Troy Day, Greg Dwyer, Gary Fornshell, Caroline Friedman, Kyle Garver, Alison Kell, Shannon Ladeau, Scott LaPatra, Jennie Lavine, Jamie Lloyd-Smith, Kerry Naish, Kim Pepin and Mark Zwart for discussions that helped shape this manuscript. NR 159 TC 8 Z9 8 U1 8 U2 39 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-4571 J9 EVOL APPL JI Evol. Appl. PD FEB PY 2016 VL 9 IS 2 BP 344 EP 354 DI 10.1111/eva.12342 PG 11 WC Evolutionary Biology SC Evolutionary Biology GA DB9NB UT WOS:000368841800003 PM 26834829 ER PT J AU Wong, D Tortorelli, S Bishop, L Sellars, EA Schimmenti, LA Gallant, N Prada, CE Hopkin, RJ Leslie, ND Berry, SA Rosenblatt, DS Fair, AL Matern, D Raymond, K Oglesbee, D Rinaldo, P Gavrilov, D AF Wong, Derek Tortorelli, Silvia Bishop, Lisa Sellars, Elizabeth A. Schimmenti, Lisa A. Gallant, Natalie Prada, Carlos E. Hopkin, Robert J. Leslie, Nancy D. Berry, Susan A. Rosenblatt, David S. Fair, Amy L. Matern, Dietrich Raymond, Kimiyo Oglesbee, Devin Rinaldo, Piero Gavrilov, Dimitar TI Outcomes of four patients with homocysteine remethylation disorders detected by newborn screening SO GENETICS IN MEDICINE LA English DT Article DE homocysteine; newborn screening; Region 4 Stork tool; Remethylation disorders; second-tier testing ID METHYLENETETRAHYDROFOLATE REDUCTASE DEFICIENCY; TANDEM MASS-SPECTROMETRY; SEVERE COMBINED IMMUNODEFICIENCY; METHIONINE SYNTHASE; COBALAMIN METABOLISM; VITAMIN-B12 THERAPY; INBORN ERROR; CBLE TYPE; HOMOCYSTINURIA; MUTATION AB Purpose: We evaluated the clinical outcome in homocysteine remethylation disorders following newborn screening (NBS) and initiation of early specific treatment. Methods: Five patients with remethylation disorders were included in this study. Results: Two asymptomatic patients (one with cblG and one with cblE) were identified by NBS using an approach that combines a post-analytical interpretive tool (available on the Region 4 Stork (R4S) collaborative project website, http://www.clir-r4s.org) and a second-tier test for total homocysteine determination. Both the initial screening and the second-tier test are performed on the same blood spot, with no additional patient contact, resulting in no false-positive outcomes. Two additional patients with methylenetetrahydrofolate reductase deficiency were detected by NBS using low methionine as a marker. Although already symptomatic despite the early diagnosis, the latter two patients greatly improved with treatment and their outcomes are compared with that of another patient with methylenetetrahydrofolate reductase deficiency and significant morbidity who was diagnosed clinically at 3 months of age. Conclusion: Early detection by NBS and timely and specific treatment considerably improve at least short-term outcomes of homocysteine remethylation disorders. When a remethylation disorder is suspected, group-specific treatment could be started prior to the completion of in vitro confirmatory testing because all disorders from this group require similar intervention. C1 [Wong, Derek; Gallant, Natalie] Univ Calif Los Angeles, David Geffen Sch Med, Div Med Genet, Dept Pediat, Los Angeles, CA 90095 USA. [Tortorelli, Silvia; Matern, Dietrich; Raymond, Kimiyo; Oglesbee, Devin; Rinaldo, Piero; Gavrilov, Dimitar] Mayo Clin, Coll Med, Biochem Genet Lab, Rochester, MN USA. [Bishop, Lisa] NHGRI, NIH, Bethesda, MD 20892 USA. [Sellars, Elizabeth A.] Univ Arkansas Med Sci, Sect Genet & Metab, Dept Pediat, Little Rock, AR 72205 USA. [Schimmenti, Lisa A.; Berry, Susan A.] Univ Minnesota, Dept Pediat, Inst Human Genet, Div Genet & Metab, Minneapolis, MN 55455 USA. [Schimmenti, Lisa A.; Berry, Susan A.] Univ Minnesota, Dept Ophthalmol, Inst Human Genet, Div Genet & Metab, Minneapolis, MN 55455 USA. [Schimmenti, Lisa A.; Berry, Susan A.] Univ Minnesota, Inst Human Genet, Div Genet & Metab, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Prada, Carlos E.; Hopkin, Robert J.; Leslie, Nancy D.] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Rosenblatt, David S.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Rosenblatt, David S.] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada. [Fair, Amy L.] Fairview Elk River Clin, Elk River, MN USA. RP Gavrilov, D (reprint author), Mayo Clin, Coll Med, Biochem Genet Lab, Rochester, MN USA. EM Gavrilov.dimitar@mayo.edu OI Berry, Susan/0000-0001-7970-688X NR 34 TC 1 Z9 1 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 EI 1530-0366 J9 GENET MED JI Genet. Med. PD FEB PY 2016 VL 18 IS 2 BP 162 EP 167 DI 10.1038/gim.2015.45 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA DC4EQ UT WOS:000369173600009 PM 25856670 ER PT J AU Kim, HY Kim, CW Park, CH Choi, JY Han, K Merchant, AT Park, YM AF Kim, Hee Yeon Kim, Chang Wook Park, Chung-Hwa Choi, Jong Young Han, Kyungdo Merchant, Anwar T. Park, Yong-Moon TI Low skeletal muscle mass is associated with non-alcoholic fatty liver disease in Korean adults: the Fifth Korea National Health and Nutrition Examination Survey SO HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL LA English DT Article DE Korea National Health and Nutrition Examination Survey; non-alcoholic fatty liver disease; sarcopenia; skeletal muscle ID EXAMINATION SURVEY KNHANES; INSULIN-RESISTANCE; METABOLIC SYNDROME; SARCOPENIC OBESITY; HEPATIC STEATOSIS; VITAMIN-D; POPULATION; INDEX; STEATOHEPATITIS; ABSORPTIOMETRY AB BACKGROUND: Sarcopenia and non-alcoholic fatty liver disease (NAFLD) share similar pathophysiological mechanisms, and the relationship between sarcopenia and NAFLD has been recently investigated. The study investigated whether low skeletal muscle mass is differentially associated with NAFLD by gender in Korean adults. METHODS: We conducted a cross-sectional analysis of the data from the Fifth Korea National Health and Nutrition Examination Survey. The skeletal muscle index (SMI) was obtained by the appendicular skeletal muscle mass divided by the weight. NAFLD was defined as a fatty liver index (FLI) >= 60 in the absence of other chronic liver disease. RESULTS: Among the included subjects, 18.3% (SE: 1.4%) in men and 7.0% (SE: 0.7%) in women were classified as having FLI-defined NAFLD. Most of the risk factors for FLI-defined NAFLD showed a significant negative correlation with the SMI in both genders. Multiple logistic regression analysis showed that low SMI was associated with FLI-defined NAFLD, independent of other metabolic and lifestyle parameters in both genders [males: odds ratio (OR)=1.35; 95% confidence interval (CI): 1.17-1.54; females: OR=1.36; 95% CI: 1.18-1.55]. The magnitude of the association between FLI-defined NAFLD and low SMI was higher in middle aged to elderly males (OR=1.50; 95% CI: 1.22-1.84) than in males less than 45 years of age (OR=1.25; 95% CI: 1.02-1.52) and in premenopausal females (OR=1.50; 95% CI: 1.12-2.03) than in postmenopausal females (OR=1.36; 95% CI: 1.20-1.54). CONCLUSIONS: Low SMI is associated with the risk of FLI-defined NAFLD independent of other well-known metabolic risk factors in both genders. This association may differ according to age group or menopausal status. Further studies are warranted to confirm this relationship. C1 [Kim, Hee Yeon; Kim, Chang Wook; Park, Chung-Hwa; Choi, Jong Young] Catholic Univ Korea, Div Hepatol, Dept Internal Med, Coll Med, 222 Banpo Daero, Seoul 06591, South Korea. [Han, Kyungdo] Catholic Univ Korea, Coll Med, Dept Biostat, 222 Banpo Daero, Seoul 06591, South Korea. [Merchant, Anwar T.] Univ S Carolina, Dept Epidemiol & Biostat, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Park, Yong-Moon] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. RP Park, YM (reprint author), NIEHS, Epidemiol Branch, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM mark.park@nih.gov NR 40 TC 2 Z9 2 U1 0 U2 5 PU ZHEJIANG UNIV SCH MEDICINE PI HANGZHOU PA FIRST AFFILIATED HOSPITAL, 79 QINGCHUN ROAD, HANGZHOU, 310003, PEOPLES R CHINA SN 1499-3872 EI 2352-9377 J9 HEPATOB PANCREAT DIS JI Hepatob. Pancreatic. Dis. Int. PD FEB PY 2016 VL 15 IS 1 BP 39 EP 47 DI 10.1016/S1499-3872(15)60030-3 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DC1GA UT WOS:000368963600006 PM 26818542 ER PT J AU Pinheiro, A Neves, F de Matos, AL Abrantes, J van der Loo, W Mage, R Esteves, PJ AF Pinheiro, Ana Neves, Fabiana de Matos, Ana Lemos Abrantes, Joana van der Loo, Wessel Mage, Rose Esteves, Pedro Jose TI An overview of the lagomorph immune system and its genetic diversity SO IMMUNOGENETICS LA English DT Review DE Lagomorphs; European rabbit; Genetic diversity; Innate immunity; Adaptive immunity ID RABBIT ORYCTOLAGUS-CUNICULUS; HEMORRHAGIC-DISEASE-VIRUS; TOLL-LIKE RECEPTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; SUSCEPTIBLE EUROPEAN RABBITS; IMMUNOGLOBULIN HEAVY-CHAINS; VARIABLE REGION GENES; ZEALAND WHITE-RABBITS; TRIM FAMILY PROTEINS; KAPPA-LIGHT CHAINS AB Our knowledge of the lagomorph immune system remains largely based upon studies of the European rabbit (Oryctolagus cuniculus), a major model for studies of immunology. Two important and devastating viral diseases, rabbit hemorrhagic disease and myxomatosis, are affecting European rabbit populations. In this context, we discuss the genetic diversity of the European rabbit immune system and extend to available information about other lagomorphs. Regarding innate immunity, we review the most recent advances in identifying interleukins, chemokines and chemokine receptors, Toll-like receptors, antiviral proteins (RIG-I and Trim5), and the genes encoding fucosyltransferases that are utilized by rabbit hemorrhagic disease virus as a portal for invading host respiratory and gut epithelial cells. Evolutionary studies showed that several genes of innate immunity are evolving by strong natural selection. Studies of the leporid CCR5 gene revealed a very dramatic change unique in mammals at the second extracellular loop of CCR5 resulting from a gene conversion event with the paralogous CCR2. For the adaptive immune system, we review genetic diversity at the loci encoding antibody variable and constant regions, the major histocompatibility complex (RLA) and T cells. Studies of IGHV and IGKC genes expressed in leporids are two of the few examples of trans-species polymorphism observed outside of the major histocompatibility complex. In addition, we review some endogenous viruses of lagomorph genomes, the importance of the European rabbit as a model for human disease studies, and the anticipated role of next-generation sequencing in extending knowledge of lagomorph immune systems and their evolution. C1 [Pinheiro, Ana; Neves, Fabiana; Abrantes, Joana; van der Loo, Wessel; Esteves, Pedro Jose] Univ Porto, CIBIO, InBIO Res Network Biodivers & Evolutionary Biol, Campus Agr Vairao,Rua Padre Armando Quintas 7, Vairao, Portugal. [Pinheiro, Ana; Esteves, Pedro Jose] Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal. [Pinheiro, Ana] SaBio IREC CSIC UCLM JCCM, Ciudad Real 13071, Spain. [Neves, Fabiana] Univ Porto, UMIB UP Unidade Multidisciplinar Invest Biomed, Rua Campo Alegre 823, P-4100 Oporto, Portugal. [de Matos, Ana Lemos] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA. [Mage, Rose] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Esteves, Pedro Jose] CESPU, Ctr Invest Tecnol Saude, Gandra, Portugal. RP Esteves, PJ (reprint author), Univ Porto, CIBIO, InBIO Res Network Biodivers & Evolutionary Biol, Campus Agr Vairao,Rua Padre Armando Quintas 7, Vairao, Portugal.; Esteves, PJ (reprint author), Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal.; Esteves, PJ (reprint author), CESPU, Ctr Invest Tecnol Saude, Gandra, Portugal. EM pjesteves@cibio.up.pt FU FCT-Foundation for Science and Technology [FCT-ANR/BIA-BIC/0043/2012]; FCT [SFRH/BD/81916/2011, SFRH/BD/71252/2010, IF/01396/2013]; FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE; National Funds through FCT-Foundation for Science and Technology [PTDC/BIA-ANM/3963/2012, FCOMP-01-0124-FEDER-028286]; "Genomics Applied To Genetic Resources"; North Portugal Regional Operational Programme (ON.2-O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF); Intramural Research Program of the NIAID, NIH FX This work is funded by national funds through FCT-Foundation for Science and Technology-under the project FCT-ANR/BIA-BIC/0043/2012. FCT also supported the doctoral fellowships of FN and AP (refs. SFRH/BD/81916/2011 and SFRH/BD/71252/2010) and the investigator grant of JA (ref. IF/01396/2013). This work is funded also by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE and by National Funds through FCT-Foundation for Science and Technology under the project PTDC/BIA-ANM/3963/2012 and FCOMP-01-0124-FEDER-028286 and "Genomics Applied To Genetic Resources" co-financed by North Portugal Regional Operational Programme 2007/2013 (ON.2-O Novo Norte), under the National Strategic Reference Framework (NSRF), through the European Regional Development Fund (ERDF). RGM was partially supported by the Intramural Research Program of the NIAID, NIH. NR 308 TC 3 Z9 3 U1 11 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0093-7711 EI 1432-1211 J9 IMMUNOGENETICS JI Immunogenetics PD FEB PY 2016 VL 68 IS 2 BP 83 EP 107 DI 10.1007/s00251-015-0868-8 PG 25 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA DC1XY UT WOS:000369012800001 PM 26399242 ER PT J AU Rhee, C Kadri, S Huang, SSS Murphy, MV Li, LL Platt, R Klompas, M AF Rhee, Chanu Kadri, Sameer Huang, Susan S. Murphy, Michael V. Li, Lingling Platt, Richard Klompas, Michael CA CDC Prevention Epictr Program TI Objective Sepsis Surveillance Using Electronic Clinical Data SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID UNITED-STATES; SURVIVING SEPSIS; SERUM LACTATE; SEPTIC SHOCK; ORGAN DYSFUNCTION; CARE-UNIT; MORTALITY; EPIDEMIOLOGY; TRENDS; HOSPITALIZATIONS AB OBJECTIVE. To compare the accuracy of surveillance of severe sepsis using electronic health record clinical data vs claims and to compare incidence and mortality trends using both methods. DESIGN. We created an electronic health record-based surveillance definition for severe sepsis using clinical indicators of infection (blood culture and antibiotic orders) and concurrent organ dysfunction (vasopressors, mechanical ventilation, and/or abnormal laboratory values). We reviewed 1,000 randomly selected medical charts to characterize the definition's accuracy and stability over time compared with a claims-based definition requiring infection and organ dysfunction codes. We compared incidence and mortality trends from 2003-2012 using both methods. SETTING. Two US academic hospitals. PATIENTS. Adult inpatients. RESULTS. The electronic health record-based clinical surveillance definition had stable and high sensitivity over time (77% in 2003-2009 vs 80% in 2012, P=.58) whereas the sensitivity of claims increased (52% in 2003-2009 vs 67% in 2012, P=.02). Positive predictive values for claims and clinical surveillance definitions were comparable (55% vs 53%, P=.65) and stable over time. From 2003 to 2012, severe sepsis incidence imputed from claims rose by 72% (95% CI, 57%-88%) and absolute mortality declined by 5.4% (95% CI, 4.6%-6.7%). In contrast, incidence using the clinical surveillance definition increased by 7.7% (95% CI, -1.1% to 17%) and mortality declined by 1.7% (95% CI, 1.1%-2.3%). CONCLUSIONS. Sepsis surveillance using clinical data is more sensitive and more stable over time compared with claims and can be done electronically. This may enable more reliable estimates of sepsis burden and trends. C1 [Rhee, Chanu; Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael] Harvard Univ, Sch Med, Dept Populat Med, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. [Rhee, Chanu] Harvard Pilgrim Hlth Care Inst, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. [Rhee, Chanu; Platt, Richard; Klompas, Michael] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Kadri, Sameer] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Huang, Susan S.] Univ Calif Irvine, Sch Med, Div Infect Dis, Irvine, CA 92717 USA. RP Rhee, C (reprint author), Harvard Univ, Sch Med, Dept Populat Med, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA.; Rhee, C (reprint author), Harvard Pilgrim Hlth Care Inst, 133 Brookline Ave,6th Fl, Boston, MA 02215 USA. EM crhee1@partners.org FU Prevention Epicenters Program of the Centers for Disease Control and Prevention [3U54 CK000172-04S1]; National Institutes of Health [T32 AI007061] FX Financial support. Prevention Epicenters Program of the Centers for Disease Control and Prevention (grant 3U54 CK000172-04S1); National Institutes of Health (grant T32 AI007061 to C.R.). NR 35 TC 5 Z9 5 U1 2 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2016 VL 37 IS 2 BP 163 EP 171 DI 10.1017/ice.2015.264 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DC3WT UT WOS:000369150400008 PM 26526737 ER PT J AU Beekmann, SE Palmore, TN Polgreen, PM Bennett, JE AF Beekmann, Susan E. Palmore, Tara N. Polgreen, Philip M. Bennett, John E. TI Adequacy of Duodenoscope Reprocessing Methods as Reported by Infectious Disease Physicians SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Editorial Material ID ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY C1 [Beekmann, Susan E.; Polgreen, Philip M.] Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA. [Palmore, Tara N.] NIH, Warren Grant Magnusen Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. [Palmore, Tara N.; Bennett, John E.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Beekmann, SE (reprint author), Dept Internal Med, SW34-GH,200 Hawkins Dr, Iowa City, IA 52245 USA. EM susan-beekmann@uiowa.edu FU Intramural NIH HHS NR 10 TC 1 Z9 1 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2016 VL 37 IS 2 BP 226 EP 228 DI 10.1017/ice.2015.256 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA DC3WT UT WOS:000369150400019 PM 26503302 ER PT J AU Luby, M Warach, SJ Albers, GW Baron, JC Cognard, C Davalos, A Donnan, GA Fiebach, JB Fiehler, J Hacke, W Lansberg, MG Liebeskind, DS Mattle, HP Oppenheim, C Schellinger, PD Wardlaw, JM Wintermark, M AF Luby, Marie Warach, Steven J. Albers, Gregory W. Baron, Jean-Claude Cognard, Christophe Davalos, Antoni Donnan, Geoffrey A. Fiebach, Jochen B. Fiehler, Jens Hacke, Werner Lansberg, Maarten G. Liebeskind, David S. Mattle, Heinrich P. Oppenheim, Catherine Schellinger, Peter D. Wardlaw, Joanna M. Wintermark, Max CA STroke Imaging Res VISTA-Imaging Investigator TI Identification of imaging selection patterns in acute ischemic stroke patients and the influence on treatment and clinical trial enrollment decision making SO INTERNATIONAL JOURNAL OF STROKE LA English DT Article DE Computed Tomography scan; clinical trial; ischemic stroke; Magnetic Resonance Imaging; stroke; thrombolysis ID PERFUSION COMPUTED-TOMOGRAPHY; NONCONTRAST CT; INFARCT CORE; THROMBOLYSIS; PENUMBRA; DIFFUSION; DIAGNOSIS; MRI AB Background and Purpose The purpose of this study was to collect precise information on the typical imaging decisions given specific clinical acute stroke scenarios. Stroke centers worldwide were surveyed regarding typical imaging used to work up representative acute stroke patients, make treatment decisions, and willingness to enroll in clinical trials. Methods STroke Imaging Research and Virtual International Stroke Trials Archive-Imaging circulated an online survey of clinical case vignettes through its website, the websites of national professional societies from multiple countries as well as through email distribution lists from STroke Imaging Research and participating societies. Survey responders were asked to select the typical imaging work-up for each clinical vignette presented. Actual images were not presented to the survey responders. Instead, the survey then displayed several types of imaging findings offered by the imaging strategy, and the responders selected the appropriate therapy and whether to enroll into a clinical trial considering time from onset, clinical presentation, and imaging findings. A follow-up survey focusing on 6h from onset was conducted after the release of the positive endovascular trials. Results We received 548 responses from 35 countries including 282 individual centers; 78% of the centers originating from Australia, Brazil, France, Germany, Spain, United Kingdom, and United States. The specific onset windows presented influenced the type of imaging work-up selected more than the clinical scenario. Magnetic Resonance Imaging usage (27-28%) was substantial, in particular for wake-up stroke. Following the release of the positive trials, selection of perfusion imaging significantly increased for imaging strategy. Conclusions Usage of vascular or perfusion imaging by Computed Tomography or Magnetic Resonance Imaging beyond just parenchymal imaging was the primary work-up (62-87%) across all clinical vignettes and time windows. Perfusion imaging with Computed Tomography or Magnetic Resonance Imaging was associated with increased probability of enrollment into clinical trials for 0-3 h. Following the release of the positive endovascular trials, selection of endovascular only treatment for 6h increased across all clinical vignettes. C1 [Luby, Marie] NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Luby, Marie] UT Southwestern Med Ctr, Seton UT Clin Res Inst Austin, Dept Neurol & Neurotherapeut, Austin, TX USA. [Warach, Steven J.] Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA. [Albers, Gregory W.; Lansberg, Maarten G.; Wintermark, Max] Stanford Univ, Sch Med, Stanford, CA USA. [Baron, Jean-Claude] Ctr Hosp St Anne, Sorbonne Paris Cite, INSERM, U894, Paris, France. [Baron, Jean-Claude] Univ Cambridge, Dept Clin Neurosci, Cambridge, England. [Cognard, Christophe] Ctr Hosp Univ Toulouse, Toulouse, France. [Davalos, Antoni] Hosp Badalona Germans Trias & Pujol, Badalona, Spain. [Donnan, Geoffrey A.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia. [Fiebach, Jochen B.] Charite, Ctr Stroke Res Berlin, Acad Neuroradiol, D-13353 Berlin, Germany. [Fiehler, Jens] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Hacke, Werner] Heidelberg Univ, Dept Neurol, Heidelberg, Germany. [Liebeskind, David S.] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Mattle, Heinrich P.] Univ Bern, Inselspital, CH-3010 Bern, Switzerland. [Oppenheim, Catherine] Univ Paris 05, Sorbonne Paris Cite, Hop St Anne, INSERM,U894, Paris, France. [Schellinger, Peter D.] Johannes Wesling Med Ctr Minden, Minden, Germany. [Wardlaw, Joanna M.] Univ Edinburgh, Div Neuroimaging Sci, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland. [Wintermark, Max] CHU Vaudois, Dept Radiol, CH-1011 Lausanne, Switzerland. RP Luby, M (reprint author), NINDS, Stroke Diagnost & Therapeut Sect Stroke Branch, NIH, 10 Ctr Dr,Room B1D 733,MSC1063, Bethesda, MD 20892 USA. EM lubym@ninds.nih.gov OI Donnan, Geoffrey/0000-0001-6324-3403; baron, jean-claude/0000-0002-5264-2588 FU Seton/UT Southwestern Clinical Research Institute of Austin, Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Austin, TX, USA; National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Seton/UT Southwestern Clinical Research Institute of Austin, Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Austin, TX, USA and the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA. NR 16 TC 0 Z9 0 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1747-4930 EI 1747-4949 J9 INT J STROKE JI Int. J. Stroke PD FEB PY 2016 VL 11 IS 2 BP 180 EP 190 DI 10.1177/1747493015616634 PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DB7QC UT WOS:000368709600009 PM 26783309 ER PT J AU Jacobson, JM Zheng, L Wilson, CC Tebas, P Matining, RM Egan, MA Eldridge, J Landay, AL Clifford, DB Luetkemeyer, AF Tiu, J Martinez, AL Janik, J Spitz, TA Hural, J McElrath, J Frahm, N AF Jacobson, Jeffrey M. Zheng, Lu Wilson, Cara C. Tebas, Pablo Matining, Roy M. Egan, Michael A. Eldridge, John Landay, Alan L. Clifford, David B. Luetkemeyer, Anne F. Tiu, Jennifer Martinez, Ana L. Janik, Jennifer Spitz, Teresa A. Hural, John McElrath, Juliana Frahm, Nicole CA ACTG A5281 Protocol Team TI The Safety and Immunogenicity of an Interleukin-12-Enhanced Multiantigen DNA Vaccine Delivered by Electroporation for the Treatment of HIV-1 Infection SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; therapeutic vaccination; DNA vaccine; interleukin-12; electroporation ID T-CELL RESPONSES; CHRONIC VIRAL-INFECTION; IN-VIVO; TREATMENT INTERRUPTION; GENE-TRANSFER; ANTIGEN; IMMUNIZATION; MACAQUES; PLASMID; IDENTIFICATION AB Background:Therapeutic vaccination is being studied in eradication and functional cure strategies for HIV-1. The Profectus Biosciences multiantigen (MAG) HIV-1 DNA vaccine encodes HIV-1 Gag/Pol, Nef/Tat/Vif, and Envelope, and interleukin-12 (IL-12) and is delivered by electroporation combined with intramuscular injection (IM-EP).Methods:Sixty-two HIV-1-infected patients on antiretroviral therapy (plasma HIV-1 RNA levels 200 copies/mL; CD4(+) T-cell counts 500 cells/mm(3)) were randomly allocated 5:1 to receive vaccine or placebo. At weeks 0, 4, and 12, 4 consecutive cohorts received 3000 g HIV MAG pDNA with 0, 50, 250, or 1000 g of IL-12 pDNA by IM-EP. A fifth cohort received HIV MAG pDNA and 1000 g of IL-12 pDNA by standard IM injection.Results:CD4(+) T cells expressing IL-2 in response to Gag and Pol and interferon- responses to Gag, Pol, and Env increased from baseline to week 14 in the low-dose (50-g) IL-12 arm vs. placebo (P < 0.05; intracellular cytokine staining). The total increase in the IL-2-expressing CD4(+) T-cell responses to any antigen was also higher in the low-dose IL-12 arm vs. placebo (P = 0.04). Cytokine responses by CD8 T cells to HIV antigens were not increased in any vaccine arm relative to placebo.Conclusions:HIV-1 MAG/low-dose IL-12 DNA vaccine delivered by IM-EP augmented CD4(+) but not CD8(+) T-cell responses to multiple HIV-1 antigens. C1 [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Diseased & HIV Med, Philadelphia, PA 19104 USA. [Zheng, Lu; Matining, Roy M.] Harvard Univ, TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wilson, Cara C.] Univ Colorado, Div Infect Dis, Denver, CO 80202 USA. [Tebas, Pablo] Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. [Egan, Michael A.; Eldridge, John] Profectus BioSci Inc, Tarrytown, NY USA. [Landay, Alan L.] Rush Univ, Sch Med, Dept Immunol & Microbiol, Chicago, IL 60612 USA. [Clifford, David B.; Spitz, Teresa A.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Luetkemeyer, Anne F.] Univ Calif San Francisco, Div HIV AIDS, San Francisco, CA 94143 USA. [Tiu, Jennifer] Social & Sci Syst Inc, Silver Spring, MD USA. [Martinez, Ana L.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Janik, Jennifer] Frontier Sci, Amherst, NY USA. [Hural, John; McElrath, Juliana; Frahm, Nicole] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Hural, John; McElrath, Juliana; Frahm, Nicole] Univ Washington, Seattle, WA 98195 USA. RP Jacobson, JM (reprint author), Drexel Univ, Coll Med, 245 N 15th St,MS 461, Philadelphia, PA 19102 USA. EM jeffrey.jacobson@drexelmed.edu FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1 AI068634, UM1 AI068636, UM1 AI106701]; NIAID [N01 AI80062C]; UCSF AIDS CRS ACTG CTU [UM1 AI069496]; Washington University in St. Louis CRS ACTG CTU Grant [U01 AI69439]; Penn Therapeutics CRS ACTG CTU Grant [UM1 AI069534-08]; CFAR Grant [5-P30-AI-045008-15]; Stanford University ACTG CTU Grant [AI069556]; UCLA CARE Center CRS ACTG CTU Grant [A1069424]; CTRC Grant [UL1 TR000124]; University of Rochester/Trillium Health ACTG CTU Grant [2UM1AI069511-08]; CRC Grant [UL1 RR024160]; University of Pittsburgh CRS ACTG CTU Grant [UM1 AI069494]; Massachusetts General Hospital (MGH) CRS ACTG CTU Grant [2UM1AI069412-08]; University of Colorado Hospital CRS ACTG CTU Grant [2UM1AI069432, UL1 TR001082]; HART CRS ACTG CTU Grant [2 UM1 AI069503-08, 2 UM1 AI068636-08]; Brigham and Women's Hospital CRS ACTG CTU Grant [2UM1AI069412-08]; University of Cincinnati CRS ACTG CTU Grant [2UM1AI069501]; Merck FX Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers UM1 AI068634, UM1 AI068636, and UM1 AI106701 and NIAID contract number N01 AI80062C, entitled "Therapeutic Immunization Against HIV with Adjuvant-Enhanced DNA and Multi-Epitope Peptide Vaccines" awarded to Profectus Biosciences, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ACTG Site Grant Numbers: UCSF AIDS CRS (Site 801) ACTG CTU Grant UM1 AI069496; Washington University in St. Louis CRS (Site 2101) ACTG CTU Grant U01 AI69439; Penn Therapeutics CRS (Site 6201) ACTG CTU Grant UM1 AI069534-08; CFAR Grant 5-P30-AI-045008-15; Stanford University (Site 501) ACTG CTU Grant AI069556; UCLA CARE Center CRS (Site 601) ACTG CTU Grant A1069424; CTRC Grant UL1 TR000124; University of Rochester/Trillium Health (Site 1101/Site 1108) ACTG CTU Grant 2UM1AI069511-08; CRC Grant UL1 RR024160; University of Pittsburgh CRS (Site 1001) ACTG CTU Grant UM1 AI069494; Massachusetts General Hospital (MGH) CRS (Site 101) ACTG CTU Grant 2UM1AI069412-08; University of Colorado Hospital CRS (Site 6101) ACTG CTU Grant 2UM1AI069432; UL1 TR001082; HART CRS (Site 31473) ACTG CTU Grant 2 UM1 AI069503-08 and 2 UM1 AI068636-08; Brigham and Women's Hospital CRS (Site 107) ACTG CTU Grant 2UM1AI069412-08; University of Cincinnati CRS (Site 2401) ACTG CTU Grant 2UM1AI069501.; M.A.E. is an employee of Profectus Biosciences (Tarrytown, NY). J.E. is an employee of Profectus Biosciences (Tarrytown, NY). J.M.J was a paid consultant to Merck. P.T. was a paid consultant to Merck and on the vaccine adjudication committee for Glaxo. DC has received support for consulting/advisory boards from Sanofi, Genentech, Quintiles, Inhibikase, BMS, GlaxoSmithKline, Millennium, Biogen Idec, Amgen, Pfizer, AstraZeneca, Cytheris, ARISE Biopharma and Merck. The remaining authors have no conflicts of interest to disclose. NR 31 TC 0 Z9 0 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD FEB 1 PY 2016 VL 71 IS 2 BP 163 EP 171 DI 10.1097/QAI.0000000000000830 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DB8YU UT WOS:000368803900006 PM 26761518 ER PT J AU Kerzerho, J McIlvaine, EJ Anthony, P Mack, WJ Wang, CH Frederick, T Operskalski, E Chen, Z Al-Harthi, L Landay, A Young, MA Tien, PC Augenbraun, M Strickler, HD Akbari, O Golub, ET Sharp, GB Kovacs, A AF Kerzerho, Jerome McIlvaine, Elizabeth J. Anthony, Patricia Mack, Wendy J. Wang, Chia-Hao Frederick, Toni Operskalski, Eva Chen, Zhi Al-Harthi, Lena Landay, Alan Young, Mary A. Tien, Phyllis C. Augenbraun, Michael Strickler, Howard D. Akbari, Omid Golub, Elizabeth T. Sharp, Gerald B. Kovacs, Andrea TI Impact of Hepatitis C Virus on the Circulating Levels of IL-7 in HIV-1 Coinfected Women SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE IL-7 level; HIV and HCV coinfection; HAART ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL HOMEOSTASIS; DISEASE PROGRESSION; INFECTED PATIENTS; HCV COINFECTION; INTERLEUKIN-7; COHORT; NAIVE; RECOVERY AB Objectives:Hepatitis C virus (HCV) infection causes an alteration in T-cell maturation and activation in patients coinfected with human immunodeficiency virus (HIV). Because interleukin 7 (IL-7) is a major cytokine controlling T-cell homeostasis, we analyzed the potential influence of HCV coinfection on circulating IL-7 levels in HIV-infected women before and after highly active antiretroviral therapy (HAART).Design and Methods:This prospective study included 56 HIV monoinfected, 55 HIV/HCV coinfected without HCV viremia, 132 HIV/HCV coinfected with HCV viremia, and 61 HIV/HCV-uninfected women for whom plasma levels of IL-7 were determined by enzyme-linked immunosorbent assay at 1 or more follow-up visits before and after HAART. Cross-sectional analyses of the associations between plasma IL-7 levels and HCV infection, demographic, clinical, and immunologic characteristics were evaluated using univariate and multivariate linear regression models before and after HAART.Results:In multivariate models, IL-7 levels were significantly higher in coinfected HCV viremic women than in HIV monoinfected women (multiplicative effect = 1.48; 95% confidence interval: 1.01 to 2.16; P = 0.04) before HAART, but were similar between these two groups among women after HAART. In addition to HCV viremia, higher IL-7 levels were associated with older age (P = 0.02), lower CD4(+) T-cell count (P = 0.0007), and higher natural killer T-cell count (P = 0.02) in women before HAART. Among HAART-treated women, only lower CD4(+) T-cell count was significantly associated with IL-7 level (P = 0.006).Conclusions:Our data demonstrate that in HIV-infected women, circulating levels of IL-7 are strongly associated with CD4(+) T-cell depletion both before and after HAART. Our data also demonstrate that HCV viremia increases circulating IL-7 levels before HAART but not after HAART in coinfected women. This suggests that the effect of HCV on lymphopenia is abrogated by HAART. C1 [Kerzerho, Jerome; Akbari, Omid] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [McIlvaine, Elizabeth J.; Mack, Wendy J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Anthony, Patricia; Wang, Chia-Hao; Frederick, Toni; Operskalski, Eva; Chen, Zhi; Kovacs, Andrea] Univ So Calif, Keck Sch Med, Maternal Child & Adolescent Ctr Infect Dis & Viro, Los Angeles, CA 90033 USA. [Al-Harthi, Lena; Landay, Alan] Rush Univ, Med Ctr, Dept Immunol, Microbiol, Chicago, IL 60612 USA. [Young, Mary A.] Georgetown Univ, Div Infect Dis, Washington, DC USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.] San Francisco Vet Affair Med Ctr, San Francisco, CA USA. [Augenbraun, Michael] SUNY Downstate Coll Med, Dept Med, Brooklyn, NY USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Golub, Elizabeth T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Sharp, Gerald B.] NIAID, Div Aids, Bethesda, MD 20892 USA. RP Kovacs, A (reprint author), USC, Keck Sch Med, Maternal Child & Adolescent Adult Ctr Infect Dis, 1000 S Fremont Ave,10220 A10N,Unit 62, Alhambra, CA 91803 USA. EM akovacs@usc.edu FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590, AI052065, R01, R56]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI Grant) [UL1 RR024131] FX Supported by the National Institute of Allergy and Infectious Diseases Grant AI052065 (A.K.) (R01 and R56). Data in this article were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (M.A.Y.); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 44 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD FEB 1 PY 2016 VL 71 IS 2 BP 172 EP 180 DI 10.1097/QAI.0000000000000832 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DB8YU UT WOS:000368803900007 PM 26761519 ER PT J AU Jitmuang, A Panackal, AA Williamson, PR Bennett, JE Dekker, JP Zelazny, AM AF Jitmuang, Anupop Panackal, Anil A. Williamson, Peter R. Bennett, John E. Dekker, John P. Zelazny, Adrian M. TI Performance of the Cryptococcal Antigen Lateral Flow Assay in Non-HIV-Related Cryptococcosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CEREBROSPINAL-FLUID; DIAGNOSIS; IMMUNOASSAY; MENINGITIS; SERUM AB The cryptococcal antigen lateral flow assay (CrAg LFA) was evaluated for the diagnosis of cryptococcosis in HIV-negative patients. The sensitivity was excellent, suggesting that this assay can replace conventional testing based on latex agglutination (LA). CrAg LFA and LA titers were correlated but were not directly comparable, with implications for conversion between assays. C1 [Jitmuang, Anupop; Dekker, John P.; Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. [Panackal, Anil A.; Williamson, Peter R.; Bennett, John E.] NIAID, Ctr Clin, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Jitmuang, Anupop] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med, Bangkok 10700, Thailand. RP Zelazny, AM (reprint author), NIH, Microbiol Serv, Dept Lab Med, Bldg 10, Bethesda, MD 20892 USA. EM azelazny@cc.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); Clinical Center, National Institutes of Health (NIH) FX The Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID) and the Clinical Center, National Institutes of Health (NIH) provided funding. NR 12 TC 2 Z9 2 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2016 VL 54 IS 2 BP 460 EP 463 DI 10.1128/JCM.02223-15 PG 4 WC Microbiology SC Microbiology GA DC3YD UT WOS:000369155100034 PM 26607986 ER PT J AU Kielczewski, JL Horai, R Jittayasothorn, Y Chan, CC Caspi, RR AF Kielczewski, Jennifer L. Horai, Reiko Jittayasothorn, Yingyos Chan, Chi-Chao Caspi, Rachel R. TI Tertiary Lymphoid Tissue Forms in Retinas of Mice with Spontaneous Autoimmune Uveitis and Has Consequences on Visual Function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; T-CELLS; B-CELLS; SJOGRENS-SYNDROME; GERMINAL-CENTERS; TH17 CELLS; DISEASE; INFLAMMATION; ACTIVATION; MICROGLIA AB During chronic inflammation, tertiary lymphoid tissue (TLT) can form within an inflamed organ, including the CNS. However, little is known about TLT formation in the neuroretina. In a novel spontaneous autoimmune mouse model of uveitis (R161H), we identified well-organized lymphoid aggregates in the retina and examined them for TLT characteristics. Presence of immune cells, tissue specific markers, and gene expression patterns typically associated with germinal centers and T follicular helper cells were examined using immunohistochemistry and gene analysis of laser capture microdissected retina. Our data revealed the retinal lymphoid structures contained CD4(+) T cells and B cells in well-defined zonal areas that expressed classic germinal center markers, peanut lectin (agglutinin) and GL-7. Gene expression analysis showed upregulation of T follicular helper cell markers, most notably CXCR5 and its ligand CXCL13, and immunohistochemical analysis confirmed CXCR5 expression, typically associated with CD4+ T follicular helper cells. Highly organized stromal cell networks, a hallmark of organized lymphoid tissue, were also present. Positive staining for phospho-Zap70 in retina-specific T cells indicated CD4+ T cells were being activated within these lymphoid structures. CD138(+)/B220(+) plasma cells were detected, suggesting the retinal lymphoid aggregates give rise to functional germinal centers, which produce Abs. Interestingly, eyes with lymphoid aggregates exhibited lower inflammatory scores by fundus examination and a slower initial rate of loss of visual function by electroretinography, compared with eyes without these structures. Our findings suggest that the lymphoid aggregates in the retina of R161H mice represent organized TLT, which impact the course of chronic uveitis. C1 [Kielczewski, Jennifer L.; Horai, Reiko; Jittayasothorn, Yingyos; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, NIH, 10 Ctr Dr,10N222, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10N222, Bethesda, MD 20892 USA. EM caspir@mail.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU National Institutes of Health Intramural Research Program in National Eye Institute [EY000184] FX This work was supported by the National Institutes of Health Intramural Research Program in National Eye Institute Project EY000184. NR 48 TC 5 Z9 5 U1 2 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2016 VL 196 IS 3 BP 1013 EP 1025 DI 10.4049/jimmunol.1501570 PG 13 WC Immunology SC Immunology GA DB6AX UT WOS:000368596600010 PM 26712943 ER PT J AU Jacek, E Tang, KS Komorowski, L Ajamian, M Probst, C Stevenson, B Wormser, GP Marques, AR Alaedini, A AF Jacek, Elzbieta Tang, Kevin S. Komorowski, Lars Ajamian, Mary Probst, Christian Stevenson, Brian Wormser, Gary P. Marques, Adriana R. Alaedini, Armin TI Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; IMMUNODOMINANT CONSERVED REGION; VARIABLE SURFACE-ANTIGEN; PERSISTENT SYMPTOMS; ANTIBIOTIC-TREATMENT; ANTIBODY-RESPONSE; HISTORY; PEPTIDE; REACTIVITY; RECOMBINATION AB Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms. C1 [Jacek, Elzbieta; Tang, Kevin S.; Ajamian, Mary; Alaedini, Armin] Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,Room 937, New York, NY 10032 USA. [Komorowski, Lars; Probst, Christian] Euroimmun AG, Inst Expt Immunol, D-23560 Lubeck, Germany. [Stevenson, Brian] Univ Kentucky, Coll Med, Lexington, KY 40536 USA. [Wormser, Gary P.] New York Med Coll, Dept Med, Div Infect Dis, Valhalla, NY 10595 USA. [Marques, Adriana R.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20814 USA. RP Alaedini, A (reprint author), Columbia Univ, Dept Med, Med Ctr, 1130 St Nicholas Ave,Room 937, New York, NY 10032 USA. EM aa819@columbia.edu OI Ajamian, Mary/0000-0001-5819-7078 FU National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R56AI093763, U54AI057158]; Lyme Research Alliance; Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health FX This work was supported by National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grants R56AI093763 (to A.A.) and U54AI057158 (to AA.; principal investigator of the Center of Excellence Grant, W.I. Lipkin), the Lyme Research Alliance (to AA.), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (to A.R.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 3 Z9 3 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2016 VL 196 IS 3 BP 1036 EP 1043 DI 10.4049/jimmunol.1501861 PG 8 WC Immunology SC Immunology GA DB6AX UT WOS:000368596600012 PM 26718339 ER PT J AU St Louis, D Romero, R Plazyo, O Arenas-Hernandez, M Panaitescu, B Xu, Y Milovic, T Xu, ZG Bhatti, G Mi, QS Drewlo, S Tarca, AL Hassan, SS Gomez-Lopez, N AF St Louis, Derek Romero, Roberto Plazyo, Olesya Arenas-Hernandez, Marcia Panaitescu, Bogdan Xu, Yi Milovic, Tatjana Xu, Zhonghui Bhatti, Gaurav Mi, Qing-Sheng Drewlo, Sascha Tarca, Adi L. Hassan, Sonia S. Gomez-Lopez, Nardhy TI Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MONOCYTE CHEMOTACTIC PROTEIN-1; TUMOR-NECROSIS-FACTOR; AMNIOTIC-FLUID INTERLEUKIN-6; HUMAN GESTATIONAL TISSUES; PRODUCE INTERFERON-GAMMA; ANTIGEN-PRESENTING CELLS; MURINE DENDRITIC CELLS; HUMAN TERM PARTURITION; INNATE IMMUNE-SYSTEM; HUMAN T-LYMPHOCYTES AB Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. Although intra-amniotic infection is a recognized cause of spontaneous preterm labor, the noninfection-related etiologies are poorly understood. In this article, we demonstrated that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of a-galactosylceramide (alpha-GalCer) induced late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent alpha-GalCer induced late PTB had bradycardia and died shortly after delivery. Yet, administration of a-GalCer in the second trimester did not cause pregnancy loss. Peroxisome proliferator activated receptor (PPAR)gamma activation, through rosiglitazone treatment, reduced the rate of a-GalCer induced late PTB and improved neonatal survival. Administration of alpha-GalCer in the third trimester suppressed PPAR gamma activation, as shown by the downregulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of alpha-GalCer in the third trimester induced an increase in the activation of conventional CD4(+) T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils, and mature dendritic cells to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of alpha-GalCer also upregulated the expression of inflammatory genes at the maternal fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with noninfection-related preterm labor/birth. Collectively, these results demonstrate that iNKT cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPAR gamma pathway has potential as a target for prevention of this syndrome. C1 [St Louis, Derek; Plazyo, Olesya; Arenas-Hernandez, Marcia; Milovic, Tatjana; Xu, Zhonghui; Bhatti, Gaurav; Drewlo, Sascha; Tarca, Adi L.; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [St Louis, Derek; Romero, Roberto; Plazyo, Olesya; Arenas-Hernandez, Marcia; Xu, Yi; Xu, Zhonghui; Bhatti, Gaurav; Tarca, Adi L.; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept HHS, Bethesda, MD 20892 USA. [St Louis, Derek; Romero, Roberto; Plazyo, Olesya; Arenas-Hernandez, Marcia; Xu, Yi; Xu, Zhonghui; Bhatti, Gaurav; Tarca, Adi L.; Hassan, Sonia S.; Gomez-Lopez, Nardhy] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, Program Perinatal Res & Obstet, Div Intramural Res,NIH,US Dept HHS, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48825 USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Panaitescu, Bogdan] Wayne State Univ, Sch Med, Dept Med, Div Neonatol, Detroit, MI 48201 USA. [Mi, Qing-Sheng] Henry Ford Hlth Syst, Program Immunol, Detroit, MI 48202 USA. [Mi, Qing-Sheng] Henry Ford Hlth Syst, Dept Dermatol, Detroit, MI 48202 USA. [Mi, Qing-Sheng; Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. RP Gomez-Lopez, N (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, 275 E Hancock St, Detroit, MI 48201 USA. EM nardhy.gomez-lopez@wayne.edu RI Gomez-Lopez, Nardhy/R-7664-2016 OI Gomez-Lopez, Nardhy/0000-0002-3406-5262 FU Wayne State University Perinatal Initiative in Maternal, Perinatal, and Child Health; Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services; National Institutes of Health/National Institute of Allergy and Infectious Diseases [1R56AI119041] FX This work was supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal, and Child Health, as well as by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services. Q.-S.M. was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant 1R56AI119041. NR 156 TC 3 Z9 3 U1 3 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2016 VL 196 IS 3 BP 1044 EP 1059 DI 10.4049/jimmunol.1501962 PG 16 WC Immunology SC Immunology GA DB6AX UT WOS:000368596600013 PM 26740111 ER PT J AU Jiang, H Promchan, K Lin, BR Lockett, S Chen, D Marshall, H Badralmaa, Y Natarajan, V AF Jiang, Hong Promchan, Kanyarat Lin, Bor-Ruei Lockett, Stephen Chen, De Marshall, Heather Badralmaa, Yunden Natarajan, Ven TI LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4(+) T Cell Activation Enhances IL-5 Production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOLOGICAL SYNAPSE; X-RECEPTOR; CYTOKINE PRODUCTION; IMMUNE-RESPONSE; GENE-EXPRESSION; DENDRITIC CELLS; TH2 DEVELOPMENT; DIFFERENTIATION; TRAFFICKING; PATHWAY AB Retinoic acids, which are metabolites of vitamin A, have been shown to be involved in multiple T cell effector responses through their binding to the retinoic acid receptor, a ligand-activated transcription factor. Because the molecular mechanism of regulation by retinoic acid is still not fully uncovered, we investigated the gene expression profile of all-trans retinoic acid (ATRA) treated human CD4(+) T cells. Leucine zipper transcription factor-like 1 (LZTFL1) was upregulated by ATRA in a dose- and time-dependent manner. The expression of LZTFL1 depended on both ATRA and TCR signaling. LZTFL1 accumulated in the plasma membrane compartment of human CD4(+) T cells, and, during immunological synapse formation, it transiently redistributed to the T cell and APC contact zone, indicating its role in T cell activation. Live-cell imaging demonstrates that at the initial stage of immunological synapse formation, LZTFL1 is concentrated at the APC contact site, and, during later stages, it relocates to the distal pole. Knockdown of LZTFL1 reduced the basal- and ATRA-induced levels of IL-5 in CD4(+) T cells, and overexpression of LZTFL1 enhanced the TCR-mediated NFAT signaling, suggesting that LZTFL1 is an important regulator of ATRA-induced T cell response. Together, these data indicate that LZTFL1 modulates T cell activation and IL-5 levels. C1 [Jiang, Hong; Promchan, Kanyarat; Lin, Bor-Ruei; Marshall, Heather; Badralmaa, Yunden; Natarajan, Ven] Frederick Natl Lab Canc Res, Leidos Biomed Res, Mol Cell Biol Lab, Frederick, MD 21702 USA. [Lockett, Stephen; Chen, De] Frederick Natl Lab Canc Res, Opt Microscopy & Anal Lab, Leidos Biomed Res, Frederick, MD 21702 USA. RP Natarajan, V (reprint author), Frederick Natl Lab Canc Res, Leidos Biomed Res, Bldg 550,Room 120, Frederick, MD 21702 USA. EM vnatarajan@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This work was supported in whole or in part by National Cancer Institute, National Institutes of Health Contract HHSN261200800001E. This work was also supported by the National Institute of Allergy and Infectious Diseases. NR 66 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2016 VL 196 IS 3 BP 1081 EP 1090 DI 10.4049/jimmunol.1500719 PG 10 WC Immunology SC Immunology GA DB6AX UT WOS:000368596600016 PM 26700766 ER PT J AU Huston, SM Ngamskulrungroj, P Xiang, RF Ogbomo, H Stack, D Li, SS Timm-McCann, M Kyei, SK Oykhman, P Kwon-Chung, KJ Mody, CH AF Huston, Shaunna M. Ngamskulrungroj, Popchai Xiang, Richard F. Ogbomo, Henry Stack, Danuta Li, Shu Shun Timm-McCann, Martina Kyei, Stephen K. Oykhman, Paul Kwon-Chung, Kyung J. Mody, Christopher H. TI Cryptococcus gattii Capsule Blocks Surface Recognition Required for Dendritic Cell Maturation Independent of Internalization and Antigen Processing SO JOURNAL OF IMMUNOLOGY LA English DT Article ID POLYSACCHARIDE CAPSULE; INFLAMMATORY RESPONSE; COCCIDIOIDES-IMMITIS; MACROPHAGE FUNCTIONS; T-LYMPHOCYTES; UNITED-STATES; NEOFORMANS; VIRULENCE; GENE; PHAGOCYTOSIS AB Cryptococcus gattii is an emerging fungal pathogen on the west coast of Canada and the United States that causes a potentially fatal infection in otherwise healthy individuals. In previous investigations of the mechanisms by which C. gattii might subvert cellmediated immunity, we found that C. gattii failed to induce dendritic cell (DC) maturation, leading to defective T cell responses. However, the virulence factor and the mechanisms of evasion of DC maturation remain unknown. The cryptococcal polysaccharide capsule is a leading candidate because of its antiphagocytic properties. Consequently, we asked if the capsule of C. gattii was involved in evasion of DC maturation. We constructed an acapsular strain of C. gattii through CAP59 gene deletion by homologous integration. Encapsulated C. gattii failed to induce human monocyte-derived DC maturation and T cell proliferation, whereas the acapsular mutant induced both processes. Surprisingly, encapsulation impaired DC maturation independent of its effect on phagocytosis. Indeed, DC maturation required extracellular receptor signaling that was dependent on TNF-alpha and p38 MAPK, but not ERK activation, and the cryptococcal capsule blocked this extracellular recognition. Although the capsule impaired phagocytosis that led to pH-dependent serine-, threonine-, and cysteine-sensitive protease-dependent Ag processing, it was insufficient to impair T cell responses. In summary, C. gattii affects two independent processes, leading to DC maturation and Ag processing. The polysaccharide capsule masked extracellular detection and reduced phagocytosis that was required for DC maturation and Ag processing, respectively. However, the T cell response was fully restored by inducing DC maturation. C1 [Huston, Shaunna M.; Xiang, Richard F.; Ogbomo, Henry; Stack, Danuta; Li, Shu Shun; Timm-McCann, Martina; Kyei, Stephen K.; Oykhman, Paul; Mody, Christopher H.] Univ Calgary, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada. [Ngamskulrungroj, Popchai] Mahidol Univ, Siriraj Hosp, Dept Microbiol, Fac Med, Bangkok 10700, Thailand. [Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Mody, Christopher H.] Univ Calgary, Dept Internal Med, Calgary, AB T2N 4N1, Canada. RP Mody, CH (reprint author), Univ Calgary, Hlth Res Innovat Ctr, Room 4AA14,3330 Hosp Dr Northwest, Calgary, AB T2N 4N1, Canada. EM cmody@ucalgary.ca OI Mody, Christopher H./0000-0001-7264-3679 FU Lung Association-Alberta & Northwest Territories; Queen Elizabeth II scholarships; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by grants from The Lung Association-Alberta & Northwest Territories (to C.H.M.). C.H.M. is the Jessie Bowden Lloyd Professor of Immunology. S.M.H. is supported by a studentship from the Lung Association-Alberta & Northwest Territories and Queen Elizabeth II scholarships. P.N. and K.J.K.-C. were supported by funds from an intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 58 TC 0 Z9 0 U1 4 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2016 VL 196 IS 3 BP 1259 EP 1271 DI 10.4049/jimmunol.1501089 PG 13 WC Immunology SC Immunology GA DB6AX UT WOS:000368596600033 PM 26740109 ER PT J AU Matsuura, K Tanaka, Y AF Matsuura, Kentaro Tanaka, Yasuhito TI Host genetic variants influencing the clinical course of hepatitis C virus infection SO JOURNAL OF MEDICAL VIROLOGY LA English DT Review DE HCV; GWAS; spontaneous clearance; fibrosis; HCC ID GENOME-WIDE ASSOCIATION; GENOTYPE 1 INFECTION; ACUTE HCV INFECTION; SINGLE-NUCLEOTIDE POLYMORPHISMS; AMINO-ACID SUBSTITUTION; GROWTH-FACTOR GENE; NON-B-HEPATITIS; HEPATOCELLULAR-CARCINOMA; SPONTANEOUS CLEARANCE; FIBROSIS PROGRESSION AB The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma. (c) 2015 Wiley Periodicals, Inc. C1 [Matsuura, Kentaro; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Nagoya, Aichi, Japan. [Matsuura, Kentaro; Tanaka, Yasuhito] Nagoya City Univ, Grad Sch Med Sci, Liver Unit, Nagoya, Aichi, Japan. [Matsuura, Kentaro] Nagoya City Univ, Grad Sch Med Sci, Dept Gastroenterol & Metab, Nagoya, Aichi, Japan. [Matsuura, Kentaro] NIH, Dept Transfus Med, Clin CenterInfect Dis & Immunogenet Sect, Bethesda, MD 20892 USA. RP Tanaka, Y (reprint author), Nagoya City Univ, Grad Sch Med Sci, Dept Virol, Liver Unit,Kawasumi Ku, Nagoya, Aichi 4678601, Japan. EM ytanaka@med.nagoya-cu.ac.jp FU Ministry of Health, Labor, and Welfare of Japan [H25-kanen-ippan-005]; Uehara Memorial Foundation FX Grant sponsor: Ministry of Health, Labor, and Welfare of Japan; Grant number: H25-kanen-ippan-005; Grant sponsor: Uehara Memorial Foundation NR 95 TC 3 Z9 3 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0146-6615 EI 1096-9071 J9 J MED VIROL JI J. Med. Virol. PD FEB PY 2016 VL 88 IS 2 BP 185 EP 195 DI 10.1002/jmv.24334 PG 11 WC Virology SC Virology GA DB8BD UT WOS:000368740500001 PM 26211651 ER PT J AU Suhre, K Schwartz, JE Sharma, VK Chen, QY Lee, JR Muthukunnar, T Dadhania, DM Ding, RC Lkle, DN Bridges, ND Williams, NM Kastenmuller, G Karoly, ED Mohney, RP Abecassis, M Friedewald, J Knechtle, SJ Becker, YT Samstein, B Shaked, A Gross, SS Suthanthiran, M AF Suhre, Karsten Schwartz, Joseph E. Sharma, Vijay K. Chen, Qiuying Lee, John R. Muthukunnar, Thangamani Dadhania, Darshana M. Ding, Ruchuang Lkle, David N. Bridges, Nancy D. Williams, Nikki M. Kastenmueller, Gabi Karoly, Edward D. Mohney, Robert P. Abecassis, Michael Friedewald, John Knechtle, Stuart J. Becker, Yolanda T. Samstein, Benjamin Shaked, Abraham Gross, Steven S. Suthanthiran, Manikkam TI Urine Metabolite Profiles Predictive of Human Kidney Allograft Status SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID GENERAL-POPULATION; METABOLOMICS; REJECTION; TRANSPLANTATION; INHIBITION; BIOMARKER AB Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3 epsilon mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy. C1 [Suhre, Karsten] Weill Cornell Med Coll Qatar, Dept Physiol & Biophys, Doha, Qatar. [Suhre, Karsten; Kastenmueller, Gabi] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, Neuherberg, Germany. [Schwartz, Joseph E.] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. [Schwartz, Joseph E.; Sharma, Vijay K.; Lee, John R.; Muthukunnar, Thangamani; Dadhania, Darshana M.; Ding, Ruchuang; Suthanthiran, Manikkam] Weill Cornell Med Ctr, New York Presbyterian Hosp, Dept Med, Div Nephrol & Hypertens, New York, NY USA. [Schwartz, Joseph E.; Sharma, Vijay K.; Lee, John R.; Muthukunnar, Thangamani; Dadhania, Darshana M.; Ding, Ruchuang; Suthanthiran, Manikkam] Weill Cornell Med Ctr, New York Presbyterian Hosp, Dept Transplantat Med, Div Nephrol & Hypertens, New York, NY USA. [Chen, Qiuying; Gross, Steven S.] Weill Cornell Coll Med, Dept Pharmacol, New York, NY USA. [Lkle, David N.] Rho Fed Syst, Chapel Hill, NC USA. [Bridges, Nancy D.; Williams, Nikki M.] NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Karoly, Edward D.; Mohney, Robert P.] Metabolon Inc, Durham, NC USA. [Abecassis, Michael] Northwestern Univ, Feinberg Sch Med, Div Surg Organ Transplantat, Chicago, IL 60611 USA. [Friedewald, John] Northwestern Univ, Feinberg Sch Med, Div Nephrol Organ Transplantat, Chicago, IL 60611 USA. [Knechtle, Stuart J.; Becker, Yolanda T.] Univ Wisconsin Hosp & Clin, Dept Surg, Div Surg, Madison, WI 53792 USA. [Samstein, Benjamin] Columbia Univ Coll Phys & Surg, Dept Surg, Div Transplantat, 630 W 168th St, New York, NY 10032 USA. [Shaked, Abraham] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. RP Suthanthiran, M (reprint author), Med Coll Weill Cornell, Div Nephrol & Hypertens, Dept Med, 525 E 68th St,Box 3, New York, NY 10065 USA. EM msuthan@med.cornell.edu OI Suhre, Karsten/0000-0001-9638-3912; Friedewald, John/0000-0002-9344-9928 FU Biomedical Research Program funds at Weill Cornell Medical College in Qatar; Qatar Foundation; National Institutes of Health [U01-AI63589, R37-AI051652, R37-HL087062]; Clinical and Translational Science Center [ULI-RR024996]; National Institutes of Diabetic and Digestive and Kidney Diseases [K08-DK087824]; Weill Cornell Clinical and Translational Science Center from the National Center for Advancing Translational Sciences [KL2-TR000458] FX This work was supported in part by Biomedical Research Program funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation, U01-AI63589, R37-AI051652 and R37-HL087062 from the National Institutes of Health, and a Clinical and Translational Science Center award (ULI-RR024996) to Weill Cornell Medical College.; Dr. Thangamani Muthukumar is a recipient of a K08-DK087824 from the National Institutes of Diabetic and Digestive and Kidney Diseases and Dr. John Lee is a recipient of a KL2 Scholars Award from the Weill Cornell Clinical and Translational Science Center (KL2-TR000458 from the National Center for Advancing Translational Sciences). NR 30 TC 5 Z9 5 U1 2 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2016 VL 27 IS 2 BP 626 EP 636 DI 10.1681/ASN.2015010107 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA DC1DS UT WOS:000368957600031 PM 26047788 ER PT J AU Kinloch, NN MacMillan, DR Le, AQ Cotton, LA Bangsberg, DR Buchbinder, S Carrington, M Fuchs, J Harrigan, PR Koblin, B Kushel, M Markowitz, M Mayer, K Milloy, MJ Schechter, MT Wagner, T Walker, BD Carlson, JM Poon, AFY Brumme, ZL AF Kinloch, Natalie N. MacMillan, Daniel R. Le, Anh Q. Cotton, Laura A. Bangsberg, David R. Buchbinder, Susan Carrington, Mary Fuchs, Jonathan Harrigan, P. Richard Koblin, Beryl Kushel, Margot Markowitz, Martin Mayer, Kenneth Milloy, M. J. Schechter, Martin T. Wagner, Theresa Walker, Bruce D. Carlson, Jonathan M. Poon, Art F. Y. Brumme, Zabrina L. TI Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE ESCAPE; SAN-FRANCISCO; CLASS-I; VANCOUVER LYMPHADENOPATHY; CELL RESPONSES; PHYLOGENETIC ANALYSIS; DISEASE PROGRESSION; HOMOSEXUAL-MEN; VIRAL-LOAD AB Human leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average similar to 2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era. C1 [Kinloch, Natalie N.; MacMillan, Daniel R.; Le, Anh Q.; Cotton, Laura A.; Poon, Art F. Y.; Brumme, Zabrina L.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bangsberg, David R.; Mayer, Kenneth] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Buchbinder, Susan; Fuchs, Jonathan; Wagner, Theresa] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Buchbinder, Susan; Fuchs, Jonathan; Kushel, Margot] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Carrington, Mary; Walker, Bruce D.] Ragon Inst Massachusetts Gen Hosp MIT & Harvard U, Cambridge, MA USA. [Harrigan, P. Richard; Milloy, M. J.; Poon, Art F. Y.; Brumme, Zabrina L.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Harrigan, P. Richard; Milloy, M. J.; Schechter, Martin T.; Poon, Art F. Y.] Univ British Columbia, Fac Med, Vancouver, BC, Canada. [Koblin, Beryl] New York Blood Ctr, New York, NY 10021 USA. [Markowitz, Martin] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Mayer, Kenneth] Fenway Community Hlth, Boston, MA USA. [Carlson, Jonathan M.] Microsoft Res, Seattle, WA USA. RP Brumme, ZL (reprint author), Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada.; Brumme, ZL (reprint author), British Columbia Ctr Excellence HIV AIDS, Vancouver, BC, Canada. EM zbrumme@sfu.ca FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Laboratory for Cancer Research; Gouvernement du Canada \ Canadian Institutes of Health Research (CIHR) [MOP-93536, HOP-115700]; Michael Smith Foundation for Health Research (MSFHR) FX Frederick National Laboratory for Cancer Research provided funding to Mary Carrington under grant number HHSN261200800001E. Intramural Research Program of the NIH, Frederick National Laboratory for Cancer Research provided funding to Mary Carrington. Gouvernement du Canada vertical bar Canadian Institutes of Health Research (CIHR) provided funding to Natalie N. Kinloch, Anh Q. Le, Art F. Y. Poon, Zabrina L. Brumme. Michael Smith Foundation for Health Research (MSFHR) provided funding to Art F. Y. Poon and Zabrina L. Brumme. Gouvernement du Canada vertical bar Canadian Institutes of Health Research (CIHR) provided funding to Zabrina L. Brumme under grant number MOP-93536. Gouvernement du Canada vertical bar Canadian Institutes of Health Research (CIHR) provided funding to Art F. Y. Poon and Zabrina L. Brumme under grant number HOP-115700. NR 81 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 3 BP 1244 EP 1258 DI 10.1128/JVI.02353-15 PG 15 WC Virology SC Virology GA DC3WW UT WOS:000369150800008 ER PT J AU Bolton, DL Pegu, A Wang, KY McGinnis, K Nason, M Foulds, K Letukas, V Schmidt, SD Chen, XJ Todd, JP Lifson, JD Rao, S Michael, NL Robb, ML Mascola, JR Koup, RA AF Bolton, Diane L. Pegu, Amarendra Wang, Keyun McGinnis, Kathleen Nason, Martha Foulds, Kathryn Letukas, Valerie Schmidt, Stephen D. Chen, Xuejun Todd, John Paul Lifson, Jeffrey D. Rao, Srinivas Michael, Nelson L. Robb, Merlin L. Mascola, John R. Koup, Richard A. TI Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs SO JOURNAL OF VIROLOGY LA English DT Article ID BROADLY NEUTRALIZING ANTIBODIES; PASSIVE TRANSFER; IN-VIVO; PHASE-I; NONHUMAN-PRIMATES; ANTIVIRAL THERAPY; CD4-BINDING SITE; RHESUS-MONKEYS; HIV RESERVOIR; T(H)1 CELLS AB Combination antiretroviral therapy (cART) administered shortly after human immunodeficiency virus type 1 (HIV-1) infection can suppress viremia and limit seeding of the viral reservoir, but lifelong treatment is required for the majority of patients. Highly potent broadly neutralizing HIV-1 monoclonal antibodies (MAbs) can reduce plasma viremia when administered during chronic HIV-1 infection, but the therapeutic potential of these antibodies during acute infection is unknown. We tested the ability of HIV-1 envelope glycoprotein-specific broadly neutralizing MAbs to suppress acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques. Four groups of macaques were infected with SHIV-SF162P3 and received (i) the CD4-binding-site MAb VRC01; (ii) a combination of a more potent clonal relative of VRC01 (VRC07-523) and a V3 glycan-dependent MAb (PGT121); (iii) daily cART, all on day 10, just prior to expected peak plasma viremia; or (iv) no treatment. Daily cART was initiated 11 days after MAb administration and was continued for 13 weeks in all treated animals. Over a period of 11 days after a single administration, MAb treatment significantly reduced peak viremia, accelerated the decay slope, and reduced total viral replication compared to untreated controls. Proviral DNA in lymph node CD4 T cells was also diminished after treatment with the dual MAb. These data demonstrate the virological effect of potent MAbs and support future clinical trials that investigate HIV-1-neutralizing MAbs as adjunctive therapy with cART during acute HIV-1 infection. C1 [Bolton, Diane L.; Michael, Nelson L.; Robb, Merlin L.] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. [Bolton, Diane L.; Robb, Merlin L.] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Pegu, Amarendra; Wang, Keyun; McGinnis, Kathleen; Foulds, Kathryn; Letukas, Valerie; Schmidt, Stephen D.; Chen, Xuejun; Todd, John Paul; Rao, Srinivas; Mascola, John R.; Koup, Richard A.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nason, Martha] NIAID, Biostat Res Branch, Div Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Lifson, Jeffrey D.] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Frederick, MD USA. [Rao, Srinivas] 640 Mem Dr, Cambridge, MA USA. RP Bolton, DL (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD USA. EM dbolton@hivresearch.org RI Schmidt, Stephen/B-5398-2012 FU Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-07-2-0067]; U.S. Department of Defense (DOD) [W81XWH-07-2-0067]; U.S. National Institute of Allergy and Infectious Diseases; National Cancer Institute [HHSN261200800001E] FX This work was supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). This research was funded in part by the U.S. National Institute of Allergy and Infectious Diseases and in part with federal funds under contract no. HHSN261200800001E from the National Cancer Institute. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 48 TC 9 Z9 9 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 3 BP 1321 EP 1332 DI 10.1128/JVI.02454-15 PG 12 WC Virology SC Virology GA DC3WW UT WOS:000369150800014 PM 26581981 ER PT J AU Kearney, MF Wiegand, A Shao, W Coffin, JM Mellors, JW Lederman, M Gandhi, RT Keele, BF Li, JZ AF Kearney, Mary F. Wiegand, Ann Shao, Wei Coffin, John M. Mellors, John W. Lederman, Michael Gandhi, Rajesh T. Keele, Brandon F. Li, Jonathan Z. TI Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy SO JOURNAL OF VIROLOGY LA English DT Article ID SEQUENTIAL 3-DRUG REGIMENS; INFECTED-CELLS; TREATMENT INTERRUPTION; REVERSE-TRANSCRIPTASE; CONTROLLED-TRIAL; INITIAL THERAPY; REPLICATION; RESERVOIR; DISCONTINUATION; PROLIFERATION AB Understanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission. C1 [Kearney, Mary F.; Wiegand, Ann] NCI, HIV Dynam & Replicat Program, Frederick, MD 21701 USA. [Shao, Wei; Keele, Brandon F.] Leidos Biomed Res Inc, Frederick Natl Labs Canc Res, Frederick, MD USA. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Mellors, John W.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Lederman, Michael] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Gandhi, Rajesh T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Li, Jonathan Z.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Keele, BF (reprint author), Leidos Biomed Res Inc, Frederick Natl Labs Canc Res, Frederick, MD USA.; Li, JZ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM kearneym@ncifcrf.gov; jli@bwh.harvard.edu FU National Institutes of Health (NIH) [AI100699, U01AI068636, UM1AI106701]; Leidos Biomedical Research, Inc. [12XS547, 13SX110]; NIH [HHSN261200800001E]; National Cancer Institute; AIDS Targeted Antiviral Program Award; FM Kirby Foundation FX This work was supported by National Institutes of Health (NIH) grants AI100699 (to J.Z.L.), U01AI068636 (to the AIDS Clinical Trials Group), and UM1AI106701 (to the Pittsburgh Virology Specialty Laboratory), and by Leidos Biomedical Research, Inc. (subcontract 12XS547 to J.W.M. and 13SX110 to J.M.C. through the National Cancer Institute), and by intramural NIH funding, including the National Cancer Institute, the AIDS Targeted Antiviral Program Award to M.F.K., and NIH Contract No. HHSN261200800001E. J.M.C. was a Research Professor of the American Cancer Society, with support from the FM Kirby Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 33 TC 9 Z9 9 U1 2 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 3 BP 1369 EP 1376 DI 10.1128/JVI.02139-15 PG 8 WC Virology SC Virology GA DC3WW UT WOS:000369150800018 PM 26581989 ER PT J AU Cavallari, I Rende, F Bona, MK Sztuba-Solinska, J Silic-Benussi, M Tognon, M LeGrice, SFJ Franchini, G D'Agostino, DM Ciminale, V AF Cavallari, Ilaria Rende, Francesca Bona, Marion K. Sztuba-Solinska, Joanna Silic-Benussi, Micol Tognon, Martina LeGrice, Stuart F. J. Franchini, Genoveffa D'Agostino, Donna M. Ciminale, Vincenzo TI Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence SO JOURNAL OF VIROLOGY LA English DT Article ID HTLV-1 GENE-EXPRESSION; REX PROTEIN; NUCLEAR RETENTION; REPLICATION; EXPORT; TRANSCRIPTION; RETROVIRUSES; ELEMENTS; LYMPHOMA; P27X-III AB Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. C1 [Cavallari, Ilaria; Rende, Francesca; Silic-Benussi, Micol; Tognon, Martina; Ciminale, Vincenzo] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy. [Bona, Marion K.] Leidos Biomed Res Inc, Frederick Natl Lab, Frederick, MD USA. [Sztuba-Solinska, Joanna; LeGrice, Stuart F. J.] NCI, Basic Res Lab, Frederick, MD 21701 USA. [Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [D'Agostino, Donna M.] Univ Padua, Dept Biomed Sci, Padua, Italy. [Ciminale, Vincenzo] IRCCS, Ist Oncol Veneto, Padua, Italy. RP Ciminale, V (reprint author), Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy.; Ciminale, V (reprint author), IRCCS, Ist Oncol Veneto, Padua, Italy. EM v.ciminale@unipd.it OI Cavallari, Ilaria/0000-0002-7430-9137 FU Intramural Research Program of National Cancer Institute; Pezcoller Foundation; University of Padua; Associazione Italiana per la Ricerca sul Cancro (AIRC) [13378]; Universita degli Studi di Padova (University of Padua) [CPDA124913/12]; AIRC-Cariverona regional grant FX Intramural Research Program of National Cancer Institute provided funding to Marion K. Bona, Joanna Sztuba-Solinska, Genoveffa Franchini, and Stuart F. J. LeGrice. Pezcoller Foundation provided funding to Micol Silic-Benussi. University of Padua provided funding to Micol Silic-Benussi. Associazione Italiana per la Ricerca sul Cancro (AIRC) provided funding to Vincenzo Ciminale under grant number 13378. Universita degli Studi di Padova (University of Padua) provided funding to Vincenzo Ciminale under grant number CPDA124913/12.; Vincenzo Ciminale also received funding from an AIRC-Cariverona regional grant. NR 45 TC 2 Z9 2 U1 3 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 3 BP 1486 EP 1498 DI 10.1128/JVI.02298-15 PG 13 WC Virology SC Virology GA DC3WW UT WOS:000369150800028 ER PT J AU Tsang, SH Wang, RR Nakamaru-Ogiso, E Knight, SAB Buck, CB You, JX AF Tsang, Sabrina H. Wang, Ranran Nakamaru-Ogiso, Eiko Knight, Simon A. B. Buck, Christopher B. You, Jianxin TI The Oncogenic Small Tumor Antigen of Merkel Cell Polyomavirus Is an Iron-Sulfur Cluster Protein That Enhances Viral DNA Replication SO JOURNAL OF VIROLOGY LA English DT Article ID SMALL-T-ANTIGEN; ACYCLIC NUCLEOSIDE PHOSPHONATES; FE-S CLUSTERS; TRANSPLANT RECIPIENTS; ZINC IONS; CARCINOMA; CIDOFOVIR; HELICASES; EXPRESSION; INFECTION AB Merkel cell polyomavirus (MCPyV) plays an important role in Merkel cell carcinoma (MCC). MCPyV small T (sT) antigen has emerged as the key oncogenic driver in MCC carcinogenesis. It has also been shown to promote MCPyV LT-mediated replication by stabilizing LT. The importance of MCPyV sT led us to investigate sT functions and to identify potential ways to target this protein. We discovered that MCPyV sT purified from bacteria contains iron-sulfur (Fe/S) clusters. Electron paramagnetic resonance analysis showed that MCPyV sT coordinates a [2Fe-2S] and a [4Fe-4S] cluster. We also observed phenotypic conservation of Fe/S coordination in the sTs of other polyomaviruses. Since Fe/S clusters are critical cofactors in many nucleic acid processing enzymes involved in DNA unwinding and polymerization, our results suggested the hypothesis that MCPyV sT might be directly involved in viral replication. Indeed, we demonstrated that MCPyV sT enhances LT-mediated replication in a manner that is independent of its previously reported ability to stabilize LT. MCPyV sT translocates to nuclear foci containing actively replicating viral DNA, supporting a direct role for sT in promoting viral replication. Mutations of Fe/S cluster-coordinating cysteines in MCPyV sT abolish its ability to stimulate viral replication. Moreover, treatment with cidofovir, a potent antiviral agent, robustly inhibits the sT-mediated enhancement of MCPyV replication but has little effect on the basal viral replication driven by LT alone. This finding further indicates that MCPyV sT plays a direct role in stimulating viral DNA replication and introduces cidofovir as a possible drug for controlling MCPyV infection. C1 [Tsang, Sabrina H.; Wang, Ranran; You, Jianxin] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nakamaru-Ogiso, Eiko] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA. [Knight, Simon A. B.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Buck, Christopher B.] NCI, Tumor Virus Mol Biol Sect, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP You, JX (reprint author), Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jianyou@mail.med.upenn.edu FU HHS \ National Institutes of Health (NIH) [R01CA187718-01A1, R01GM097409] FX HHS vertical bar National Institutes of Health (NIH) provided funding to Jianxin You under grant number R01CA187718-01A1. HHS vertical bar National Institutes of Health (NIH) provided funding to Eiko Nakamaru-Ogiso under grant number R01GM097409. NR 61 TC 2 Z9 2 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 3 BP 1544 EP 1556 DI 10.1128/JVI.02121-15 PG 13 WC Virology SC Virology GA DC3WW UT WOS:000369150800033 ER PT J AU Wu, JJ Avey, D Li, WW Gillen, J Fu, BS Miley, W Whitby, D Zhu, FX AF Wu, Jian-jun Avey, Denis Li, Wenwei Gillen, Joseph Fu, Bishi Miley, Wendell Whitby, Denise Zhu, Fanxiu TI ORF33 and ORF38 of Kaposi's Sarcoma-Associated Herpesvirus Interact and Are Required for Optimal Production of Infectious Progeny Viruses SO JOURNAL OF VIROLOGY LA English DT Article ID UL21 TEGUMENT PROTEINS; EPSTEIN-BARR-VIRUS; SIMPLEX-VIRUS; HUMAN CYTOMEGALOVIRUS; PSEUDORABIES VIRUS; SECONDARY ENVELOPMENT; VIRION PROTEIN; DNA-SEQUENCES; GAMMA-HERPESVIRUSES; CYTOPLASMIC TAIL AB We recently showed that the interaction between Kaposi's sarcoma-associated herpesvirus (KSHV) tegument proteins ORF33 and ORF45 is crucial for progeny virion production, but the exact functions of KSHV ORF33 during lytic replication were unknown (J. Gillen, W. Li, Q. Liang, D. Avey, J. Wu, F. Wu, J. Myoung, and F. Zhu, J Virol 89: 4918-4931, 2015, http://dx.doi.org/10.1128/JVI.02925-14). Therefore, here we investigated the relationship between ORF33 and ORF38, whose counterparts in both alpha-and betaherpesviruses interact with each other. Using specific monoclonal antibodies, we found that both proteins are expressed during the late lytic cycle with similar kinetics and that both are present in mature virions as components of the tegument. Furthermore, we confirmed that ORF33 interacts with ORF38. Interestingly, we observed that ORF33 tightly associates with the capsid, whereas ORF38 associates with the envelope. We generated ORF33-null, ORF38-null, and double-null mutants and found that these mutants apparently have identical phenotypes: the mutations caused no apparent effect on viral gene expression but reduced the yield of progeny virion by about 10-fold. The progeny virions also lack certain virion component proteins, including ORF45. During viral lytic replication, the virions associate with cytoplasmic vesicles. We also observed that ORF38 associates with the membranes of vesicles and colocalizes with the Golgi membrane or early endosome membrane. Further analyses of ORF33/ORF38 mutants revealed the reduced production of virion-containing vesicles, suggesting that ORF33 and ORF38 are involved in the transport of newly assembled viral particles into cytoplasmic vesicles, a process important for viral maturation and egress. C1 [Wu, Jian-jun; Avey, Denis; Li, Wenwei; Gillen, Joseph; Fu, Bishi; Zhu, Fanxiu] Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. [Miley, Wendell; Whitby, Denise] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, Viral Oncol Sect, Frederick, MD USA. RP Zhu, FX (reprint author), Florida State Univ, Dept Biol Sci, B-157, Tallahassee, FL 32306 USA. EM fzhu@bio.fsu.edu OI Zhu, Fanxiu/0000-0002-4189-7008; Wu, Jianjun/0000-0003-4518-8361 FU HHS \ National Institutes of Health (NIH) [R01DE016680, F31 CA183250, HHSN261200800001E] FX HHS vertical bar National Institutes of Health (NIH) provided funding to Fanxiu Zhu under grant number R01DE016680. HHS vertical bar National Institutes of Health (NIH) provided funding to Denis R. Avey under grant number F31 CA183250. HHS vertical bar National Institutes of Health (NIH) provided funding to Denise Whitby under grant number HHSN261200800001E. NR 70 TC 1 Z9 1 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 4 BP 1741 EP 1756 DI 10.1128/JVI.02738-15 PG 16 WC Virology SC Virology GA DC3XL UT WOS:000369152700005 ER PT J AU Alfano, N Kolokotronis, SO Tsangaras, K Roca, AL Xu, WQ Eiden, MV Greenwood, AD AF Alfano, Niccolo Kolokotronis, Sergios-Orestis Tsangaras, Kyriakos Roca, Alfred L. Xu, Wenqin Eiden, Maribeth V. Greenwood, Alex D. TI Episodic Diversifying Selection Shaped the Genomes of Gibbon Ape Leukemia Virus and Related Gammaretroviruses SO JOURNAL OF VIROLOGY LA English DT Article ID C-TYPE VIRUS; FUSOGENIC MEMBRANE GLYCOPROTEIN; LONG TERMINAL REPEAT; INFECTED CELL-LINE; NUCLEOTIDE-SEQUENCE; KOALA RETROVIRUS; GENE-THERAPY; DNA; ALIGNMENT; RNA AB Gibbon ape leukemia viruses (GALVs) are part of a larger group of pathogenic gammaretroviruses present across phylogenetically diverse host species of Australasian mammals. Despite the biomedical utility of GALVs as viral vectors and in cancer gene therapy, full genome sequences have not been determined for all of the five identified GALV strains, nor has a comprehensive evolutionary analysis been performed. We therefore generated complete genomic sequences for each GALV strain using hybridization capture and high-throughput sequencing. The four strains of GALV isolated from gibbons formed a monophyletic clade that was closely related to the woolly monkey virus (WMV), which is a GALV strain that likely originated in a gibbon host. The GALV-WMV clade in turn formed a sister group to the koala retroviruses (KoRVs). Genomic signatures of episodic diversifying selection were detected among the gammaretroviruses with concentration in the env gene across the GALV strains that were particularly oncogenic and KoRV strains that were potentially exogenous, likely reflecting their adaptation to the host immune system. In vitro studies involving vectors chimeric between GALV and KoRV-B established that variable regions A and B of the surface unit of the envelope determine which receptor is used by a viral strain to enter host cells. C1 [Alfano, Niccolo; Tsangaras, Kyriakos; Greenwood, Alex D.] Leibniz Inst Zoo & Wildlife Res, Berlin, Germany. [Kolokotronis, Sergios-Orestis] Fordham Univ, Dept Biol Sci, Bronx, NY 10458 USA. [Kolokotronis, Sergios-Orestis] Amer Museum Nat Hist, Sackler Inst Comparat Genom, New York, NY 10024 USA. [Kolokotronis, Sergios-Orestis] Amer Museum Nat Hist, Div Invertebrate Zool, New York, NY 10024 USA. [Roca, Alfred L.] Univ Illinois, Dept Anim Sci, Urbana, IL USA. [Xu, Wenqin; Eiden, Maribeth V.] NIMH, Sect Directed Gene Transfer, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. [Greenwood, Alex D.] Free Univ Berlin, Dept Vet Med, Berlin, Germany. [Tsangaras, Kyriakos] Cyprus Inst Neurol & Genet, Nicosia, Cyprus. RP Greenwood, AD (reprint author), Leibniz Inst Zoo & Wildlife Res, Berlin, Germany.; Greenwood, AD (reprint author), Free Univ Berlin, Dept Vet Med, Berlin, Germany. EM greenwood@izw-berlin.de RI Kolokotronis, Sergios-Orestis/A-1910-2009 OI Kolokotronis, Sergios-Orestis/0000-0003-3309-8465 FU National Institute of Mental Health [1ZIAMH002592]; International Max Planck Research School for Infectious Diseases and Immunology; HHS \ NIH \ National Institute of General Medical Sciences (NIGMS) [R01 GM092706]; Morris Animal Foundation (MAF) [D14ZO-94] FX National Institute of Mental Health Intramural Research Program provided funding to Maribeth Eiden under grant number 1ZIAMH002592. International Max Planck Research School for Infectious Diseases and Immunology provided funding to Niccolo Alfano. HHS vertical bar NIH vertical bar National Institute of General Medical Sciences (NIGMS) provided funding to Sergios Kolokotronis, Alfred Roca, and Alex David Greenwood under grant number R01 GM092706. Morris Animal Foundation (MAF) provided funding to Alex David Greenwood under grant number D14ZO-94. NR 66 TC 5 Z9 5 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 4 BP 1757 EP 1772 DI 10.1128/JVI.02745-15 PG 16 WC Virology SC Virology GA DC3XL UT WOS:000369152700006 ER PT J AU Datta, SAK Clark, PK Fan, LX Ma, BY Harvin, DP Sowder, RC Nussinov, R Wang, YX Rein, A AF Datta, Siddhartha A. K. Clark, Patrick K. Fan, Lixin Ma, Buyong Harvin, Demetria P. Sowder, Raymond C., II Nussinov, Ruth Wang, Yun-Xing Rein, Alan TI Dimerization of the SP1 Region of HIV-1 Gag Induces a Helical Conformation and Association into Helical Bundles: Implications for Particle Assembly SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS TYPE-1 GAG; IN-VITRO; MOLECULAR-DYNAMICS; MATURATION INHIBITOR; POTENTIAL FUNCTIONS; SPACER PEPTIDE; LIQUID WATER; PROTEIN; DOMAIN; BEVIRIMAT AB HIV-1 immature particle (virus-like particle [VLP]) assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We previously investigated the role of SP1, a "spacer" between CA and NC, in VLP assembly. We found that small changes in SP1 drastically disrupt assembly and that a peptide representing the sequence around the CA-SP1 junction is helical at high but not low concentrations. We suggested that by virtue of such a concentration-dependent change, this region could act as a molecular switch to activate HIV-1 Gag for VLP assembly. A leucine zipper domain can replace NC in Gag and still lead to the efficient assembly of VLPs. We find that SP1 mutants also disrupt assembly by these Gag-Zip proteins and have now studied a small fragment of this Gag-Zip protein, i.e., the CA-SP1 junction region fused to a leucine zipper. Dimerization of the zipper places SP1 at a high local concentration, even at low total concentrations. In this context, the CA-SP1 junction region spontaneously adopts a helical conformation, and the proteins associate into tetramers. Tetramerization requires residues from both CA and SP1. The data suggest that once this region becomes helical, its propensity to self-associate could contribute to Gag-Gag interactions and thus to particle assembly. There is complete congruence between CA/SP1 sequences that promote tetramerization when fused to zippers and those that permit the proper assembly of full-length Gag; thus, equivalent interactions apparently participate in VLP assembly and in SP1-Zip tetramerization. C1 [Datta, Siddhartha A. K.; Harvin, Demetria P.; Rein, Alan] NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Clark, Patrick K.] Leidos Biomed Res Inc, Retroviral Replicat Lab, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Fan, Lixin] Leidos Biomed Res Inc, Struct Biophys Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. [Ma, Buyong; Nussinov, Ruth] Leidos Biomed Res Inc, Canc & Inflammat Program, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Sowder, Raymond C., II] Leidos Biomed Res Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. [Wang, Yun-Xing] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Datta, SAK; Rein, A (reprint author), NCI, HIV Dynam & Replicat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM dattasi@mail.nih.gov; reina@mail.nih.gov RI Ma, Buyong/F-9491-2011; OI Ma, Buyong/0000-0002-7383-719X; Datta, Siddhartha/0000-0002-4098-7490 FU HHS \ NIH \ National Cancer Institute (NCI) [HHSN26120080001E] FX Intramural AIDS Targeted Antiviral Therapy Program provided funding to Siddhartha A. K. Datta, Demetria Harvin, and Alan Rein. HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Patrick K. Clark, Lixin Fan, Buyong Ma, Raymond C. Sowder, and Ruth Nussinov under grant number HHSN26120080001E. HHS vertical bar NIH vertical bar National Cancer Institute (NCI) provided funding to Siddhartha A. K. Datta, Demetria Harvin, Yun-Xing Wang, and Alan Rein. NR 55 TC 5 Z9 5 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 4 BP 1773 EP 1787 DI 10.1128/JVI.02061-15 PG 15 WC Virology SC Virology GA DC3XL UT WOS:000369152700007 ER PT J AU Campbell, EM Weingart, J Sette, P Opp, S Sastri, J O'Connor, SK Talley, S Diaz-Griffero, F Hirsch, V Bouamr, F AF Campbell, Edward M. Weingart, Jared Sette, Paola Opp, Silvana Sastri, Jaya O'Connor, Sarah K. Talley, Sarah Diaz-Griffero, Felipe Hirsch, Vanessa Bouamr, Fadila TI TRIM5 alpha-Mediated Ubiquitin Chain Conjugation Is Required for Inhibition of HIV-1 Reverse Transcription and Capsid Destabilization SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS TRIM5-ALPHA; TRIM PROTEINS; RETROVIRAL RESTRICTION; INNATE; RECOGNITION; DOMAIN; INTERMEDIATE; ASSOCIATION; INFECTION; IMMUNITY AB Rhesus macaque TRIM5 alpha (rhTRIM5 alpha) is a retroviral restriction factor that inhibits HIV-1 infection. Previous studies have revealed that TRIM5 alpha restriction occurs via a two-step process. The first step is restriction factor binding, which is sufficient to inhibit infection. The second step, which is sensitive to proteasome inhibition, prevents the accumulation of reverse transcription products in the target cell. However, because of the pleotropic effects of proteasome inhibitors, the molecular mechanisms underlying the individual steps in the restriction process have remained poorly understood. In this study, we have fused the small catalytic domain of herpes simplex virus UL36 deubiquitinase (DUb) to the N-terminal RING domain of rhTRIM5 alpha, which results in a ubiquitination-resistant protein. Cell lines stably expressing this fusion protein inhibited HIV-1 infection to the same degree as a control fusion to a catalytically inactive DUb. However, reverse transcription products were substantially increased in the DUb-TRIM5 alpha fusion relative to the catalytically inactive control or the wild-type (WT) TRIM5 alpha. Similarly, expression of DUb-rhTRIM5 alpha resulted in the accumulation of viral cores in target cells following infection, while the catalytically inactive control and WT rhTRIM5 alpha induced the abortive disassembly of viral cores, indicating a role for ubiquitin conjugation in rhTRIM5 alpha-mediated destabilization of HIV-1 cores. Finally, DUb-rhTRIM5 alpha failed to activate NF-kappa B signaling pathways compared to controls, demonstrating that this ubiquitination-dependent activity is separable from the ability to restrict retroviral infection. C1 [Campbell, Edward M.; Weingart, Jared; Talley, Sarah; Bouamr, Fadila] Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL USA. [Sette, Paola; Sastri, Jaya; O'Connor, Sarah K.; Hirsch, Vanessa; Bouamr, Fadila] NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Opp, Silvana; Diaz-Griffero, Felipe] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. RP Campbell, EM (reprint author), Loyola Univ Chicago, Stritch Sch Med, Dept Microbiol & Immunol, Maywood, IL USA.; Bouamr, F (reprint author), NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM ecampbell@luc.edu; bouamrf@mail.nih.gov FU HHS \ National Institutes of Health (NIH) [AI093258-02, AI087390-07]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) FX This work was funded by HHS vertical bar National Institutes of Health (NIH) under grant AI093258-02. This work was funded by HHS vertical bar National Institutes of Health (NIH) under grant AI087390-07. Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to Vanessa M. Hirsch. Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID) provided funding to Fadila BOUAMR. NR 39 TC 4 Z9 4 U1 4 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2016 VL 90 IS 4 BP 1849 EP 1857 DI 10.1128/JVI.01948-15 PG 9 WC Virology SC Virology GA DC3XL UT WOS:000369152700013 ER PT J AU Weaver, GC Villar, RF Kanekiyo, M Nabel, GJ Mascola, JR Lingwood, D AF Weaver, Grant C. Villar, Rina F. Kanekiyo, Masaru Nabel, Gary J. Mascola, John R. Lingwood, Daniel TI In vitro reconstitution of B cell receptor-antigen interactions to evaluate potential vaccine candidates SO NATURE PROTOCOLS LA English DT Article ID NEUTRALIZING ANTIBODIES; HEMAGGLUTININ-STEM; INFLUENZA ANTIBODIES; MEMORY; RECOGNITION; EXPRESSION; MATURATION; IMMUNOGEN; RESPONSES; BINDING AB Predicting immune responses before vaccination is challenging because of the complexity of the governing parameters. Nevertheless, recent work has shown that B cell receptor (BCR)-antigen engagement in vitro can prove a powerful means of informing the design of antibody-based vaccines. We have developed this principle into a two-phased immunogen evaluation pipeline to rank-order vaccine candidates. In phase 1, recombinant antigens are screened for reactivity to the germline precursors that produce the antibody responses of interest. To both mimic the architecture of initial antigen engagement and facilitate rapid immunogen screening, these antibodies are expressed as membrane-anchored IgM (mIgM) in 293F indicator cells. In phase 2, the binding hits are multimerized by nanoparticle or proteoliposome display, and they are evaluated for BCRCR triggering in an engineered B cell line displaying the IgM sequences of interest. Key developments that complement existing methodology in this area include the following: (i) introduction of a high-throughput screening step before evaluation of more time-intensive BCRCR-triggering analyses; (ii) generalizable multivalent antigen-display platforms needed for BCRCR activation; and (iii) engineered use of a human B cell line that does not display endogenous antibody, but only ectopically expressed BCRCR sequences of interest. Through this pipeline, the capacity to initiate favorable antibody responses is evaluated. The entire protocol can be completed within 2.5 months. C1 [Weaver, Grant C.; Villar, Rina F.; Lingwood, Daniel] MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Weaver, Grant C.; Villar, Rina F.; Lingwood, Daniel] Harvard Univ, Cambridge, MA 02138 USA. [Kanekiyo, Masaru; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nabel, Gary J.] Sanofi, Cambridge, MA USA. RP Lingwood, D (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.; Lingwood, D (reprint author), Harvard Univ, Cambridge, MA 02138 USA. EM dlingwood@mgh.harvard.edu FU Harvard University Center for AIDS Research (CFAR) grant [P30 AI060354]; Broad-Ragon ENDHIV Catalytic grant; William F. Milton Fund; Gilead Sciences Research Scholars Program in HIV FX The authors thank members of the Lingwood laboratory for critical reading of the manuscript, S. Perfetto (Vaccine Research Center, National Institutes of Health (NIH)) for flow cytometry advice, and J. Boyington and J. Whittle (Vaccine Research Center, NIH) for key discussions. This work was supported by the following awards to D.L.: a Harvard University Center for AIDS Research (CFAR) grant (P30 AI060354); a Broad-Ragon ENDHIV Catalytic grant; the William F. Milton Fund; and the Gilead Sciences Research Scholars Program in HIV. NR 48 TC 1 Z9 1 U1 6 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1754-2189 EI 1750-2799 J9 NAT PROTOC JI Nat. Protoc. PD FEB PY 2016 VL 11 IS 2 BP 193 EP 213 DI 10.1038/nprot.2016.009 PG 21 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DC2YK UT WOS:000369084500001 PM 26741406 ER PT J AU Restifo, NP Smyth, MJ Snyder, A AF Restifo, Nicholas P. Smyth, Mark J. Snyder, Alexandra TI Acquired resistance to immunotherapy and future challenges SO NATURE REVIEWS CANCER LA English DT Review ID T-CELL; CTLA-4 BLOCKADE; CANCER-IMMUNOTHERAPY; METASTATIC MELANOMA; CLINICAL-RESPONSE; ADAPTIVE IMMUNITY; TUMOR-DEVELOPMENT; PD-1 BLOCKADE; GENETIC-BASIS; IPILIMUMAB AB Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. C1 [Restifo, Nicholas P.] NCI, Ctr Canc Res, Bldg 10 CRC,Room 3-5762,9000 Rockville Pike, Bethesda, MD 20892 USA. [Restifo, Nicholas P.] NIH, Ctr Regenerat Med, Bldg 10 CRC,Room 3-5762,9000 Rockville Pike, Bethesda, MD 20892 USA. [Smyth, Mark J.] QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Brisbane, Qld 4006, Australia. [Smyth, Mark J.] Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia. [Snyder, Alexandra] Mem Sloan Kettering Canc Ctr, Dept Med, 300 East 66th St, New York, NY 10065 USA. RP Restifo, NP (reprint author), NCI, Ctr Canc Res, Bldg 10 CRC,Room 3-5762,9000 Rockville Pike, Bethesda, MD 20892 USA.; Restifo, NP (reprint author), NIH, Ctr Regenerat Med, Bldg 10 CRC,Room 3-5762,9000 Rockville Pike, Bethesda, MD 20892 USA.; Smyth, MJ (reprint author), QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Brisbane, Qld 4006, Australia.; Smyth, MJ (reprint author), Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia.; Snyder, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 300 East 66th St, New York, NY 10065 USA. EM restifo@nih.gov; mark.smyth@qimrberghofer.edu.au; snyderca@mskcc.org RI Smyth, Mark/H-8709-2014 OI Smyth, Mark/0000-0001-7098-7240 NR 48 TC 14 Z9 14 U1 8 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X EI 1474-1768 J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2016 VL 16 IS 2 BP 121 EP 126 DI 10.1038/nrc.2016.2 PG 6 WC Oncology SC Oncology GA DC4ID UT WOS:000369183400010 PM 26822578 ER PT J AU Guerreiro, R Escott-Price, V Darwent, L Parkkinen, L Ansorge, O Hernandez, DG Nalls, MA Clark, L Honig, L Marder, K van der Flier, W Holstege, H Louwersheimer, E Lemstra, A Scheltens, P Rogaeva, E St George-Hyslop, P Londos, E Zetterberg, H Ortega-Cubero, S Pastor, P Ferman, TJ Graff-Radford, NR Ross, OA Barber, I Braae, A Brown, K Morgan, K Maetzler, W Berg, D Troakes, C Al-Sarraj, S Lashley, T Compta, Y Revesz, T Lees, A Cairns, NJ Halliday, GM Mann, D Pickering-Brown, S Powell, J Lunnon, K Lupton, MK Dickson, D Hardy, J Singleton, A Bras, J AF Guerreiro, Rita Escott-Price, Valentina Darwent, Lee Parkkinen, Laura Ansorge, Olaf Hernandez, Dena G. Nalls, Michael A. Clark, Lorraine Honig, Lawrence Marder, Karen van der Flier, Wiesje Holstege, Henne Louwersheimer, Eva Lemstra, Afina Scheltens, Philip Rogaeva, Ekaterina St George-Hyslop, Peter Londos, Elisabet Zetterberg, Henrik Ortega-Cubero, Sara Pastor, Pau Ferman, Tanis J. Graff-Radford, Neill R. Ross, Owen A. Barber, Imelda Braae, Anne Brown, Kristelle Morgan, Kevin Maetzler, Walter Berg, Daniela Troakes, Claire Al-Sarraj, Safa Lashley, Tammaryn Compta, Yaroslau Revesz, Tamas Lees, Andrew Cairns, Nigel J. Halliday, Glenda M. Mann, David Pickering-Brown, Stuart Powell, John Lunnon, Katie Lupton, Michelle K. Dickson, Dennis Hardy, John Singleton, Andrew Bras, Jose CA Int Parkinson's Dis Gen Consortium TI Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases SO NEUROBIOLOGY OF AGING LA English DT Article DE Dementia with Lewy bodies; Alzheimer's disease; Parkinson's disease; Genetic correlation ID HERITABILITY; ASSOCIATION; CONSORTIUM; DIAGNOSIS; RISK AB The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD. (C) 2016 The Authors. Published by Elsevier Inc. C1 [Guerreiro, Rita; Darwent, Lee; Zetterberg, Henrik; Bras, Jose] UCL, Inst Neurol, Dept Mol Neurosci, 8-11 Queen Sq,DRC,Box 16, London WC1N 3AR, England. [Escott-Price, Valentina] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Gen, Cardiff CF10 3AX, S Glam, Wales. [Parkkinen, Laura; Ansorge, Olaf] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford Parkinsons Dis Ctr, Oxford, England. [Hernandez, Dena G.; Nalls, Michael A.; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hernandez, Dena G.] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany. [Clark, Lorraine; Honig, Lawrence; Marder, Karen] Columbia Univ, Taub Inst Alzheimer Dis & Aging Brain, New York, NY USA. [Clark, Lorraine; Honig, Lawrence] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Marder, Karen] Columbia Univ, Dept Neurol, New York, NY USA. [van der Flier, Wiesje; Holstege, Henne; Louwersheimer, Eva; Lemstra, Afina; Scheltens, Philip] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [van der Flier, Wiesje; Holstege, Henne; Louwersheimer, Eva; Lemstra, Afina; Scheltens, Philip] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Rogaeva, Ekaterina; St George-Hyslop, Peter] Univ Toronto, Dept Med, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Natl Inst Hlth Res, Biomed Res Unit Dementia, Cambridge, England. [Londos, Elisabet] Lund Univ, Inst Clin Sci Malmo, Clin Memory Res Unit, Lund, Sweden. [Zetterberg, Henrik] Univ Gothenburg, Clin Neurochem Lab, Dept Psychiat & Neurochem, Inst Neurosci & Physiol,Sahlgrenska Acad, Gothenburg, Sweden. [Ortega-Cubero, Sara; Pastor, Pau] Univ Navarra, Ctr Appl Med Res CIMA, Div Neurosci, Neurogenet Lab, E-31080 Pamplona, Spain. [Ortega-Cubero, Sara; Pastor, Pau] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, CIBERNED, Madrid, Spain. [Pastor, Pau] Univ Barcelona, Sch Med, Memory Unit, Dept Neurol,Univ Hosp Mutua Terrassa, Barcelona, Spain. [Pastor, Pau] Univ Barcelona, Sch Med, Movement Disorders Unit, Dept Neurol,Univ Hosp Mutua Terrassa, Barcelona, Spain. [Ferman, Tanis J.] Mayo Clin, Dept Psychiat, Jacksonville, FL 32224 USA. [Ferman, Tanis J.] Mayo Clin, Dept Psychol, Jacksonville, FL 32224 USA. [Graff-Radford, Neill R.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Ross, Owen A.; Dickson, Dennis] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Barber, Imelda; Braae, Anne; Brown, Kristelle; Morgan, Kevin] Univ Nottingham, Translat Cell Sci Human Genet, Sch Life Sci, Queens Med Ctr, Nottingham NG7 2RD, England. [Maetzler, Walter; Berg, Daniela] Univ Tubingen, Ctr Neurol, Dept Neurodegenerat, Hertie Inst Clin Brain Res, Tubingen, Germany. [Maetzler, Walter; Berg, Daniela] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Troakes, Claire; Al-Sarraj, Safa] Kings Coll London, Dept Clin Neurosci, Inst Psychiat, MRC London Neurodegenerat Dis Brain Bank, London, England. [Lashley, Tammaryn; Compta, Yaroslau; Revesz, Tamas; Lees, Andrew] UCL Inst Neurol, Dept Mol Neurosci, Queen Sq Brain Bank, London, England. [Compta, Yaroslau] Hosp Clin Univ Barcelona IDIBAPS, Clin Neurosci Inst ICN, Neurol Serv, Parkinsons Dis & Movement Disorders Unit, Barcelona, Spain. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Neurol, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA. [Halliday, Glenda M.] Neurosci Res Australia, Sydney, NSW, Australia. [Halliday, Glenda M.] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW, Australia. [Mann, David; Pickering-Brown, Stuart] Univ Manchester, Fac Med & Human Sci, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England. [Powell, John; Lupton, Michelle K.] Kings Coll London, Dept Basic & Clin Neurosci, Inst Psychiat Psychol & Neurosci, London, England. [Lunnon, Katie] Univ Exeter, Univ Exeter Med Sch, Inst Clin & Biomed Sci, Exeter, Devon, England. [Hardy, John] UCL Inst Neurol, Dept Mol Neurosci, Reta Lila Weston Res Labs, London, England. RP Bras, J (reprint author), UCL, Inst Neurol, Dept Mol Neurosci, 8-11 Queen Sq,DRC,Box 16, London WC1N 3AR, England. EM j.bras@ucl.ac.uk RI Halliday, Glenda/E-8555-2011; Pastor, Pau/C-9834-2009; Powell, John/G-4412-2011; Hardy, John/C-2451-2009; Lashley, Tammaryn/D-2583-2009; Singleton, Andrew/C-3010-2009; Maetzler, Walter/A-6796-2011; Revesz, Tamas/A-8732-2010; OI Halliday, Glenda/0000-0003-0422-8398; Pastor, Pau/0000-0002-7493-8777; Powell, John/0000-0001-6124-439X; Revesz, Tamas/0000-0003-2501-0259; Escott-Price, Valentina/0000-0003-1784-5483; Pickering-Brown, Stuart/0000-0003-1561-6054; Lunnon, Katie/0000-0001-7570-6065 FU Alzheimer's Society; Parkinson's UK Innovation Award [K-1204]; Lewy Body Society; Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]; University of Sheffield; MRC Protein Phosphorylation Unit at the University of Dundee; Spanish Ministry of Science and Innovation [SAF2006-10126, SAF2010-22329-C02-01, SAF2013-47939-R]; UTE project FIMA; Medical Research Council (MRC); Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK); Autistica UK; NIHR Oxford Biomedical Research Centre; Stichting Dioraphte fond; Stichting VUMC fond; Neuroscience Research Australia; University of New South Wales; National Health and Medical Research Council of Australia; Wellcome Trust; Medical Research Council; Canadian Institutes of Health Research; Ontario Research Fund; ARUK; Big Lottery Fund; Taub Institute; Panasci Fund; Parkinson's Disease Foundation; NIH [NS060113, P50AG008702, P50NS038370, UL1TR000040]; Michael J. Fox Foundation, NINDS [NS078086]; Mangurian Foundation for Lewy body research; Queen Square Brain Bank at the UCL Institute of Neurology; NIHR UCLH Biomedical Research Centre; Queen Square Dementia Biomedical Research Unit; National Institute for Health Research (NIHR) Dementia Biomedical Research Unit; Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; King's College Hospital, London; National Institute on Aging, National Institutes of Health, Department of Health and Human Services [AG000951-12] FX Rita Guerreiro and Jose Bras are supported by Research Fellowships from the Alzheimer's Society. This work was supported in part by a Parkinson's UK Innovation Award (K-1204) in collaboration with the Lewy Body Society and by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee and by an anonymous Foundation. The authors would like to acknowledge Elena Lorenzo for her technical assistance. This study was supported in part by grants from the Spanish Ministry of Science and Innovation SAF2006-10126 (2006-2009) and SAF2010-22329-C02-01 (2011-2013) and SAF2013-47939-R (2013-2015) to Pau Pastor and by the UTE project FIMA to Pau Pastor. They acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Centre. The sample collection and database of the Amsterdam Dementia Cohort was funded by Stichting Dioraphte and Stichting VUMC fonds. Glenda M. Halliday is a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia. For the neuropathologically confirmed samples from Australia, brain tissue was received from the Sydney Brain Bank, which is supported by Neuroscience Research Australia, the University of New South Wales, and the National Health and Medical Research Council of Australia. This study was also partially funded by the Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research, Ontario Research Fund. The Nottingham Genetics Group is supported by ARUK and The Big Lottery Fund. The effort from Columbia University was supported by the Taub Institute, the Panasci Fund, the Parkinson's Disease Foundation, and NIH grants NS060113 (Lorraine Clark), P50AG008702 (P.I. Scott Small), P50NS038370 (P.I. R. Burke), and UL1TR000040 (P.I. H. Ginsberg). Owen A. Ross is supported by the Michael J. Fox Foundation, NINDS R01# NS078086. The Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS P50 #NS072187) and is supported by the Mangurian Foundation for Lewy body research. This work has received support from The Queen Square Brain Bank at the UCL Institute of Neurology. Some of the tissue samples studies were provided by the MRC London Neurodegenerative Diseases Brain Bank and the Brains for Dementia Research project (funded by Alzheimer's Society and ARUK). This research was supported in part by the NIHR UCLH Biomedical Research Centre, the Queen Square Dementia Biomedical Research Unit, the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit and Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College Hospital, London. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project AG000951-12. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust and the Medical Research Council. NR 12 TC 3 Z9 3 U1 3 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2016 VL 38 AR 214.e7 DI 10.1016/j.neurobiolaging.2015.10.028 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DC1QL UT WOS:000368991300025 PM 26643944 ER PT J AU Shi, CH Mao, CY Zhang, SY Yang, J Song, B Wu, P Zuo, CT Liu, YT Ji, Y Yang, ZH Wu, J Zhuang, ZP Xu, YM AF Shi, Chang-he Mao, Cheng-yuan Zhang, Shu-yu Yang, Jing Song, Bo Wu, Ping Zuo, Chuan-tao Liu, Yu-tao Ji, Yan Yang, Zhi-hua Wu, Jun Zhuang, Zheng-ping Xu, Yu-ming TI CHCHD2 gene mutations in familial and sporadic Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE CHCHD2; PET; ADPD ID REVEALS; NETWORK; VPS35 AB Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinson's disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations. (C) 2016 Elsevier Inc. All rights reserved. C1 [Shi, Chang-he; Mao, Cheng-yuan; Zhang, Shu-yu; Yang, Jing; Song, Bo; Liu, Yu-tao; Ji, Yan; Yang, Zhi-hua; Wu, Jun; Xu, Yu-ming] Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. [Wu, Ping; Zuo, Chuan-tao] Fudan Univ, Shanghai Med Coll, Huashan Hosp, PET Ctr,Dept Nucl Med, Shanghai 200433, Peoples R China. [Zhuang, Zheng-ping] NINDS, Surg Neurol Branch, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Xu, YM (reprint author), Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, 1 Jian She East Rd, Zhengzhou 450000, Henan, Peoples R China. EM xuyuming@zzu.edu.cn FU National Natural Science Foundation of China [81530037, 81471158, U1404311] FX This work was supported by grant 81530037 and 81471158 from the National Natural Science Foundation of China (to Dr. Yu-ming Xu) and grant U1404311 from the National Natural Science Foundation of China (to Dr. Chang-he Shi). We would like to thank the family for their participation in this study. Study conception, design, and organization (Chang-he Shi, Cheng-yuan Mao, and Yu-ming Xu); acquisition of data (Chang-he Shi, Cheng-yuan Mao, Shu-yu Zhang, Jing Yang, Bo Song, Ping Wu, Chuan-tao Zuo, Zhi-hua Yang, and Yu-ming Xu); analysis and interpretation of data (Chang-he Shi, Cheng-yuan Mao, Ping Wu, Yu-tao Liu, Ji, Jun Wu, Zheng-ping Zhuang, and Yu-ming Xu); drafting of the article (Chang-he Shi, Cheng-yuan Mao, and Yu-ming Xu); obtained funding (Chang-he Shi and Yu-ming Xu); administrative, technical, and material support (Chang-he Shi, Cheng-yuan Mao, Shu-yu Zhang, and Jing Yang); and study supervision (Chang-he Shi, Bo Song, JunWu, and Yu-ming Xu) (Shi et al., 2014). NR 25 TC 11 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD FEB PY 2016 VL 38 AR 217.e9 DI 10.1016/j.neurobiolaging.2015.10.040 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA DC1QL UT WOS:000368991300033 PM 26705026 ER PT J AU Clifton, RG Evans, M Cahill, AG Franks, PW Gallagher, D Phelan, S Pomeroy, J Redman, LM Van Horn, L AF Clifton, Rebecca G. Evans, Mary Cahill, Alison G. Franks, Paul W. Gallagher, Dympna Phelan, Suzanne Pomeroy, Jeremy Redman, Leanne M. Van Horn, Linda CA LIFE-Moms Res Grp TI Design of lifestyle intervention trials to prevent excessive gestational weight gain in women with overweight or obesity SO OBESITY LA English DT Article ID BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIAL; PREGNANCY OUTCOMES; PRETERM BIRTH; CESAREAN-DELIVERY; MATERNAL OBESITY; RISK; DIETARY; COMPLICATIONS; HYPERTENSION AB ObjectiveThe Lifestyle Interventions for Expectant Moms (LIFE-Moms) Consortium is designed to determine, in pregnant women with overweight or obesity, whether various behavioral and lifestyle interventions reduce excessive gestational weight gain (GWG) and subsequent adverse maternal and neonatal outcomes and obesity in offspring. The design and planning process of the LIFE-Moms Consortium is described. MethodsThe LIFE-Moms Consortium is a collaboration among seven clinical centers, a Research Coordinating Unit, and the NIH designed to support each clinical center's conduct of a separate trial of a unique intervention. Specific common measures, procedures, and eligibility criteria are consistent across the seven trials allowing data to be combined in exploratory analyses and/or compared readily. ResultsNumerous committees and working groups were created to define common measures and outcomes during pregnancy and through 1 year postpartum, develop Consortium policies, and oversee progress of the trials. The primary outcome for the Consortium is excessive GWG. Secondary outcomes include maternal, neonatal, and infant anthropometric measures, physical activity, sleep, and complications of pregnancy and delivery. ConclusionsA multi-center consortium of independent, lifestyle interventions with common measures and outcomes may enhance the ability to identify promising interventions for improving outcomes in pregnant women and their offspring. C1 [Clifton, Rebecca G.] George Washington Univ, Ctr Biostat, Washington, DC USA. [Evans, Mary] NIDDK, Bethesda, MD 20892 USA. [Cahill, Alison G.] Washington Univ, Sch Med, St Louis, MO USA. [Franks, Paul W.] Lund Univ, Skane Univ Hosp Malmo, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. [Gallagher, Dympna] St Lukes Roosevelt Hosp, Dept Med, New York, NY 10025 USA. [Gallagher, Dympna] Columbia Univ, New York, NY USA. [Phelan, Suzanne] Calif Polytech State Univ San Luis Obispo, Dept Kinesiol, San Luis Obispo, CA 93407 USA. [Pomeroy, Jeremy] NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. [Redman, Leanne M.] Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. [Van Horn, Linda] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Clifton, RG (reprint author), George Washington Univ, Ctr Biostat, Washington, DC USA. EM rclifton@bsc.gwu.edu FU National Institutes of Health (NIH) through The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK094418, U01 DK094463, U01 DK094416, 5U01 DK094466]; National Heart, Lung, and Blood Institute (NHLBI) [U01 HL114344, U01 HL114377]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U01 HD072834]; NIDDK Obesity Nutrition Research Centers [P30 DK026687, P30 DK072476, P30 DK56341]; National Center for Advancing Translational Sciences Clinical and Translational Science Awards [U54 GM104940, U54 MD007587, UL1 RR024992]; National Institute on Minority Health and Health Disparities [S21MD001830]; EXODIAB-Excellence of diabetes research in Sweden FX LIFE-Moms is supported by the National Institutes of Health (NIH) through The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, U01 DK094418, U01 DK094463, U01 DK094416, 5U01 DK094466 [RCU]), The National Heart, Lung, and Blood Institute (NHLBI, U01 HL114344, U01 HL114377), and The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, U01 HD072834). In addition, the National Center for Complementary and Integrative Health (NCCIH), the NIH Office of Research in Women's Health (ORWH), the Office of Behavioral and Social Science Research (OBSSR), the Indian Health Service, and the Intramural Research Program of the NIDDK contributed support. Additional support was received from the NIDDK Obesity Nutrition Research Centers (P30 DK026687, P30 DK072476, P30 DK56341), National Center for Advancing Translational Sciences Clinical and Translational Science Awards (U54 GM104940, U54 MD007587, UL1 RR024992), National Institute on Minority Health and Health Disparities (S21MD001830), and EXODIAB-Excellence of diabetes research in Sweden. NR 37 TC 2 Z9 2 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2016 VL 24 IS 2 BP 305 EP 313 DI 10.1002/oby.21330 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DC3SQ UT WOS:000369139500008 ER PT J AU Therkelsen, KE Pedley, A Rosenquist, KJ Hoffmann, U Massaro, JM Murabito, JM Fox, CS AF Therkelsen, Kate E. Pedley, Alison Rosenquist, Klara J. Hoffmann, Udo Massaro, Joseph M. Murabito, Joanne M. Fox, Caroline S. TI Adipose tissue attenuation as a marker of adipose tissue quality: Associations with six-year changes in body weight SO OBESITY LA English DT Article DE epidemiology; adipose tissue; population studies; obesity ID COMPUTED TOMOGRAPHIC ATTENUATION; INSULIN SENSITIVITY; ABDOMINAL FAT; OBESE INDIVIDUALS; CONTROLLED-TRIAL; RISK-FACTORS; FRAMINGHAM; EXERCISE; HEART; DIET AB ObjectiveWeight gain is associated with fat volume increases, but associations with fat quality are less well characterized The associations of weight change with visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume and attenuation were investigated. MethodsComputed tomography abdominal scans were acquired on a Framingham Heart Study subset (N=836; 40.2% women; mean age 45.7years), a mean of 6.1years apart. Fat attenuation estimated fat quality. ResultsMean weight change was +2.0 (SD 6.8; IQR -0.7, 5.0)kg in women and +2.7 (SD 6.0; IQR -0.5, 5.4)kg in men. Per 2.5kg weight increase in women, VAT volume increased 126cm(3) (95% CI, 112-140, p<0.0001), SAT volume increased 258cm(3) (95% CI, 239-278, p<0.0001), and fat attenuation decreased (i.e., fat quality worsened) in VAT and SAT (p<0.0001). Increasing VAT volume was associated with decreasing fat attenuation even after accounting for weight change. Relative to weight-stable women (n=129), women who lost >2.5kg (n=58) had smaller SAT attenuation decreases (p<0.0001). Similar patterns were seen in men. ConclusionsWeight gain was associated with decreases in fat attenuation independent of VAT and SAT volume changes. These findings highlighted the associations of weight gain and worsening fat attenuation, suggesting fat attenuation may be dynamic. C1 [Therkelsen, Kate E.; Pedley, Alison; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Therkelsen, Kate E.; Pedley, Alison; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Rosenquist, Klara J.] North Shore Phys Grp, Dept Endocrinol, Peabody, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Div Intramural Res, Framingham, MA USA.; Fox, CS (reprint author), NHLBI, Ctr Populat Studies, Framingham, MA USA.; Fox, CS (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Fox, CS (reprint author), Brigham & Womens Hosp, Div Endocrinol & Metab, 75 Francis St, Boston, MA 02115 USA. EM foxca@nhlbi.nih.gov FU [N01-HC-25195] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. NR 30 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2016 VL 24 IS 2 BP 499 EP 505 DI 10.1002/oby.21337 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DC3SQ UT WOS:000369139500032 PM 26694629 ER PT J AU Ma, JT Hwang, SJ McMahon, GM Curhan, GC Mclean, RR Murabito, JM Fox, CS AF Ma, Jiantao Hwang, Shih-Jen McMahon, Gearoid M. Curhan, Gary C. Mclean, Robert R. Murabito, Joanne M. Fox, Caroline S. TI Mid-adulthood cardiometabolic risk factor profiles of sarcopenic obesity SO OBESITY LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; UBIQUITIN-PROTEASOME PATHWAY; OLDER-ADULTS; INSULIN-RESISTANCE; METABOLIC SYNDROME; DIABETES-MELLITUS; BODY-COMPOSITION; MUSCLE STRENGTH; HEALTH; PREVALENCE AB ObjectiveMidlife and contemporaneous cardiometabolic risk factors associated with sarcopenic obesity were examined. MethodsUtilizing BMI and sex-specific 24-h urinary creatinine excretion, 1,019 participants from the Framingham cohorts were categorized as non-sarcopenia non-obese (NSNO), non-obese sarcopenia, non-sarcopenic obesity, and sarcopenic obesity. Cardiometabolic risk factors were quantified by standard laboratory assessment cross-sectionally and 10, 20, and 30 years before sarcopenic obesity assessment. ResultsNSNO, sarcopenia, obesity, and sarcopenic obesity accounted for 30.0%, 39.6%, 20.0%, and 10.4% of study participants, respectively. Cross-sectionally, participants with sarcopenic obesity had a higher proportion of hypertension, metabolic syndrome, and type 2 diabetes than those with NSNO or sarcopenia (all P<0.03). Similar patterns were observed retrospectively at 10, 20, and 30 years. Compared with NSNO or sarcopenia, sarcopenic obesity was associated with a higher prevalence of type 2 diabetes at 10 years and hypertension and metabolic syndrome at all three time points before baseline (all P<0.03). Individuals with sarcopenic obesity had more type 2 diabetes than those with obesity alone at baseline and 10 years prior (all P<0.001). ConclusionsOlder adults with sarcopenic obesity had more adverse midlife cardiometabolic risks, particularly diabetes 10 years earlier, which suggests the importance of early identification of risk factors associated with sarcopenic obesity. C1 [Ma, Jiantao; Hwang, Shih-Jen; McMahon, Gearoid M.; Murabito, Joanne M.; Fox, Caroline S.] NHLBI, Framingham Heart Study & Populat Sci Branch, Framingham, MA USA. [McMahon, Gearoid M.; Curhan, Gary C.] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [McMahon, Gearoid M.; Curhan, Gary C.] Harvard Univ, Sch Med, Boston, MA USA. [Mclean, Robert R.] Inst Aging Res, Hebrew SeniorLife, Boston, MA USA. [Mclean, Robert R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study & Populat Sci Branch, Framingham, MA USA. EM foxca@nhlbi.nih.gov FU Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health [N01-HC-25195]; Boston University School of Medicine FX This work was conducted in part using resources and data from the Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (N01-HC-25195) and Boston University School of Medicine. NR 38 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD FEB PY 2016 VL 24 IS 2 BP 526 EP 534 DI 10.1002/oby.21356 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA DC3SQ UT WOS:000369139500035 PM 26813531 ER PT J AU Cagigi, A Cotugno, N Rinaldi, S Santilli, V Rossi, P Palma, P AF Cagigi, Alberto Cotugno, Nicola Rinaldi, Stefano Santilli, Veronica Rossi, Paolo Palma, Paolo TI Downfall of the current antibody correlates of influenza vaccine response in yearly vaccinated subjects: Toward qualitative rather than quantitative assays SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Review DE repeated immunization; long-lasting immunologic memory; antibody vs; memory B-cell responses ID KIDNEY-TRANSPLANTED PATIENTS; B-CELL RESPONSES; ANTIRETROVIRAL THERAPY; GERMINAL-CENTERS; INFECTION; VIRUS; SIGNATURES; IMMUNITY; SYSTEMS; IMMUNOGENICITY AB Response to seasonal influenza vaccination is currently evaluated by antibody correlates that estimate vaccine seroconversion as well as immune protection. These correlates rely on the general dogmas surrounding seasonal influenza vaccination; that is, that vaccine-induced antibodies would exclusively generate immunity to influenza vaccine strains and that protective immunity would wane before the next season. Here, we summarize recently reported data on immunity to seasonal influenza in healthy individuals and rediscuss results on yearly vaccinated pediatric immunocompromised patients that together highlight the need for revision of the current correlates of vaccine response to shift from quantitative to qualitative measurements. C1 [Cagigi, Alberto; Cotugno, Nicola; Santilli, Veronica; Rossi, Paolo; Palma, Paolo] Bambino Gesu Pediat Hosp, Unit Immune & Infect Dis, DPUO, Univ Dept Pediat, Rome, Italy. [Cotugno, Nicola; Rinaldi, Stefano; Rossi, Paolo] Univ Roma Tor Vergata, Dept Syst Med, Chair Pediat, Rome, Italy. RP Cagigi, A (reprint author), NIAID, Biodef Res Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40-2609B, Bethesda, MD USA. EM alberto.cagigi@gmail.com RI Cagigi, Alberto/K-4824-2016; OI Cagigi, Alberto/0000-0002-3567-9514; Palma, Paolo/0000-0002-3066-4719; Cotugno, Nicola/0000-0002-7748-1581; ROSSI, PAOLO/0000-0003-2620-7918 NR 35 TC 2 Z9 2 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0905-6157 EI 1399-3038 J9 PEDIAT ALLERG IMM-UK JI Pediatr. Allergy Immunol. PD FEB PY 2016 VL 27 IS 1 BP 22 EP 27 DI 10.1111/pai.12483 PG 6 WC Allergy; Immunology; Pediatrics SC Allergy; Immunology; Pediatrics GA DB8VO UT WOS:000368795400004 PM 26480951 ER PT J AU Pickering, CM Grady, C Medvar, B Emamian, M Sandoval, PC Zhao, Y Yang, CR Jung, HJ Chou, CL Knepper, MA AF Pickering, Christina M. Grady, Cameron Medvar, Barbara Emamian, Milad Sandoval, Pablo C. Zhao, Yue Yang, Chin-Rang Jung, Hyun Jun Chou, Chung-Lin Knepper, Mark A. TI Proteomic profiling of nuclear fractions from native renal inner medullary collecting duct cells SO PHYSIOLOGICAL GENOMICS LA English DT Article DE aquaporin-2; LC-MS/MS; kidney; transcription; transcription factor; chromatin; mRNA splicing ID VASOPRESSIN SIGNALING NETWORK; TANDEM MASS-SPECTRA; LC-MS/MS ANALYSIS; RAT-KIDNEY; QUANTITATIVE PHOSPHOPROTEOMICS; WATER PERMEABILITY; INTRACELLULAR CA2+; MODIFIED PEPTIDES; SYSTEMS BIOLOGY; MESSENGER-RNA AB Pickering CM, Grady C, Medvar B, Emamian M, Sandoval PC, Zhao Y, Yang CR, Jung HJ, Chou CL, Knepper MA. Proteomic profiling of nuclear fractions from native renal inner medullary collecting duct cells. Physiol Genomics 48: 154-166, 2016. First published October 27, 2015; doi:10.1152/physiolgenomics.00090.2015.-Thecontrol of renal water excretion occurs in part by regulation of transcription in response to vasopressin in cells of the collecting duct. A systems biology-based approach to understanding transcriptional control in renal collecting duct cells depends on knowledge of what transcription factors and other regulatory proteins are present in the cells' nuclei. The goal of this article is to report comprehensive proteomic profiling of cellular fractions enriched in nuclear proteins from native inner medullary collecting duct (IMCD) cells of the rat. Multidimensional separation procedures and state-of-the art protein mass spectrometry produced 18 GB of spectral data that allowed the high-stringency identification of 5,048 proteins in nuclear pellet (NP) and nuclear extract (NE) fractions of biochemically isolated rat IMCD cells (URL: https://helixweb.nih.gov/ESBL/Database/IMCD_Nucleus/). The analysis identified 369 transcription factor proteins out of the 1,371 transcription factors coded by the rat genome. The analysis added 1,511 proteins to the recognized proteome of rat IMCD cells, now amounting to 8,290 unique proteins. Analysis of samples treated with the vasopressin analog dDAVP (1 nM for 30 min) or its vehicle revealed 99 proteins in the NP fraction and 88 proteins in the NE fraction with significant changes in spectral counts (Fisher exact test, P < 0.005). Among those altered by vasopressin were seven distinct histone proteins, all of which showed decreased abundance in the NP fraction, consistent with a possible effect of vasopressin to induce chromatin remodeling. The results provide a data resource for future studies of vasopressin-mediated transcriptional regulation in the renal collecting duct. C1 [Pickering, Christina M.; Grady, Cameron; Medvar, Barbara; Emamian, Milad; Sandoval, Pablo C.; Zhao, Yue; Yang, Chin-Rang; Jung, Hyun Jun; Chou, Chung-Lin; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N307,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov FU Division of Intramural Research of the NHLBI [HL-001285, HL-006129]; National Institute for Biomedical Imaging and Bioengineering; Korea Health Industry Development Institute of the Korea Ministry of Health and Welfare; National Institutes of Health [HI13C1211] FX The study was carried out in the Division of Intramural Research of the NHLBI (Projects HL-001285 and HL-006129, M. A. Knepper). C. M. Pickering is an undergraduate student from the Department of Chemical Engineering at Auburn University and was a member of the Biomedical Engineering Student Internship Program supported by the National Institute for Biomedical Imaging and Bioengineering (June-August, 2014). C. Grady was a member of the NHLBI Student Summer Internship Program (May-August, 2015). H. J. Jung is the recipient of the Korean Visiting Scientist Training Award, supported by the Korea Health Industry Development Institute of the Korea Ministry of Health and Welfare in cooperation with National Institutes of Health (HI13C1211). NR 70 TC 2 Z9 2 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 EI 1531-2267 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD FEB 1 PY 2016 VL 48 IS 2 BP 154 EP 166 DI 10.1152/physiolgenomics.00090.2015 PG 13 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA DC3FY UT WOS:000369106300008 PM 26508704 ER PT J AU Mian, OY Khattab, MH Hedayati, M Coulter, J Abubaker-Sharif, B Schwaninger, JM Veeraswamy, RK Brooks, JD Hopkins, L Shinohara, DB Cornblatt, B Nelson, WG Yegnasubramanian, S DeWeese, TL AF Mian, Omar Y. Khattab, Mohamed H. Hedayati, Mohammad Coulter, Jonathan Abubaker-Sharif, Budri Schwaninger, Julie M. Veeraswamy, Ravi K. Brooks, James D. Hopkins, Lisa Shinohara, Debika Biswal Cornblatt, Brian Nelson, William G. Yegnasubramanian, Srinivasan DeWeese, Theodore L. TI GSTP1 Loss Results in Accumulation of Oxidative DNA Base Damage and Promotes Prostate Cancer Cell Survival Following Exposure to Protracted Oxidative Stress SO PROSTATE LA English DT Article DE prostate; GSTP1; oxidative stress; cancer ID GLUTATHIONE-S-TRANSFERASE; PROLIFERATIVE INFLAMMATORY ATROPHY; CPG ISLAND; PI; HYPERMETHYLATION; EXPRESSION; CARCINOGENESIS; RESISTANCE; STEM AB BACKGROUND. Epigenetic silencing of glutathione S-transferase pi (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS. GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1-transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS. GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS. The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, antineoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis. (C) 2015 Wiley Periodicals, Inc. C1 [Mian, Omar Y.; Hedayati, Mohammad; Coulter, Jonathan; Abubaker-Sharif, Budri; DeWeese, Theodore L.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD 21287 USA. [Khattab, Mohamed H.; Abubaker-Sharif, Budri; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21287 USA. [Schwaninger, Julie M.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Veeraswamy, Ravi K.] Emory Univ, Dept Vasc Surg, Atlanta, GA 30322 USA. [Brooks, James D.] Stanford Univ, Dept Urol, Palo Alto, CA 94304 USA. [Hopkins, Lisa] St Peters Univ Hosp Breast Ctr, New Brunswick, NJ USA. [Shinohara, Debika Biswal; Nelson, William G.; Yegnasubramanian, Srinivasan; DeWeese, Theodore L.] Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. [Cornblatt, Brian] Nuramax Labs, Edgewood, MD USA. RP DeWeese, TL (reprint author), Johns Hopkins Univ Hosp, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. EM deweese@jhmi.edu OI Coulter, Jonathan/0000-0003-0380-9254; Abubaker-Sharif, Bedri/0000-0001-5003-7934 FU NCI/NIH [P30CA006973, R01CA183965, P50CA058236]; Prostate Cancer Foundation; Commonwealth Foundation; Masenhimer Fellowship FX Grant sponsor: NCI/NIH; Grant numbers: P30CA006973; R01CA183965; P50CA058236; Grant sponsor: Prostate Cancer Foundation; Grant sponsor: Commonwealth Foundation; Grant sponsor: Masenhimer Fellowship. NR 28 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD FEB 1 PY 2016 VL 76 IS 2 BP 199 EP 206 DI 10.1002/pros.23111 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA DB9BJ UT WOS:000368810600007 PM 26447830 ER PT J AU Landegren, N Sharon, D Freyhult, E Hallgren, A Eriksson, D Edqvist, PH Bensing, S Wahlberg, J Nelson, LM Gustafsson, J Husebye, ES Anderson, MS Snyder, M Kampe, O AF Landegren, Nils Sharon, Donald Freyhult, Eva Hallgren, Asa Eriksson, Daniel Edqvist, Per-Henrik Bensing, Sophie Wahlberg, Jeanette Nelson, Lawrence M. Gustafsson, Jan Husebye, Eystein S. Anderson, Mark S. Snyder, Michael Kampe, Olle TI Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1 SO SCIENTIFIC REPORTS LA English DT Article ID CANDIDIASIS-ECTODERMAL DYSTROPHY; SYNDROME TYPE-I; CHRONIC MUCOCUTANEOUS CANDIDIASIS; ENDOPLASMIC-RETICULUM; DISULFIDE-ISOMERASE; ADDISONS-DISEASE; MALE-INFERTILITY; T-CELLS; AUTOANTIBODIES; GENE AB Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance. C1 [Landegren, Nils; Hallgren, Asa; Eriksson, Daniel; Kampe, Olle] Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden. [Landegren, Nils; Freyhult, Eva; Hallgren, Asa; Eriksson, Daniel; Kampe, Olle] Uppsala Univ, Dept Med Sci, Sci Life Lab, S-75105 Uppsala, Sweden. [Sharon, Donald; Snyder, Michael] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Sharon, Donald] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. [Freyhult, Eva] Uppsala Univ, Dept Med Sci Canc Pharmacol & Computat Med, S-75105 Uppsala, Sweden. [Edqvist, Per-Henrik] Uppsala Univ, Dept Immunol Genet & Pathol, S-75105 Uppsala, Sweden. [Edqvist, Per-Henrik] Sci Life Lab, Uppsala, Sweden. [Bensing, Sophie] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Wahlberg, Jeanette] Linkoping Univ, Dept Endocrinol, Linkoping, Sweden. [Wahlberg, Jeanette] Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden. [Wahlberg, Jeanette] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Nelson, Lawrence M.] NICHHD, Integrat Reprod Med Grp, Intramural Res Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Gustafsson, Jan] Uppsala Univ, Dept Womens & Childrens Hlth, S-75105 Uppsala, Sweden. [Husebye, Eystein S.] Univ Bergen, Dept Clin Sci, Bergen, Norway. [Husebye, Eystein S.] Haukeland Hosp, Dept Med, N-5021 Bergen, Norway. [Anderson, Mark S.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. RP Landegren, N (reprint author), Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.; Landegren, N (reprint author), Uppsala Univ, Dept Med Sci, Sci Life Lab, S-75105 Uppsala, Sweden. EM nils.landegren@ki.se OI Kampe, Olle/0000-0001-6091-9914 FU Swedish Research Council; Formas Research Council; Torsten Soderberg Foundation; Ragnar Soderberg Foundation; Novonordisk Foundation; Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA FX We thank the tissue profiling facility at Science for Life Laboratory for excellent technical assistance. We also thank Aleksander Giwercman for kindly providing serum samples from males with idiopathic infertility and the Swedish Addison Registry for providing samples from females with gonadal insufficiency. The work was supported by the Swedish Research Council, the Formas Research Council, The Torsten and Ragnar Soderbergs Foundations, the Novonordisk Foundation and the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA. NR 45 TC 3 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 1 PY 2016 VL 6 AR 20104 DI 10.1038/srep20104 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC1SI UT WOS:000368996700001 PM 26830021 ER PT J AU Simpson, EA Miller, GM Ferrari, PF Suomi, SJ Paukner, A AF Simpson, Elizabeth A. Miller, Grace M. Ferrari, Pier F. Suomi, Stephen J. Paukner, Annika TI Neonatal imitation and early social experience predict gaze following abilities in infant monkeys SO SCIENTIFIC REPORTS LA English DT Article ID JOINT VISUAL-ATTENTION; MIRROR NEURON SYSTEM; FACIAL GESTURES; INDIVIDUAL-DIFFERENCES; RHESUS MACAQUES; MACACA-MULATTA; EYE GAZE; AUTISM; SKILLS; MECHANISM AB Individuals vary in their social skills and motivation, the causes of which remain largely unknown. Here we investigated whether an individual's propensity to interact with others measured within days after birth, and differences in infants' early social environment, may predict a later social skill. Specifically, we tested whether neonatal imitation-newborns' capacity to match modelled actions-and social experience in the first months of life predict gaze following (directing attention to locations where others look), in infant macaques (Macaca mulatta; n = 119). Facial gesture imitation in the first week of life predicted gaze following at 7 months of age. Imitators were better at gaze following than non-imitators, suggesting neonatal imitation may be an early marker predicting socio-cognitive functioning. In addition, infants with rich social environments outperformed infants with less socialization, suggesting early social experiences also support the development of infants' gaze following competence. The present study offers compelling evidence that an individual difference present from birth predicts a functional social cognitive skill in later infancy. In addition, this foundational skill-gaze following-is plastic, and can be improved through social interactions, providing infants with a strong foundation for later social interaction and learning. C1 [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, Coral Gables, FL USA. [Simpson, Elizabeth A.; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-43100 Parma, Italy. [Simpson, Elizabeth A.; Miller, Grace M.; Suomi, Stephen J.; Paukner, Annika] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. [Miller, Grace M.] Univ Virginia, Clin & Sch Psychol, Charlottesville, VA USA. RP Paukner, A (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Poolesville, MD USA. EM pauknera@mail.nih.gov OI Simpson, Elizabeth/0000-0003-2715-2533 FU Division of Intramural Research, NICHD; NICHD [P01HD064653] FX We thank Angela Ruggiero, Michelle Miller, and the staff and volunteers of the Laboratory of Comparative Ethology for help with data collection. Supported by the Division of Intramural Research, NICHD, and NICHD P01HD064653. NR 58 TC 1 Z9 1 U1 5 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 1 PY 2016 VL 6 AR 20233 DI 10.1038/srep20233 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC1QT UT WOS:000368992200001 PM 26831763 ER PT J AU Beydoun, HA Beydoun, MA Jeng, HA Zonderman, AB Eid, SM AF Beydoun, Hind A. Beydoun, May A. Jeng, Hueiwang Anna Zonderman, Alan B. Eid, Shaker M. TI Bisphenol-A and Sleep Adequacy among Adults in the National Health and Nutrition Examination Surveys SO SLEEP LA English DT Article DE bisphenol-A; endocrine disruptor; sleep duration; sleep disorder; survey ID METABOLIC SYNDROME; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; ENDOCRINE DISRUPTORS; CARDIOVASCULAR-DISEASE; NHANES 2003-2006; UNITED-STATES; OLDER-ADULTS; RISK-FACTORS; LIFE-STYLE AB Study Objectives: To evaluate bisphenol-A (BPA) level and its relationship to sleep adequacy in a nationally representative sample of U.S. adults. Methods: A population-based cross-sectional study was conducted using 2005-2010 National Health and Nutrition Examination Survey whereby data were collected using in-person interviews, physical examination and laboratory testing. BPA level was measured in urine samples and analyzed as loge-transformed variable and in quartiles (< 0.9 ng/mL; 0.9 to < 1.9 ng/mL; 1.9 to < 3.7 ng/mL; 3.7+ ng/mL). Sleep adequacy was operationalized with three questions: "How much sleep do you usually get at night on weekdays or workdays?", "Have you ever told a doctor or other health professionals that you have trouble sleeping?" and "Have you ever been told by a doctor or other health professional that you have a sleep disorder?" Sleep duration was further categorized as (< 6 h, >= 6 h); (< 7 h, 7-8 h, > 8 h); (< 5 h, 5-6 h, 7-8 h, >= 9 h). Linear, binary, and ordinal logistic regression models were constructed. Results: Loge-transformed BPA level was inversely related to sleep duration defined, in hours, as a continuous variable, a dichotomous variable (>= 6, < 6), or an ordinal variable (>= 9, 7-8, 5-6, < 5), after adjustment for confounders. Help-seeking behavior for sleep problems and diagnosis with sleep disorders were not significantly associated with loge-transformed BPA level in fully adjusted models. Conclusions: Loge-transformed BPA level may be associated with fewer hours of sleep among U.S. adults, with implications for prevention. Further research involving diverse populations are needed to confirm these study findings. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, 651 Colley Ave Room 401, Norfolk, VA 23501 USA. [Beydoun, May A.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Intramural Res Program, Baltimore, MD 21224 USA. [Jeng, Hueiwang Anna] Old Dominion Univ, Dept Community & Environm Hlth, Norfolk, VA USA. [Eid, Shaker M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, 651 Colley Ave Room 401, Norfolk, VA 23501 USA. EM baydouha@evms.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA/NIH/IRP) FX This was not an industry supported study. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA/NIH/IRP). The authors have indicated no financial conflicts of interest. The work was performed at the Eastern Virginia Medical School, Norfolk, VA. NR 105 TC 0 Z9 0 U1 1 U2 9 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD FEB 1 PY 2016 VL 39 IS 2 BP 467 EP 476 DI 10.5665/sleep.5466 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DC0WH UT WOS:000368938100023 PM 26446109 ER PT J AU Andas, HT Enger, A Oiestad, AML Vindenes, V Christophersen, AS Huestis, MA Oiestad, EL AF Andas, Hilde T. Enger, Asle Oiestad, Ase Marit L. Vindenes, Vigdis Christophersen, Asbjorg S. Huestis, Marilyn A. Oiestad, Elisabeth L. TI Extended Detection of Amphetamine and Methamphetamine in Oral Fluid SO THERAPEUTIC DRUG MONITORING LA English DT Article DE oral fluid; amphetamine; methamphetamine; detection time; intercept oral fluid collection device ID TANDEM MASS-SPECTROMETRY; URINARY-EXCRETION; DRUG-ABUSE; PHARMACOKINETICS; BLOOD; SMOKING; HUMANS; PLASMA; MS/MS AB Background:Amphetamine and methamphetamine are popular drugs of abuse worldwide and are important components of drug monitoring programs. Windows of detection for amphetamine and methamphetamine in oral fluid after high doses have not been investigated. Repeated high-dose ingestions are likely to cause positive samples for extended periods. Common routes of administration of amphetamine/methamphetamine in Norway are oral intake or injection. The aim of this study was to investigate windows of detection for amphetamine and methamphetamine in oral fluid from drug addicts under sustained abstinence during detoxification.Methods:Twenty-five patients admitted to a closed detoxification unit were included in this study. Oral fluid samples were collected daily in the morning and evening, and urine every morning for 10 days. A blood sample was drawn during the first 5 days after admission if the patient consented. Oral fluid results were compared with urine results to determine whether a new ingestion occurred. Oral fluid was collected with the Intercept oral fluid collection device. In-house cutoff concentrations for amphetamine and methamphetamine were 6.8 and 7.5 mcg/L, respectively, in oral fluid, and 135 and 149 mcg/L, respectively, in urine.Results:Amphetamines were detected in 11 oral fluid, 5 urine, and 2 blood specimens from 25 patients. Patients self-reported amphetamines intake of up to 0.5-2 g daily. Windows of detection for amphetamine and methamphetamine in oral fluid were up to 8 days, longer than in urine at the applied cutoff values.Conclusions:These data confirm that oral fluid is a viable alternative to urine for monitoring amphetamine abuse, and that these substances might be detected in oral fluid for at least 1 week after ingestion of high doses. Such long detection times were, as far as we are aware, never reported previously for oral fluid amphetamines. C1 [Andas, Hilde T.; Oiestad, Ase Marit L.; Vindenes, Vigdis; Christophersen, Asbjorg S.; Oiestad, Elisabeth L.] Norwegian Inst Publ Hlth, Div Forens Sci, Oslo, Norway. [Enger, Asle] Trasoppklinikken, Oslo, Norway. [Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, IRP, NIH, Baltimore, MD USA. [Oiestad, Elisabeth L.] Univ Oslo, Sch Pharm, Dept Pharmaceut Chem, Oslo, Norway. RP Oiestad, EL (reprint author), Norwegian Inst Publ Hlth, Div Forens Sci, Oslo, Norway.; Oiestad, EL (reprint author), Univ Oslo, Sch Pharm, Dept Pharmaceut Chem, Oslo, Norway. EM elisabeth.oiestad@fhi.no NR 28 TC 2 Z9 2 U1 5 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0163-4356 EI 1536-3694 J9 THER DRUG MONIT JI Ther. Drug Monit. PD FEB PY 2016 VL 38 IS 1 BP 114 EP 119 DI 10.1097/FTD.0000000000000248 PG 6 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA DB8YJ UT WOS:000368802800015 PM 26402425 ER PT J AU Rebholz, CM Grams, ME Lutsey, PL Hoofnagle, AN Misialek, JR Inker, LA Levey, AS Selvin, E Hsu, CY Kimmel, PL Vasan, RS Eckfeldt, JH Coresh, J AF Rebholz, Casey M. Grams, Morgan E. Lutsey, Pamela L. Hoofnagle, Andrew N. Misialek, Jeffrey R. Inker, Lesley A. Levey, Andrew S. Selvin, Elizabeth Hsu, Chi-yuan Kimmel, Paul L. Vasan, Ramachandran S. Eckfeldt, John H. Coresh, Josef CA Chronic Kidney Dis Biomarkers TI Biomarkers of Vitamin D Status and Risk of ESRD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Biological markers; chronic renal failure; end-stage renal disease (ESRD); risk factors; vitamin D-binding protein; vitamin D; mineral metabolism biomarker; vitamin D insufficiency ID CHRONIC KIDNEY-DISEASE; FIBROBLAST GROWTH FACTOR-23; D-BINDING PROTEIN; MINERAL METABOLISM; ATHEROSCLEROSIS RISK; D DEFICIENCY; SERUM; 1,25-DIHYDROXYVITAMIN-D; 25-HYDROXYVITAMIN-D; ASSOCIATION AB Background: Disordered mineral metabolism is characteristic of decreased kidney function. However, the prospective associations between circulating levels of vitamin D binding protein, vitamin D, and end-stage renal disease (ESRD) have not been extensively evaluated in epidemiologic studies. Study Design: Nested case-control study. Setting & Participants: Middle-aged black and white men and women from 4 US communities. Predictors: Baseline levels of vitamin D binding protein, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH](2)D) were measured in blood samples collected at study visit 4 (1996-1998) of the ARIC (Atherosclerosis Risk in Communities) Study. Outcome: ESRD cases (n = 184) were identified through hospitalization diagnostic codes from 1996 to 2008 and were frequency matched to controls (n = 251) on categories of estimated glomerular filtration rate, albuminuria, diabetes mellitus, sex, and race. Measurements: Logistic regression was used to estimate the association between mineral metabolism biomarkers (vitamin D binding protein, 25(OH)D, and 1,25(OH)(2)D) and incident ESRD, adjusting for age, sex, race, estimated glomerular filtration rate, albuminuria, diabetes mellitus, hypertension, education, specimen type, and serum levels of calcium, phosphate, and parathyroid hormone. Results: Higher vitamin D binding protein levels were associated with elevated risk for incident ESRD (OR, 1.76; 95% Cl, 1.22-2.54; P = 0.003). Higher free and bioavailable 25(OH)D levels were associated with reduced risk for incident ESRD (ORs of 0.65 [95% Cl, 0.46-0.92; P = 0.02] and 0.63 [95% Cl, 0.43-0.91; P = 0.02] for free and bioavailable 25[OH]D, respectively). There was no association between ESRD and overall levels of 25(OH)D (OR, 0.83; 95% Cl, 0.58-1.19; P = 0.3) or 1,25(OH)(2)D (OR, 0.73; 95% Cl, 0.48-1.13; P = 0.2). Limitations: Lack of direct measurement of free and bioavailable vitamin D. Conclusions: In the general population, blood levels of vitamin D binding protein were positively associated and blood levels of free and bioavailable 25(OH)D were inversely associated with new-onset ESRD during follow-up. (C) 2016 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Rebholz, Casey M.; Grams, Morgan E.; Selvin, Elizabeth; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Rebholz, Casey M.; Grams, Morgan E.; Selvin, Elizabeth; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Grams, Morgan E.] Johns Hopkins Sch Med, Dept Med, Div Nephrol, Baltimore, MD USA. [Lutsey, Pamela L.; Misialek, Jeffrey R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Hoofnagle, Andrew N.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Inker, Lesley A.; Levey, Andrew S.] Tufts Med Ctr, Dept Med, William B Schwartz Div Nephrol, Boston, MA USA. [Selvin, Elizabeth; Coresh, Josef] Johns Hopkins Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD USA. [Hsu, Chi-yuan] Univ Calif San Francisco, Sch Med, Dept Med, Div Nephrol, San Francisco, CA USA. [Kimmel, Paul L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Dept Med, Boston, MA 02118 USA. [Eckfeldt, John H.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Rebholz, CM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Ste 2-600, Baltimore, MD 21287 USA. EM crebhol1@jhu.edu OI Grams, Morgan/0000-0002-4430-6023; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK089174]; NHLBI [R01HL103706]; NIDDK [U01DK085689] FX The ARIC Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This work was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK089174 (Principal Investigator: E. Selvin) and NHLBI grant R01HL103706 (Principal Investigator: P. Lutsey). Additional support is provided by U01DK085689 from the NIDDK (Chronic Kidney Disease Biomarkers Consortium). The study sponsors had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. NR 40 TC 2 Z9 2 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2016 VL 67 IS 2 BP 235 EP 242 DI 10.1053/j.ajkd.2015.08.026 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA DB3NQ UT WOS:000368418800015 PM 26475393 ER PT J AU Torres, OB Antoline, JFG Li, FY Jalah, R Jacobson, AE Rice, KC Alving, CR Matyas, GR AF Torres, Oscar B. Antoline, Joshua F. G. Li, Fuying Jalah, Rashmi Jacobson, Arthur E. Rice, Kenner C. Alving, Carl R. Matyas, Gary R. TI A simple nonradioactive method for the determination of the binding affinities of antibodies induced by hapten bioconjugates for drugs of abuse SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Heroinhapten; Competition ELISA; Equilibrium dialysis; UPLC/MS/MS; Apparent dissociation constant (K-d); Antibody affinity ID LINKED IMMUNOSORBENT ASSAY; SIMPLE CHEMICAL-COMPOUNDS; MINIMAL CROSS-REACTIVITY; DIACETYLMORPHINE HEROIN; MONOCLONAL-ANTIBODIES; MASS-SPECTROMETRY; MORPHINE; RADIOIMMUNOASSAY; VACCINE; SPECIFICITY AB The accurate analytical measurement of binding affinities of polyclonal antibody in sera to heroin, 6-acetylmorphine (6-AM), and morphine has been a challenging task. A simple nonradioactive method that uses deuterium-labeled drug tracers and equilibrium dialysis (ED) combined with ultra performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) to measure the apparent dissociation constant (K (d)) of antibodies to 6-AM and morphine is described. The method can readily detect antibodies with K (d) in the low nanomolar range. Since heroin is rapidly degraded in sera, esterase inhibitors were included in the assay, greatly reducing heroin hydrolysis. MS/MS detection directly measured the heroin in the assay after overnight ED, thereby allowing the quantitation of % bound heroin in lieu of K (d) as an alternative measurement to assess heroin binding to polyclonal antibody sera. This is the first report that utilizes a solution-based assay to quantify heroin-antibody binding without being confounded by the presence of 6-AM and morphine and to measure K (d) of polyclonal antibody to 6-AM. Hapten surrogates 6-AcMorHap, 6-PrOxyHap, MorHap, DiAmHap, and DiPrOxyHap coupled to tetanus toxoid (TT) were used to generate high affinity antibodies to heroin, 6-AM, and morphine. In comparison to competition ED-UPLC/MS/MS which gave K (d) values in the nanomolar range, the commonly used competition enzyme-linked immunosorbent assay (ELISA) measured the 50 % inhibition concentration (IC50) values in the micromolar range. Despite the differences in K (d) and IC50 values, similar trends in affinities of hapten antibodies to heroin, 6-AM, and morphine were observed by both methods. Competition ED-UPLC/MS/MS revealed that among the five TT-hapten bioconjugates, TT-6-AcMorHap and TT-6-PrOxyHap induced antibodies that bound heroin, 6-AM, and morphine. In contrast, TT-MorHap induced antibodies that poorly bound heroin, while TT-DiAmHap and TT-DiPrOxyHap induced antibodies either did not bind or poorly bound to heroin, 6-AM, and morphine. This simple and nonradioactive method can be extended to other platforms, such as oxycodone, cocaine, nicotine, and methamphetamine for the selection of the lead hapten design during substance abuse vaccine development. C1 [Torres, Oscar B.; Jalah, Rashmi; Alving, Carl R.; Matyas, Gary R.] Walter Reed Army Inst Res, Lab Adjuvant & Antigen Res, US Mil HIV Res Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. [Torres, Oscar B.; Jalah, Rashmi] Henry M Jackson Fdn Adv Mil Med, US Mil HIV Res Program, 6720A Rockledge Dr, Bethesda, MD 20817 USA. [Antoline, Joshua F. G.; Li, Fuying; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Mol Targets & Medicat Discovery Branch, NIH,US Dept HHS, 9800 Med Dr, Bethesda, MD 20892 USA. [Antoline, Joshua F. G.; Li, Fuying; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, 9800 Med Dr, Bethesda, MD 20892 USA. [Li, Fuying] WuXi AppTec Shanghai Co Ltd, 288 FuTe Rd, Shanghai 200131, Peoples R China. RP Matyas, GR (reprint author), Walter Reed Army Inst Res, Lab Adjuvant & Antigen Res, US Mil HIV Res Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM gmatyas@hivresearch.org OI Matyas, Gary/0000-0002-2074-2373 FU Intramural NIH HHS; NIDA NIH HHS [1DP1DA034787-01, DP1 DA034787] NR 50 TC 1 Z9 1 U1 5 U2 19 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 EI 1618-2650 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD FEB PY 2016 VL 408 IS 4 BP 1191 EP 1204 DI 10.1007/s00216-015-9223-z PG 14 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DB7TZ UT WOS:000368720600016 PM 26677020 ER PT J AU Yoshioka, Y Ono, M Maeda, A Kilts, TM Hara, ES Khattab, H Ueda, J Aoyama, E Oohashi, T Takigawa, M Young, MF Kuboki, T AF Yoshioka, Yuya Ono, Mitsuaki Maeda, Azusa Kilts, Tina M. Hara, Emilio Satoshi Khattab, Hany Ueda, Junji Aoyama, Eriko Oohashi, Toshitaka Takigawa, Masaharu Young, Marian F. Kuboki, Takuo TI CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-beta 3 function SO BONE LA English DT Article DE Bone marrow stromal cell (BMSC); Chondrogenesis; CCN4/WISP-1; TGF-beta 3; Articular cartilage ID TISSUE-GROWTH-FACTOR; NECROSIS-FACTOR-ALPHA; JAPANESE WOMEN; BONE TURNOVER; TNF-ALPHA; OSTEOARTHRITIS; CHONDROCYTES; EXPRESSION; CARTILAGE; PROTEIN-1 AB The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-beta 3 (TGF-beta 3). Overexpression of CCN4 enhanced TGF-beta 3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-beta 3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation-western blot analysis revealed that CCN4 bound to TGF-beta 3 and regulated the ability of TGF-beta 3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-beta 3. (c) 2015 Elsevier Inc. All rights reserved. C1 [Yoshioka, Yuya; Ono, Mitsuaki; Maeda, Azusa; Hara, Emilio Satoshi; Khattab, Hany; Ueda, Junji; Kuboki, Takuo] Okayama Univ, Dept Oral Rehabil & Regenerat Med, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Ono, Mitsuaki] Okayama Univ, Dept Mol Biol & Biochem, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Maeda, Azusa; Kilts, Tina M.; Young, Marian F.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Hara, Emilio Satoshi] Okayama Univ, Dept Biomat, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. [Khattab, Hany; Aoyama, Eriko; Oohashi, Toshitaka; Takigawa, Masaharu] Okayama Univ, Adv Res Ctr Oral & Craniofacial Sci, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008530, Japan. RP Ono, M (reprint author), Okayama Univ, Dept Oral Rehabil & Regenerat Med, Grad Sch Med Dent & Pharmaceut Sci, Kita Ku, 2-5-1 Shikata Cho, Okayama, Okayama 7008525, Japan. EM mitsuaki@md.okayama-u.ac.jp RI Hara, Emilio/B-3922-2017 OI Hara, Emilio/0000-0001-7374-3487 FU JSPS KAKENHI [23890122, 26861639]; NIH, NIDCR FX This study was supported in part by JSPS KAKENHI Grant Numbers #23890122 and #26861639 and the Intramural Program of the NIH, NIDCR. NR 30 TC 0 Z9 0 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD FEB PY 2016 VL 83 BP 162 EP 170 DI 10.1016/j.bone.2015.11.007 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DB5RJ UT WOS:000368571000020 PM 26555637 ER PT J AU Shankar, RK Giri, N Lodish, MB Butman, JA Patronas, NJ Sinaii, N Keil, M Alter, BP Stratakis, CA AF Shankar, Roopa Kanakatti Giri, Neelam Lodish, Maya B. Butman, John A. Patronas, Nicholas J. Sinaii, Ninet Keil, Meg Alter, Blanche P. Stratakis, Constantine A. TI Pituitary abnormalities in patients with Fanconi anaemia SO CLINICAL ENDOCRINOLOGY LA English DT Letter C1 [Shankar, Roopa Kanakatti; Lodish, Maya B.; Keil, Meg; Stratakis, Constantine A.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Giri, Neelam; Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Butman, John A.; Patronas, Nicholas J.] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. RP Shankar, RK (reprint author), Virginia Commonwealth Univ, Childrens Hosp Richmond, Richmond, VA 23284 USA. EM lodishma@mail.nih.gov OI Kanakatti Shankar, Roopa/0000-0001-9653-8865 NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD FEB PY 2016 VL 84 IS 2 BP 307 EP 309 DI 10.1111/cen.12883 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DB2NI UT WOS:000368345300024 ER PT J AU Woods, AJ Antal, A Bikson, M Boggio, PS Brunoni, AR Celnik, P Cohen, LG Fregni, F Herrmann, CS Kappenman, ES Knotkova, H Liebetanz, D Miniussi, C Miranda, PC Paulus, W Priori, A Reato, D Stagg, C Wenderoth, N Nitsche, MA AF Woods, A. J. Antal, A. Bikson, M. Boggio, P. S. Brunoni, A. R. Celnik, P. Cohen, L. G. Fregni, F. Herrmann, C. S. Kappenman, E. S. Knotkova, H. Liebetanz, D. Miniussi, C. Miranda, P. C. Paulus, W. Priori, A. Reato, D. Stagg, C. Wenderoth, N. Nitsche, M. A. TI A technical guide to tDCS, and related non-invasive brain stimulation tools SO CLINICAL NEUROPHYSIOLOGY LA English DT Review DE Transcranial electrical stimulation (tES); Transcranial direct current stimulation (tDCS); Transcranial alternating current stimulation (tACS); Transcranial random noise stimulation (tRNS); Technical guide; Methodology review; Safety; Design ID ALTERNATING-CURRENT STIMULATION; HUMAN MOTOR CORTEX; TRANSCRANIAL CURRENT STIMULATION; RANDOM NOISE STIMULATION; DORSOLATERAL PREFRONTAL CORTEX; SPINAL DC STIMULATION; RISK-TAKING BEHAVIOR; ELECTRIC-FIELDS; CURRENT-DENSITY; WORKING-MEMORY AB Transcranial electrical stimulation (tES), including transcranial direct and alternating current stimulation (tDCS, tACS) are non-invasive brain stimulation techniques increasingly used for modulation of central nervous system excitability in humans. Here we address methodological issues required for tES application. This review covers technical aspects of tES, as well as applications like exploration of brain physiology, modelling approaches, tES in cognitive neurosciences, and interventional approaches. It aims to help the reader to appropriately design and conduct studies involving these brain stimulation techniques, understand limitations and avoid shortcomings, which might hamper the scientific rigor and potential applications in the clinical domain. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. C1 [Woods, A. J.] Univ Florida, Ctr Cognit Aging & Memory, Dept Aging & Geriatr Res, Inst Aging,McKnight Brain Inst,Dept Neurosci, Gainesville, FL 32610 USA. [Antal, A.; Liebetanz, D.; Paulus, W.; Nitsche, M. A.] Univ Gottingen, Univ Med Ctr, Dept Clin Neurophysiol, Gottingen, Germany. [Bikson, M.; Reato, D.] CUNY City Coll, Dept Biomed Engn, New York, NY USA. [Boggio, P. S.] Univ Prebiteriana Mackenzie, Social & Cognit Neurosci Lab, Sao Paulo, SP, Brazil. [Boggio, P. S.] Univ Prebiteriana Mackenzie, Dev Disorders Program, Ctr Hlth & Biol Sci, Sao Paulo, SP, Brazil. [Brunoni, A. R.] Univ Sao Paulo, Serv Interdisciplinary Neuromodulat, Dept & Inst Psychiat, Sao Paulo, Brazil. [Celnik, P.] Johns Hopkins Med Inst, Dept Phys Med & Rehabil, Baltimore, MD 21205 USA. [Cohen, L. G.] NINCDS, NIH, Human Cort Physiol & Neurorehabilitat Sect, Bethesda, MD 20892 USA. [Fregni, F.] Harvard Univ, Lab Neuromodulat, Ctr Clin Res Learning, Dept Phys Med & Rehabil, Cambridge, MA 02138 USA. [Herrmann, C. S.] Carl von Ossietzky Univ Oldenburg, Expt Psychol Lab, Ctr Excellence Hearing4all, Dept Psychol,Fac Med & Hlth Sci, Oldenburg, Germany. [Kappenman, E. S.] Univ Calif Davis, Ctr Mind & Brain, Davis, CA 95616 USA. [Kappenman, E. S.] Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. [Knotkova, H.] MJHS Inst Innovat Palliat Care, New York, NY USA. [Miniussi, C.] Univ Brescia, Neurosci Sect, Dept Clin & Expt Sci, Brescia, Italy. [Miniussi, C.] IRCCS Ctr San Giovanni Dio Fatebenefratelli, Cognit Neurosci Sect, Brescia, Italy. [Miranda, P. C.] Univ Lisbon, Fac Ciencias, Inst Biophys & Biomed Engn IBEB, Lisbon, Portugal. [Priori, A.] Univ Milan, Direttore Clin Neurolog 3, Osped San Paolo, Milan, Italy. [Stagg, C.] Univ Oxford, Ctr Funct MRI, Brain FMRIB, Nuffield Dept Clin Neurosci, Oxford, England. [Stagg, C.] Univ Oxford, Dept Psychiat, Oxford Ctr Human Brain Activ OHBA, Oxford, England. [Wenderoth, N.] Swiss Fed Inst Technol, Neural Control Movement Lab, Dept Hlth Sci & Technol, Zurich, Switzerland. [Nitsche, M. A.] Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany. [Nitsche, M. A.] Ruhr Univ Bochum, BG Univ Hosp Bergmannsheil, Dept Neurol, Bochum, Germany. RP Woods, AJ (reprint author), Univ Florida, Ctr Cognit Aging & Memory, Dept Aging & Geriatr Res, Inst Aging,McKnight Brain Inst,Dept Neurosci, Gainesville, FL 32610 USA. EM ajwoods@ufl.edu RI Miranda, Pedro/A-5643-2013; Wenderoth, Nicole/D-7262-2015; Miniussi, Carlo/E-7602-2010; Paulus, Walter/A-3544-2009; OI Miranda, Pedro/0000-0002-6793-8111; Wenderoth, Nicole/0000-0002-3246-9386; Miniussi, Carlo/0000-0002-5436-4745; Paulus, Walter/0000-0001-5549-8377; Stagg, Charlotte/0000-0002-5542-5036; Russowsky Brunoni, Andre/0000-0002-6310-3571 FU NIH/NCATS CTSA [UL1TR000064, KL2 TR000065]; Center for Cognitive Aging and Memory at the University of Florida; McKnight Brain Research Foundation; Brain & Behavior Research Foundation [2013/20493]; Sao Paulo State Foundation (FAPESP) [2012/20911-5]; National Council for Scientific and Technological Development (CNPq) [2013/470904]; German Ministry for Research and Education [01GQ1424E, 01EE1501, 03IPT605E]; German Research Council [NI683/4-2, NI683/6-1]; Foundation for Science and Technology (FCT), Portugal FX This technical guide is the spontaneous work of the authors and article selection was made based on the scope of the paper. The authors would like to thank Nicole Nissim, M.S. for her assistance in formatting the manuscript. AJW was supported in part by NIH/NCATS CTSA grant UL1TR000064 and KL2 TR000065, the Center for Cognitive Aging and Memory at the University of Florida, and the McKnight Brain Research Foundation. A.R.B. is supported by grants from the Brain & Behavior Research Foundation (2013/20493), Sao Paulo State Foundation (FAPESP, 2012/20911-5) and National Council for Scientific and Technological Development (CNPq, 2013/470904). M.A.N receives funding by the German Ministry for Research and Education (grants 01GQ1424E, 01EE1501, 03IPT605E), and the German Research Council (grants NI683/4-2, NI683/6-1). P.C.M. was supported in part by the Foundation for Science and Technology (FCT), Portugal. NR 217 TC 30 Z9 30 U1 19 U2 64 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2016 VL 127 IS 2 BP 1031 EP 1048 DI 10.1016/j.clinph.2015.11.012 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DB3UW UT WOS:000368439100019 PM 26652115 ER PT J AU Shields, J Park, JE Srivanitchapoom, P Paine, R Thirugnanasambandam, N Kukke, SN Hallett, M AF Shields, Jessica Park, Jung E. Srivanitchapoom, Prachaya Paine, Rainer Thirugnanasambandam, Nivethida Kukke, Sahana N. Hallett, Mark TI Probing the interaction of the ipsilateral posterior parietal cortex with the premotor cortex using a novel transcranial magnetic stimulation technique SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Parietal cortex; Connectivity; Motor cortex; Transcranial magnetic stimulation ID PRIMARY MOTOR CORTEX; INPUT-OUTPUT PROPERTIES; CORTICOSPINAL PATHWAY; MACAQUE MONKEY; MICROSTRUCTURE; CONNECTIONS; MODULATION; RESPONSES; HUMANS; EXERTS AB Objective: Functional imaging studies have shown that control of planned movement involves a distributed network that involves the premotor (PMv) and posterior parietal cortices (PPC). Similarly, anatomical studies show that these regions are densely interconnected via white matter tracts. We therefore hypothesized that the PPC influence over the motor cortex is partly via a connection with the PMv. Methods: Using a novel three-pulse ipsilateral transcranial magnetic stimulation technique, we preconditioned the PPC (80% RMT) at ISIs from 4-15 ms prior to stimulating the PMv and M1 at ISIs of 4 and 6 ms. Results: As previously shown, PMv-M1 paired-pulse stimulation resulted in inhibition of the MEP (90% RMT, 4-6 ms) and PPC-M1 paired-pulse stimulation resulted in facilitation of the MEP (90% RMT, 4-8 ms). PPC-M1 paired-pulse stimulation at 80% RMT preconditioning had no effect on M1. PPC-PMv-M1 stimulation resulted in reversal of inhibition observed with PMv-M1 stimulation at ISIs ranging from 6 to 15 ms. Conclusions: The reversal of inhibition observed with PPC-PMv-M1 stimulation suggests that the parietal connection to the PMv plays a role in the modulation of M1. Significance: This is the first study to stimulate three intrahemispheric regions in order to test a disynaptic connection with M1. The described network may be important in a variety of movement disorders. Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [Shields, Jessica; Park, Jung E.; Srivanitchapoom, Prachaya; Paine, Rainer; Thirugnanasambandam, Nivethida; Kukke, Sahana N.; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH Bldg 10 Room 7D37,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov FU NINDS Intramural Program; NIH FX The study was supported by the NINDS Intramural Program. The authors would like to thank Nguyet Dang for her technical assistance and Tianxia Wu for her statistical assistance. This research was made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from Pfizer Inc., The Leona M. and Harry B. Helmsley Charitable Trust, and the HHMI, as well as other private donors. NR 23 TC 2 Z9 2 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2016 VL 127 IS 2 BP 1475 EP 1480 DI 10.1016/j.clinph.2015.06.031 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DB3UW UT WOS:000368439100070 PM 26253032 ER PT J AU Goey, AK Chau, CH Sissung, TM Cook, KM Venzon, DJ Castro, A Ransom, TR Henrich, CJ McKee, TC McMahon, JB Grkovic, T Cadelis, MM Copp, BR Gustafson, KR Figg, WD AF Goey, A. K. Chau, C. H. Sissung, T. M. Cook, K. M. Venzon, D. J. Castro, A. Ransom, T. R. Henrich, C. J. McKee, T. C. McMahon, J. B. Grkovic, T. Cadelis, M. M. Copp, B. R. Gustafson, K. R. Figg, W. D. TI MARINE PYRROLOIMINOQUINONE ALKALOIDS: A PROMISING NOVEL CLASS OF HIF-1A/P300 INHIBITORS IN ONCOLOGY. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Goey, A. K.; Chau, C. H.; Sissung, T. M.; Cook, K. M.; Venzon, D. J.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. [Castro, A.; Ransom, T. R.; Henrich, C. J.; McKee, T. C.; McMahon, J. B.; Gustafson, K. R.] NCI, Frederick, MD 21701 USA. [Grkovic, T.; Cadelis, M. M.; Copp, B. R.] Univ Auckland, Auckland 1, New Zealand. RI Figg Sr, William/M-2411-2016; Copp, Brent/D-3706-2009 OI Copp, Brent/0000-0001-5492-5269 NR 0 TC 0 Z9 0 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-005 BP S76 EP S77 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600272 ER PT J AU Peer, CJ Strope, JD Beedie, S Ley, AM Theodore, WH Figg, WD Sissung, T AF Peer, C. J. Strope, J. D. Beedie, S. Ley, A. M. Theodore, W. H. Figg, W. D. Sissung, T. TI ALCOHOL AND ALDEHYDE DEHYDROGENASES CONTRIBUTE TO SEXUAL DIMORPHISM OF ZOLPIDEM. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Peer, C. J.; Strope, J. D.; Beedie, S.; Ley, A. M.; Figg, W. D.; Sissung, T.] NCI, Bethesda, MD 20892 USA. [Theodore, W. H.] NINDS, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-089 BP S98 EP S98 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600353 ER PT J AU Peer, CJ Schmidt, KT Nogueira, MF Eisner, J Moore, W Figg, WD AF Peer, C. J. Schmidt, K. T. Nogueira Filho, M. F. Eisner, J. Moore, W. Figg, W. D. TI PHARMACOKINETIC ANALYSIS OF THE ORAL CYP17 INHIBITOR VT464 TO DESCRIBE TIME-DEPENDENT CHANGES IN CLEARANCE IN MEN WITH METASTATIC CASTRATE-RESISTANT PROSTATE CANCER SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Peer, C. J.; Schmidt, K. T.; Nogueira Filho, M. F.; Figg, W. D.] NCI, Bethesda, MD 20892 USA. [Eisner, J.; Moore, W.] Innocrin Pharmaceut Inc, Durham, NC USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PI-019 BP S36 EP S36 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600122 ER PT J AU Rotroff, D Gaikwad, NW Reuter, JM Smith, C Kucera, HR Nguyen, TV Rubinow, DR Motsinger-Reif, AA Schmidt, PJ Kaddurah-Daouk, R AF Rotroff, D. Gaikwad, N. W. Reuter, J. M. Smith, C. Kucera, H. R. Nguyen, T. Vi Rubinow, D. R. Motsinger-Reif, A. A. Schmidt, P. J. Kaddurah-Daouk, R. TI PHARMACOMETABOLOMICS SIGNATURES FROM WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER ADMINISTERED ESTRADIOL AND PROGESTERONE TREATMENT SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Rotroff, D.; Smith, C.; Motsinger-Reif, A. A.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Gaikwad, N. W.; Kucera, H. R.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Gaikwad, N. W.; Kucera, H. R.] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. [Reuter, J. M.; Schmidt, P. J.] NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Nguyen, T. Vi] McGill Univ, Dept Psychiat, Ctr Hlth, Montreal, PQ, Canada. [Nguyen, T. Vi] McGill Univ, Dept Obstet Gynecol, Ctr Hlth, Montreal, PQ, Canada. [Rubinow, D. R.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Kaddurah-Daouk, R.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 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 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PWI-1 BP S29 EP S30 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600097 ER PT J AU Rotroff, D Gaikwad, NW Reuter, JM Smith, C Kucera, HR Nguyen, TV Rubinow, DR Motsinger-Reif, AA Schmidt, PJ Kaddurah-Daouk, R AF Rotroff, D. Gaikwad, N. W. Reuter, J. M. Smith, C. Kucera, H. R. Nguyen, T. Vi Rubinow, D. R. Motsinger-Reif, A. A. Schmidt, P. J. Kaddurah-Daouk, R. TI PHARMACOMETABOLOMICS SIGNATURES FROM WOMEN WITH PREMENSTRUAL DYSPHORIC DISORDER ADMINISTERED ESTRADIOL AND PROGESTERONE TREATMENT. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Rotroff, D.; Smith, C.; Motsinger-Reif, A. A.] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Gaikwad, N. W.; Kucera, H. R.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Gaikwad, N. W.; Kucera, H. R.] Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. [Reuter, J. M.; Schmidt, P. J.] NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Nguyen, T. Vi] McGill Univ, Dept Psychiat, Ctr Hlth, Montreal, PQ, Canada. [Nguyen, T. Vi] McGill Univ, Dept Obstet Gynecol, Ctr Hlth, Montreal, PQ, Canada. [Rubinow, D. R.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Kaddurah-Daouk, R.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. NR 0 TC 0 Z9 0 U1 1 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 SU 1 MA PT-22 BP S19 EP S19 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600054 ER PT J AU Wells, MA Vendrov, KC Edin, ML Ferslew, BC Brouwer, KL Barritt, AS Zeldin, DC Lee, CR AF Wells, M. A. Vendrov, K. C. Edin, M. L. Ferslew, B. C. Brouwer, K. L. Barritt, A. S. Zeldin, D. C. Lee, C. R. TI TRANSLATIONAL EVALUATION OF THE RELATIONSHIP BETWEEN BIOMARKERS OF CYTOCHROME P450-MEDIATED EICOSANOID METABOLISM AND NON-ALCOHOLIC STEATOHEPATITIS (NASH). SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Wells, M. A.; Vendrov, K. C.; Ferslew, B. C.; Brouwer, K. L.; Lee, C. R.] UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Edin, M. L.; Zeldin, D. C.] NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. [Barritt, A. S.] UNC Sch Med, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 2 U2 2 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 SU 1 MA PII-026 BP S82 EP S82 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600291 ER PT J AU Yan, J Stangl, BL Westman, JG Schwandt, ML Spagnolo, P Momenan, R Hodgkinson, C Goldman, D Ramchandani, VA AF Yan, J. Stangl, B. L. Westman, J. G. Schwandt, M. L. Spagnolo, P. Momenan, R. Hodgkinson, C. Goldman, D. Ramchandani, V. A. TI ROLE OF FATTY ACID AMIDE HYDROLASE (FAAH) GENETIC POLYMORPHISM IN EXPOSURE-RESPONSE RELATIONSHIPS DURING IV ALCOHOL SELF-ADMINISTRATION (IV-ASA) IN SOCIAL DRINKERS. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Clinical-Pharmacology-and-Therapeutics (ASCPT) CY MAR 08-12, 2016 CL San Diego, CA SP Amer Soc Clin Pharmacol & Therapeut C1 [Yan, J.; Stangl, B. L.; Westman, J. G.; Schwandt, M. L.; Spagnolo, P.; Momenan, R.; Hodgkinson, C.; Goldman, D.; Ramchandani, V. A.] NIAAA, Bethesda, MD USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9236 EI 1532-6535 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2016 VL 99 SU 1 MA PII-074 BP S94 EP S94 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB7JZ UT WOS:000368692600339 ER PT J AU Sweeney, DA Akrami, K Malhotra, A AF Sweeney, Daniel A. Akrami, Kevan Malhotra, Atul TI Improved Outcomes in Critically Ill Patients With AIDS: How Does This Trend Continue? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE acquired immunodeficiency syndrome; antiretroviral therapy; intensive care; mortality; noninvasive ventilation ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; INTENSIVE-CARE-UNIT; ANTIRETROVIRAL THERAPY; RESPIRATORY-FAILURE; ERA; ICU; SURVIVAL; IMPACT C1 [Sweeney, Daniel A.; Malhotra, Atul] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, La Jolla, CA 92093 USA. [Akrami, Kevan] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA. [Akrami, Kevan] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Sweeney, DA (reprint author), Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, La Jolla, CA 92093 USA. FU NHLBI NIH HHS [K24 HL093218, R01 HL085188] NR 14 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2016 VL 44 IS 2 BP 446 EP 447 DI 10.1097/CCM.0000000000001492 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA DB4SO UT WOS:000368503700025 PM 26771791 ER PT J AU Fung, KL Kapoor, K Pixley, JN Talbert, DJ Kwit, ADT Ambudkar, SV Gottesman, MM AF Fung, King Leung Kapoor, Khyati Pixley, Jessica N. Talbert, Darrell J. Kwit, Alexandra D. T. Ambudkar, Suresh V. Gottesman, Michael M. TI Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; MAMMALIAN-CELLS; CANCER; GENE; PERMEABILITY; PROTEIN; CACO-2; ASSAYS AB The ATP-binding cassette (ABC) transporter superfamily includes several membrane-bound proteins that are critical to drug pharmacokinetics and disposition. Pharmacologic evaluation of these proteins in vitro remains a challenge. In this study, human ABC transporters were expressed in polarized epithelial cell monolayers transduced using the BacMam baculovirus gene transfer system. The purpose of the study was to evaluate the efficacy of BacMam baculovirus to transduce cells grown in monolayers. In a porcine kidney cell line, LLC-PK1 cells, baculoviral transduction is successful only via the apical side of a polarized monolayer. We observed that recombinant ABC transporters were expressed on the cell surface with post-translational modification. Furthermore, sodium butyrate played a critical role in recombinant protein expression, and preincubation in the presence of tunicamycin or thapsigargin enhanced protein expression. Cells overexpressing human P-glycoprotein (P-gp) showed vectorial basolateral-to-apical transport of [H-3]-paclitaxel, which could be reversed by the inhibitor tariquidar. Similarly, coexpression of human P-gp and ABCG2 in LLC-PK1 cells resulted in higher transport of mitoxantrone, which is a substrate for both transporters, than in either P-gp-or ABCG2-expressing cells alone. Taken together, our results indicate that a high level of expression of efflux transporters in a polarized cell monolayer is technically feasible with the BacMam baculovirus system C1 [Fung, King Leung; Kapoor, Khyati; Pixley, Jessica N.; Talbert, Darrell J.; Kwit, Alexandra D. T.; Ambudkar, Suresh V.; Gottesman, Michael M.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural Research Program of the National Institutes of Health National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute, Center for Cancer Research. NR 24 TC 1 Z9 1 U1 1 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2016 VL 44 IS 2 BP 180 EP 188 DI 10.1124/dmd.115.066506 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB3MX UT WOS:000368416900003 PM 26622052 ER PT J AU Weidner, LD Fung, KL Kannan, P Moen, JK Kumar, JS Mulder, J Innis, RB Gottesman, MM Hall, MD AF Weidner, Lora D. Fung, King Leung Kannan, Pavitra Moen, Janna K. Kumar, Jeyan S. Mulder, Jan Innis, Robert B. Gottesman, Michael M. Hall, Matthew D. TI Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MULTIDRUG-RESISTANT CELLS; DRUG EFFLUX TRANSPORTERS; BLOOD-BRAIN-BARRIER; IN-VIVO; ABC TRANSPORTERS; CANCER; RADIOTRACERS; EXPRESSION; XR9576 AB Since its development, tariquidar (TQR; XR9576; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [C-11] TQR into the brain can be explained by its high-affinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes. C1 [Weidner, Lora D.; Kannan, Pavitra; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Fung, King Leung; Moen, Janna K.; Kumar, Jeyan S.; Gottesman, Michael M.; Hall, Matthew D.] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Weidner, Lora D.; Mulder, Jan] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. RP Hall, MD (reprint author), NIH, Natl Ctr Adv Translat Sci, Chem Genom Ctr, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM matthew.hall@nih.gov RI Mulder, Jan/G-3909-2011; OI Mulder, Jan/0000-0003-3717-5018; Kannan, Pavitra/0000-0002-9170-6062 FU Intramural Research Program of the National Institutes of Health (National Institute of Mental Health); Intramural Research Program of the National Institutes of Health (National Cancer Institute) FX This study was funded by the Intramural Research Program of the National Institutes of Health (National Institute of Mental Health and National Cancer Institute). NR 28 TC 2 Z9 2 U1 5 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2016 VL 44 IS 2 BP 275 EP 282 DI 10.1124/dmd.115.067785 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB3MX UT WOS:000368416900011 PM 26658428 ER PT J AU White, AJ Chen, J Teitelbaum, SL McCullough, LE Xu, X Cho, YH Conway, K Beyea, J Stellman, SD Steck, SE Mordukhovich, I Eng, SM Terry, MB Engel, LS Hatch, M Neugut, AI Hibshoosh, H Santella, RM Gammon, MD AF White, Alexandra J. Chen, Jia Teitelbaum, Susan L. McCullough, Lauren E. Xu, Xinran Cho, Yoon Hee Conway, Kathleen Beyea, Jan Stellman, Steven. D. Steck, Susan E. Mordukhovich, Irina Eng, Sybil M. Terry, Mary Beth Engel, Lawrence S. Hatch, Maureen Neugut, Alfred I. Hibshoosh, Hanina Santella, Regina M. Gammon, Marilie D. TI Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer SO ENVIRONMENTAL RESEARCH LA English DT Article DE Methylation; Smoking; Environmental tobacco smoke; Air pollution; Grilled meat ID CPG ISLAND HYPERMETHYLATION; ONE-CARBON METABOLISM; INDOOR AIR-POLLUTION; DNA METHYLATION; TOBACCO-SMOKE; EPIDEMIOLOGIC EVIDENCE; RISK-FACTORS; EXPOSURE; BLOOD; HYPOMETHYLATION AB Background: Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer. Methods: In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RAR beta (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST] methylation (OR=2.79, 95% CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86). Discussion: PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence. Published by Elsevier Inc. C1 [White, Alexandra J.; McCullough, Lauren E.; Conway, Kathleen; Mordukhovich, Irina; Engel, Lawrence S.; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Chen, Jia; Teitelbaum, Susan L.; Xu, Xinran] Dept Prevent Med, New York, NY USA. [Chen, Jia] Dept Oncol Sci, New York, NY USA. [Chen, Jia] Ichan Sch Med Mt Sinai, Dept Pediat, New York, NY USA. [Xu, Xinran] Roche Prod Dev Asia Pacific, Dept Biometr, Shanghai, Peoples R China. [Cho, Yoon Hee] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Beyea, Jan] Dept Consulting Publ Interest CIPI, Lambertville, NJ USA. [Santella, Regina M.] Columbia Univ, Dept Environm Hlth Sci, New York, NY USA. [Stellman, Steven. D.; Eng, Sybil M.; Terry, Mary Beth; Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, New York, NY USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, New York, NY USA. [Hibshoosh, Hanina] Columbia Univ, Dept Pathol, New York, NY USA. [Hibshoosh, Hanina] Columbia Univ, Dept Cell Biol, New York, NY USA. [Steck, Susan E.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Hatch, Maureen] NCI, Dept Div Canc Epidemiol, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. [Hatch, Maureen] NCI, Dept Div Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP White, AJ (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. EM whitea@unc.edu OI Engel, Lawrence/0000-0001-9268-4830; Beyea, Jan/0000-0002-0547-880X FU National Institutes of Health [R25 CA57726, R01CA109753, UO1CA/ES66572, 3R01CA109753-04S1, P30CA013696, CA094061, P30ES009089, P30ES10126]; Department of Defense [BC031746, W81XWH-06-1-0298] FX Supported in part by Grants from the: National Institutes of Health (R25 CA57726, UO1CA/ES66572, R01CA109753, 3R01CA109753-04S1, P30CA013696, CA094061, P30ES009089 and P30ES10126); and Department of Defense (BC031746 and W81XWH-06-1-0298). NR 52 TC 2 Z9 2 U1 3 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 EI 1096-0953 J9 ENVIRON RES JI Environ. Res. PD FEB PY 2016 VL 145 BP 93 EP 100 DI 10.1016/j.envres.2015.11.033 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DB0SV UT WOS:000368218700011 PM 26671626 ER PT J AU Birnbaum, LS Dutton, ND Cusack, C Mennemeyer, ST Pavuk, M AF Birnbaum, Linda S. Dutton, N. D. Cusack, C. Mennemeyer, S. T. Pavuk, M. TI Anniston community health survey: Follow-up and dioxin analyses (ACHS-II)-methods SO ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH LA English DT Article DE Polychlorinated biphenyls; PCBs; Dioxins; PCDDs; PCDFs; PBDEs; Heavy metals; Anniston ID POLYCHLORINATED-BIPHENYLS; HALF-LIVES; PCB; RESIDENTS; EXPOSURE AB High serum concentrations of polychlorinated biphenyls (PCBs) have been reported previously among residents of Anniston, Alabama, where a PCB production facility was located in the past. As the second of two cross-sectional studies of these Anniston residents, the Anniston Community Health Survey: Follow-Up and Dioxin Analyses (ACHS-II) will yield repeated measurements to be used to evaluate changes over time in ortho-PCB concentrations and selected health indicators in study participants. Dioxins, non-ortho PCBs, other chemicals, heavy metals, and a variety of additional clinical tests not previously measured in the original ACHS cohort will be examined in ACHS-II. The follow-up study also incorporates a questionnaire with extended sections on diet and occupational history for a more comprehensive assessment of possible exposure sources. Data collection for ACHS-II from 359 eligible participants took place in 2014, 7 to 9 years after ACHS. C1 [Birnbaum, Linda S.] NCI, NIH, Res Triangle Pk, NC 27709 USA. [Dutton, N. D.] Agcy Tox Subst & Dis Registry, Oak Ridge Inst Sci & Educ, Res Participat Program, Atlanta, GA USA. [Cusack, C.; Pavuk, M.] Agcy Tox Subst & Dis Registry, Atlanta, GA USA. [Mennemeyer, S. T.] Univ Alabama Birmingham, Birmingham, AL USA. RP Birnbaum, LS (reprint author), NCI, NIH, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov FU National Cancer Institute through Centers for Disease Control and Prevention (CDC) (IAA) [11-AT1-001-00, 12-AT-12-ANNISTON]; ATSDR; ATSDR (CDC) [200-2011-40834] FX The study was funded by the National Cancer Institute (Dr. Linda Birnbaum) through interagency agreements with the Centers for Disease Control and Prevention (CDC) (IAA#: 11-AT1-001-00; IAA#: 12-AT-12-ANNISTON) and by ATSDR. Dr. Pavuk, of ATSDR, is the study's principal investigator (PI). Data collection for this study was funded via contract from ATSDR to the University of Alabama at Birmingham (UAB) (CDC Contract No. 200-2011-40834; Prof. S. Mennemeyer, PI). NR 23 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0944-1344 EI 1614-7499 J9 ENVIRON SCI POLLUT R JI Environ. Sci. Pollut. Res. PD FEB PY 2016 VL 23 IS 3 BP 2014 EP 2021 DI 10.1007/s11356-015-4684-3 PG 8 WC Environmental Sciences SC Environmental Sciences & Ecology GA DB2YO UT WOS:000368376800006 PM 25982988 ER PT J AU Ekuase, EJ van't Erve, TJ Rahaman, A Robertson, LW Duffel, MW Luthe, G AF Ekuase, E. J. van't Erve, T. J. Rahaman, A. Robertson, L. W. Duffel, M. W. Luthe, G. TI Mechanistic insights into the specificity of human cytosolic sulfotransferase 2A1 (hSULT2A1) for hydroxylated polychlorinated biphenyls through the use of fluoro-tagged probes SO ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH LA English DT Article DE F-tagged probes; QSAR; hSULT2A1; Polychlorinated biphenyls; Hydroxylated polychlorinated biphenyls; Sulfotransferase; Computational chemistry; 4-Hydroxy-3,5-dichlorobiphenyl ID POLYBROMINATED DIPHENYL ETHERS; POLARIZABLE CONTINUUM MODEL; PCB METABOLITES; OH-PCBS; MONOFLUORINATED ANALOGS; INTENDED USE; INHIBITORS; BLOOD; NEUROTOXICITY; TOXICITY AB Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity. C1 [Ekuase, E. J.; Duffel, M. W.] Univ Iowa, Dept Pharmaceut Sci & Expt Therapeut, Iowa City, IA USA. [van't Erve, T. J.; Robertson, L. W.; Luthe, G.] Univ Iowa, Dept Occupat & Environm Hlth, Iowa City, IA 52242 USA. [van't Erve, T. J.; Luthe, G.] Saxion Univ Appl Sci, Inst Life Sci, Enschede, Netherlands. [van't Erve, T. J.; Robertson, L. W.; Duffel, M. W.; Luthe, G.] Univ Iowa, Interdisciplinary Grad Program Human Toxicol, Iowa City, IA USA. [Rahaman, A.] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. [Luthe, G.] LuthePharma, D-48599 Gronau, Germany. [van't Erve, T. J.] NIEHS, Immun Inflammat & Dis Lab, Res Triangle Pk, NC 27709 USA. RP van't Erve, TJ (reprint author), Univ Iowa, Dept Occupat & Environm Hlth, Iowa City, IA 52242 USA. EM thomas.vanterve@nih.gov OI van 't Erve, Thomas/0000-0002-3260-6627 FU National Institutes of Health [R01 CA038683, P42ES 013661]; University of Iowa Environmental Health Sciences Research Center (NIH) [P30 ES05605]; Alexander von Humboldt Foundation; Tech for Future fund, an initiative of the Saxion University of Applied Sciences; Tech for Future fund, an initiative of the Windesheim University of Applied Sciences; regional government Overijsel, The Netherlands FX This work was supported by the National Institutes of Health through research grants R01 CA038683 and P42ES 013661. We also acknowledge programmatic support through the University of Iowa Environmental Health Sciences Research Center (NIH grant P30 ES05605). Partial support was provided to Dr. Gregor Luthe by the Alexander von Humboldt Foundation. The project was financially supported by the Tech for Future fund, an initiative of the Saxion and Windesheim Universities of Applied Sciences and the regional government Overijsel, The Netherlands. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the granting agencies. NR 56 TC 0 Z9 0 U1 3 U2 12 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0944-1344 EI 1614-7499 J9 ENVIRON SCI POLLUT R JI Environ. Sci. Pollut. Res. PD FEB PY 2016 VL 23 IS 3 BP 2119 EP 2127 DI 10.1007/s11356-015-4886-8 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA DB2YO UT WOS:000368376800016 PM 26165989 ER PT J AU Mach, J Huizer-Pajkos, A Mitchell, SJ McKenzie, C Phillips, L Kane, A Jones, B de Cabo, R Cogger, V Le Couteur, DG Hilmer, SN AF Mach, John Huizer-Pajkos, Aniko Mitchell, Sarah J. McKenzie, Catriona Phillips, Leo Kane, Alice Jones, Brett de Cabo, Rafael Cogger, Victoria Le Couteur, David G. Hilmer, Sarah N. TI The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats SO FUNDAMENTAL & CLINICAL PHARMACOLOGY LA English DT Article DE ageing; isoniazid; liver; pharmacokinetics; toxicity ID DRUG-METABOLIZING-ENZYMES; GENETIC POLYMORPHISMS; TUBERCULOSIS PATIENTS; INDUCED HEPATITIS; COVALENT BINDING; LIVER-INJURY; IN-VITRO; HYDRAZINE; CYP2E1; CYTOCHROME-P450 AB Isoniazid is the first-line treatment for tuberculosis; however, its use is limited by hepatotoxicity. Age-related differences in isoniazid pharmacokinetics and hepatotoxicity are uncertain. We aimed to investigate these in young (3 +/- 0 months, n = 26) and old (23.0 +/- 0.2 months, n = 27) male Fischer 344 rats following a low- or high-dose toxic regimen of isoniazid or vehicle (4 doses/day over 2 days; low: 100, 75, 75, 75 mg/kg; high: 150, 105, 105, 105 mg/kg i.p. every 3 h). Fifteen hours after the last dose, animals were euthanized and sera and livers were prepared for analysis. Isoniazid treatment increased serum hepatotoxicity markers (alanine and aspartate transaminase) in young animals but not in old animals, and only reached significance with the high dose in young animals. Isoniazid treatment caused a trend towards an increase in necrosis in young animals with both doses. In contrast, microvesicular steatosis was increased in old isoniazid-treated animals, reaching significance only with the low dose (steatosis prevalence in old: vehicle 1/9, isoniazid 4/5; P < 0.05). Among isoniazid-treated animals, concentrations of toxic intermediates acetylhydrazine and hydrazine were higher in old than young animals (P < 0.05). With both doses, hepatic cytochrome P450 2E1 activity was higher in young animals compared with old (P < 0.05). There were no other age effects seen on any of the other measured enzymes involved in isoniazid metabolism (N-acetyl transferase, amidase, glutathione-S-transferase). These results show age-related changes in isoniazid pharmacokinetics may contribute towards differential patterns of toxicity and confirm that standard hepatotoxicity markers do not detect isoniazid-induced microvesicular steatosis. C1 [Mach, John; Huizer-Pajkos, Aniko; Kane, Alice; Hilmer, Sarah N.] Kolling Inst Med Res, Lab Ageing & Pharmacol, Sydney, NSW, Australia. [Mach, John; Huizer-Pajkos, Aniko; Kane, Alice; Hilmer, Sarah N.] Royal N Shore Hosp, Dept Clin Pharmacol & Aged Care, Sydney, NSW, Australia. [Mach, John; Kane, Alice; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; Hilmer, Sarah N.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA. [McKenzie, Catriona] Royal Prince Alfred Hosp, Dept Pathol, Sydney, NSW, Australia. [Phillips, Leo] Kolling Inst Med Res, Mass Spec Imaging & Prote Lab, Sydney, NSW, Australia. [Jones, Brett] Kolling Inst Med Res, Dept Gastroenterol, Sydney, NSW, Australia. [Cogger, Victoria; Le Couteur, David G.] Concord Hosp, Ctr Educ & Res Ageing, Ageing & Alzheimers Inst, Sydney, NSW, Australia. [Cogger, Victoria; Le Couteur, David G.] Concord Hosp, Anzac Res Inst, Sydney, NSW, Australia. [Cogger, Victoria; Le Couteur, David G.] Univ Sydney, Sydney, NSW 2006, Australia. RP Hilmer, SN (reprint author), Kolling Inst Med Res, Lab Ageing & Pharmacol, Sydney, NSW, Australia. EM sarah.hilmer@sydney.edu.au RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Kane, Alice/0000-0002-4303-0491; , rafael/0000-0003-2830-5693 FU National Health and Medical Research Council [570968]; Geoff and Elaine Penney Ageing Research Unit, Royal North Shore Hospital; Intramural Research Program of the National Institute on Aging; Intramural Research Program of the National Institute on Aging, National Institutes of Health FX The work was supported by the National Health and Medical Research Council (project grant number #570968), the Geoff and Elaine Penney Ageing Research Unit, Royal North Shore Hospital and the Intramural Research Program of the National Institute on Aging. RdC and SJM are supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 56 TC 1 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0767-3981 EI 1472-8206 J9 FUND CLIN PHARMACOL JI Fundam. Clin. Pharmacol. PD FEB PY 2016 VL 30 IS 1 BP 23 EP 34 DI 10.1111/fcp.12157 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB9IF UT WOS:000368828900003 PM 26454000 ER PT J AU Fan, RZ Wang, YF Yan, Q Ding, Y Weeks, DE Lu, ZH Ren, HB Cook, RJ Xiong, MM Swaroop, A Chew, EY Chen, W AF Fan, Ruzong Wang, Yifan Yan, Qi Ding, Ying Weeks, Daniel E. Lu, Zhaohui Ren, Haobo Cook, Richard J. Xiong, Momiao Swaroop, Anand Chew, Emily Y. Chen, Wei TI Gene-Based Association Analysis for Censored Traits Via Fixed Effect Functional Regressions SO GENETIC EPIDEMIOLOGY LA English DT Article DE rare variants; common variants; association study; complex diseases; functional data analysis; Cox models ID LINEAR-MODELS; QUANTITATIVE TRAITS; MACULAR DEGENERATION; VARIANTS; LEVEL AB Genetic studies of survival outcomes have been proposed and conducted recently, but statistical methods for identifying genetic variants that affect disease progression are rarely developed. Motivated by our ongoing real studies, here we develop Cox proportional hazard models using functional regression (FR) to perform gene-based association analysis of survival traits while adjusting for covariates. The proposed Cox models are fixed effect models where the genetic effects of multiple genetic variants are assumed to be fixed. We introduce likelihood ratio test (LRT) statistics to test for associations between the survival traits and multiple genetic variants in a genetic region. Extensive simulation studies demonstrate that the proposed Cox RF LRT statistics have well-controlled type I error rates. To evaluate power, we compare the Cox FR LRT with the previously developed burden test (BT) in a Cox model and sequence kernel association test (SKAT), which is based on mixed effect Cox models. The Cox FR LRT statistics have higher power than or similar power as Cox SKAT LRT except when 50%/50% causal variants had negative/positive effects and all causal variants are rare. In addition, the Cox FR LRT statistics have higher power than Cox BT LRT. The models and related test statistics can be useful in the whole genome and whole exome association studies. An age-related macular degeneration dataset was analyzed as an example. Genet Epidemiol 40: 133-143, 2016. (C) 2016 Wiley Periodicals, Inc. C1 [Fan, Ruzong; Wang, Yifan; Lu, Zhaohui] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. [Yan, Qi; Chen, Wei] Univ Pittsburgh, Childrens Hosp Pittsburgh, Div Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA. [Ding, Ying; Weeks, Daniel E.; Chen, Wei] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15224 USA. [Weeks, Daniel E.; Chen, Wei] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15224 USA. [Ren, Haobo] Regeneron Pharmaceut Inc, Basking Ridge, NJ USA. [Cook, Richard J.] Univ Waterloo, Dept Stat & Actuarial Sci, Waterloo, ON N2L 3G1, Canada. [Xiong, Momiao] Univ Texas Houston, Human Genet Ctr, Houston, TX USA. [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Fan, RZ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA.; Chen, W (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, Div Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA. EM fanr@mail.nih.gov; wei.chen@chp.edu OI Ding, Ying/0000-0003-1352-1000; Swaroop, Anand/0000-0002-1975-1141; Weeks, Daniel/0000-0001-9410-7228 FU Intramural NIH HHS [ZIA HD008918-03, Z99 HD999999, ZIA HD008918-02]; NEI NIH HHS [R01 EY024226, R01EY024226]; NHGRI NIH HHS [R01 HG007358, R01HG007358] NR 35 TC 3 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2016 VL 40 IS 2 BP 133 EP 143 DI 10.1002/gepi.21947 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA DB7VS UT WOS:000368725400005 PM 26782979 ER PT J AU Kirschner, LS Stratakis, CA AF Kirschner, Lawrence S. Stratakis, Constantine A. TI 5th International ACC Symposium: The New Genetics of Benign Adrenocortical Neoplasia: Hyperplasias, Adenomas, and Their Implications for Progression into Cancer SO HORMONES & CANCER LA English DT Review ID ADRENAL CUSHINGS-SYNDROME; ALDOSTERONE-PRODUCING ADENOMAS; PROTEIN-KINASE-A; PKA CATALYTIC SUBUNIT; CARNEY COMPLEX; SOMATIC MUTATIONS; KCNJ5 MUTATIONS; HEPATOCELLULAR-CARCINOMA; CORTICAL CARCINOMA; REGULATORY SUBUNIT AB Genetic tools for the analysis of human tumors have developed rapidly over the past 20 years. Adrenocortical neoplasms have been subject to multiple analyses using these new genetic tools. Analysis of adrenocortical carcinomas (ACCs) has been complicated by the fact that these tumors tend to exhibit multiple somatic abnormalities, so that identifying driver mutations is complex task. In contrast, benign adrenocortical neoplasms have proven to be a fertile ground for the identification of the genetic causes of adrenocortical adenomas, as well as a variety of adrenocortical hyperplasia. Analysis of cortisol-producing adrenocortical adenomas has revealed alterations leading to enhanced signaling through the cAMP-dependent protein kinase (PKA) pathway. In contrast, macronodular cortisol-producing neoplasias have been shown to result from mutations in the ARMC5 gene, whose function is not yet quite so clear. In contrast, adrenal tumors resulting in excess production of the blood pressure hormone aldosterone almost always result from abnormalities of calcium handling, both in single adenomas and in bilateral hyperplasias. In both cases, there is elevation of a signaling pathway responsible both for hormone secretion and for gland growth and maintenance, thus confirming the linkage of these two output of cellular physiology. The connection between the benign hyperplasia observed in these states and adrenocortical carcinogenesis is not nearly as clear, although genetic studies are beginning to elucidate the relationship between benign and malignant tumors of this gland. C1 [Kirschner, Lawrence S.] Ohio State Univ, Wexner Med Ctr, Div Endocrinol Diabet & Metab, Dept Internal Med, 460 W 12th Ave,Rm 510, Columbus, OH 43210 USA. [Stratakis, Constantine A.] NICHHD, NIH, 31 Ctr Dr Room 2A46 MSC 2425, Bethesda, MD 20892 USA. RP Kirschner, LS (reprint author), Ohio State Univ, Wexner Med Ctr, Div Endocrinol Diabet & Metab, Dept Internal Med, 460 W 12th Ave,Rm 510, Columbus, OH 43210 USA.; Stratakis, CA (reprint author), NICHHD, NIH, 31 Ctr Dr Room 2A46 MSC 2425, Bethesda, MD 20892 USA. EM Lawrence.Kirschner@osumc.edu; stratakc@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (CAS); [CA016058] FX This work was supported, in part, by grant CA016058 to the Ohio State University Comprehensive Cancer Center (LSK) and by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (CAS). NR 72 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD FEB PY 2016 VL 7 IS 1 SI SI BP 9 EP 16 DI 10.1007/s12672-015-0246-x PG 8 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DB7LS UT WOS:000368697400003 PM 26684645 ER PT J AU Dallal, CM Lacey, JV Pfeiffer, RM Bauer, DC Falk, RT Buist, DSM Cauley, JA Hue, TF LaCroix, AZ Tice, JA Veenstra, TD Xu, X Brinton, LA AF Dallal, Cher M. Lacey, James V., Jr. Pfeiffer, Ruth M. Bauer, Douglas C. Falk, Roni T. Buist, Diana S. M. Cauley, Jane A. Hue, Trisha F. LaCroix, Andrea Z. Tice, Jeffrey A. Veenstra, Timothy D. Xu, Xia Brinton, Louise A. CA B-FIT Res Grp TI Estrogen Metabolism and Risk of Postmenopausal Endometrial and Ovarian Cancer: the B similar to FIT Cohort SO HORMONES & CANCER LA English DT Article ID FRACTURE INTERVENTION TRIAL; ENDOGENOUS ESTRADIOL METABOLITES; SEX STEROID-HORMONES; BREAST-CANCER; CIRCULATING LEVELS; WOMEN; 16-ALPHA-HYDROXYESTRONE; PROLIFERATION; ALENDRONATE; QUINONES AB Estrogen metabolites may have different genotoxic and mitogenic properties yet their relationship with endometrial and ovarian cancer risk remains unclear. Within the Breast and Bone Follow-up to the Fracture Intervention Trial (B similar to FIT, n = 15,595), we conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Participants included 66 endometrial and 67 ovarian cancer cases diagnosed during follow-up (similar to 10 years) and subcohorts of 346 and 416 women, respectively, after relevant exclusions. Serum concentrations were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox proportional hazard regression. Exposures were categorized in tertiles (T) and analyzed individually, as metabolic pathways (C-2, -4, or -16) and as ratios to parent estrogens (estradiol, estrone). Estradiol was significantly associated with increased endometrial cancer risk (BMI-adjusted HRT3vsT1 = 4.09, 95 % CI 1.70, 9.85; p trend = 0.003). 2-Hydroxyestrone and 16 alpha-hydroxyestrone were not associated with endometrial risk after estradiol adjustment (2-OHE1:HRT3vsT1 = 1.97, 95 % CI 0.78, 4.94; 16-OHE1:HRT3vsT1 = 1.50, 95 % CI 0.65, 3.46; p trend = 0.16 and 0.36, respectively). Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment (2-pathway catechols-to-methylated: HRT3vsT1 = 4.02, 95 % CI 1.60, 10.1; 4-pathway catechols-to-methylated: HRT3vsT1 = 4.59, 95 % CI 1.64, 12.9; p trend = 0.002 for both). Estrogens and estrogen metabolites were not associated with ovarian cancer risk; however, larger studies are needed to better evaluate these relationships. Estrogen metabolism may be important in endometrial carcinogenesis, particularly with less extensive methylation of 2- or 4-pathway catechols associated with elevated endometrial cancer risk. C1 [Dallal, Cher M.] Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD 20742 USA. [Dallal, Cher M.; Falk, Roni T.; Brinton, Louise A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Lacey, James V., Jr.] Beckman Res Inst City Hope, Div Canc Etiol, Dept Populat Sci, Duarte, CA USA. [Pfeiffer, Ruth M.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bauer, Douglas C.; Tice, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA USA. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Bauer, Douglas C.; Hue, Trisha F.] Univ San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94117 USA. [LaCroix, Andrea Z.] Univ Calif San Diego, Dept Family & Prevent Med, Div Epidemiol, San Diego, CA 92103 USA. [Veenstra, Timothy D.] C2N Diagnost, St Louis, MO USA. [Veenstra, Timothy D.; Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MA USA. RP Dallal, CM (reprint author), Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD 20742 USA.; Dallal, CM (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM cdallal@umd.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU Merck Research Laboratories; National Cancer Institute, Department of Health and Human Services, USA [N02-CP-01019]; Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute FX The original FIT study was funded by Merck Research Laboratories. B similar to FIT was funded by the National Cancer Institute (contract #N02-CP-01019), Department of Health and Human Services, USA. Dr. Cher Dallal was supported by the Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute. NR 35 TC 6 Z9 6 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD FEB PY 2016 VL 7 IS 1 SI SI BP 49 EP 64 DI 10.1007/s12672-015-0237-y PG 16 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DB7LS UT WOS:000368697400010 PM 26728471 ER PT J AU Hartman, TJ Sisti, JS Hankinson, SE Xu, X Eliassen, AH Ziegler, R AF Hartman, Terryl J. Sisti, Julia S. Hankinson, Susan E. Xu, Xia Eliassen, A. Heather Ziegler, Regina TI Alcohol Consumption and Urinary Estrogens and Estrogen Metabolites in Premenopausal Women SO HORMONES & CANCER LA English DT Article ID MENSTRUAL-CYCLE CHARACTERISTICS; 2-TO 3-YEAR PERIOD; BREAST-CANCER RISK; POSTMENOPAUSAL WOMEN; HORMONE CONCENTRATIONS; ASSOCIATION; PLASMA; PROLACTIN; REPRODUCIBILITY; APOPTOSIS AB In a cross-sectional analysis, we evaluated the associations of usual total alcohol and wine intake with a comprehensive profile of mid-luteal phase urinary estrogens and estrogen metabolites (referred to jointly as EM) in a sample of 603 premenopausal women participating in the Nurses' Health Study II (NHSII). A total of 15 individual EM (pmol/mg creatinine) were measured by a liquid chromatography/tandem mass spectrometry (LC-MS/MS) method with high accuracy and reproducibility. We used linear mixed models to calculate the adjusted geometric means of individual EM, EM grouped by metabolic pathways, and pathway ratios by category of alcohol intake with non-drinkers of alcohol as the referent. Total alcohol intake was not associated with total EM but was positively associated with estradiol (26 % higher among women consuming > 15 g/day vs. non-drinkers; P trend = 0.03). Wine consumption was positively associated with a number of EM measures including estradiol (22 % higher among women consuming a parts per thousand yen5 drinks/week vs. non-drinkers, P trend < 0.0001). In conclusion, the total alcohol intake was positively and significantly associated with urinary estradiol levels. Some differences in urinary estrogen metabolites were observed with wine drinking, when compared with non-drinkers. This study strengthens the evidence that alcohol consumption might play a role in breast cancer and other estrogen-related conditions. Additional studies of premenopausal women are needed to further explore the association of alcohol, particularly the specific types of alcohol, on patterns of estrogen metabolism in blood, urine, and tissue. C1 [Hartman, Terryl J.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE,CNR 3035, Atlanta, GA 30322 USA. [Hartman, Terryl J.] Emory Univ, Winship Canc Inst, 1518 Clifton Rd NE,CNR 3035, Atlanta, GA 30322 USA. [Sisti, Julia S.; Hankinson, Susan E.; Eliassen, A. Heather] Harvard Univ, TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Sisti, Julia S.; Hankinson, Susan E.; Eliassen, A. Heather] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Sisti, Julia S.; Hankinson, Susan E.; Eliassen, A. Heather] Harvard Univ, Sch Med, Boston, MA USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Xu, Xia] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc Res Technol Program, Frederick, MD USA. [Ziegler, Regina] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hartman, TJ (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE,CNR 3035, Atlanta, GA 30322 USA.; Hartman, TJ (reprint author), Emory Univ, Winship Canc Inst, 1518 Clifton Rd NE,CNR 3035, Atlanta, GA 30322 USA. EM tjhartm@emory.edu FU NIH [UM1 CA176726, R01 CA67262]; National Cancer Institute (NCI) [CA67262, CA50385]; Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics; NCI [HHSN261200900001E]; Leidos Biomedical Research, Inc.; [R25 CA098566]; [T32 CA900137] FX This study was supported by NIH UM1 CA176726 (Walter C. Willett) and R01 CA67262 (Susan E. Hankinson), and by Research Grants CA67262 and CA50385 from the National Cancer Institute (NCI). It was also supported by the Intramural Research Program of the NCI Division of Cancer Epidemiology and Genetics and with the federal funds of the NCI awarded under Contract HHSN261200900001E to SAIC-Frederick, now Leidos Biomedical Research, Inc. Julia Sisti was supported by training grants R25 CA098566 and T32 CA900137. We would like to thank the participants and staff of the Nurses' Health Studies for their valuable contributions. The authors assume full responsibility for analyses and interpretation of these data. NR 41 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD FEB PY 2016 VL 7 IS 1 SI SI BP 65 EP 74 DI 10.1007/s12672-015-0249-7 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA DB7LS UT WOS:000368697400011 PM 26728472 ER PT J AU Cushman, WC Whelton, PK Fine, LJ Wright, JT Reboussin, DM Johnson, KC Oparil, S AF Cushman, William C. Whelton, Paul K. Fine, Lawrence J. Wright, Jackson T. Reboussin, David M. Johnson, Karen C. Oparil, Suzanne CA SPRINT Study Res Grp TI SPRINT Trial Results Latest News in Hypertension Management SO HYPERTENSION LA English DT Editorial Material ID BLOOD-PRESSURE CONTROL; RANDOMIZED-TRIAL; STRATEGIES C1 [Cushman, William C.] Vet Affairs Med Ctr, Prevent Med Sect, Memphis, TN USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Fine, Lawrence J.] NHLBI, Clin Applicat & Prevent Branch, Bethesda, MD 20892 USA. [Wright, Jackson T.] Case Western Reserve Univ, Div Nephrol & Hypertens, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Reboussin, David M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Johnson, Karen C.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38104 USA. [Oparil, Suzanne] Univ Alabama Birmingham, Div Cardiovasc Sci, Birmingham, AL USA. RP Cushman, WC (reprint author), Univ Tennessee, Hlth Sci Ctr, Vet Affairs Med Ctr, Prevent Med Sect, 111Q,1030 Jefferson Ave, Memphis, TN 38104 USA. EM william.cushman@va.gov FU NHLBI NIH HHS [HHSN268200900040C]; NIDDK NIH HHS [P30 DK079626] NR 6 TC 25 Z9 26 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2016 VL 67 IS 2 BP 263 EP 265 DI 10.1161/HYPERTENSIONAHA.115.06722 PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DB4AG UT WOS:000368454500005 PM 26553234 ER PT J AU Zachariah, JP Hwang, S Hamburg, NM Benjamin, EJ Larson, MG Levy, D Vita, JA Sullivan, LM Mitchell, GF Vasan, RS AF Zachariah, Justin P. Hwang, Susan Hamburg, Naomi M. Benjamin, Emelia J. Larson, Martin G. Levy, Daniel Vita, Joseph A. Sullivan, Lisa M. Mitchell, Gary F. Vasan, Ramachandran S. TI Circulating Adipokines and Vascular Function Cross-Sectional Associations in a Community-Based Cohort SO HYPERTENSION LA English DT Article DE adipokines; biomarkers; epidemiology; obesity; vascular function ID ACID-BINDING PROTEIN; ARTERIAL STIFFNESS; INSULIN-RESISTANCE; METABOLIC SYNDROME; SERUM RETINOL-BINDING-PROTEIN-4; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR EVENTS; DIABETES-MELLITUS; AORTIC STIFFNESS; BLOOD-PRESSURE AB Adipokines may be potential mediators of the association between excess adiposity and vascular dysfunction. We assessed the cross-sectional associations of circulating adipokines with vascular stiffness in a community-based cohort of younger adults. We related circulating concentrations of leptin and leptin receptor, adiponectin, retinol-binding protein 4, and fatty acid-binding protein 4 to vascular stiffness measured by arterial tonometry in 3505 Framingham Third Generation cohort participants free of cardiovascular disease (mean age 40 years, 53% women). Separate regression models estimated the relations of each adipokine to mean arterial pressure and aortic stiffness, as carotid femoral pulse wave velocity, adjusting for age, sex, smoking, heart rate, height, antihypertensive treatment, total and high-density lipoprotein cholesterol, diabetes mellitus, alcohol consumption, estimated glomerular filtration rate, glucose, and C-reactive protein. Models evaluating aortic stiffness also were adjusted for mean arterial pressure. Mean arterial pressure was positively associated with blood retinol-binding protein 4, fatty acid-binding protein 4, and leptin concentrations (all P<0.001) and inversely with adiponectin (P=0.002). In fully adjusted models, mean arterial pressure was positively associated with retinol-binding protein 4 and leptin receptor levels (P<0.002 both). In fully adjusted models, aortic stiffness was positively associated with fatty acid-binding protein 4 concentrations (P=0.02), but inversely with leptin and leptin receptor levels (P0.03 both). In our large community-based sample, circulating concentrations of select adipokines were associated with vascular stiffness measures, consistent with the hypothesis that adipokines may influence vascular function and may contribute to the relation between obesity and hypertension. C1 [Zachariah, Justin P.] Harvard Univ, Boston Childrens Hosp, Dept Cardiol, Sch Med, Cambridge, MA 02138 USA. [Zachariah, Justin P.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Hwang, Susan; Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Hamburg, Naomi M.; Benjamin, Emelia J.; Vita, Joseph A.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiovasc Med, Boston, MA 02215 USA. [Benjamin, Emelia J.; Larson, Martin G.; Levy, Daniel; Vita, Joseph A.; Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Benjamin, Emelia J.; Larson, Martin G.; Levy, Daniel; Vita, Joseph A.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Zachariah, JP (reprint author), Texas Childrens Hosp, Baylor Coll Med, Pediat Cardiol, 6621 Fannin St,West Tower 19, Houston, TX 77030 USA. EM justinzachariah@yahoo.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung and Blood Institute (NHLBI) [N01-HC-25195, HHSN268201500001I, R01-DK-080739, R01-HL-107385 R01-HL-126136, 1RO1-HL-70100, HL111335] FX This research is supported, in part, by National Heart, Lung and Blood Institute (NHLBI) contract N01-HC-25195 and HHSN268201500001I (R.S. Vasan), R01-DK-080739 (R.S. Vasan) and R01-HL-107385 R01-HL-126136 (R.S. Vasan, G.F. Mitchell), 1RO1-HL-70100 (E.J. Benjamin), and HL111335 (J.P. Zachariah). NR 50 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD FEB PY 2016 VL 67 IS 2 BP 294 EP 300 DI 10.1161/HYPERTENSIONAHA.115.05949 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DB4AG UT WOS:000368454500014 PM 26628673 ER PT J AU Anuradha, R Munisankar, S Bhootra, Y Jagannathan, J Dolla, C Kumaran, P Shen, K Nutman, TB Babu, S AF Anuradha, Rajamanickam Munisankar, Saravanan Bhootra, Yukti Jagannathan, Jeeva Dolla, Chandrakumar Kumaran, Paul Shen, Kui Nutman, Thomas B. Babu, Subash TI Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment SO INFECTION AND IMMUNITY LA English DT Article ID HELMINTH-PARASITES; PROTECTIVE IMMUNITY; RESPONSES; MICE; SUSCEPTIBILITY; MECHANISMS; EXPRESSION; RESISTANCE; DIVERSITY; DISEASES AB Strongyloides stercoralis is a soil-transmitted helminth organism that infects similar to 50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human S. stercoralis infection. To study the systemic cytokine profile characteristic of Strongyloides infection, we measured the circulating levels of a large panel of pro-and anti-inflammatory cytokines in asymptomatic, infected individuals (n = 32) and compared them to those in uninfected, controls (n = 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-1 beta [IL-1 beta]) and significantly higher levels of antiinflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor beta [TGF-beta]). Moreover, treatment of Strongyloides infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-gamma, TNF-alpha, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1 beta) and decreased levels of anti-inflammatory (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-beta) cytokines following treatment. Thus, S. stercoralis infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection. C1 [Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukti; Jagannathan, Jeeva; Babu, Subash] Natl Inst Health, NIRT, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Dolla, Chandrakumar; Kumaran, Paul] Natl Inst Res TB, Madras, Tamil Nadu, India. [Shen, Kui] NIAID, Bioinformat & Computat Biosci Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nutman, Thomas B.; Babu, Subash] NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Natl Inst Health, NIRT, Int Ctr Excellence Res, Madras, Tamil Nadu, India.; Babu, S (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sbabu@mail.nih.gov FU Division of Intramural Research, NIAID, NIH FX This work was funded by the Division of Intramural Research, NIAID, NIH. The funders had no role in study design, data collection or interpretation, or the decision to publish. NR 39 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD FEB PY 2016 VL 84 IS 2 BP 425 EP 431 DI 10.1128/IAI.01354-15 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA DC0BY UT WOS:000368883000005 PM 26597982 ER PT J AU Shah, NN Cole, DE Lester-McCully, CM Wayne, AS Warren, KE Widemann, BC AF Shah, Nirali N. Cole, Diane E. Lester-McCully, Cynthia M. Wayne, Alan S. Warren, Katherine E. Widemann, Brigitte C. TI Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo (R)) after intravenous administration in Non-human primates SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Non-human primate model; Cerebrospinal fluid; Pharmacokinetics; Vincristine sulfate liposomes injection ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ENCAPSULATED VINCRISTINE; LONG-TERM; PHARMACODYNAMICS; CANCER; DRUGS; MODEL AB Purpose Vincristine sulfate liposomes injection (VSLI, Marqibo (R)) is an FDA approved encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical pharmacokinetics show VSLI to be a long-circulating, slow release formulation that is confined to plasma, and prior data on cerebrospinal fluid (CSF) pharmacokinetics are lacking. We report our results comparing CSF and plasma pharmacokinetic parameters of intravenous aqueous vincristine to intravenous VSLI using an established non-human primate (NHP) model. Methods Three adult male rhesus monkeys (Macaca mulatta) were administered 0.1 mg/kg (1.2 mg/m(2) human-equivalent dose) of vincristine or VSLI in a crossover pharmacokinetic study. Serial paired blood and CSF samples were obtained before infusion, at the end of infusion (EOI) and at various time points thereafter. Results In contrast to standard vincristine, which had a multi-exponential plasma disappearance curve with a median initial (EOI to 30 min post-infusion) half-life (T-1/2) of 4.8 min (range, 4.4-5.0 min) and terminal T-1/2 of 24.3 h, a near-monoexponential curve with a median T-1/2 of 17.9 h (range, 13.9-21.5 h) hours was calculated with VSLI. The ratios Cl (VCR):Cl (VSLI) for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample after administration of either formulation. Conclusions In three animals, each serving as their own control, we demonstrate that the pharmacokinetic profile of VSLI shows markedly prolonged clearance (approximately 400-fold lower) of total vincristine in comparison to the standard aqueous formulation, enhancing our understanding of VSLI pharmacokinetics. Several clinical trials incorporating VSLI as substitution for standard vincristine are in progress. C1 [Shah, Nirali N.; Cole, Diane E.; Lester-McCully, Cynthia M.; Warren, Katherine E.; Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1W-3750,9000, Bethesda, MD 20892 USA. [Wayne, Alan S.] Univ So Calif, Div Hematol Oncol & Blood & Marrow Transplantat, Childrens Ctr Canc & Blood Dis,Keck Sch Med, Childrens Hosp Los Angeles,Norris Comprehens Canc, Los Angeles, CA 90033 USA. RP Shah, NN (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1W-3750,9000, Bethesda, MD 20892 USA. EM Nirali.Shah@nih.gov FU Intramural Research Program of 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 16 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2016 VL 34 IS 1 BP 61 EP 65 DI 10.1007/s10637-015-0311-x PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DB7VP UT WOS:000368725100006 PM 26661090 ER PT J AU Hubbard, JM Kim, G Borad, MJ Johnson, E Qin, R Lensing, J Puttabasavaiah, S Wright, J Erlichman, C Grothey, A AF Hubbard, Joleen M. Kim, George Borad, Mitesh J. Johnson, Elizabeth Qin, Rui Lensing, Janet Puttabasavaiah, Suneetha Wright, John Erlichman, Charles Grothey, Axel TI Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Colorectal cancer; Systemic therapy; Antiangiogenesis ID METASTATIC COLORECTAL-CANCER; TARGETED THERAPY; SOLID TUMORS; ONCOLOGY-GROUP; BREAST-CANCER; GROWTH-FACTOR; FLUOROURACIL; LEUCOVORIN; IRINOTECAN; OXALIPLATIN AB Background A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. Results Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control > 12 months. Conclusions The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. C1 [Hubbard, Joleen M.; Lensing, Janet; Puttabasavaiah, Suneetha; Erlichman, Charles; Grothey, Axel] Mayo Clin Rochester, 200 First St SW, Rochester, MN 55905 USA. [Kim, George] Univ Florida Hlth Oncol, Jacksonville, FL USA. [Borad, Mitesh J.] Mayo Clin Scottsdale, Scottsdale, AZ USA. [Johnson, Elizabeth] Mayo Clin Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. [Qin, Rui] Regeneron Pharmaceut Inc, Basking Ridge, NJ USA. [Wright, John] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Invest Drug Branch, Bethesda, MD 20892 USA. RP Hubbard, JM (reprint author), Mayo Clin Rochester, 200 First St SW, Rochester, MN 55905 USA. EM hubbard.joleen@mayo.edu FU CTSA from National Center for Advancing Translational Sciences (NCATS), a component of National Institutes of Health (NIH) [UL1 TR000135]; NCI [CA69912, CA15083, UL1TR000135] FX This publication was made possible by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.; Supported by NCI Grants CA69912, CA15083 and UL1TR000135. NR 25 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2016 VL 34 IS 1 BP 96 EP 103 DI 10.1007/s10637-015-0308-5 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DB7VP UT WOS:000368725100010 PM 26581401 ER PT J AU Chiu, JW Hotte, SJ Kollmannsberger, CK Renouf, DJ Cescon, DW Hedley, D Chow, S Moscow, J Chen, Z Perry, M Diaz-Padilla, I Tan, D Hirte, H McWhirter, E Chen, H Siu, LL Bedard, PL AF Chiu, Joanne W. Hotte, Sebastien J. Kollmannsberger, Christian K. Renouf, Daniel J. Cescon, David W. Hedley, David Chow, Sue Moscow, Jeffrey Chen, Zhuo Perry, Meghan Diaz-Padilla, Ivan Tan, David Hirte, Hal McWhirter, Elaine Chen, Helen Siu, Lillian L. Bedard, Philippe L. TI A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI#9041) SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE AMG386; Trebananib; Temsirolimus; Phase 1; Combination therapy ID RENAL-CELL CARCINOMA; BREAST-CANCER; OPEN-LABEL; ANGIOGENESIS; ANGIOPOIETIN-2; COMBINATION; PHARMACOKINETICS; BEVACIZUMAB; EXPRESSION; SORAFENIB AB Background There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity. Methods Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2. Results Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade a parts per thousand yen 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD a parts per thousand yen 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment. Conclusions The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia. C1 [Chiu, Joanne W.; Cescon, David W.; Hedley, David; Chow, Sue; Chen, Zhuo; Perry, Meghan; Diaz-Padilla, Ivan; Tan, David; Siu, Lillian L.; Bedard, Philippe L.] Univ Hlth Network, Div Med Oncol & Hematol, Princess Margaret Canc Ctr, Suite 5-125,610 Univ Ave, Toronto, ON M5G 2M9, Canada. [Chiu, Joanne W.; Cescon, David W.; Hedley, David; Chow, Sue; Chen, Zhuo; Perry, Meghan; Diaz-Padilla, Ivan; Tan, David; Siu, Lillian L.; Bedard, Philippe L.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Hotte, Sebastien J.; Hirte, Hal; McWhirter, Elaine] Juravinski Canc Ctr, Hamilton, ON, Canada. [Hotte, Sebastien J.; Hirte, Hal; McWhirter, Elaine] Escarpment Canc Res Inst, Hamilton, ON, Canada. [Kollmannsberger, Christian K.; Renouf, Daniel J.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Moscow, Jeffrey; Chen, Helen] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Bedard, PL (reprint author), Univ Hlth Network, Div Med Oncol & Hematol, Princess Margaret Canc Ctr, Suite 5-125,610 Univ Ave, Toronto, ON M5G 2M9, Canada.; Bedard, PL (reprint author), Univ Toronto, Dept Med, Toronto, ON, Canada. EM philippe.bedard@uhn.ca FU National Cancer Institute [U01-CA-132123, UM1CA186644] FX This research was supported by the National Cancer Institute Grants #U01-CA-132123 and #UM1CA186644. NR 29 TC 1 Z9 2 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2016 VL 34 IS 1 BP 104 EP 111 DI 10.1007/s10637-015-0313-8 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA DB7VP UT WOS:000368725100011 PM 26686201 ER PT J AU Delitala, AP Terracciano, A Fiorillo, E Orru, V Schlessinger, D Cucca, F AF Delitala, Alessandro P. Terracciano, Antonio Fiorillo, Edoardo Orru, Valeria Schlessinger, David Cucca, Francesco TI Depressive symptoms, thyroid hormone and autoimmunity in a population-based cohort from Sardinia SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Free thyroxine; Depression; Thyroid hormone; Depressive symptoms; Center for Epidemiologic Studies Depression Scale ID POSITRON-EMISSION-TOMOGRAPHY; TRICYCLIC ANTIDEPRESSANTS; ARTERIAL STIFFNESS; COGNITIVE FUNCTION; MOOD DISORDERS; HYPOTHYROIDISM; BRAIN; HYPERTHYROIDISM; ASSOCIATION; STATE AB Objective: To evaluate the association between depressive symptoms and thyroid autoimmunity, and the effect of thyroid hormone on the risk of depression. Methods: We included 3138 individuals from SardiNIA project, none of whom was taking thyroid medication and antidepressants. Thyrotropin (TSH), free thyroxine (FT4), and antibodies against thyroperoxidase (TP0Ab) were measured in all the sample. Depressive symptoms were assessed with Center for Epidemiologic Studies Depression Scale (CES-D). Results: We found no association between TP0Ab and depressive symptoms and no linear association between TSH or FT4 levels and depressive symptoms. However, individuals in the lowest and highest FT4 quintiles showed a higher CES-D score compared to individuals in the middle quintile. In addition, participants in the lowest and highest FT4 quintiles had an increased risk of CES-D >= 16 with odds ratios of 1.44 (95% CI=1.09-1.89) and 1.33 (95% CI =1.01-1.77), respectively. Limitations: Cross-sectional design of the study. Conclusions: A U-shaped relation was found between FT4 and depressive symptoms: compared to average FT4 values, both high and low thyroid function was associated with more depressive symptoms. Further studies are necessary to determine the exact cause-effect relation of this association. (c) 2015 Elsevier BY. All rights reserved. C1 [Delitala, Alessandro P.] Azienda Osped Univ Sassari, I-07100 Sassari, Italy. [Terracciano, Antonio] Florida State Univ, Coll Med, Dept Geriatr, Tallahassee, FL 32306 USA. [Fiorillo, Edoardo; Orru, Valeria; Cucca, Francesco] CNR, IRGB, Cagliari, Italy. [Schlessinger, David] NIA, NIH, DHHS, Baltimore, MD 21224 USA. [Cucca, Francesco] Azienda Osped Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. RP Delitala, AP (reprint author), Azienda Osped Univ Sassari, Via Michele Coppino 26a, I-07100 Sassari, Italy. EM aledelitala@tiscali.it; antonio.terracciano@med.fsu.edu; edoardofiorillo@gmail.com; v.orru@tiscali.it; SchlessingerD@grc.nia.nih.gov; francesco.cucca@irgb.cnr.it RI Delitala, Alessandro/L-3194-2016; OI Delitala, Alessandro/0000-0003-1729-8969; Orro, Valeria/0000-0002-6047-4625 FU NIA NIH HHS [N01 AG012109] NR 47 TC 1 Z9 1 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD FEB PY 2016 VL 191 BP 82 EP 87 DI 10.1016/j.jad.2015.11.019 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DB1FL UT WOS:000368253400012 PM 26655116 ER PT J AU Hall, BE Zhang, L Sun, ZJ Utreras, E Prochazkova, M Cho, A Terse, A Arany, P Dolan, JC Schmidt, BL Kulkarni, AB AF Hall, B. E. Zhang, L. Sun, Z. J. Utreras, E. Prochazkova, M. Cho, A. Terse, A. Arany, P. Dolan, J. C. Schmidt, B. L. Kulkarni, A. B. TI Conditional TNF-alpha Overexpression in the Tooth and Alveolar Bone Results in Painful Pulpitis and Osteitis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE inflammation; facial pain; cytokine(s); toothache; animal model; Cdk5 ID NECROSIS-FACTOR-ALPHA; OROFACIAL PAIN; INDUCED ARTHRITIS; NOCICEPTION; MODELS; HYPERALGESIA; ODONTOBLASTS; INFLAMMATION; DEFICIENCY; ACTIVATION AB Tumor necrosis factor-alpha(TNF-alpha) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-alpha expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-alpha and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-alpha(glo)) that could be used to conditionally overexpress TNF-alpha. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-alpha in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-alpha(glo) mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-alpha(glo) mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-alpha(glo) mice, we have shown that TNF-alpha expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain. C1 [Hall, B. E.; Prochazkova, M.; Cho, A.; Terse, A.; Arany, P.; Kulkarni, A. B.] Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Room 130,MSC 4395, Bethesda, MD USA. [Zhang, L.; Sun, Z. J.] Wuhan Univ, Sch & Hosp Stomatol, State Key Lab Breeding Base Basic Sci Stomatol, Wuhan 430072, Peoples R China. [Zhang, L.; Sun, Z. J.] Wuhan Univ, Sch & Hosp Stomatol, Key Lab Oral Biomed, Minist Educ, Wuhan 430072, Peoples R China. [Utreras, E.] Univ Chile, Fac Sci, Lab Cellular & Mol Mechanism Pain, Santiago, Chile. [Dolan, J. C.; Schmidt, B. L.] NYU, Coll Dent, Sch Dent, NYU Bluestone Ctr Clin Res,Dept Oral & Maxillofac, New York, NY USA. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Lab Cell & Dev Biol, NIH, 30 Convent Dr,Room 130,MSC 4395, Bethesda, MD USA. EM ashok.kulkarni@nih.gov FU National Natural Science Foundation of China; Chilean National Fund for Scientific, Technological Development and Innovation, Santiago, Chile [FONDECYT 1151043]; Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health FX We thank Dr. Jerry Feng for providing us DMP1-Cre mice. We also thank Drs. Harish Pant and Niru Amin for their expert advice and help in carrying out Cdk5 kinase assay. These studies were supported by National Natural Science Foundation of China; the Chilean National Fund for Scientific, Technological Development and Innovation (FONDECYT 1151043), Santiago, Chile; and the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health. All authors were funded by their own institutions to perform all work relating to the present study. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 30 TC 4 Z9 4 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD FEB PY 2016 VL 95 IS 2 BP 188 EP 195 DI 10.1177/0022034515612022 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DB4TY UT WOS:000368507500009 PM 26503912 ER PT J AU Liu, XM White, S Peng, B Johnson, AD Brody, JA Li, AH Huang, ZY Carroll, A Wei, P Gibbs, R Klein, RJ Boerwinkle, E AF Liu, Xiaoming White, Simon Peng, Bo Johnson, Andrew D. Brody, Jennifer A. Li, Alexander H. Huang, Zhuoyi Carroll, Andrew Wei, Peng Gibbs, Richard Klein, Robert J. Boerwinkle, Eric TI WGSA: an annotation pipeline for human genome sequencing studies SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID FUNCTIONAL PREDICTIONS; VARIANTS; DATABASE; DBNSFP; SNPS C1 [Liu, Xiaoming; Li, Alexander H.; Wei, Peng; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, 1200 Herman Pressler St,E529, Houston, TX 77030 USA. [Liu, Xiaoming; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [White, Simon; Huang, Zhuoyi; Gibbs, Richard; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Peng, Bo] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Johnson, Andrew D.] NHLBI, Framingham Heart Study, Bldg 10, Bethesda, MD 20892 USA. [Johnson, Andrew D.] NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Brody, Jennifer A.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Carroll, Andrew] DNAnexus, Mountain View, CA USA. [Wei, Peng] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Biostat, Houston, TX 77030 USA. [Klein, Robert J.] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Liu, XM (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, 1200 Herman Pressler St,E529, Houston, TX 77030 USA.; Liu, XM (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. EM Xiaoming.Liu@uth.tmc.edu RI Johnson, Andrew/G-6520-2013; OI Peng, Bo/0000-0001-8225-2284 FU US National Institutes of Health [5RC2HL102419, U54HG003273] FX This study was supported by the US National Institutes of Health (5RC2HL102419 and U54HG003273). NR 8 TC 5 Z9 5 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2016 VL 53 IS 2 BP 111 EP 112 DI 10.1136/jmedgenet-2015-103423 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA DB4SF UT WOS:000368502700004 PM 26395054 ER PT J AU Sakurai, T Sakurai, A Vaisman, BL Amar, MJ Liu, CY Gordon, SM Drake, SK Pryor, M Sampson, ML Yang, L Freeman, LA Remaley, AT AF Sakurai, Toshihiro Sakurai, Akiko Vaisman, Boris L. Amar, Marcelo J. Liu, Chengyu Gordon, Scott M. Drake, Steven K. Pryor, Milton Sampson, Maureen L. Yang, Ling Freeman, Lita A. Remaley, Alan T. TI Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptides SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CARDIOVASCULAR-DISEASE; HUMAN PLASMA; A-I; SERUM TRIGLYCERIDES; CHOLESTEROL EFFLUX; AMPHIPATHIC HELIX; TRANSGENIC MICE; HEPATIC LIPASE; CII DEFICIENCY AB Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 +/- 281.2 mg/dl) and low HDL cholesterol (31.4 +/- 14.7 mg/dl) compared with wild-type mice (TG, 55.9 +/- 13.3 mg/dl; HDL cholesterol, 55.9 +/- 14.3 mg/dl). TGs were found in light (density < 1.063 g/ml) lipoproteins in the size range of very-low-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 mu mol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 +/- 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency. C1 [Sakurai, Toshihiro; Sakurai, Akiko; Vaisman, Boris L.; Amar, Marcelo J.; Liu, Chengyu; Gordon, Scott M.; Pryor, Milton; Freeman, Lita A.; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, Cardiopulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, Transgen Core Facil, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sampson, Maureen L.; Remaley, Alan T.] NIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Drake, Steven K.] NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. [Yang, Ling] NHLBI, Lab Obes & Metab Dis, NIH, Bldg 10, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), 10 Ctr Dr,Bldg 10,Room 2C433, Bethesda, MD 20892 USA. EM aremaley1@cc.nih.gov RI Yang, Ling/F-4404-2016 FU intramural National Institutes of Health funds from the National Heart, Lung, and Blood Institute FX This research was supported by intramural National Institutes of Health funds from the National Heart, Lung, and Blood Institute. NR 60 TC 6 Z9 6 U1 2 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2016 VL 356 IS 2 BP 341 EP 353 DI 10.1124/jpet.115.229740 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB5UL UT WOS:000368579000013 PM 26574515 ER PT J AU Carlin, JL Tosh, DK Xiao, CY Pinol, RA Chen, ZM Salvemini, D Gavrilova, O Jacobson, KA Reitman, ML AF Carlin, Jesse Lea Tosh, Dilip K. Xiao, Cuiying Pinol, Ramon A. Chen, Zhoumou Salvemini, Daniela Gavrilova, Oksana Jacobson, Kenneth A. Reitman, Marc L. TI Peripheral Adenosine A(3) Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H-1 Receptors SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CHRONIC NEUROPATHIC PAIN; BODY-TEMPERATURE; MAST-CELLS; H-2-RECEPTOR ANTAGONIST; NERVOUS-SYSTEM; METABOLIC-RATE; DAILY TORPOR; HEART-RATE; IN-VIVO; MOUSE AB Adenosine can induce hypothermia, as previously demonstrated for adenosine A(1) receptor (A(1)AR) agonists. Here we use the potent, specific A(3)AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A(3)AR. The hypothermic effect of A(3)AR agonists is independent of A(1)AR activation, as the effect was fully intact in mice lacking A(1)AR but abolished in mice lacking A(3)AR. A(3)AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A(3)AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A(3)AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H-1 (but not H-2 or H-4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A(3)AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A(3)AR agonists act on peripheralmast cells, causing histamine release, which stimulates central histamine H-1 receptors to induce hypothermia. This mechanism suggests that A(3)AR agonists will probably not be useful for clinical induction of hypothermia. C1 [Carlin, Jesse Lea; Xiao, Cuiying; Pinol, Ramon A.; Reitman, Marc L.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Tosh, Dilip K.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core, NIH, Bethesda, MD 20892 USA. [Chen, Zhoumou; Salvemini, Daniela] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. RP Reitman, ML (reprint author), NIDDK, NIH, Bldg 10 CRC,Room 5-5940,10 Ctr Dr, Bethesda, MD 20892 USA. EM marc.reitman@nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Reitman, Marc/0000-0002-0426-9475 FU Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK075063, ZIA DK031117]; National Cancer Institute [RO1CA169519] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [ZIA DK075063; ZIA DK031117] and by the National Cancer Institute [RO1CA169519]. D.S. is a cofounder of BioIntervene Inc. NR 71 TC 3 Z9 3 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2016 VL 356 IS 2 BP 474 EP 482 DI 10.1124/jpet.115.229872 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB5UL UT WOS:000368579000025 PM 26606937 ER PT J AU Goldstein, DS Jinsmaa, Y Sullivan, P Holmes, C Kopin, IJ Sharabi, Y AF Goldstein, David S. Jinsmaa, Yunden Sullivan, Patti Holmes, Courtney Kopin, Irwin J. Sharabi, Yehonatan TI Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID AMINO-ACID DECARBOXYLASE; VIRUS TYPE-1 VECTOR; PARKINSONS-DISEASE; TYROSINE-HYDROXYLASE; B INHIBITOR; CEREBROSPINAL-FLUID; ALPHA-SYNUCLEIN; RAT-BRAIN; IN-VIVO; PLASMA AB According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson's disease. C1 [Goldstein, David S.; Jinsmaa, Yunden; Sullivan, Patti; Holmes, Courtney; Kopin, Irwin J.] NINDS, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res,NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Sharabi, Yehonatan] Tel Aviv Univ, Hypertens Unit, Chaim Sheba Med Ctr, Tel Hashomer, Israel. RP Goldstein, DS (reprint author), 9000 Rockville Pike,Bldg 10,Rm 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural Research Program of the National Institutes of Health National Institute of Neurologic Disorders and Stroke [1ZIANS003125] FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute of Neurologic Disorders and Stroke (Project 1ZIANS003125). NR 50 TC 5 Z9 5 U1 1 U2 10 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2016 VL 356 IS 2 BP 483 EP 492 DI 10.1124/jpet.115.230201 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DB5UL UT WOS:000368579000026 PM 26574516 ER PT J AU Vannier, DM Somerman, MJ AF Vannier, David M. Somerman, Martha J. TI Integrating the domains of dentistry and research A perspective from the National Institute of Dental and Craniofacial Research SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Editorial Material ID OSTEONECROSIS; BISPHOSPHONATE; ASSOCIATION; NECROSIS; JAWS C1 [Vannier, David M.] Natl Inst Dent & Craniofacial Res, Sci Commun Branch, NIH, 31 Ctr Dr,Room 5B55, Bethesda, MD 20892 USA. [Somerman, Martha J.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Vannier, DM (reprint author), Natl Inst Dent & Craniofacial Res, Sci Commun Branch, NIH, 31 Ctr Dr,Room 5B55, Bethesda, MD 20892 USA. EM david.vannier@nih.gov NR 15 TC 2 Z9 2 U1 0 U2 0 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD FEB PY 2016 VL 147 IS 2 BP 77 EP 79 DI 10.1016/j.adaj.2015.12.005 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DB9KT UT WOS:000368835500001 PM 26809691 ER PT J AU Alves, G Wang, GH Ogurtsov, AY Drake, SK Gucek, M Suffredini, AF Sacks, DB Yu, YK AF Alves, Gelio Wang, Guanghui Ogurtsov, Aleksey Y. Drake, Steven K. Gucek, Marjan Suffredini, Anthony F. Sacks, David B. Yu, Yi-Kuo TI Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article DE Pathogen identification; Microorganism classification; Statistical significance; Mass spectrometry; Proteomics ID DESORPTION-IONIZATION-TIME; MICROBIAL GENE IDENTIFICATION; PATHOGEN IDENTIFICATION; SPECIES IDENTIFICATION; NONFERMENTING BACTERIA; RAPID IDENTIFICATION; INFECTIOUS-DISEASES; UNIVERSAL BIOSENSOR; DATABASE SEARCHES; ESCHERICHIA-COLI AB Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple 'fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html. C1 [Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. [Drake, Steven K.; Suffredini, Anthony F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov FU Intramural Research Program of the National Library of Medicine, the National Heart, Lung, Blood Institute; Clinical Center at the National Institutes of Health; National Institutes of Health FX The authors thank Dr. Matthew Monroe for providing them with the PNNL dataset. The authors thank the administrative group of the National Institutes of Health Biowulf Clusters, where all the computational tasks were carried out. This work was supported by the Intramural Research Program of the National Library of Medicine, the National Heart, Lung, Blood Institute, and the Clinical Center at the National Institutes of Health. Funding for Open Access publication charges for this article was provided by the National Institutes of Health. NR 75 TC 1 Z9 1 U1 7 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1044-0305 EI 1879-1123 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD FEB PY 2016 VL 27 IS 2 BP 194 EP 210 DI 10.1007/s13361-015-1271-2 PG 17 WC Biochemical Research Methods; Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy GA DB7PO UT WOS:000368708000002 PM 26510657 ER PT J AU Zhong, C Cui, KR Wilhelm, C Hu, GQ Mao, KR Belkaid, Y Zhao, KJ Zhu, JF AF Zhong, Chao Cui, Kairong Wilhelm, Christoph Hu, Gangqing Mao, Kairui Belkaid, Yasmine Zhao, Keji Zhu, Jinfang TI Group 3 innate lymphoid cells continuously require the transcription factor GATA-3 after commitment SO NATURE IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; TYPE-2 IMMUNITY; BET; RESPONSES; FATE; DIFFERENTIATION; INFLAMMATION; LYMPHOCYTES; BACTERIA AB The transcription factor GATA-3 is indispensable for the development of all innate lymphoid cells (ILCs) that express the interleukin 7 receptor alpha-chain (IL-7R alpha). However, the function of low GATA-3 expression in committed group 3 ILCs (ILC3 cells) has not been identified. We found that GATA-3 regulated the homeostasis of ILC3 cells by controlling IL-7Ra expression. In addition, GATA-3 served a critical function in the development of the NKp46(+) ILC3 subset by regulating the balance between the transcription factors T-bet and ROR gamma t. Among NKp46(+) ILC3 cells, although GATA-3 positively regulated genes specific to the NKp46(+) ILC3 subset, it negatively regulated genes specific to lymphoid tissue-inducer (LTi) or LTi-like ILC3 cells. Furthermore, GATA-3 was required for IL-22 production in both ILC3 subsets. Thus, despite its low expression, GATA-3 was critical for the homeostasis, development and function of ILC3 subsets. C1 [Zhong, Chao; Zhu, Jinfang] NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cui, Kairong; Hu, Gangqing; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Wilhelm, Christoph; Belkaid, Yasmine] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Wilhelm, Christoph] Univ Bonn, Inst Clin Chem & Clin Pharmacol, Univ Hosp Bonn, Bonn, Germany. [Mao, Kairui] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Mol & Cellular Immunoregulat Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fzhu@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU US National Institutes of Health; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute FX We thank D.R. Littman (New York University) for Rorc-Cre mice on the C57BL/6 background; A. Singer (National Cancer Institute) for Tg-hCD2-Il7ra mice on the C57BL/6 background; C. Dulac (Harvard) for Tbx21-Cre mice; D. Artis (University of Pennsylvania) for C. rodentium strain DBS100; A. Bhandoola, R. Germain, J. O'Shea, P. Schwartzberg and A. Sher for critical reading of our manuscript; L. Guo for suggestions and technical assistance in analyzing ILCs; K. Weng for assistance in cell sorting; L. Feigenbaum for assistance in generating ROR gamma t-E2-Crimson mice; and the DNA Sequencing and Computational Biology Core of the National Heart, Lung, and Blood Institute for sequencing the RNA-Seq and ChIP-Seq libraries. Supported by the Intramural Research Program of the US National Institutes of Health, the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. NR 33 TC 16 Z9 16 U1 4 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2016 VL 17 IS 2 BP 169 EP 178 DI 10.1038/ni.3318 PG 10 WC Immunology SC Immunology GA DB5RO UT WOS:000368571500010 PM 26595886 ER PT J AU Malhotra, D Linehan, JL Dileepan, T Lee, YJ Purtha, WE Lu, JV Nelson, RW Fife, BT Orr, HT Anderson, MS Hogquist, KA Jenkins, MK AF Malhotra, Deepali Linehan, Jonathan L. Dileepan, Thamotharampillai Lee, You Jeong Purtha, Whitney E. Lu, Jennifer V. Nelson, Ryan W. Fife, Brian T. Orr, Harry T. Anderson, Mark S. Hogquist, Kristin A. Jenkins, Marc K. TI Tolerance is established in polyclonal CD4(+) T cells by distinct mechanisms, according to self-peptide expression patterns SO NATURE IMMUNOLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; PANCREATIC BETA-CELLS; IN-VIVO; TRANSGENIC MICE; LISTERIA-MONOCYTOGENES; PERIPHERAL TOLERANCE; ANTIGEN PRESENTATION; TRANSCRIPTION FACTOR; NEGATIVE SELECTION; CLONAL DELETION AB Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptide's presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns. C1 [Malhotra, Deepali; Linehan, Jonathan L.; Dileepan, Thamotharampillai; Nelson, Ryan W.; Jenkins, Marc K.] Univ Minnesota, Sch Med, Ctr Immunol, Dept Microbiol & Immunol, Minneapolis, MN 55455 USA. [Lee, You Jeong; Hogquist, Kristin A.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Ctr Immunol, Minneapolis, MN 55455 USA. [Purtha, Whitney E.; Lu, Jennifer V.; Anderson, Mark S.] Univ Calif San Francisco, Diabet Ctr, San Francisco, CA 94143 USA. [Fife, Brian T.] Univ Minnesota, Sch Med, Dept Med, Ctr Immunol, Minneapolis, MN 55455 USA. [Orr, Harry T.] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Inst Translat Neurosci, Minneapolis, MN 55455 USA. [Linehan, Jonathan L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. RP Jenkins, MK (reprint author), Univ Minnesota, Sch Med, Ctr Immunol, Dept Microbiol & Immunol, Minneapolis, MN 55455 USA. EM Jenki002@umn.edu OI Malhotra, Deepali/0000-0002-8215-7639; Fife, Brian/0000-0001-9826-5637; Jenkins, Marc/0000-0001-8009-7655 FU US National Institutes of Health [P01 AI35296, F32 AI114050, T32 GM008244, F30 DK093242, T32 AI07313, K99 AI114884]; Wallin Neuroscience Discovery Fund; Juvenile Diabetes Research Foundation [2-2011-662] FX We thank D. Mueller for reviewing the manuscript; J. Walter and O. Rainwater for technical assistance; P. Lauer (and Aduro Biotech) for the Lm-eGFP strain PL1113. Supported by the US National Institutes of Health (P01 AI35296 to M.K.J. and K.A.H.; F32 AI114050 to D.M.; T32 GM008244 and F30 DK093242 to R.W.N.; T32 AI07313 to J.L.L.; K99 AI114884 to Y.J.L.), the Wallin Neuroscience Discovery Fund (to H.T.O. and M.K.J.) and the Juvenile Diabetes Research Foundation (2-2011-662 to B.T.F.). NR 50 TC 13 Z9 13 U1 7 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 EI 1529-2916 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2016 VL 17 IS 2 BP 187 EP 195 DI 10.1038/ni.3327 PG 9 WC Immunology SC Immunology GA DB5RO UT WOS:000368571500012 PM 26726812 ER PT J AU Datiles, MB Ansari, RR Yoshida, J Brown, H Zambrano, AI Tian, J Vitale, S Zigler, JS Ferris, FL West, SK Stark, WJ AF Datiles, Manuel B., III Ansari, Rafat R. Yoshida, Junko Brown, Holly Zambrano, Andrea I. Tian, Jing Vitale, Susan Zigler, J. Samuel, Jr. Ferris, Frederick L., III West, Sheila K. Stark, Walter J. TI Longitudinal Study of Age-Related Cataract Using Dynamic Light Scattering Loss of alpha-Crystallin Leads to Nuclear Cataract Development SO OPHTHALMOLOGY LA English DT Article ID HUMAN LENS; ENVIRONMENTAL-FACTORS; PROTEIN DIFFUSIVITY; EYE; POPULATION; OXIDATION; VITRECTOMY; MECHANISM; CHAPERONE AB Purpose: To conduct a longitudinal study on age-related nuclear cataracts using dynamic light scattering (DLS) to determine if cataract progression is associated with loss of the unbound form of the lens molecular chaperone protein, a-crystallin. Design: Natural history and cohort study. Participants: Patients 30 years of age or older of either gender seeking treatment at the Wilmer Eye Institute Cornea-Cataract Department. Methods: All patients underwent a comprehensive dilated eye examination every 6 months, including slit-lamp grading of their lenses using the Age-Related Eye Disease Study (AREDS) clinical lens grading system and obtaining an estimate of unbound alpha-crystallin level in the nucleus, the alpha-crystallin index (ACI), using the National Aeronautics and Space Administration-National Eye Institute DLS device. We used a random effects statistical model to examine the relationship of lens opacity changes over time with ACI changes. Main Outcome Measures: a-Crystallin Index (ACI) and AREDS nuclear cataract grade. Results: Forty-five patients (66 eyes) 34 to 79 years of age with AREDS nuclear lens grades of 0 to 3.0 were followed up every 6 months for a mean of 19 months (range, 6-36 months). We found that lenses with the lowest baseline levels of ACI had the most rapid progression of cataracts, whereas lenses with higher ACI at baseline had no or slower cataract progression. Lenses that lost a-crystallin at the highest rates during the study also had faster progression of nuclear cataracts than lenses with a slower rate of ACI loss. Kaplan-Meier survival curves showed that lenses with the lowest initial ACI had the highest risk of undergoing cataract surgery. Conclusions: This longitudinal study corroborates our previous cross-sectional study finding that higher levels of unbound a-crystallin as assessed by ACI are associated with lower risk of cataract formation and that loss of ACI over time is associated with cataract formation and progression. This study suggested that assessment of ACI with the DLS device could be used as a surrogate for lens opacity risk in clinical studies, and for assessing nuclear cataract events in studies where cataract development may be a side effect of a drug or device. (C) 2016 Published by Elsevier on behalf of the American Academy of Ophthalmology. C1 [Datiles, Manuel B., III; Vitale, Susan; Ferris, Frederick L., III] NEI, NIH, Bethesda, MD 20892 USA. [Ansari, Rafat R.] John H Glenn Res Ctr, Natl Aeronaut & Space Adm, Cleveland, OH USA. [Brown, Holly; Zambrano, Andrea I.; Tian, Jing; Zigler, J. Samuel, Jr.; West, Sheila K.; Stark, Walter J.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Yoshida, Junko] Univ Tokyo, Dept Ophthalmol, Tokyo 113, Japan. RP Datiles, MB (reprint author), NEI, Off Clin Director, NIH, 10 Ctr Dr,Bldg 10,Room 10N226, Bethesda, MD 20892 USA. EM DatilesM@NEI.NIH.GOV FU National Aeronautics and Space Administration-National Eye Institute, National Institute of Health; Kwok Research Fund, Hong Kong, China; Stark-Mosher Center for Cataract and Corneal Disease Research Fund, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD FX Supported in part by the National Aeronautics and Space Administration-National Eye Institute, National Institute of Health, Interagency Agreement; the Kwok Research Fund, Hong Kong, China; and the Stark-Mosher Center for Cataract and Corneal Disease Research Fund, Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, MD. The sponsors and funding organizations had no role in the design or conduct of this research. NR 47 TC 4 Z9 4 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2016 VL 123 IS 2 BP 248 EP 254 DI 10.1016/j.ophtha.2015.10.007 PG 7 WC Ophthalmology SC Ophthalmology GA DB2TK UT WOS:000368362200015 PM 26545319 ER PT J AU Rhew, IC Hawkins, JD Murray, DM Fagan, AA Oesterle, S Abbott, RD Catalano, RF AF Rhew, Isaac C. Hawkins, J. David Murray, David M. Fagan, Abigail A. Oesterle, Sabrina Abbott, Robert D. Catalano, Richard F. TI Evaluation of Community-Level Effects of Communities That Care on Adolescent Drug Use and Delinquency Using a Repeated Cross-Sectional Design SO PREVENTION SCIENCE LA English DT Article DE Community prevention; Substance use; Delinquency; Group-randomized trial; Repeated cross-sectional design; Adolescence ID SERVICE SYSTEM TRANSFORMATION; YOUTH PROBLEM BEHAVIORS; PREVENTION SYSTEM; THAT-CARE; TRANSLATIONAL RESEARCH; RANDOMIZED-TRIAL; MEASURING RISK; SUBSTANCE USE; IMPLEMENTATION; INTERVENTION AB The Communities That Care (CTC) prevention system has shown effects on reducing incidence and prevalence of problem behaviors among a panel of youth followed from 5th through 12th grade. The present report examines whether similar intervention effects could be observed using a repeated cross-sectional design in the same study. Data were from a community-randomized trial of 24 US towns. Cross-sectional samples of sixth, eighth, and tenth graders were surveyed at four waves. Two-stage ANCOVA analyses estimated differences between CTC and control communities in community-level prevalence of problem behaviors for each grade, adjusting for baseline prevalence. No statistically significant reductions in prevalence of problem behaviors were observed at any grade in CTC compared to control communities. Secondary analyses examined intervention effects within a "pseudo cohort" where cross-sectional data were used from sixth graders at baseline and tenth graders 4 years later. When examining effects within the pseudo cohort, CTC compared to control communities showed a significantly slower increase from sixth to tenth grade in lifetime smokeless tobacco use but not for other outcomes. Exploratory analyses showed significantly slower increases in lifetime problem behaviors within the pseudo cohort for CTC communities with high, but not low, prevention program saturation compared to control communities. Although CTC demonstrated effects in a longitudinal panel from the same community-randomized trial, we did not find similar effects on problem behaviors using a repeated cross-sectional design. These differences may be due to a reduced ability to detect effects because of potential cohort effects, accretion of those who were not exposed, and attrition of those who were exposed to CTC programming in the repeated cross-sectional sample. C1 [Rhew, Isaac C.] Univ Washington, Dept Psychiat & Behav Sci, Ctr Study Hlth & Risk Behav, 1100 NE 45th St,300, Seattle, WA 98105 USA. [Hawkins, J. David; Oesterle, Sabrina; Catalano, Richard F.] Univ Washington, Sch Social Work, Social Dev Res Grp, 9725 3rd Ave NE,401, Seattle, WA 98115 USA. [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, NIH, 6100 Executive Blvd,2B03, Rockville, MD 20892 USA. [Fagan, Abigail A.] Univ Florida, Dept Sociol & Criminol & Law, 3219 Turlington Hall,POB 117330, Gainesville, FL 32611 USA. [Abbott, Robert D.] Univ Washington, Coll Educ, Box 353600, Seattle, WA 98195 USA. RP Rhew, IC (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Ctr Study Hlth & Risk Behav, 1100 NE 45th St,300, Seattle, WA 98105 USA. EM rhew@uw.edu; jdh@u.washington.edu; david.murray2@nih.gov; afagan@ufl.edu; soe@u.washington.edu; abbottr@u.washington.edu; catalano@u.washington.edu RI Figueroa Ossa, Ulda Omar/N-5821-2016; OI Murray, David/0000-0003-0797-9269 FU National Institute on Drug Abuse [R01 DA015183]; National Cancer Institute; National Institute of Child Health and Human Development; National Institute of Mental Health; Center for Substance Abuse Prevention; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the National Institute on Drug Abuse (R01 DA015183), with co-funding from the National Cancer Institute, the National Institute of Child Health and Human Development, the National Institute of Mental Health, the Center for Substance Abuse Prevention, and the National Institute on Alcohol Abuse and Alcoholism. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 29 TC 0 Z9 0 U1 6 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD FEB PY 2016 VL 17 IS 2 BP 177 EP 187 DI 10.1007/s11121-015-0613-4 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DB7KA UT WOS:000368692700004 PM 26462492 ER PT J AU Resnik, DB Elmore, SA AF Resnik, David B. Elmore, Susan A. TI Ensuring the Quality, Fairness, and Integrity of Journal Peer Review: A Possible Role of Editors SO SCIENCE AND ENGINEERING ETHICS LA English DT Article DE Peer review; Quality; Fairness; Integrity; Ethics; Reliability; Bias; Editors; Publication ID RANDOMIZED CONTROLLED-TRIAL; RETRACTED ARTICLE. SEE; MASKING AUTHOR IDENTITY; PUBLICATION BIAS; GENDER BIAS; CLINICAL-RESEARCH; DECISION-MAKING; RECOMMENDATIONS; MANUSCRIPT; IMPROVE AB A growing body of literature has identified potential problems that can compromise the quality, fairness, and integrity of journal peer review, including inadequate review, inconsistent reviewer reports, reviewer biases, and ethical transgressions by reviewers. We examine the evidence concerning these problems and discuss proposed reforms, including double-blind and open review. Regardless of the outcome of additional research or attempts at reforming the system, it is clear that editors are the linchpin of peer review, since they make decisions that have a significant impact on the process and its outcome. We consider some of the steps editors should take to promote quality, fairness and integrity in different stages of the peer review process and make some recommendations for editorial conduct and decision-making. C1 [Resnik, David B.] NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. [Elmore, Susan A.] NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop CU 03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) FX David B. Resnik is Associate Editor of Accountability in Research. Susan A. Elmore is Editor and Editor-in-Chief of Toxicologic Pathology. This research is supported by the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or U.S. government. NR 84 TC 9 Z9 9 U1 8 U2 26 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1353-3452 EI 1471-5546 J9 SCI ENG ETHICS JI Sci. Eng. Ethics PD FEB PY 2016 VL 22 IS 1 BP 169 EP 188 DI 10.1007/s11948-015-9625-5 PG 20 WC Ethics; Engineering, Multidisciplinary; History & Philosophy Of Science; Multidisciplinary Sciences; Philosophy SC Social Sciences - Other Topics; Engineering; History & Philosophy of Science; Science & Technology - Other Topics; Philosophy GA DB7NN UT WOS:000368702500009 PM 25633924 ER PT J AU Mener, DJ Betz, J Yaffe, K Harris, TB Helzner, EP Satterfield, S Houston, DK Strotmeyer, ES Pratt, SR Simonsick, EM Lin, FR AF Mener, David J. Betz, Joshua Yaffe, Kristine Harris, Tamara B. Helzner, Elizabeth P. Satterfield, Suzanne Houston, Denise K. Strotmeyer, Elsa S. Pratt, Sheila R. Simonsick, Eleanor M. Lin, Frank R. CA Hlth ABC Study TI Apolipoprotein E Allele and Hearing Thresholds in Older Adults SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE apolipoprotein E; hearing thresholds; hearing loss; cognition; aging; dementia ID INCIDENT DEMENTIA; COGNITIVE DECLINE; UNITED-STATES; ASSOCIATION AB Background: Whether apolipoprotein E (APOE) E4 allele status which is associated with an increased risk of cognitive decline is also associated with hearing impairment is unknown. Methods: We studied 1833 men and women enrolled in the Health, Aging and Body Composition study. Regression models adjusted for demographic and cardiovascular risk factors were used to assess the cross-sectional association of APOE-E4 status with individual pure tone hearing thresholds and the 4-frequency pure tone average (0.5-4 kHz) in the better hearing ear. Results: Compared to participants with no APOE-E4 alleles, participants with 1 allele had better thresholds at 4.0 kHz ( = -2.72 dB, P = .013) and 8.0 kHz ( = -3.05 kHz, P = .006), and participants with 2 alleles had better hearing thresholds at 1.0 kHz ( = -8.56 dB, P = .021). Conclusion: Our results suggest that APOE-E4 allele status may be marginally associated with better hearing thresholds in older adults. C1 [Mener, David J.; Lin, Frank R.] Johns Hopkins Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Betz, Joshua] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Betz, Joshua; Lin, Frank R.] Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Helzner, Elizabeth P.] Suny Downstate Med Ctr, Dept Epidemiol & Biostat, Brooklyn, NY 11203 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Houston, Denise K.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Pratt, Sheila R.] VA Pittsburgh Healthcare Ctr, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Pratt, Sheila R.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Lin, FR (reprint author), Johns Hopkins Ctr Aging & Hlth, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM flin1@jhmi.edu OI Strotmeyer, Elsa/0000-0002-4093-6036; Betz, Joshua/0000-0003-4488-9799 FU National Institute On Deafness and Other Communication Disorders [K23DC011279]; Triological Society/American College of Surgeons Clinician Scientist Award; Eleanor Schwartz Charitable Foundation; National Institute on Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute on Aging FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr. Lin was supported by a grant from the National Institute On Deafness and Other Communication Disorders (K23DC011279), by the Triological Society/American College of Surgeons Clinician Scientist Award, and the Eleanor Schwartz Charitable Foundation. This research was supported by National Institute on Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Dr. Pratt was supported with resources and the use of facilities at the Veteran Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. NR 12 TC 0 Z9 0 U1 5 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 EI 1938-2731 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD FEB PY 2016 VL 31 IS 1 BP 34 EP 39 DI 10.1177/1533317514537549 PG 6 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA DB0CG UT WOS:000368175600004 PM 24906966 ER PT J AU Zhang, Y Rodriguez, L Peng, G Hsueh, E AF Zhang, Y. Rodriguez, L. Peng, G. Hsueh, E. TI Inhibition of Colon Cancer Growth and Migration by Polyamine Synthesis Inhibition and AMP Kinase Activation SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 69th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 02-05, 2016 CL Boston, MA SP Soc Surg Oncol C1 [Zhang, Y.; Peng, G.; Hsueh, E.] St Louis Univ, Surg, St Louis, MO 63103 USA. [Rodriguez, L.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2016 VL 23 SU 1 MA P98 BP S78 EP S78 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA DB0FW UT WOS:000368185000202 ER PT J AU Fornetti, J Flanders, KC Henson, PM Tan, AC Borges, VF Schedin, P AF Fornetti, J. Flanders, K. C. Henson, P. M. Tan, A-C Borges, V. F. Schedin, P. TI Mammary epithelial cell phagocytosis downstream of TGF-beta 3 is characterized by adherens junction reorganization SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID GROWTH-FACTOR-BETA; CARCINOMA IN-SITU; RECEPTOR TYROSINE KINASE; GLAND INVOLUTION; BREAST-CANCER; APOPTOTIC CELLS; RHO-GTPASES; EXPRESSION; CADHERIN; DEATH AB After weaning, during mammary gland involution, milk-producing mammary epithelial cells undergo apoptosis. Effective clearance of these dying cells is essential, as persistent apoptotic cells have a negative impact on gland homeostasis, future lactation and cancer susceptibility. In mice, apoptotic cells are cleared by the neighboring epithelium, yet little is known about how mammary epithelial cells become phagocytic or whether this function is conserved between species. Here we use a rat model of weaning-induced involution and involuting breast tissue from women, to demonstrate apoptotic cells within luminal epithelial cells and epithelial expression of the scavenger mannose receptor, suggesting conservation of phagocytosis by epithelial cells. In the rat, epithelial transforming growth factor-beta (TGF-beta) signaling is increased during involution, a pathway known to promote phagocytic capability. To test whether TGF-beta enhances the phagocytic ability of mammary epithelial cells, non-transformed murine mammary epithelial EpH4 cells were cultured to achieve tight junction impermeability, such as occurs during lactation. TGF-beta 3 treatment promoted loss of tight junction impermeability, reorganization and cleavage of the adherens junction protein E-cadherin (E-cad), and phagocytosis. Phagocytosis correlated with junction disruption, suggesting junction reorganization is necessary for phagocytosis by epithelial cells. Supporting this hypothesis, epithelial cell E-cad reorganization and cleavage were observed in rat and human involuting mammary glands. Further, in the rat, E-cad cleavage correlated with increased gamma-secretase activity and beta-catenin nuclear localization. In vitro, pharmacologic inhibitors of gamma-secretase or beta-catenin reduced the effect of TGF-beta 3 on phagocytosis to near baseline levels. However, beta-catenin signaling through LiCl treatment did not enhance phagocytic capacity, suggesting a model in which both reorganization of cell junctions and beta-catenin signaling contribute to phagocytosis downstream of TGF-a3. Our data provide insight into how mammary epithelial cells contribute to apoptotic cell clearance, and in light of the negative consequences of impaired apoptotic cell clearance during involution, may shed light on involution-associated breast pathologies. C1 [Fornetti, J.; Henson, P. M.] Univ Colorado Anschutz Med Campus, Reprod Sci Program, Aurora, CO USA. [Fornetti, J.] Oklahoma Med Res Fdn, Program Immunobiol & Canc, Oklahoma City, OK 73104 USA. [Flanders, K. C.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Henson, P. M.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Henson, P. M.] Univ Colorado Anschutz Med Campus, Integrated Dept Immunol, Aurora, CO USA. [Tan, A-C; Borges, V. F.] Univ Colorado Anschutz Med Campus, Div Med Oncol, Dept Med, Aurora, CO USA. [Borges, V. F.; Schedin, P.] Univ Colorado Anschutz Med Campus, Womens Breast Canc Translat Program, Aurora, CO USA. [Schedin, P.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Schedin, P.] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97239 USA. RP Schedin, P (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, 3181 SW Sam Jackson Pk Rd,Mail Code L215, Portland, OR 97239 USA. EM Schedin@ohsu.edu OI Tan, Aik Choon/0000-0003-2955-8369 FU Department of Defense [BC093130, BC104000]; University of Colorado's NIH/NCI Tissue Biobanking and Processing Grant [P30CA046934]; National Institute of Health [5R01CA169175]; Safeway and Grohne Family Foundation; NIH/NCATS Colorado CTSI [UL1 TR001082]; [HL114381] FX We thank Peggy Neville for insightful discussion regarding mammary epithelial cell biology; Patricia Bell, Qiuchen Guo, Mona Hamermesh, Ethan Cabral, Hadley Holden and Eileen Engelberg for technical assistance; Sonali Jindal for pathologic review of human breast tissue, mannose receptor IHC and human TUNEL staining; Xiao-Jing Wang for insightful discussion and critical review of this manuscript; and Steven Anderson, Elizabeth Wellberg and Troy Schedin for assistance in performing gene array analysis. In addition, we thank the patients for their contribution to this research. This work was supported, in part, by the Department of Defense Predoctoral Training Award BC093130 to JF; the University of Colorado's NIH/NCI Tissue Biobanking and Processing Grant P30CA046934; the Department of Defense Breast Cancer Research Program Grant BC104000, the National Institute of Health Grant 5R01CA169175 and Safeway and Grohne Family Foundation Awards to PS and VB; and by grant HL114381 to P.M. Imaging was performed in the University of Colorado Advanced Light Microscopy Core Facility supported in part by NIH/NCATS Colorado CTSI grant number UL1 TR001082. NR 69 TC 3 Z9 3 U1 4 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2016 VL 23 IS 2 BP 185 EP 196 DI 10.1038/cdd.2015.82 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DA8NN UT WOS:000368062200001 PM 26113040 ER PT J AU Qi, Y Liu, H Daniels, MP Zhang, G Xu, H AF Qi, Y. Liu, H. Daniels, M. P. Zhang, G. Xu, H. TI Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration SO CELL DEATH AND DIFFERENTIATION LA English DT Article ID CELL-DEATH; OXIDATIVE STRESS; SPASTIC PARAPLEGIA; HUMAN-DISEASE; FUSION; OPA1; DEGRADATION; YME1L; NEURODEGENERATION; MUTATIONS AB Mitochondrial AAA (ATPases Associated with diverse cellular Activities) proteases i-AAA (intermembrane space-AAA) and m-AAA (matrix-AAA) are closely related and have major roles in inner membrane protein homeostasis. Mutations of m-AAA proteases are associated with neuromuscular disorders in humans. However, the role of i-AAA in metazoans is poorly understood. We generated a deletion affecting Drosophila i-AAA, dYME1L (dYME1L(del)). Mutant flies exhibited premature aging, progressive locomotor deficiency and neurodegeneration that resemble some key features of m-AAA diseases. dYME1Ldel flies displayed elevated mitochondrial unfolded protein stress and irregular cristae. Aged dYME1Ldel flies had reduced complex I (NADH/ ubiquinone oxidoreductase) activity, increased level of reactive oxygen species (ROS), severely disorganized mitochondrial membranes and increased apoptosis. Furthermore, inhibiting apoptosis by targeting dOmi (Drosophila Htra2/ Omi) or DIAP1, or reducing ROS accumulation suppressed retinal degeneration. Our results suggest that i-AAA is essential for removing unfolded proteins and maintaining mitochondrial membrane architecture. Loss of i-AAA leads to the accumulation of oxidative damage and progressive deterioration of membrane integrity, which might contribute to apoptosis upon the release of proapoptotic molecules such as dOmi. Containing ROS level could be a potential strategy to manage mitochondrial AAA protease deficiency. C1 [Qi, Y.; Daniels, M. P.; Xu, H.] NHLBI, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Liu, H.] NCI, NIH, Bethesda, MD 20892 USA. [Zhang, G.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Xu, H (reprint author), NHLBI, Mol Genet Lab, NIH, 10 Ctr Dr,Bldg 10,6C212, Bethesda, MD 20892 USA. EM hong.xu@nih.gov RI Xu, Hong/H-9997-2016 OI Xu, Hong/0000-0003-1049-1184 FU NHLBI FX We thank F Chanut and Y Chen for comments on the manuscript; P Connelly and C Brantner at NHLBI EM Core for technical assistance; J Phillips, P Meier, the TRiP at Harvard Medical School, National Institute of Genetics and Mitsubishi Kagaku Institute of Life Sciences, and Bloomington stock center for fly stocks; X Zhu for Drosophila embryonic cDNA library; E Alnemri, G Juhasz and Hybridoma Bank for antibodies; BestGene for embryonic injection service. This work was supported by NHLBI intramural program. NR 67 TC 4 Z9 4 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 EI 1476-5403 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2016 VL 23 IS 2 BP 291 EP 302 DI 10.1038/cdd.2015.94 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DA8NN UT WOS:000368062200011 PM 26160069 ER PT J AU Liu, X Cao, YF Ran, RX Dong, PP Gonzalez, FJ Wu, X Huang, T Chen, JX Fu, ZW Li, RS Liu, YZ Sun, HZ Fang, ZZ AF Liu, Xin Cao, Yun-Feng Ran, Rui-Xue Dong, Pei-Pei Gonzalez, Frank J. Wu, Xue Huang, Ting Chen, Jian-Xin Fu, Zhi-Wei Li, Rong-Shan Liu, Yong-Zhe Sun, Hong-Zhi Fang, Zhong-Ze TI New insights into the risk of phthalates: Inhibition of UDP-glucuronosyltransferases SO CHEMOSPHERE LA English DT Article DE Phthalates; UDP-glucuronosyltransferases (UGTs); Di-n-octyl ortho-phthalate (DNOP); Diphenyl phthalate (DPhP) ID METABOLIZING ENZYME; RECEPTOR; ESTERS; MILK; GENE; RAT AB Wide utilization of phthalates-containing products results in the significant exposure of humans to these compounds. Many adverse effects of phthalates have been documented in rodent models, but their effects in humans exposed to these chemicals remain unclear until more mechanistic studies on phthalate toxicities can be carried out. To provide new insights to predict the potential adverse effects of phthalates in humans, the recent study investigated the inhibition of representative phthalates di-n-octyl ortho-phthalate (DNOP) and diphenyl phthalate (DPhP) towards the important xenobiotic and endobiotic-metabolizing UDP-glucuronosyltransferases (UGTs). An in vitro UGTs incubation system was employed to study the inhibition of DNOP and DPhP towards UGT isoforms. DPhP and DNOP weakly inhibited the activities of UGT1A1, UGT1A7, and UGT1A8. 100 mu M of DNOP inhibited the activities of UGT1A3, UGT1A9, and UGT2B7 by 41.8% (p < 0.01), 45.6% (p < 0.01), and 48.8% (p < 0.01), respectively. 100 mu M of DPhP inhibited the activity of UGT1A3, UGT1A6, and UGT1A9 by 81.8 (p < 0.001), 49.1% (p < 0.05), and 76.4% (p < 0.001), respectively. In silica analysis was used to explain the stronger inhibition of DPhP than DNOP t9wards UGT1A3 activity. Kinetics studies were carried our to determine mechanism of inhibition of UGT1A3 by DPhP. Both Dixon and Lineweaver-Burk plots showed the competitive inhibition of DPhP towards UGT1A3. The inhibition kinetic parameter (KO was calculated to be 0.89 mu M. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1>[I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), these studies predicted in vivo drug-drug interaction might occur when the plasma concentration of DPhP was above 0.089 mu M. Taken together, this study reveales the potential for adverse effects of phthalates DNOP and DPhP as a result of UGT inhibition. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Liu, Xin; Sun, Hong-Zhi] Liaoning Med Univ, Affiliated Hosp 1, Jinzhou, Liaoning, Peoples R China. [Cao, Yun-Feng; Huang, Ting; Chen, Jian-Xin] Shanghai Inst Planned Parenthood Res, Key Lab Contracept & Devices Res NPFPC, Shanghai Engn & Technol Res Ctr Reprod Hlth Drug, Shanghai, Peoples R China. [Ran, Rui-Xue; Li, Rong-Shan] Tianjin Med Univ, Sch Pharm, Tianjin Key Lab Technol Enabling Dev Clin Therape, Tianjin 300070, Peoples R China. [Liu, Yong-Zhe; Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin 300070, Peoples R China. [Dong, Pei-Pei] Dalian Med Univ, Inst Integrat Med, Dalian, Peoples R China. [Wu, Xue; Fu, Zhi-Wei] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian, Peoples R China. [Wu, Xue; Fu, Zhi-Wei] Liaoning Med Univ, Affiliated Hosp 1, Dalian, Peoples R China. [Wu, Xue; Fu, Zhi-Wei] Dalian Univ, Affiliated Zhongshan Hosp, Dalian 116012, Peoples R China. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Fang, ZZ (reprint author), Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, 22 Qixiangtai Rd, Tianjin 300070, Peoples R China. EM fangzhongze@tmu.edu.cn FU National Natural Science Foundation of China [81202586, 81202587, 81202588, 81303146]; Tianjin Project of Thousand Youth Talents; Tianjin city FX This work was supported by the National Natural Science Foundation of China (No. 81202586, 81202587, 81202588, 81303146), Tianjin Project of Thousand Youth Talents, and Tianjin city funded international projects to culture selected outstanding postdoctoral. NR 20 TC 6 Z9 6 U1 5 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 EI 1879-1298 J9 CHEMOSPHERE JI Chemosphere PD FEB PY 2016 VL 144 BP 1966 EP 1972 DI 10.1016/j.chemosphere.2015.10.076 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA DA4MQ UT WOS:000367774400249 PM 26547877 ER PT J AU Nagineni, CN William, A Cherukuri, A Samuel, W Hooks, JJ Detrick, B AF Nagineni, Chandrasekharam N. William, Abitha Cherukuri, Aswini Samuel, William Hooks, John J. Detrick, Barbara TI Inflammatory cytokines regulate secretion of VEGF and chemokines by human conjunctival fibroblasts: Role in dysfunctional tear syndrome SO CYTOKINE LA English DT Article DE Conjunctival fibroblasts; Dysfunctional tear syndrome; VEGF; Chemokines; Inflammation ID DRY EYE SYNDROME; OCULAR SURFACE; EXPRESSION; CORNEAL; DISEASE; LIMBAL AB Ocular surface inflammation is one of the primary mechanisms associated with dysfunctional tear syndrome (DTS), also known as dry eye disease. DTS, more prevalent in older populations, causes ocular discomfort and visual disturbance due to dryness on the surface layer in the eye. We used human conjunctival fibroblast cultures (HCJVF) to investigate the effects of inflammatory cytokines IFN-gamma, TNF-alpha and IL-1 beta (ITI) on the secretions of VEGF and chemokines. Our results demonstrate the elevated secretion of angiogenic VEGF molecules by ITI without affecting anti-angiogenic molecules, PEDF, endostatin, thrombospondin and sVEGF-R1. The secretion of interferon-gamma inducible chemokines, CXCL9, -10, -11 by HCJVF were significantly enhanced by ITI. Our in vitro study supports previously reported observations of elevated VEGF and chemokines in tear fluids of DTS patients, reiterating the role of inflammatory reactions in DTS. Published by Elsevier Ltd. C1 [Nagineni, Chandrasekharam N.; William, Abitha; Hooks, John J.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Cherukuri, Aswini; Samuel, William] NEI, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. RP Nagineni, CN (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. EM naginenic@mail.nih.gov FU Intramural Research Program of the National Eye Institute, NIH FX This study was supported by the Intramural Research Program of the National Eye Institute, NIH. NR 15 TC 0 Z9 0 U1 4 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 EI 1096-0023 J9 CYTOKINE JI Cytokine PD FEB PY 2016 VL 78 BP 16 EP 19 DI 10.1016/j.cyto.2015.11.016 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA DB0TZ UT WOS:000368221700003 PM 26615568 ER PT J AU Sumner, AE Duong, MT Aldana, PC Ricks, M Tulloch-Reid, MK Lozier, JN Chung, ST Sacks, DB AF Sumner, Anne E. Duong, Michelle T. Aldana, Paola C. Ricks, Madia Tulloch-Reid, Marshall K. Lozier, Jay N. Chung, Stephanie T. Sacks, David B. TI A1C Combined With Glycated Albumin Improves Detection of Prediabetes in Africans: The Africans in America Study SO DIABETES CARE LA English DT Article ID LIFE-STYLE INTERVENTION; TYPE-2 DIABETES-MELLITUS; GLUCOSE-TOLERANCE; INSULIN SENSITIVITY; HEMOGLOBIN A1C; FOLLOW-UP; RISK; POPULATION; PREVALENCE; ATHEROSCLEROSIS AB OBJECTIVE Slowing the diabetes epidemic in Africa requires improved detection of prediabetes. A1C, a form of glycated hemoglobin A, is recommended for diagnosing prediabetes. The glycated proteins, fructosamine and glycated albumin (GA), are hemoglobin-independent alternatives to A1C, but their efficacy in Africans is unknown. Our goals were to determine the ability of A1C, fructosamine, and GA to detect prediabetes in U.S.-based Africans and the value of combining A1C with either fructosamine or GA. RESEARCH DESIGN AND METHODS Oral glucose tolerance tests (OGTT) were performed in 217 self-identified healthy African immigrants (69% male, age 39 +/- 10 years [mean +/- SD], BMI 27.6 +/- 4.5 kg/m(2)). A1C, fructosamine, and GA were measured. Prediabetes was diagnosed by American Diabetes Association criteria for glucose obtained from a 2-h OGTT. The thresholds to diagnose prediabetes by A1C, fructosamine, and GA were the cutoff at the upper tertile for each variable: >= 5.7% (39 mmol/mol) (range 4.2-6.6% [22.4-48.6 mmol/mol]), >= 230 mu mol/L (range 161-269 mu mol/L), and >= 13.35% (range 10.20-16.07%), respectively. RESULTS Prediabetes occurred in 34% (74 of 217). The diagnostic sensitivities of A1C, fructosamine, and GA were 50%, 41%, and 42%, respectively. The P values for comparison with A1C were both > 0.3. Combining A1C with either fructosamine or GA increased sensitivities. However, the sensitivity of A1C combined with fructosamine was not better than for A1C alone (72% vs. 50%, P = 0.172). In contrast, the sensitivity of A1C combined with GA was higher than for A1C alone (78% vs. 50%, P < 0.001). CONCLUSIONS As individual tests, A1C, fructosamine, and GA detected <= 50% of Africans with prediabetes. However, combining A1C with GA made it possible to identify nearly 80% of Africans with prediabetes. C1 [Sumner, Anne E.; Duong, Michelle T.; Aldana, Paola C.; Ricks, Madia; Chung, Stephanie T.] NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Tulloch-Reid, Marshall K.] Univ W Indies, Res Inst Trop Med, Kingston 7, Jamaica. [Lozier, Jay N.; Sacks, David B.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDKD, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. EM annes@intra.niddk.nih.gov FU intramural program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH; Intramural Research Program of the NIH Clinical Center FX A.E.S., M.T.D., P.C.A., M.R., and S.T.C. were supported by the intramural program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH. J.N.L. and D.B.S. were supported by the Intramural Research Program of the NIH Clinical Center. NR 39 TC 4 Z9 4 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2016 VL 39 IS 2 BP 271 EP 277 DI 10.2337/dc15-1699 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DB4XF UT WOS:000368516200020 PM 26681716 ER PT J AU Zhang, Z Zheng, YA Zhang, X Liu, C Joyce, BT Kibbe, WA Hou, LF Zhang, W AF Zhang, Zhou Zheng, Yinan Zhang, Xu Liu, Cong Joyce, Brian Thomas Kibbe, Warren A. Hou, Lifang Zhang, Wei TI Linking short tandem repeat polymorphisms with cytosine modifications in human lymphoblastoid cell lines SO HUMAN GENETICS LA English DT Article ID COPY NUMBER VARIATION; GENOME-WIDE VARIATION; GENE-EXPRESSION; DNA METHYLATION; ALZHEIMERS-DISEASE; REGULATORY REGIONS; COMPLEX TRAITS; HAPLOTYPE MAP; SNPS; ARCHITECTURE AB Inter-individual variation in cytosine modifications has been linked to complex traits in humans. Cytosine modification variation is partially controlled by single nucleotide polymorphisms (SNPs), known as modified cytosine quantitative trait loci (mQTL). However, little is known about the role of short tandem repeat polymorphisms (STRPs), a class of structural genetic variants, in regulating cytosine modifications. Utilizing the published data on the International HapMap Project lymphoblastoid cell lines (LCLs), we assessed the relationships between 721 STRPs and the modification levels of 283,540 autosomal CpG sites. Our findings suggest that, in contrast to the predominant cis-acting mode for SNP-based mQTL, STRPs are associated with cytosine modification levels in both cis-acting (local) and trans-acting (distant) modes. In local scans within the +/- 1 Mb windows of target CpGs, 21, 9, and 21 cis-acting STRP-based mQTL were detected in CEU (Caucasian residents from Utah, USA), YRI (Yoruba people from Ibadan, Nigeria), and the combined samples, respectively. In contrast, 139,420, 76,817, and 121,866 trans-acting STRP-based mQTL were identified in CEU, YRI, and the combined samples, respectively. A substantial proportion of CpG sites detected with local STRP-based mQTL were not associated with SNP-based mQTL, suggesting that STRPs represent an independent class of mQTL. Functionally, genetic variants neighboring CpG-associated STRPs are enriched with genome-wide association study (GWAS) loci for a variety of complex traits and diseases, including cancers, based on the National Human Genome Research Institute (NHGRI) GWAS Catalog. Therefore, elucidating these STRP-based mQTL in addition to SNP-based mQTL can provide novel insights into the genetic architectures of complex traits. C1 [Zhang, Zhou] Northwestern Univ, Feinberg Sch Med, Driskill Grad Program Life Sci, Chicago, IL 60611 USA. [Zhang, Zhou; Zheng, Yinan; Joyce, Brian Thomas; Hou, Lifang; Zhang, Wei] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Zheng, Yinan] Northwestern Univ, Feinberg Sch Med, Inst Publ Hlth & Med, Chicago, IL 60611 USA. [Zhang, Xu] Univ Illinois, Dept Med, Hematol Oncol Sect, Chicago, IL 60612 USA. [Liu, Cong] Univ Illinois, Dept Bioengn, Chicago, IL 60612 USA. [Joyce, Brian Thomas] Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60612 USA. [Kibbe, Warren A.] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20850 USA. [Hou, Lifang; Zhang, Wei] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Zhang, Wei] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. RP Zhang, W (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM wei.zhang1@northwestern.edu RI Zheng, Yinan/E-5775-2017 FU National Institutes of Health [R21HG006367, R21CA187869]; Robert H. Lurie Comprehensive Cancer Center-Developmental Funds [P30CA060553] FX This work was partially supported by grants from the National Institutes of Health: R21HG006367 (to WZ), R21CA187869 (to WZ and LH), and The Robert H. Lurie Comprehensive Cancer Center-Developmental Funds P30CA060553 (to WZ). NR 59 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD FEB PY 2016 VL 135 IS 2 BP 223 EP 232 DI 10.1007/s00439-015-1628-4 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA DB0GQ UT WOS:000368187000007 PM 26714498 ER PT J AU Blair, CK Robien, K Inoue-Choi, M Rahn, W Lazovich, D AF Blair, Cindy K. Robien, Kim Inoue-Choi, Maki Rahn, Wendy Lazovich, DeAnn TI Physical inactivity and risk of poor quality of life among elderly cancer survivors compared to women without cancer: the Iowa Women's Health Study SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Quality of life; Physical activity; Survivorship; Cohort; Cancer survivors ID RANDOMIZED CONTROLLED-TRIAL; POPULATION-BASED SAMPLE; UNITED-STATES; STYLE FACTORS; OLDER-ADULTS; BREAST; ASSOCIATIONS; GUIDELINES; ADHERENCE; EXERCISE AB Few studies have examined lifestyle factors and quality of life (QOL) in cancer survivors compared to a cancer-free group. Compared to active cancer-free women, we examined the association between physical inactivity and QOL in elderly cancer survivors and similar-aged women without cancer. Participants included 1776 cancer survivors and 12,599 cancer-free women enrolled in the Iowa Women's Health Study in 1986 who completed the SF36 QOL assessment in 2004 (ages 73-88 years). The odds of poor QOL were computed for each SF36 subscale (> 0.5 SD below mean score of cancer-free women) associated with physical inactivity (moderate-vigorous activity < once/week) between four groups based on the cross-classification of cancer history (no/yes) and physical inactivity (no/yes) (referent group = active cancer-free women). Compared with the referent group, inactive cancer survivors were significantly more likely to report poor QOL for each SF36 subscale (odds ratios 1.8 to 4.7), independent of age, comorbidity, body mass index (BMI), and diet quality. The greatest odds for poor QOL occurred for general health, vitality, and physical function. These increased odds occurred regardless of whether survivors were inactive at both baseline (1986) and follow-up or became inactive sometime after baseline. Among physically active women, cancer survivors had similar QOL as cancer-free women. These findings provide evidence on the importance of leisure-time physical activity in older women and support the need for interventions to help older women maintain or regain a physically active lifestyle. Survivors who remain or become physically active as they age report better mental and physical QOL. C1 [Blair, Cindy K.; Lazovich, DeAnn] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Robien, Kim] George Washington Univ, Sch Publ Hlth, Milken Inst, Dept Exercise & Nutr Sci, Washington, DC USA. [Inoue-Choi, Maki] NCI, Div Canc Epidemiol & Genet, Natl Inst Minor Hlth & Hlth Dispar, Washington, DC USA. [Rahn, Wendy] Univ Minnesota, Dept Polit Sci, Minneapolis, MN 55454 USA. [Lazovich, DeAnn] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55454 USA. RP Blair, CK (reprint author), Univ Minnesota, Div Epidemiol & Community Hlth, 1300 South Second St,Suite 300, Minneapolis, MN 55454 USA. EM blair016@umn.edu OI Robien, Kim/0000-0002-2120-2280 FU National Cancer Institute [R01 CA039742] FX We are grateful to the women who so generously gave of their time to participate in the Iowa Women's Health Study. Supported by the National Cancer Institute R01 CA039742. NR 38 TC 0 Z9 0 U1 4 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD FEB PY 2016 VL 10 IS 1 BP 103 EP 112 DI 10.1007/s11764-015-0456-9 PG 10 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA DA9SD UT WOS:000368149000010 PM 26008207 ER PT J AU Shiels, MS Robbins, HA Engels, EA AF Shiels, Meredith S. Robbins, Hilary A. Engels, Eric A. TI Younger age at cancer diagnosis may be driven by age structure of the HCV population SO JOURNAL OF HEPATOLOGY LA English DT Letter C1 [Shiels, Meredith S.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Robbins, Hilary A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Shiels, MS (reprint author), NCI, NIH, 9609 Med Ctr Dr,Room 6E-218 MSC 9767, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [T32 CA009314] NR 6 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 EI 1600-0641 J9 J HEPATOL JI J. Hepatol. PD FEB PY 2016 VL 64 IS 2 BP 516 EP 517 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA DB1PF UT WOS:000368280200026 PM 26555270 ER PT J AU Ali, M Mwendwa, DT Sims, R Ricks, M Sumner, AE AF Ali, Mana Mwendwa, Denee T. Sims, Regina Ricks, Madia Sumner, Anne E. TI Age at Immigration and Kidney Function among Self-Identified Healthy Africans in the United States SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE African immigrants; Age at immigration; Kidney function; Estimated glomerular filtration rate ID STAGE RENAL-DISEASE; RACIAL-DIFFERENCES; CARDIOVASCULAR-DISEASE; FAMILY-HISTORY; RISK; RESIDENCE; LIFE; HYPERTENSION; ASSOCIATION; POPULATION AB Kidney disease disparately affects those of African descent. Age trends have generally been established for kidney function in the overall US population, but the contribution of age at the time of immigration for African immigrants is unknown. To examine the independent and joint effects of age and age at the time of immigration, and kidney function. Estimated glomerular filtration rate (eGFR) was calculated for 93 African immigrants (60 % male; mean age = 33.5). Hierarchical regression and post hoc analyses revealed a significant age x age at the time of immigration interaction after accounting for traditional risk factors among those who immigrated at age a parts per thousand currency sign21. Younger age at the time of immigration to the US may exacerbate an inverse relationship between age and kidney function in a self-identified healthy African immigrant sample. Investigation of biopsychosocial factors associated with kidney health among African immigrants is warranted. C1 [Ali, Mana; Mwendwa, Denee T.] Howard Univ, Dept Psychol, Washington, DC 20059 USA. [Sims, Regina] Univ Delaware, Sch Nursing, Newark, DE USA. [Ricks, Madia; Sumner, Anne E.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Ali, M (reprint author), Howard Univ, Dept Psychol, 525 Bryant St NW,Room N-179,CB Powell Bldg, Washington, DC 20059 USA. EM Ms.manaali@gmail.com FU NIDDK, NIH FX Madia Ricks and Anne E. Sumner were supported by the Intramural Program of NIDDK, NIH. NR 50 TC 0 Z9 0 U1 2 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD FEB PY 2016 VL 18 IS 1 BP 194 EP 201 DI 10.1007/s10903-014-0138-0 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DB0DX UT WOS:000368179900023 PM 25420783 ER PT J AU Nickel, JC Stephens, A Landis, JR Mullins, C van Bokhoven, A Lucia, MS Ehrlich, GD AF Nickel, J. Curtis Stephens, Alisa Landis, J. Richard Mullins, Chris van Bokhoven, Adrie Lucia, M. Scott Ehrlich, Garth D. CA MAPP Res Network TI Assessment of the Lower Urinary Tract Microbiota during Symptom Flare in Women with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study SO JOURNAL OF UROLOGY LA English DT Article DE microbiota; infection; cystitis; interstitial; symptom assessment ID INTERSTITIAL CYSTITIS; BLADDER; BACTERIURIA; INFECTION AB Purpose: We compared culture independent assessment of microbiota of the lower urinary tract in standard culture negative female patients with urological chronic pelvic pain syndrome who reported symptom flare vs those who did not report a flare. Materials and Methods: Initial stream (VB1) and midstream (VB2) urine specimens (233 patients with urological chronic pelvic pain syndrome) were analyzed with Ibis T-5000 Universal Biosensor system technology for comprehensive identification of microorganism species. Differences between flare and nonflare groups for presence or number of different species within a higher level group (richness) were examined by permutational multivariate analysis of variance and logistic regression. Results: Overall 81 species (35 genera) were detected in VB1 and 73 (33) in VB2. Mean (SD) VB1 and VB2 species count per person was 2.6 (1.5) and 2.4 (1.5) for 86 flare cases and 2.8 (1.3) and 2.5 (1.5) for 127 nonflare cases, respectively. Overall the species composition did not significantly differ between flare and nonflare cases at any level (p = 0.14 species, p = 0.95 genus in VB1 and VB2, respectively) in multivariate analysis for richness. Univariate analysis, unadjusted as well as adjusted, confirmed a significantly greater prevalence of fungi (Candida and Saccharomyces) in the flare group (15.7%) compared to the nonflare group in VB2 (3.9%) (p = 0.01). When adjusted for antibiotic use and menstrual phase, women who reported a flare remained more likely to have fungi present in VB2 specimens (OR 8.3, CI 1.7-39.4). Conclusions: Among women with urological chronic pelvic pain syndrome the prevalence of fungi (Candida and Saccharomyces sp.) was significantly greater in those who reported a flare compared to those who did not. C1 [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON K7L 2V7, Canada. [Stephens, Alisa; Landis, J. Richard] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Ehrlich, Garth D.] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA. [Ehrlich, Garth D.] Drexel Univ, Coll Med, Dept Otolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Mullins, Chris] NIDDK, NIH, Bethesda, MD 20892 USA. [van Bokhoven, Adrie; Lucia, M. Scott] Univ Colorado, Dept Pathol, Aurora, CO USA. RP Nickel, JC (reprint author), Queens Univ, Dept Urol, Kingston, ON K7L 2V7, Canada. EM jcn@queensu.ca FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health MAPP Network Awards [U01DK82370, U01DK82342, U01DK82315, U01DK82344, U01DK82325, U01DK82345, U01DK82333, U01DK82316] FX Supported by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health MAPP Network Awards U01DK82370, U01DK82342, U01DK82315, U01DK82344, U01DK82325, U01DK82345, U01DK82333 and U01DK82316. NR 19 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD FEB PY 2016 VL 195 IS 2 BP 356 EP 362 DI 10.1016/j.juro.2015.09.075 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DA8KZ UT WOS:000368054800038 PM 26410734 ER PT J AU Liu, XX Lu, XY Song, KM Blackman, MR AF Liu, Xunxian Lu, Xinyue Song, Kaimei Blackman, Marc R. TI Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DIFFERENTIATION-RELATED PROTEIN; WNT CORECEPTOR LRP6; BETA-CATENIN; ALZHEIMERS-DISEASE; NEGATIVE REGULATOR; INSULIN-RESISTANCE; DROPLET PROTEINS; C/EBP-ALPHA; CYCLIN D1; C-MYC AB Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/beta-catenin complexes (AG beta C) as Wnt decreases Dishevelled/PLIN2 but increases AG beta C/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt-increased AG beta C/PLIN2 associations and beta-catenin T-cell factor signaling (beta-CTS). Revealing that PLIN2 is a GSK3-associated protein, the study explored PLIN2-mediated effects on GSK3/GSK3 substrates. PLIN2 siRNA reduces inhibitory GSK3 levels and lithium chloride (LiCl)-upregulated beta-catenin or CCAAT/enhancer binding protein alpha (c/EBP alpha) expression. OA treatment decreases LiCl-increased c/EBP alpha via PLIN2-c/EBP alpha dissociation. In addition to PLIN2 overexpression increasing beta-CTS, PLIN2 depletion or overexpression drops or adds expression of GSK3 substrates, such as beta-catenin, c/EBP alpha,c-Myc, cyclin D1, and insulin receptor substrate 1, and cell growth/survival. PLIN2 N or C terminus overexpression that is associated with higher levels of the substrates suggests that those substrates bind to specific regions of PLIN2. Mimicking the possible high lipid concentrations in cells in the human body under conditions of hyperlipidemia/obesity, OA-treated cells gain or reduce GSK3 substrate expression in parallel with a decrease (a Wnt-like effect) or increase in GSK3 activity, likely regulated by GSK3/PLIN2/GSK3 substrate associations. C1 [Liu, Xunxian; Blackman, Marc R.] NIH, Intramural Res Programs, Natl Ctr Complementary & Integrat Hlth, Bethesda, MD 20892 USA. [Lu, Xinyue] NIDDKD, Lab Cellular & Dev Biol, NIH, Bethesda, MD USA. [Song, Kaimei] NIAID, ImmunoTechnol Sect, Immunol Lab, Vaccine Res Ctr,NIH, Bethesda, MD 20892 USA. RP Lu, XY (reprint author), MacroGenics Inc, Rockville, MD 20850 USA. EM xunxianl@mail.nih.gov; Marc.Blackman@va.gov FU NIH/NCCAM [2006-07, 2007-2014] FX NIH/NCCAM Intramural Funding provided funding to Xunxian Liu and Marc R. Blackman under grant number 2006-07. NIH/NCCAM Intramural Funding provided funding to Xunxian Liu under grant number 2007-2014. NR 57 TC 1 Z9 1 U1 1 U2 6 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 3 BP 421 EP 437 DI 10.1128/MCB.00510-15 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DB2KS UT WOS:000368337900004 PM 26598603 ER PT J AU Dupre, KB Cruz, AV McCoy, AJ Delaville, C Gerber, CM Eyring, KW Walters, JR AF Dupre, Kristin B. Cruz, Ana V. McCoy, Alex J. Delaville, Claire Gerber, Colin M. Eyring, Katherine W. Walters, Judith R. TI Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Abnormal involuntary movements; Beta; Dopamine; Dyskinesia; Gamma; L-dopa; Local field potential; Motor cortex; Oscillations; Parkinson's disease ID 5-HT1A RECEPTOR STIMULATION; 6-HYDROXYDOPAMINE LESIONED RATS; LEVODOPA-INDUCED DYSKINESIAS; HUMAN SUBTHALAMIC NUCLEUS; MOVEMENT-RELATED ACTIVITY; DEEP BRAIN-STIMULATION; SELF-PACED MOVEMENTS; BASAL GANGLIA OUTPUT; PRIMARY MOTOR CORTEX; HEMIPARKINSONIAN RATS AB Prolonged L-dopa treatment in Parkinson's disease (PD) often leads to the expression of abnormal involuntary movements known as L-dopa-induced dyskinesia. Recently, dramatic 80 Hz oscillatory local field potential (LFP) activity within the primary motor cortex has been linked to dyskinetic symptoms in a rodent model of PD and attributed to stimulation of cortical dopamine D1 receptors. To characterize the relationship between high gamma (70-110 Hz) cortical activity and the development of L-dopa-induced dyskinesia, cortical LFP and spike signals were recorded in hemiparkinsonian rats treated with L-dopa for 7 days, and dyskinesia was quantified using the abnormal involuntary movements (AIMs) scale. The relationship between high gamma and dyskinesia was further probed by assessment of the effects of pharmacological agents known to induce or modulate dyskinesia expression. Findings demonstrate that AIMs and high gamma LFP power increase between days 1 and 7 of L-dopa priming. Notably, high beta (25-35 Hz) power associated with parkinsonian bradykinesia decreased as AIMs and high gamma LP power increased during priming. After priming, rats were treated with the D1 agonist SKF81297 and the D2 agonist quinpirole. Both dopamine agonists independently induced AIMs and high gamma cortical activity that were similar to that induced by L-dopa, showing that this LFP activity is neither D1 nor D2 receptor specific. The serotonin 1A receptor agonist 8-OH-DPAT reduced L-dopa- and DA agonist-induced AIMs and high gamma power to varying degrees, while the serotonin 1A antagonist WAY100635 reversed these effects. Unexpectedly, as cortical high gamma power increased, phase locking of cortical pyramidal spiking to high gamma oscillations decreased, raising questions regarding the neural substrate(s) responsible for high gamma generation and the functional correlation between high gamma and dyskinesia. Published by Elsevier Inc. C1 [Dupre, Kristin B.; Cruz, Ana V.; McCoy, Alex J.; Delaville, Claire; Gerber, Colin M.; Eyring, Katherine W.; Walters, Judith R.] NINDS, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Walters, JR (reprint author), NINDS, Neurophysiol Pharmacol Sect, NIH, 35 Convent Dr,Bldg 35,Room 1C905, Bethesda, MD 20892 USA. EM waltersj@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH). We thank Tom Talbot, Daryl Bandy, and Newlin Morgan in the section of Instrumentation, National Institute of Mental Health-National Institute of Neurological Disorders and Stroke for design and fabrication of the rotary treadmill. NR 80 TC 5 Z9 5 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2016 VL 86 BP 1 EP 15 DI 10.1016/j.nbd.2015.11.009 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DB2FQ UT WOS:000368324100001 PM 26586558 ER PT J AU Baumann, MH Volkow, ND AF Baumann, Michael H. Volkow, Nora D. TI Abuse of New Psychoactive Substances: Threats and Solutions SO NEUROPSYCHOPHARMACOLOGY LA English DT Review C1 [Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Volkow, Nora D.] NIDA, Off Director, NIH, Rockville, MD USA. RP Baumann, MH (reprint author), NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, 333 Cassell Dr,Suite 4400, Baltimore, MD 21224 USA. EM mbaumann@mail.nih.gov FU Intramural NIH HHS NR 6 TC 3 Z9 3 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2016 VL 41 IS 3 BP 663 EP 665 DI 10.1038/npp.2015.260 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DA8VI UT WOS:000368084100003 PM 26303285 ER PT J AU Akula, N Wendland, JR Choi, KH McMahon, FJ AF Akula, Nirmala Wendland, Jens R. Choi, Kwang H. McMahon, Francis J. TI An Integrative Genomic Study Implicates the Postsynaptic Density in the Pathogenesis of Bipolar Disorder SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID COEXPRESSION NETWORK ANALYSIS; LARGE GENE LISTS; RNA-SEQ; PREFRONTAL CORTEX; WIDE ASSOCIATION; NONCODING RNA; BRAIN; SCHIZOPHRENIA; TRANSCRIPTOME; EXPRESSION AB Genome-wide association studies (GWAS) have identified several common variants associated with bipolar disorder (BD), but the biological meaning of these findings remains unclear. Integrative genomics-the integration of GWAS signals with gene expression data-may illuminate genes and gene networks that have key roles in the pathogenesis of BD. We applied weighted gene co-expression network analysis (WGCNA), which exploits patterns of co-expression among genes, to brain transcriptome data obtained by sequencing of poly-A RNA derived from postmortem dorsolateral prefrontal cortex from people with BD, along with age-and sex-matched controls. WGCNA identified 33 gene modules. Many of the modules corresponded closely to those previously reported in human cortex. Three modules were associated with BD, enriched for genes differentially expressed in BD, and also enriched for signals in prior GWAS of BD. Functional analysis of genes within these modules revealed significant enrichment of several functionally related sets of genes, especially those involved in the postsynaptic density (PSD). These results provide convergent support for the hypothesis that dysregulation of genes involved in the PSD is a key factor in the pathogenesis of BD. If replicated in larger samples, these findings could point toward new therapeutic targets for BD. C1 [Akula, Nirmala; Wendland, Jens R.; McMahon, Francis J.] NIMH, Human Genet Branch, IRP, NIH,US Dept HHS, Bethesda, MD 20892 USA. [Choi, Kwang H.] Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. RP Akula, N (reprint author), NIMH, Human Genet Branch, IRP, NIH,US Dept HHS, Bldg 35,Room 1A-100,35 Convent Dr, Bethesda, MD 20892 USA. EM akulan@mail.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS; NIMH NIH HHS [ZIA MH002810]; PHS HHS [ZIAMH002810] NR 47 TC 4 Z9 4 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2016 VL 41 IS 3 BP 886 EP 895 DI 10.1038/npp.2015.218 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA DA8VI UT WOS:000368084100025 PM 26211730 ER PT J AU Ida, C Yamashita, S Tsukada, M Sato, T Eguchi, T Tanaka, M Ogata, S Fujii, T Nishi, Y Ikegami, S Moss, J Miwa, M AF Ida, Chieri Yamashita, Sachiko Tsukada, Masaki Sato, Teruaki Eguchi, Takayuki Tanaka, Masakazu Ogata, Shin Fujii, Takahiro Nishi, Yoshisuke Ikegami, Susumu Moss, Joel Miwa, Masanao TI An enzyme-linked immunosorbent assay-based system for determining the physiological level of poly(ADP-ribose) in cultured cells SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Poly(ADP-ribose) polymerase; Poly(ADP-ribose) glycohydrolase; Antibody; ELISA; HeLa cells ID ADP-RIBOSYLATION; IN-VITRO; BINDING; PROTEIN; DNA; IDENTIFICATION; POLYMERASE; VIVO; QUANTIFICATION; TRANSCRIPTION AB PolyADP-ribosylation is mediated by poly(ADP-ribose) (PAR) polymerases (PARPs) and may be involved in various cellular events, including chromosomal stability, DNA repair, transcription, cell death, and differentiation. The physiological level of PAR is difficult to determine in intact cells because of the rapid synthesis of PAR by PARPs and the breakdown of PAR by PAR-degrading enzymes, including poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3. Artifactual synthesis and/or degradation of PAR likely occurs during lysis of cells in culture. We developed a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the physiological levels of PAR in cultured cells. We immediately inactivated enzymes that catalyze the synthesis and degradation of PAR. We validated that trichloroacetic acid is suitable for inactivating PARPs, PARG, and other enzymes involved in metabolizing PAR in cultured cells during cell lysis. The PAR level in cells harvested with the standard radioimmunoprecipitation assay buffer was increased by 450-fold compared with trichloroacetic acid for lysis, presumably because of activation of PARPs by DNA damage that occurred during cell lysis. This ELISA can be used to analyze the biological functions of polyADP-ribosylation under various physiological conditions in cultured cells. (C) 2015 Elsevier Inc. All rights reserved. C1 [Ida, Chieri; Yamashita, Sachiko; Tsukada, Masaki; Sato, Teruaki; Eguchi, Takayuki; Fujii, Takahiro; Nishi, Yoshisuke; Ikegami, Susumu; Miwa, Masanao] Nagahama Inst Biosci & Technol, Fac Biosci, Nagahama, Shiga 5260829, Japan. [Ida, Chieri] Coll Nagoya Womens Univ, Dept Appl Life Studies, Nagoya, Aichi 4678610, Japan. [Tanaka, Masakazu] Kansai Med Univ, Dept Microbiol, Hirakata, Osaka 5731010, Japan. [Ogata, Shin] Mie Univ, Grad Sch Bioresources, Lab Mol & Cellular Biol, Tsu, Mie 5148507, Japan. [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. RP Miwa, M (reprint author), Nagahama Inst Biosci & Technol, Fac Biosci, Nagahama, Shiga 5260829, Japan. EM m_miwa@nagahama-i-bio.ac.jp FU Japan Society for the Promotion of Science [23590350]; Intramural Research Program (National Heart, Lung, and Blood Institute [NHLBI], National Institutes of Health [NIH]) FX We thank Y. Kuroda, T. Kida, and N. Ota of the Nagahama Institute of Bioscience and Technology, Japan, for technical assistance. This work was supported partly by Grants-in-Aid for Scientific Research (23590350) from the Japan Society for the Promotion of Science. J.M. was supported by the Intramural Research Program (National Heart, Lung, and Blood Institute [NHLBI], National Institutes of Health [NIH]). NR 39 TC 2 Z9 2 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 1 PY 2016 VL 494 BP 76 EP 81 DI 10.1016/j.ab.2015.10.014 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DA4HV UT WOS:000367761900014 PM 26548958 ER PT J AU Shah, PH George, AK Moreira, DM Alom, M Okhunov, Z Salami, S Waingankar, N Schwartz, MJ Vira, MA Richstone, L Kavoussi, LR AF Shah, Paras H. George, Arvin K. Moreira, Daniel M. Alom, Manaf Okhunov, Zhamshid Salami, Simpa Waingankar, Nikhil Schwartz, Michael J. Vira, Manish A. Richstone, Lee Kavoussi, Louis R. TI To clamp or not to clamp? Long-term functional outcomes for elective off-clamp laparoscopic partial nephrectomy SO BJU INTERNATIONAL LA English DT Article DE glomerular filtration rate; ischaemia; laparoscopy; nephrectomy; renal neoplasms ID CHRONIC KIDNEY-DISEASE; WARM ISCHEMIA; SOLITARY KIDNEY; RENAL-FUNCTION; TUMORS; MORTALITY; INJURY; COHORT; IMPACT AB Objective To evaluate whether elective off-clamp laparoscopic partial nephrectomy (LPN) affords long-term renal functional benefit compared with the on-clamp approach. Patients and Methods This is a retrospective review of patients who underwent elective LPN between 2006 and 2011. Patients were followed longitudinally for up to 5 years. In all, 315 patients with radiographic evidence of a solitary renal mass and normal-appearing contralateral kidney underwent elective LPN; 209 were performed on-clamp vs 106 off-clamp. One patient who required conversion from LPN to open PN was excluded from the study. Additionally, four patients in the on-clamp cohort who underwent subsequent radical nephrectomy for local-regional recurrence were excluded from longitudinal functional evaluation after their procedure. The primary objective was to evaluate differences in postoperative estimated glomerular filtration rate (eGFR) between hilar clamping groups. Subgroup analyses were performed for patients with clamp times >30 min and those with baseline renal insufficiency (eGFR <60 mL/min/1.73m(2)). Risk of developing worsened or new-onset renal insufficiency was also compared. Results The mean preoperative eGFR was similar between the on-clamp and off-clamp cohorts (80.7 vs 84.1 mL/min/1.73m(2), P > 0.05). Univariable and multivariable analyses did not show significant differences in postoperative eGFR between both groups among all-comers, those with clamp times >30 min, and patients with baseline renal insufficiency. Risk of chronic kidney disease was not diminished by the off-clamp approach with up to 5 years of follow-up. Conclusions Progressive recovery of renal function after hilar clamping in the elective setting eclipses short-term functional benefit achieved with off-clamp LPN by 6 months; there was no significant difference in eGFR or the percentage incidence of chronic kidney disease between the on-clamp and off-clamp cohorts with up to 5 years follow-up. As such, eliminating transient ischaemia during elective LPN does not confer clinical benefit. C1 [Shah, Paras H.; George, Arvin K.; Moreira, Daniel M.; Alom, Manaf; Okhunov, Zhamshid; Salami, Simpa; Waingankar, Nikhil; Schwartz, Michael J.; Vira, Manish A.; Richstone, Lee; Kavoussi, Louis R.] Smith Inst Urol, Dept Urol, New Hyde Pk, NY 11040 USA. [George, Arvin K.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Moreira, Daniel M.] Mayo Clin, Dept Urol, Rochester, MN USA. [Okhunov, Zhamshid] Univ Calif Irvine, Dept Urol, Irvine, CA USA. [Waingankar, Nikhil] Fox Chase Canc Ctr, Div Urol Oncol, Philadelphia, PA 19111 USA. RP Shah, PH (reprint author), Smith Inst Urol, 405 Lakeville Rd,Suite M41, New Hyde Pk, NY 11040 USA. EM pshah1023@gmail.com FU Arthur Smith Institute for Urology FX Paras H. Shah and Daniel M. Moreira had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. This work was supported by the Arthur Smith Institute for Urology. NR 31 TC 2 Z9 2 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD FEB PY 2016 VL 117 IS 2 BP 293 EP 299 DI 10.1111/bju.13309 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DA3RW UT WOS:000367717300019 PM 26348366 ER PT J AU Angst, J Paksarian, D Cui, L Merikangas, KR Hengartner, MP Ajdacic-Gross, V Rossler, W AF Angst, J. Paksarian, D. Cui, L. Merikangas, K. R. Hengartner, M. P. Ajdacic-Gross, V. Roessler, W. TI The epidemiology of common mental disorders from age 20 to 50: results from the prospective Zurich cohort Study SO EPIDEMIOLOGY AND PSYCHIATRIC SCIENCES LA English DT Article DE Epidemiology; prevalence; prospective; psychiatric disorders ID SUBSTANCE USE DISORDERS; OF-ONSET DISTRIBUTIONS; LIFETIME PREVALENCE; CATCHMENT-AREA; YOUNG-ADULTS; FOLLOW-UP; DEPRESSION; HEALTH; CHILDHOOD; COMMUNITY AB Background: There are only a small number of prospective studies that have systematically evaluated standardised diagnostic criteria for mental disorder for more than a decade. The aim of this study is to present the approximated overall and sex-specific cumulative incidence of mental disorder in the Zurich cohort study, a prospective cohort study of 18-19 years olds from the canton of Zurich, Switzerland, who were followed through age 50. Method: A stratified sample of 591 participants were interviewed with the Structured Psychopathological Interview and Rating of the Social Consequences of Psychological Disturbances for Epidemiology, a semi-structured interview that uses a bottom-up approach to assess the past-year presence of 15 psychiatric syndromes. Seven interview waves took place between 1979 and 2008. Approximated cumulative incidence was estimated using Kaplan-Meier methods. Results: Rates of mental disorder were considerably higher than those generally reported in cross-sectional surveys. We found rates ranging from 32.5% for major depressive disorder to 1.2% for Bipolar I disorder. The cumulative probability of experiencing any of the mental disorders assessed by age 50 was 73.9%, the highest reported to date. We also found that rates differed by sex for most disorders, with females generally reporting higher rates of mood, anxiety and phobic disorder, and males reporting higher rates of substance- and alcohol-related disorders. Conclusions: These findings confirm those of other long-term prospective studies that indicate the nearly universal nature of disturbances of emotion and behaviour across the life span. Greater community awareness of the normative nature of these experiences is warranted. An important area of future research is study long-term course and stability to determine who among those with such disturbances suffer from chronic disabling mental disorders. Such longitudinal studies may aid in directing services and intervention efforts where they are most needed. C1 [Angst, J.; Hengartner, M. P.; Ajdacic-Gross, V.; Roessler, W.] Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, CH-8032 Zurich, Switzerland. [Paksarian, D.; Cui, L.; Merikangas, K. R.] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Hengartner, M. P.] Zurich Univ Appl Sci, Dept Appl Psychol, Zurich, Switzerland. [Roessler, W.] Univ Sao Paulo, Inst Psychiat, Lab Neurosci LIM 27, Sao Paulo, Brazil. RP Angst, J (reprint author), Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, Lenggstr 31,POB 1931, CH-8032 Zurich, Switzerland. EM jules.angst@uzh.ch OI Hengartner, Michael/0000-0002-2956-2969 FU Swiss National Science Foundation [3200-050881.97/1, 32-50881.97] FX This work was supported by Grant numbers 3200-050881.97/1 and 32-50881.97 of the Swiss National Science Foundation. NR 33 TC 12 Z9 13 U1 10 U2 25 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 2045-7960 EI 2045-7979 J9 EPIDEMIOL PSYCH SCI JI Epidemiol. Psychiatr. Sci. PD FEB PY 2016 VL 25 IS 1 BP 24 EP 32 DI 10.1017/S204579601500027X PG 9 WC Psychiatry SC Psychiatry GA DA6DC UT WOS:000367891300006 PM 25802979 ER PT J AU Simon, SL Zeman, GH AF Simon, Steven L. Zeman, Gary H. TI NCRP PROGRAM AREA COMMITTEE 6: RADIATION MEASUREMENTS AND DOSIMETRY SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; biological indicators; dose assessment; dosimetry ID DOSE RECONSTRUCTION AB Program Area Committee (PAC) 6 of the National Council on Radiation Protection and Measurements provides guidance for radiation measurements and dosimetryone of the most fundamental scientific areas of the Council's expertise. Seminal reports published by PAC 6 over many decades have documented the scientific and technical foundations of radiation measurements and dosimetry for generations of radiation scientists and radiation protection professionals. Ongoing work of PAC 6 is driven by advancing technology, such as development of new types of instruments, biodosimetry and nanotechnology; by evolving understanding of radiation hazards, such as effects on the lens of the eye and risks as from some high-dose medical imaging procedures; and by new situations faced in the modern socio-political environment including radiological and nuclear threats. The activities of PAC 6 are intended to formulate and document the dosimetric framework for radiological science to address these ever-emerging challenges. C1 [Simon, Steven L.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zeman, Gary H.] IIT, Chicago, IL 60616 USA. RP Simon, SL (reprint author), NCI, Radiat Epidemiol Branch, NIH, 9609 Med Ctr Dr,Room 7E442,MSC 9978, Bethesda, MD 20892 USA. EM ssimon@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 19 TC 0 Z9 0 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2016 VL 110 IS 2 BP 113 EP 115 DI 10.1097/HP.0000000000000405 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA DA5CC UT WOS:000367818700007 PM 26717161 ER PT J AU FitzGerald, TJ Bishop-Jodoin, M Followill, DS Galvin, J Knopp, MV Michalski, JM Rosen, MA Bradley, JD Shankar, LK Laurie, F Cicchetti, MG Moni, J Coleman, CN Deye, JA Capala, J Vikram, B AF FitzGerald, Thomas J. Bishop-Jodoin, Maryann Followill, David S. Galvin, James Knopp, Michael V. Michalski, Jeff M. Rosen, Mark A. Bradley, Jeffrey D. Shankar, Lalitha K. Laurie, Fran Cicchetti, M. Giulia Moni, Janaki Coleman, C. Norman Deye, James A. Capala, Jacek Vikram, Bhadrasain TI Imaging and Data Acquisition in Clinical Trials for Radiation Therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review ID RADIOTHERAPY QUALITY-ASSURANCE; CHILDRENS ONCOLOGY GROUP; BREAST-CANCER; ADJUVANT CHEMOTHERAPY; PREMENOPAUSAL WOMEN; COOPERATIVE GROUP; PROTOCOL AB Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials. (C) 2016 Elsevier Inc. All rights reserved. C1 [FitzGerald, Thomas J.; Cicchetti, M. Giulia; Moni, Janaki] Univ Massachusetts, Sch Med, Mem Med Ctr, Imaging & Radiat Oncol Core Rhode Isl, Worcester, MA USA. [Bishop-Jodoin, Maryann; Laurie, Fran] Univ Massachusetts, Sch Med, Imaging & Radiat Oncol Core Rhode Isl, Worcester, MA USA. [Followill, David S.] Univ Texas MD Anderson Canc Ctr, Imaging & Radiat Oncol Core Houston, Houston, TX 77030 USA. [Galvin, James] Thomas Jefferson Univ, Imaging & Radiat Oncol Core Philadelphia, Philadelphia, PA 19107 USA. [Knopp, Michael V.] Ohio State Univ, Wexner Med Ctr, Imaging & Radiat Oncol Core Ohio, Columbus, OH 43210 USA. [Michalski, Jeff M.] Washington Univ, Sch Med, Imaging & Radiat Oncol Core St Louis, St Louis, MO USA. [Rosen, Mark A.] Univ Penn Hlth Syst, Imaging & Radiat Oncol Core Philadelphia, Philadelphia, PA USA. [Bradley, Jeffrey D.] Washington Univ, Sch Med Radiat Oncol, St Louis, MO USA. [Shankar, Lalitha K.; Coleman, C. Norman; Deye, James A.; Capala, Jacek; Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, Rockville, MD USA. RP FitzGerald, TJ (reprint author), Imaging & Radiat Oncol Core Rhode Isl, 640 George Washington Hwy,Bldg B,Ste 201, Lincoln, RI 02865 USA. EM Thomas.Fitzgerald@umassmed.edu FU National Institutes of Health/National Cancer Institute [CI U24 CA180803] FX This project was supported by National Institutes of Health/National Cancer Institute grant CI U24 CA180803. NR 21 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD FEB 1 PY 2016 VL 94 IS 2 BP 404 EP 411 DI 10.1016/j.ijrobp.2015.10.028 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DA0XX UT WOS:000367522000023 PM 26853346 ER PT J AU Hanish, AE Butman, JA Thomas, F Yao, JH Han, JC AF Hanish, Alyson E. Butman, John A. Thomas, Francine Yao, Jianhua Han, Joan C. TI Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency SO JOURNAL OF SLEEP RESEARCH LA English DT Article DE 11p deletion; ELISA; WAGR syndrome ID HABITS QUESTIONNAIRE; WAGR SYNDROME; ANIRIDIA; PLASMA; DEFICIENCY; CHILDREN; RHYTHM; GLAND; GENE AB In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/-); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross-sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/- (age 15.3 +/- 9.9years) and 17 healthy controls (16.0 +/- 7.2years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6-sulphatoxymelatonin concentrations were measured by enzyme-linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13years old. Pineal volume was fivefold lower in PAX6+/- versus controls (mean +/- SD: 25 +/- 15 versus 129 +/- 50L, P<0.001). Midnight serum cortisol was similar in PAX6+/- versus controls (P=0.14). Midnight serum melatonin was >twofold lower in PAX6+/- versus controls [median (25th-75th): 28 (22-42) versus 71 (46-88)pgmL(-1), P<0.001]. First morning void urinary 6-sulphatoxymelatonin was fourfold lower in PAX6+/- versus controls [11 (6-26) versus 45 (34-61)ngmg(-1) Cr, P=0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/- versus controls (48 +/- 6 versus 41 +/- 5, P=0.03). The current findings suggest that PAX6+/- is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/-. C1 [Hanish, Alyson E.; Han, Joan C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Hanish, Alyson E.] NINR, NIH, Bethesda, MD 20892 USA. [Hanish, Alyson E.] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. [Butman, John A.; Thomas, Francine; Yao, Jianhua] NIH, Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. RP Han, JC (reprint author), Le Bonheur Childrens Hosp, Dept Pediat, 50 North Dunlap St,Room 476R, Memphis, TN 38103 USA. EM jhan14@uthsc.edu FU Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [1ZIAHD008898-02]; National Institute of Nursing Research of the National Institutes of Health (NIH); NIH Bench-to-Bedside Program FX This study was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1ZIAHD008898-02) and the National Institute of Nursing Research of the National Institutes of Health (NIH), and by the NIH Bench-to-Bedside Program. NR 25 TC 0 Z9 0 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1105 EI 1365-2869 J9 J SLEEP RES JI J. Sleep Res. PD FEB PY 2016 VL 25 IS 1 BP 16 EP 22 DI 10.1111/jsr.12345 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DA2IQ UT WOS:000367618900004 PM 26439359 ER PT J AU Bae, J Kim, S Kannan, K Louis, GMB AF Bae, Jisuk Kim, Sungduk Kannan, Kurunthachalam Louis, Germaine M. Buck TI Couples' urinary concentrations of benzophenone-type ultraviolet filters and the secondary sex ratio SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Benzophenones; Endocrine disruptors; Fertility; Sex ratio; Sunscreen agents ID BODY TOPICAL APPLICATION; PERSONAL CARE PRODUCTS; FOOD CONTACT PLASTICS; YEAST 2-HYBRID ASSAY; UV FILTERS; ESTROGENIC ACTIVITY; BISPHENOL-A; IN-VITRO; UNITED-STATES; DEVELOPMENTAL TOXICITY AB The secondary sex ratio (SSR), defined as the ratio of males to females at birth, has been investigated in relation to endocrine disruptors to search for environmental toxicants perturbing human sex selection. Benzophenone (BP)-type ultraviolet (UV) filters, which are used in sunscreens and personal care products, have been reported to exert estrogenic and anti-androgenic activities. This study aimed to evaluate the association between maternal, paternal, and couple urinary concentrations of BP-type UV filters and the SSR, given the absence of previous investigation. The study cohort comprised 220 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and who had a singleton birth during the follow-up period. Couples' urinary concentrations of five BP-type UV filters (ng/mL) were measured using triple-quadrupole tandem mass spectrometry: 2,4-dihydroxybenzophenone (BP-1), 2,2',4,4'-tetrahydroxybenzophenone BP-2), 2-hydroxy-4-methoxybenzophenone (BP-3), 2,2'-dihydroxy-4-methoxybenzophenone (BP-8), and 4-hydroxybenzophenone (4-OH-BP). Modified Poisson regression models were used to estimate the relative risks (RRs) of a male birth for each BP-type UV filter, after adjusting for potential confounders. When maternal and paternal urinary BP-type UV filter concentrations were modeled jointly, both maternal BP-2 (2nd vs 1st tertile, RR, 0.62, 95% confidence interval [CI], 0.43-0.91) and paternal BP-2 (3rd vs 1st tertile, RR, 0.67, 95% CI, 0.45-0.99; p-trend, 0.04) were significantly associated with an excess of zfemale births. Contrarily, maternal 4-OH-BP was significantly associated with an excess of male births (2nd vs 1st tertile, RR, 1.87,95% CI, 1.27-2.74; 3rd vs 1st tertile, RR, 1.80,95% CI, 1.13-2.87; p-trend, 0.02). Our findings provide the first evidence suggesting that BP-type UV filters may affect the SSR. However, future corroboration is needed, given the exploratory design of this study. (C) 2015 Elsevier B.V. All rights reserved. C1 [Bae, Jisuk] Catholic Univ Daegu, Sch Med, Dept Prevent Med, Daegu 42472, South Korea. [Kim, Sungduk; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD 20852 USA. [Kannan, Kurunthachalam] New York State Dept Hlth, Wadsworth Ctr, Albany, NY 12201 USA. [Kannan, Kurunthachalam] SUNY Albany, Sch Publ Hlth, Dept Environm Hlth Sci, Albany, NY 12201 USA. RP Bae, J (reprint author), Catholic Univ Daegu, Sch Med, Dept Prevent Med, 33 Duryugongwon Ro 17 Gil, Daegu 42472, South Korea. EM jialove@cu.ac.kr; kims2@mail.nih.gov; kurunthachalam.kannan@health.ny.gov; louisg@mail.nih.gov OI Bae, Jisuk/0000-0002-5809-5394; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [VFTB057303] FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358). Dr. Bae was supported by the Korea-US Visiting Scientist Training Award (VSTA) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (award #VFTB057303). NR 73 TC 1 Z9 1 U1 10 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 EI 1879-1026 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 1 PY 2016 VL 543 BP 28 EP 36 DI 10.1016/j.scitotenv.2015.11.019 PN A PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA DA2OL UT WOS:000367635600004 PM 26575635 ER PT J AU Litzelman, K Green, PA Yabroff, KR AF Litzelman, Kristin Green, Paige A. Yabroff, K. Robin TI Cancer and quality of life in spousal dyads: spillover in couples with and without cancer-related health problems SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Caregivers; Quality of life; Depressed mood; Spillover; Dyadic ID FAMILY CAREGIVERS; BREAST-CANCER; DISTRESS; DEPRESSION; PATIENT; INTERVENTIONS; METAANALYSIS; EXPERIENCE; SURVIVORS; SYMPTOMS AB Poor health of one spouse can adversely influence the partner's health outcomes ("spillover"). This study aimed to estimate quality of life spillover among spouses and to determine how presence of cancer influenced these effects. We examined data on husband-wife dyads with cancer-related health problems, medical events, or disabilities (n = 910) and matched comparison dyads from the 2004-2012 Medical Expenditures Panel Survey, a population-based survey of the USA. Mental and physical health-related quality of life and depressed mood were reported at two time points (T1 and T2, 11 months apart on average). Dyadic multilevel models evaluated the cross-lagged impact of HRQoL and depressed mood at T1 on spouses' HRQoL at T2, controlling for sociodemographics and health conditions. Small but statistically significant spillover was observed for mental and physical HRQoL among couples with cancer. Spillover occurred from both the spouse to the survivor and from survivor to spouse. Depressed mood, in particular, showed stronger spillover effects from the spouse to the survivor than the inverse. Similar effects were not observed in dyads without cancer. Screening for and treating poor HRQoL and depressed mood concurrently in both cancer survivors, and their spouses may positively influence HRQoL outcomes. Future research is needed to further elucidate these findings and determine whether a concurrent approach to psychosocial care in survivors and their spouses may improve long-term outcomes. C1 [Litzelman, Kristin; Green, Paige A.; Yabroff, K. Robin] NCI, Rockville, MD 20850 USA. RP Litzelman, K (reprint author), NCI, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM Kristin.litzelman@nih.gov OI Green, Paige/0000-0001-7886-8924; Yabroff, K. Robin/0000-0003-0644-5572 FU Intramural NIH HHS [Z99 CA999999] NR 40 TC 3 Z9 3 U1 4 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD FEB PY 2016 VL 24 IS 2 BP 763 EP 771 DI 10.1007/s00520-015-2840-4 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DA0AD UT WOS:000367458200030 PM 26143040 ER PT J AU Anand, A Anandi, P Jain, NA Lu, K Dunavin, N Hourigan, CS Le, RQ Chokshi, PD Ito, S Stroncek, DF Sabatino, M Barrett, AJ Battiwalla, M AF Anand, Ankit Anandi, Prathima Jain, Natasha A. Lu, Kit Dunavin, Neil Hourigan, Christopher S. Le, Robert Q. Chokshi, Puja D. Ito, Sawa Stroncek, David F. Sabatino, Marianna Barrett, A. John Battiwalla, Minoo TI CD34+selection and the severity of oropharyngeal mucositis in total body irradiation-based allogeneic stem cell transplantation SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Oropharyngeal mucositis; T cell depleted transplantation; CD34 selection; Oral mucositis; Quality of life; Allogeneic; Stem cell transplant; Methotrexate; Total body irradiation ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; ORAL MUCOSITIS; METHYLENETETRAHYDROFOLATE REDUCTASE; GVHD PROPHYLAXIS; MYELOGENOUS LEUKEMIA; PALIFERMIN; METHOTREXATE; TRIAL; POLYMORPHISMS AB The purpose of the present study was to evaluate the impact of ex vivo T cell depleted (TCD) by CD34+ selection on the incidence and severity of oropharyngeal mucositis (OM) after myeloablative allogeneic stem cell transplant (allo-SCT) with total body irradiation (TBI) conditioning. This approach has the advantage of avoiding methotrexate for graft versus host disease (GVHD) prophylaxis. We analyzed the incidence and severity of OM in a cohort of 105 consecutive patients who underwent CD34+ selected (peripheral blood stem cells (PBSCs) from human leukocyte antigen (HLA)-identical siblings) allo-SCT with total body irradiation (TBI) conditioning. OM was graded by the World Health organization (WHO) and the Bearman regimen-related toxicity (RRT) scales. The incidence of WHO grade 3-4 OM was 34.3 %. There were no cases of grade 3-4 OM by the RRT scale. Significant correlation was found between the severity of OM and the use of intravenous (IV) narcotic medications (r (2) = 0.15, p = 0.004), total parenteral nutrition (TPN; r (2) = 0.68, p < 0.001), and hospital length of stay (LOS) (r (2) = 0.12, p = 0.01). TBI-induced OM can inflict significant morbidity in the early transplant period, and the incidence of WHO grade 3-4 OM can exceed 50 % when methotrexate is used for GVHD prophylaxis. In the CD34+ selected setting, methotrexate is avoided and the incidence of WHO grade 3-4 OM, use of TPN, and need for narcotic analgesia appear to be lower than historic evidence from standard T-replete allogeneic transplantation. We conclude that toxicity from OM is tolerable in CD34+ selected allo-SCT and should be prospectively measured in randomized trials comparing CD34+ selection versus T-replete transplantation. C1 [Anand, Ankit; Anandi, Prathima; Jain, Natasha A.; Lu, Kit; Dunavin, Neil; Hourigan, Christopher S.; Le, Robert Q.; Chokshi, Puja D.; Ito, Sawa; Barrett, A. John; Battiwalla, Minoo] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Stroncek, David F.; Sabatino, Marianna] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Battiwalla, M (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM minoo.battiwalla@nih.gov RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 FU NHLBI, NIH FX This work was supported by the intramural research program of the NHLBI, NIH. NR 30 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD FEB PY 2016 VL 24 IS 2 BP 815 EP 822 DI 10.1007/s00520-015-2848-9 PG 8 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA DA0AD UT WOS:000367458200036 PM 26190358 ER PT J AU Insel, TR AF Insel, Thomas R. TI Translating Oxytocin Neuroscience to the Clinic: A National Institute of Mental Health Perspective SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID VASOPRESSIN; CHALLENGE; BEHAVIOR C1 [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov NR 10 TC 9 Z9 9 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2016 VL 79 IS 3 BP 153 EP 154 DI 10.1016/j.biopsych.2015.02.002 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA CZ9DK UT WOS:000367397800003 PM 26723108 ER PT J AU Marusich, JA Antonazzo, KR Blough, BE Brandt, SD Kavanagh, PV Partilla, JS Baumann, MH AF Marusich, Julie A. Antonazzo, Kateland R. Blough, Bruce E. Brandt, Simon D. Kavanagh, Pierce V. Partilla, John S. Baumann, Michael H. TI The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue SO NEUROPHARMACOLOGY LA English DT Article DE 5-(2-Aminopropyl)indole (5-IT); 6-(2-Aminopropyl)indole (6-IT); 3,4-Methylenedioxymethamphetamine (MDMA); Locomotor activity; Monoamine releaser; Synthetic stimulants ID CONSTITUENT 3,4-METHYLENEDIOXYPYROVALERONE MDPV; DUAL DOPAMINE/SEROTONIN RELEASERS; FUNCTIONAL OBSERVATIONAL BATTERY; BIOGENIC-AMINE TRANSPORTERS; BATH SALTS; SEROTONIN RELEASE; RHESUS-MONKEYS; SYNTHETIC STIMULANTS; DESIGNER CATHINONES; LOCOMOTOR-ACTIVITY AB In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Marusich, Julie A.; Antonazzo, Kateland R.; Blough, Bruce E.] RTI Int, Ctr Drug Discovery, Res Triangle Pk, NC 27709 USA. [Brandt, Simon D.] Liverpool John Moores Univ, Sch Pharm & Biomol Sci, Liverpool L3 3AF, Merseyside, England. [Kavanagh, Pierce V.] St James Hosp, Trinity Ctr Hlth Sci, Sch Med, Dept Pharmacol & Therapeut, Dublin 8, Ireland. [Partilla, John S.; Baumann, Michael H.] NIDA, Designer Drug Res Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Marusich, JA (reprint author), RTI Int, 3040 Cornwallis Rd,138 Hermann, Res Triangle Pk, NC 27709 USA. EM jmarusich@rti.org OI Brandt, Simon/0000-0001-8632-5372 FU Intramural Research Program at NIDA; RTI International internal research and development funds; NIH/NIDA Grant [DA12970] FX The authors thank Tim Lefever and Tony Landavazo for technical assistance. Research was generously supported by the Intramural Research Program at NIDA, RTI International internal research and development funds, and NIH/NIDA Grant DA12970. These sources of funding did not play any role in study design, data collection, analysis, and interpretation, in writing the report, or in the decision to submit the article for publication. NR 73 TC 2 Z9 2 U1 4 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2016 VL 101 BP 68 EP 75 DI 10.1016/j.neuropharm.2015.09.004 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DA0JQ UT WOS:000367483800007 PM 26362361 ER PT J AU Hjorth, S Karlsson, C Jucaite, A Varnas, K Hamren, UW Johnstrom, P Gulyas, B Donohue, SR Pike, VW Halldin, C Farde, L AF Hjorth, Stephan Karlsson, Cecilia Jucaite, Aurelija Varnas, Katarina Hamren, Ulrika Wahlby Johnstrom, Peter Gulyas, Balazs Donohue, Sean R. Pike, Victor W. Halldin, Christer Farde, Lars TI A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates SO NEUROPHARMACOLOGY LA English DT Article DE Cannabinoid 1 receptor (CB1R) antagonists; Obesity; Positron emission tomography (PET); Receptor occupancy; [C-11]SD5024; Rimonabant; Taranabant ID POSITRON-EMISSION-TOMOGRAPHY; CB1R INVERSE AGONIST; HUMAN BRAIN; OVERWEIGHT PATIENTS; RISK-FACTORS; IN-VITRO; CARDIOVASCULAR RISK; NEUTRAL ANTAGONISM; VIVO EVALUATION; WEIGHT-LOSS AB There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [C-11]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CBIR with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for. optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around similar to 20-30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of 'neutral' vs. 'classical' CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [C-11]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding. (C) 2015 Elsevier Ltd. All rights reserved. C1 [Hjorth, Stephan] AstraZeneca R&D, CVMD Innovat Med, Biosci, S-43183 Molndal, Sweden. [Karlsson, Cecilia] AstraZeneca R&D, CVMD Translat Med Unit, Early Clin Dev, Innovat Med, S-43183 Molndal, Sweden. [Jucaite, Aurelija; Johnstrom, Peter; Farde, Lars] Karolinska Inst, AstraZeneca Translat Sci Ctr, Stockholm, Sweden. [Jucaite, Aurelija; Johnstrom, Peter; Farde, Lars] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Varnas, Katarina; Gulyas, Balazs; Halldin, Christer] Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, Stockholm, Sweden. [Hamren, Ulrika Wahlby] AstraZeneca R&D, Quantitat Clin Pharmacol, Early Clin Dev, Innovat Med, S-43183 Molndal, Sweden. [Donohue, Sean R.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Karlsson, C (reprint author), AstraZeneca R&D, CVMD Translat Med Unit, Early Clin Dev, Innovat Med, Pepparedsleden 1, S-43183 Molndal, Sweden. EM Cecilia.Karlsson@astrazeneca.com FU Intramural Research Program of the National Institute of Mental Health (NIMH) [ZIA MH002793-13] FX SRD and VWP were supported by the Intramural Research Program of the National Institute of Mental Health (NIMH; project # ZIA MH002793-13). NR 54 TC 0 Z9 0 U1 2 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2016 VL 101 BP 519 EP 530 DI 10.1016/j.neuropharm.2015.03.002 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA DA0JQ UT WOS:000367483800048 PM 25791528 ER PT J AU Shridhar, K Walia, GK Aggarwal, A Gulati, S Geetha, AV Prabhakaran, D Dhillon, PK Rajaraman, P AF Shridhar, Krithiga Walia, Gagandeep Kaur Aggarwal, Aastha Gulati, Smriti Geetha, A. V. Prabhakaran, Dorairaj Dhillon, Preet K. Rajaraman, Preetha TI DNA methylation markers for oral pre-cancer progression: A critical review SO ORAL ONCOLOGY LA English DT Review DE DNA methylation; Oral pre-cancer; Bio-marker; Epigenetics; Leukoplakia; Oral sub-mucous fibrosis; Promoter regions; CpG sites; Tumour suppressor genes; Diagnostic marker ID SQUAMOUS-CELL CARCINOMA; GENE PROMOTER HYPERMETHYLATION; EARLY DYSPLASTIC LESIONS; EPITHELIAL DYSPLASIA; CANCER; HEAD; EPIGENETICS; INDIA; P16; RECOMMENDATIONS AB Although oral cancers are generally preceded by a well-established pre-cancerous stage, there is a lack of well-defined clinical and morphological criteria to detect and signal progression from pre-cancer to malignant tumours. We conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as a potential diagnostic biomarker predicting progression. We identified all relevant human studies published in English prior to 30th April 2015 that examined DNA methylation (%) in oral pre-cancer by searching PubMed, Web-of-Science and Embase databases using combined key-searches. Twenty-one studies (18-cross-sectional; 3-longitudinal) were eligible for inclusion in the review, with sample sizes ranging from 4 to 156 affected cases. Eligible studies examined promoter region hyper-methylation of tumour suppressor genes in pathways including cell-cycle-control (n = 15), DNA-repair (n = 7), cell-cycle-signalling (n = 4) and apoptosis (n = 3). Hyper-methylated loci reported in three or more studies included p16, p14, MGMT and DAPK. Two longitudinal studies reported greater p16 hyper-methylation in pre-cancerous lesions transformed to malignancy compared to lesions that regressed (57-63.6% versus 8-32.1%; p < 0.01). The one study that explored epigenome-wide methylation patterns reported three novel hyper-methylated loci (TRHDE; ZNF454; KCNAB3). The majority of reviewed studies were small, cross-sectional studies with poorly defined control groups and lacking validation. Whilst limitations in sample size and study design preclude definitive conclusions, current evidence suggests a potential utility of DNA methylation patterns as a diagnostic biomarker for oral pre-cancer progression. Robust studies such as large epigenome-wide methylation explorations of oral pre-cancer with longitudinal tracking are needed to validate the currently reported signals and identify new risk-loci and the biological pathways of disease progression. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license. C1 [Shridhar, Krithiga; Walia, Gagandeep Kaur; Aggarwal, Aastha; Gulati, Smriti; Geetha, A. V.; Prabhakaran, Dorairaj; Dhillon, Preet K.] Publ Hlth Fdn India, Ctr Chron Condit & Injuries, Gurgaon 122002, Haryana, India. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, Gurgaon, Haryana, India. [Prabhakaran, Dorairaj] London Sch Hyg & Trop Med, London WC1, England. [Rajaraman, Preetha] NCI, Ctr Global Hlth, NIH, DHHS, Bethesda, MD 20892 USA. RP Shridhar, K (reprint author), Publ Hlth Fdn India, Ctr Chron Condit & Injuries, 4th Floor,Plot 47,Sect 44, Gurgaon 122002, Haryana, India. EM g.krithiga@phfi.org OI , Smriti/0000-0002-3126-1911; Prabhakaran, Dorairaj/0000-0002-3172-834X FU PHFI-UKC Wellcome Trust Capacity Building Programme-Extension Phase; Wellcome Trust Strategic award - South Asia Network for Chronic Disease (SANCD) [WT 084674] FX Dr. Krithiga Shridhar is supported by PHFI-UKC Wellcome Trust Capacity Building Programme-Extension Phase and by Wellcome Trust Strategic award - South Asia Network for Chronic Disease (SANCD) (WT 084674). NR 55 TC 4 Z9 5 U1 3 U2 33 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 EI 1879-0593 J9 ORAL ONCOL JI Oral Oncol. PD FEB PY 2016 VL 53 BP 1 EP 9 DI 10.1016/j.oraloncology.2015.11.012 PG 9 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA DA0YI UT WOS:000367523100001 PM 26690652 ER PT J AU Elahi, S Homstad, A Vaidya, H Stout, J Hall, G Wu, GH Conlon, P Routh, JC Wiener, JS Ross, SS Nagaraj, S Wigfall, D Foreman, J Adeyemo, A Gupta, IR Brophy, PD Rabinovich, CE Gbadegesin, RA AF Elahi, Shan Homstad, Alison Vaidya, Himani Stout, Jennifer Hall, Gentzon Wu, Guanghong Conlon, Peter, Jr. Routh, Jonathan C. Wiener, John S. Ross, Sherry S. Nagaraj, Shashi Wigfall, Delbert Foreman, John Adeyemo, Adebowale Gupta, Indra R. Brophy, Patrick D. Rabinovich, C. Egla Gbadegesin, Rasheed A. TI Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux SO PEDIATRIC NEPHROLOGY LA English DT Article DE Vesicoureteral reflux; Tenascin genes; Joint hypermobility; Urinary tract infection; Reflux nephropathy ID EHLERS-DANLOS-SYNDROME; URINARY-TRACT; CONGENITAL-ANOMALIES; KIDNEY; MUTATIONS; ROBO2; LOCUS; CAKUT; SOX17; TNXB AB Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9 %) families had FPVUR and 2/55 (4 %) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12 %) families (9 % in TNXB and 3 % in ROBO2). In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts. C1 [Elahi, Shan; Homstad, Alison; Vaidya, Himani; Stout, Jennifer; Conlon, Peter, Jr.; Routh, Jonathan C.; Wiener, John S.; Nagaraj, Shashi; Wigfall, Delbert; Foreman, John; Rabinovich, C. Egla; Gbadegesin, Rasheed A.] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. [Homstad, Alison; Vaidya, Himani; Hall, Gentzon; Wu, Guanghong; Gbadegesin, Rasheed A.] Duke Mol Physiol Inst, Durham, NC USA. [Hall, Gentzon; Wu, Guanghong] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Routh, Jonathan C.; Wiener, John S.; Ross, Sherry S.] Duke Univ, Med Ctr, Div Urol, Dept Surg, Durham, NC 27710 USA. [Ross, Sherry S.] Univ N Carolina, Sch Med, Dept Urol, Pediat Urol, Chapel Hill, NC USA. [Adeyemo, Adebowale] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Gupta, Indra R.] McGill Univ, Dept Pediat & Human Genet, Montreal, PQ, Canada. [Brophy, Patrick D.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. RP Gbadegesin, RA (reprint author), Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. EM rasheed.gbadegesin@duke.edu OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R21DK096200]; Bayden Collins Pediatric Kidney Disease Research Fund, Duke University Medical Center; Doris Duke Clinical Research Mentorship grant FX This study was supported by the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R21DK096200 and the Bayden Collins Pediatric Kidney Disease Research Fund, Duke University Medical Center. RG is the recipient of the Doris Duke Clinical Research Mentorship grant. We would like to thank the personnel of the genomic core of the Duke Molecular Physiology Institute (DMPI) and most importantly the participants in the study. NR 22 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X EI 1432-198X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD FEB PY 2016 VL 31 IS 2 BP 247 EP 253 DI 10.1007/s00467-015-3203-6 PG 7 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA CZ9ZZ UT WOS:000367457800010 PM 26408188 ER PT J AU Ramamoorthy, S Cidlowski, JA AF Ramamoorthy, Sivapriya Cidlowski, John A. TI Corticosteroids Mechanisms of Action in Health and Disease SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE Glucocorticoid; Glucocorticoid receptor; Glucocorticoid signaling; Hypothalamic-pituitary-adrenal axis; Isoforms; Phosphorylation; Polymorphism ID GLUCOCORTICOID-RECEPTOR-BETA; NF-KAPPA-B; TRANSLATIONAL ISOFORMS; GENE-EXPRESSION; MESSENGER-RNA; DNA-BINDING; TRANSCRIPTIONAL ACTIVITY; SERINE-PHOSPHORYLATION; SELECTIVE REGULATION; RESPONSE ELEMENTS AB Glucocorticoids are primary stress hormones that regulate a variety of physiologic processes and are essential for life. The actions of glucocorticolds are predominantly mediated through the classic glucocorticoid receptor (GR). GRs are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and biologic responses across tissues. The conventional belief that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a diverse collection of receptor isoforms. This article provides an overview of the molecular mechanisms that regulate glucocorticoid actions, highlights the dynamic nature of hormone signaling, and discusses the molecular properties of the GR isoforms. C1 [Ramamoorthy, Sivapriya; Cidlowski, John A.] NIEHS, Signal Transduct Lab, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, POB 12233,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences FX Support provided by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences. NR 87 TC 12 Z9 12 U1 5 U2 19 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-857X EI 1558-3163 J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD FEB PY 2016 VL 42 IS 1 BP 15 EP + DI 10.1016/j.rdc.2015.08.002 PG 18 WC Rheumatology SC Rheumatology GA CZ1RB UT WOS:000366881900004 PM 26611548 ER PT J AU Lin, TY Luo, JN Shinomiya, K Ting, CY Lu, ZY Meinertzhagen, IA Lee, CH AF Lin, Tzu-Yang Luo, Jiangnan Shinomiya, Kazunori Ting, Chun-Yuan Lu, Zhiyuan Meinertzhagen, Ian A. Lee, Chi-Hon TI Mapping chromatic pathways in the Drosophila visual system SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE color vision; GRASP; lobula; retina; phototaxis ID MUSHROOM BODY CALYX; PHOTORECEPTOR CELLS; SPECTRAL PREFERENCE; PROJECTION NEURONS; ADHESION MOLECULE; MOTION DETECTION; COLOR-VISION; FLY RETINA; CIRCUIT; R7 AB In Drosophila, color vision and wavelength-selective behaviors are mediated by the compound eye's narrow-spectrum photoreceptors R7 and R8 and their downstream medulla projection (Tm) neurons Tm5a, Tm5b, Tm5c, and Tm20 in the second optic neuropil or medulla. These chromatic Tm neurons project axons to a deeper optic neuropil, the lobula, which in insects has been implicated in processing and relaying color information to the central brain. The synaptic targets of the chromatic Tm neurons in the lobula are not known, however. Using a modified GFP reconstitution across synaptic partners (GRASP) method to probe connections between the chromatic Tm neurons and 28 known and novel types of lobula neurons, we identify anatomically the visual projection neurons LT11 and LC14 and the lobula intrinsic neurons Li3 and Li4 as synaptic targets of the chromatic Tm neurons. Single-cell GRASP analyses reveal that Li4 receives synaptic contacts from over 90% of all four types of chromatic Tm neurons, whereas LT11 is postsynaptic to the chromatic Tm neurons, with only modest selectivity and at a lower frequency and density. To visualize synaptic contacts at the ultrastructural level, we develop and apply a two-tag double-labeling method to label LT11's dendrites and the mitochondria in Tm5c's presynaptic terminals. Serial electron microscopic reconstruction confirms that LT11 receives direct contacts from Tm5c. This method would be generally applicable to map the connections of large complex neurons in Drosophila and other animals. J. Comp. Neurol. 524:213-227, 2016. (c) 2015 Wiley Periodicals, Inc. C1 [Lin, Tzu-Yang; Luo, Jiangnan; Ting, Chun-Yuan; Lee, Chi-Hon] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Lin, Tzu-Yang] Grad Inst Life Sci, Natl Def Med Ctr, Taipei 114, Taiwan. [Shinomiya, Kazunori; Lu, Zhiyuan; Meinertzhagen, Ian A.] Dalhousie Univ, Life Sci Ctr, Dept Psychol & Neurosci, Halifax, NS B3H 4R2, Canada. RP Lee, CH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bldg 18T,Room 106,MSC 5431, Bethesda, MD 20892 USA. EM leechih@mail.nih.gov OI Meinertzhagen, Ian/0000-0002-6578-4526 FU National Institutes of Health Intramural Research Program; Eunice Kennedy Shriver National Institute of Child Health and Human Development [Z01-HD008776]; Natural Sciences and Engineering Research Council of Canada [A-0000065]; Ministry of Science and Technology, Taiwan [MOST103-2311-B-016-001-MY2] FX Grant sponsor: National Institutes of Health Intramural Research Program; Grant sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development; Grant number: Z01-HD008776 (to C.-H.L.); Grant sponsor: Natural Sciences and Engineering Research Council of Canada; Grant number: A-0000065 (to I.A.M.); Grant sponsor: Ministry of Science and Technology, Taiwan; Grant number: MOST103-2311-B-016-001-MY2 (to T.-Y.L). NR 45 TC 6 Z9 6 U1 2 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD FEB 1 PY 2016 VL 524 IS 2 BP 213 EP 227 DI 10.1002/cne.23857 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA CY7QV UT WOS:000366604700001 PM 26179639 ER PT J AU Chaemsaithong, P Romero, R Korzeniewski, SJ Martinez-Varea, A Dong, Z Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L AF Chaemsaithong, Piya Romero, Roberto Korzeniewski, Steven J. Martinez-Varea, Alicia Dong, Zhong Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami TI A rapid interleukin-6 bedside test for the identification of intra-amniotic inflammation in preterm labor with intact membranes SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Acute chorioamnionitis; acute funisitis; biomarkers; ELISA; microbial invasion of the amniotic cavity; prematurity; preterm birth; point of care test ID AMNIOTIC-FLUID INTERLEUKIN-6; TUMOR-NECROSIS-FACTOR; BLOOD-CELL COUNT; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; MONOCYTE CHEMOTACTIC PROTEIN-1; LEUKEMIA INHIBITORY FACTOR; POLYMERASE-CHAIN-REACTION; C-REACTIVE PROTEIN; MICROBIAL INVASION; PREMATURE RUPTURE AB Objective: Preterm birth is associated with 5-18% of pregnancies and is the leading cause of neonatal morbidity and mortality. Amniotic fluid (AF) interleukin-6 (IL-6) is a key cytokine for the identification of intra-amniotic inflammation, and patients with an elevated AF IL-6 are at risk for impending preterm delivery. However, results of the conventional method of measurement (enzyme-linked immunosorbent assay; ELISA) are usually not available in time to inform care. The objective of this study was to determine whether a point of care (POC) test or lateral-flow-based immunoassay for measurement of AF IL-6 concentrations can identify patients with intra-amniotic inflammation and/or infection and those destined to deliver spontaneously before term among women with preterm labor and intact membranes.Methods: One-hundred thirty-six women with singleton pregnancies who presented with symptoms of preterm labor and underwent amniocentesis were included in this study. Amniocentesis was performed at the time of diagnosis of preterm labor. AF Gram stain and AF white blood cell counts were determined. Microbial invasion of the amniotic cavity (MIAC) was defined according to the results of AF culture (aerobic and anaerobic as well as genital mycoplasmas). AF IL-6 concentrations were determined by both lateral flow-based immunoassay and ELISA. The primary outcome was intra-amniotic inflammation, defined as AF ELISA IL-62600pg/ml.Results: (1) AF IL-6 concentrations determined by a POC test have high sensitivity (93%), specificity (91%) and a positive likelihood ratio of 10 for the identification of intra-amniotic inflammation by using a threshold of 745pg/ml; (2) the POC test and ELISA for IL-6 perform similarly in the identification of MIAC, acute inflammatory lesions of placenta and patients at risk of impending spontaneous preterm delivery.Conclusion: A POC AF IL-6 test can identify intra-amniotic inflammation in women who present with preterm labor and intact membranes and those who will subsequently deliver spontaneously before 34 weeks of gestation. Results can be available within 20min - this has important clinical implications and opens avenues for early diagnosis as well as treatment of intra-amniotic inflammation/infection. C1 [Chaemsaithong, Piya; Romero, Roberto; Korzeniewski, Steven J.; Martinez-Varea, Alicia; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Perinatol Res Branch, Program Perinatal Res & Obstet,NIH, Bethesda, MD USA. [Chaemsaithong, Piya; Romero, Roberto; Korzeniewski, Steven J.; Martinez-Varea, Alicia; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Perinatol Res Branch, Program Perinatal Res & Obstet,NIH, Detroit, MI USA. [Chaemsaithong, Piya; Korzeniewski, Steven J.; Martinez-Varea, Alicia; Dong, Zhong; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); and, in part, with Federal funds from NICHD, NIH under Contract no. HHSN275201300006C. NR 159 TC 9 Z9 10 U1 1 U2 6 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD FEB 1 PY 2016 VL 29 IS 3 BP 349 EP 359 DI 10.3109/14767058.2015.1006620 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CY9RR UT WOS:000366744500001 PM 25758618 ER PT J AU Chaemsaithong, P Romero, R Korzeniewski, SJ Martinez-Varea, A Dong, Z Yoon, BH Hassan, SS Chaiworapongsa, T Yeo, L AF Chaemsaithong, Piya Romero, Roberto Korzeniewski, Steven J. Martinez-Varea, Alicia Dong, Zhong Yoon, Bo Hyun Hassan, Sonia S. Chaiworapongsa, Tinnakorn Yeo, Lami TI A point of care test for interleukin-6 in amniotic fluid in preterm prelabor rupture of membranes: a step toward the early treatment of acute intra-amniotic inflammation/infection SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Acute chorioamnionitis; acute funisitis; amniocentesis; biomarkers; ELISA; microbial invasion of the amniotic cavity; preterm labor; rapid interleukin-6 ID FETAL INFLAMMATORY RESPONSE; BIRTH-WEIGHT INFANTS; BLOOD-CELL COUNT; PREMATURE RUPTURE; MICROBIAL INVASION; HISTOLOGIC CHORIOAMNIONITIS; INTACT MEMBRANES; CEREBRAL-PALSY; RISK-FACTORS; HISTOPATHOLOGIC CHORIOAMNIONITIS AB Objective: Preterm prelabor rupture of membranes (preterm PROM) accounts for 30-40% of spontaneous preterm deliveries and thus is a major contributor to perinatal morbidity and mortality. An amniotic fluid (AF) interleukin-6 (IL-6) concentration is a key cytokine for the identification of intra-amniotic inflammation, patients at risk of impending preterm delivery and adverse pregnancy complications. The conventional method to determine IL-6 concentrations in AF is an enzyme-linked immunosorbent assay (ELISA). However, this technique is not available in clinical settings, and the results may take several days. A lateral flow-based immunoassay, or point of care (POC) test, has been developed to address this issue. The objective of this study was to compare the performance of AF IL-6 determined by the POC test to that determined by ELISA for the identification of intra-amniotic inflammation in patients with preterm PROM.Materials and methods: This retrospective cohort study includes 56 women with singleton pregnancies who presented with preterm PROM. Amniocentesis was performed at the time of diagnosis, and AF was analyzed using cultivation techniques for aerobic and anaerobic bacteria as well as genital mycoplasmas. AF Gram stain and AF white blood cell counts were determined. AF IL-6 concentrations were measured using both lateral flow-based immunoassay and ELISA. The primary outcome was intra-amniotic inflammation defined as AF ELISA IL-62600pg/ml. A previously determined cut-off of 745pg/ml was used to define a positive POC test.Results: (1) The POC test for AF IL-6 concentrations had 97% sensitivity and 96% specificity for the identification of intra-amniotic inflammation, as defined using ELISA among patients with preterm PROM and (2) the diagnostic performance of the POC test for IL-6 was strongly correlated to that of an ELISA test for the identification of intra-amniotic inflammation and was equivalent for the identification of acute inflammatory placental lesions and microbial invasion of the amniotic cavity (MIAC).Conclusion: A POC AF IL-6 test can identify intra-amniotic inflammation in patients with preterm PROM. Results can be available within 20min - this makes it possible to implement interventions designed to treat intra-amniotic inflammation and improve pregnancy outcomes. C1 [Chaemsaithong, Piya; Romero, Roberto; Korzeniewski, Steven J.; Martinez-Varea, Alicia; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Res, Perinatol Res Branch, Program Perinatal Res & Obstet,NIH, Detroit, MI USA. [Chaemsaithong, Piya; Korzeniewski, Steven J.; Martinez-Varea, Alicia; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Yeo, Lami] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Romero, Roberto] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Romero, Roberto; Korzeniewski, Steven J.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Wayne State Univ, NICHD, Perinatol Res Branch, NIH,DHHS,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH); NICHD, NIH [HHSN275201300006C] FX This research was supported, in part, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (NICHD/NIH) and, in part, with Federal funds from NICHD, NIH under contract no. HHSN275201300006C. NR 114 TC 9 Z9 9 U1 0 U2 8 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD FEB 1 PY 2016 VL 29 IS 3 BP 360 EP 367 DI 10.3109/14767058.2015.1006621 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CY9RR UT WOS:000366744500002 PM 25758620 ER PT J AU Burger, R Chowell, G Mulet, P Villada, LM AF Buerger, Raimund Chowell, Gerardo Mulet, Pep Villada, Luis M. TI MODELLING THE SPATIAL-TEMPORAL PROGRESSION OF THE 2009 A/H1N1 INFLUENZA PANDEMIC IN CHILE SO MATHEMATICAL BIOSCIENCES AND ENGINEERING LA English DT Article DE Spatial-temporal SEIR model; pandemic; metapopulation model; stability of disease-free equilibrium ID EPIDEMIC MODEL; TRANSMISSION DYNAMICS; GLOBAL STABILITY; VIRUS; SEASONALITY; TRANSPORTATION; TEMPERATURE; MULTIGROUP; HUMIDITY; MOBILITY AB A spatial-temporal transmission model of 2009 A/H1N1 pandemic influenza across Chile, a country that spans a large latitudinal range, is developed to characterize the spatial variation in peak timing of that pandemic as a function of local transmission rates, spatial connectivity assumptions for Chilean regions, and the putative location of introduction of the novel virus into the country. Specifically, a metapopulation SEIR (susceptible-exposed-infected-removed) compartmental model that tracks the transmission dynamics of influenza in 15 Chilean regions is calibrated. The model incorporates population mobility among neighboring regions and indirect mobility to and from other regions via the metropolitan central region ("hub region"). The stability of the disease-free equilibrium of this model is analyzed and compared with the corresponding stability in each region, concluding that stability may occur even with some regions having basic reproduction numbers above 1. The transmission model is used along with epidemiological data to explore C1 [Buerger, Raimund; Villada, Luis M.] Univ Concepcion, CI2MA, Concepcion, Chile. [Buerger, Raimund] Univ Concepcion, Dept Ingn Matemat, Concepcion, Chile. [Chowell, Gerardo] Georgia State Univ, Sch Publ Hlth, Atlanta, GA 30303 USA. [Chowell, Gerardo] Arizona State Univ, Simon A Levin Math & Computat Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Mulet, Pep] Univ Valencia, Dept Matemat, E-46100 Burjassot, Spain. [Villada, Luis M.] Univ Bio Bio, GIMNAP, Dept Matemat, Concepcion, Chile. RP Burger, R (reprint author), Univ Concepcion, CI2MA, Casilla 160-C, Concepcion, Chile. EM rburger@ing-mat.udec.cl; gchowen@gsu.edu; mulet@uv.es; lvillada@ubiobio.cl FU Fondecyt project [1130154, 11140708]; Conicyt project Anillo [ACT1118]; Red Doctoral REDOC.CTA, MINEDUC project at Universidad de Concepcion [UCO1202]; BASAL project CMM, Universidad de Chile; Centro de Investigacion en Ingenieria Matematica (Cl2MA), Universidad de Concepcion; Centro CRHIAM Proyecto Conicyt Fondap [15130015]; Spanish MINECO projects [MTM2011-22741, MTM2014-54388-P] FX RB is supported by Fondecyt project 1130154; Conicyt project Anillo ACT1118 (ANANUM); Red Doctoral REDOC.CTA, MINEDUC project UCO1202 at Universidad de Concepcion; BASAL project CMM, Universidad de Chile and Centro de Investigacion en Ingenieria Matematica (Cl2MA), Universidad de Concepcion; and Centro CRHIAM Proyecto Conicyt Fondap 15130015. PM is supported by Spanish MINECO projects MTM2011-22741 and MTM2014-54388-P. LMV is supported by Fondecyt project 11140708. NR 52 TC 1 Z9 1 U1 1 U2 48 PU AMER INST MATHEMATICAL SCIENCES-AIMS PI SPRINGFIELD PA PO BOX 2604, SPRINGFIELD, MO 65801-2604 USA SN 1547-1063 EI 1551-0018 J9 MATH BIOSCI ENG JI Math. Biosci. Eng. PD FEB PY 2016 VL 13 IS 1 BP 43 EP 65 DI 10.3934/mbe.2016.13.43 PG 23 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA CU5AO UT WOS:000363544100003 PM 26776260 ER PT J AU So, J Prestin, A Lee, L Wang, YF Yen, J Chou, WYS AF So, Jiyeon Prestin, Abby Lee, Lyndon Wang, Yafei Yen, John Chou, Wen-Ying Sylvia TI What Do People Like to "Share" About Obesity? A Content Analysis of Frequent Retweets About Obesity on Twitter SO HEALTH COMMUNICATION LA English DT Article ID SOCIAL MEDIA; EMOTION; INFORMATION; PREVALENCE; KNOWLEDGE; RESPONSES; EXPOSURE; CAMPAIGN; IMPACT AB Twitter has been recognized as a useful channel for the sharing and dissemination of health information, owing in part to its retweet function. This study reports findings from a content analysis of frequently retweeted obesity-related tweets to identify the prevalent beliefs and attitudes about obesity on Twitter, as well as key message features that prompt retweeting behavior conducive to maximizing the reach of health messages on Twitter. The findings show that tweets that are emotionally evocative, humorous, and concern individual-level causes for obesity were more frequently retweeted than their counterparts. Specifically, tweets that evoke amusement were retweeted most frequently, followed by tweets evoking contentment, surprise, and anger. In regard to humor, derogatory jokes were more frequently retweeted than nonderogatory ones, and in terms of specific types of humor, weight-related puns, repartee, and parody were shared frequently. Consistent with extant literature about obesity, the findings demonstrated the predominance of the individual-level (e.g., problematic diet, lack of exercise) over social-level causes for obesity (e.g., availability of cheap and unhealthy food). Implications for designing social-media-based health campaign messages are discussed. C1 [So, Jiyeon] Univ Georgia, Dept Commun Studies, Athens, GA 30602 USA. [Prestin, Abby; Chou, Wen-Ying Sylvia] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Lee, Lyndon] Univ Georgia, Dept Finance, Athens, GA 30602 USA. [Wang, Yafei; Yen, John] Penn State Univ, Coll Informat Sci & Technol, University Pk, PA 16802 USA. RP So, J (reprint author), Univ Georgia, Dept Commun Studies, 601 Caldwell Hall, Athens, GA 30602 USA. EM jso@uga.edu NR 61 TC 6 Z9 6 U1 11 U2 88 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD FEB 1 PY 2016 VL 31 IS 2 BP 193 EP 206 DI 10.1080/10410236.2014.940675 PG 14 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA CU7WD UT WOS:000363751600006 PM 26086083 ER PT J AU Sial, OK Warren, BL Alcantara, LF Parise, EM Bolanos-Guzman, CA AF Sial, Omar K. Warren, Brandon L. Alcantara, Lyonna F. Parise, Eric M. Bolanos-Guzman, Carlos A. TI Vicarious social defeat stress: Bridging the gap between physical and emotional stress SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Emotional stress; PTSD; Depression; Social defeat; Witness stress ID HURTFUL WORDS; ANIMAL-MODELS; DISORDER; SUSCEPTIBILITY; SEQUELAE; BURDEN; PTSD; MICE AB Background: Animal models capable of differentiating the neurobiological intricacies between physical and emotional stress are scarce. Current models rely primarily on physical stressors (e.g., chronic unpredictable or mild stress, social defeat, learned helplessness), and neglect the impact of psychological stress alone. This is surprising given extensive evidence that a traumatic event needs not be directly experienced to produce enduring perturbations on an individual's health and psychological well-being. Post-traumatic stress disorder (PTSD), a highly debilitating neuropsychiatric disorder characterized by intense fear of trauma-related stimuli, often occurs in individuals that have only witnessed a traumatic event. New method: By modifying the chronic social defeat stress (CSDS) paradigm to include a witness component (witnessing the social defeat of another mouse), we demonstrate a novel behavioral paradigm capable of inducing a robust behavioral syndrome reminiscent of PTSD in emotionally stressed adult mice. Results: We describe the vicarious social defeat stress (VSDS) model that is capable of inducing a host of behavioral deficits that include social avoidance and other depressive- and anxiety-like phenotypes in adult male mice. VSDS exposure induces weight loss and spike in serum corticosterone (CORT) levels. A month after stress, these mice retain the social avoidant phenotype and have an increased CORT response when exposed to subsequent stress. Comparison with existing method(s): The VSDS is a novel paradigm capable of inducing emotional stress by isolating physical stress/confrontation in mice. Conclusions: The VSDS model can be used to study the short- and long-term neurobiological consequences of exposure to emotional stress in mice. (C) 2015 Elsevier B.V. All rights reserved. C1 [Sial, Omar K.; Alcantara, Lyonna F.; Parise, Eric M.; Bolanos-Guzman, Carlos A.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Sial, Omar K.; Alcantara, Lyonna F.; Parise, Eric M.; Bolanos-Guzman, Carlos A.] Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. [Warren, Brandon L.] Natl Inst Drug Abuse, Behav Neurosci Res Branch, Baltimore, MD USA. RP Bolanos-Guzman, CA (reprint author), Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA.; Bolanos-Guzman, CA (reprint author), Florida State Univ, Program Neurosci, Tallahassee, FL 32306 USA. EM bolanos@psy.fsu.edu OI Parise, Eric/0000-0001-5364-5820 FU National Institute on Drug Abuse [R01DA026854]; NRSA from the National Institute of Mental Health (NIMH) [F31MH103939]; McKnight Fellowship from the Florida State Educational fund FX This work was supported by a grant from the National Institute on Drug Abuse R01DA026854 to CABG. EMP was supported by an NRSA F31MH103939 from the National Institute of Mental Health (NIMH). LFA was supported by a McKnight Fellowship from the Florida State Educational fund. We are grateful to Rachael Elliott and John Chalcraft for the artwork. NR 27 TC 2 Z9 2 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 30 PY 2016 VL 258 BP 94 EP 103 DI 10.1016/j.jneumeth.2015.10.012 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA DC4OB UT WOS:000369199100010 PM 26545443 ER PT J AU Cole, HA Cui, F Ocampo, J Burke, TL Nikitina, T Nagarajavel, V Kotomura, N Zhurkin, VB Clark, DJ AF Cole, Hope A. Cui, Feng Ocampo, Josefina Burke, Tara L. Nikitina, Tatiana Nagarajavel, V. Kotomura, Naoe Zhurkin, Victor B. Clark, David J. TI Novel nucleosomal particles containing core histones and linker DNA but no histone H1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BASE-PAIR RESOLUTION; CHICKEN ERYTHROCYTE CHROMATIN; EXONUCLEASE-III; SACCHAROMYCES-CEREVISIAE; ELECTROSTATIC MECHANISM; MICROCOCCAL NUCLEASE; ANGSTROM RESOLUTION; ESCHERICHIA-COLI; MINOR-GROOVE; YEAST AB Eukaryotic chromosomal DNA is assembled into regularly spaced nucleosomes, which play a central role in gene regulation by determining accessibility of control regions. The nucleosome contains similar to 147 bp of DNA wrapped similar to 1.7 times around a central core histone octamer. The linker histone, H1, binds both to the nucleosome, sealing the DNA coils, and to the linker DNA between nucleosomes, directing chromatin folding. Micrococcal nuclease (MNase) digests the linker to yield the chromatosome, containing H1 and similar to 160 bp, and then converts it to a core particle, containing similar to 147 bp and no H1. Sequencing of nucleosomal DNA obtained after MNase digestion (MNase-seq) generates genome-wide nucleosome maps that are important for understanding gene regulation. We present an improved MNase-seq method involving simultaneous digestion with exonuclease III, which removes linker DNA. Remarkably, we discovered two novel intermediate particles containing 154 or 161 bp, corresponding to 7 bp protruding from one or both sides of the nucleosome core. These particles are detected in yeast lacking H1 and in H1-depleted mouse chromatin. They can be reconstituted in vitro using purified core histones and DNA. We propose that these 'proto-chromatosomes' are fundamental chromatin subunits, which include the H1 binding site and influence nucleosome spacing independently of H1. C1 [Cole, Hope A.; Ocampo, Josefina; Burke, Tara L.; Nagarajavel, V.; Kotomura, Naoe; Clark, David J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. [Cui, Feng] Rochester Inst Technol, Thomas H Gosnell Sch Life Sci, Rochester, NY 14623 USA. [Nikitina, Tatiana; Zhurkin, Victor B.] NCI, NIH, Bldg 37,Room 3035A, Bethesda, MD 20892 USA. [Nagarajavel, V.] Lerner Res Inst NE 50, Genom Med Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. [Kotomura, Naoe] Fujita Hlth Univ, Sch Med, Dept Biochem, Toyoake, Aichi 47011, Japan. RP Clark, DJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA.; Zhurkin, VB (reprint author), NCI, NIH, Bldg 37,Room 3035A, Bethesda, MD 20892 USA. EM zhurkin@nih.gov; clarkda@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NICHD and NCI) FX Intramural Research Program of the National Institutes of Health (NICHD and NCI). Funding for open access charge: Intramural Research Program of the National Institutes of Health (NICHD). NR 54 TC 4 Z9 4 U1 4 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 29 PY 2016 VL 44 IS 2 BP 573 EP 581 DI 10.1093/nar/gkv943 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF3RY UT WOS:000371266000017 PM 26400169 ER PT J AU Westmoreland, JW Resnick, MA AF Westmoreland, James W. Resnick, Michael A. TI Recombinational repair of radiation-induced double-strand breaks occurs in the absence of extensive resection SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA END RESECTION; SISTER-CHROMATID EXCHANGE; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; PROMOTES RESECTION; GENE CONVERSION; HUMAN-CELLS; CHROMOSOME; CHOICE; DAMAGE AB Recombinational repair provides accurate chromosomal restitution after double-strand break (DSB) induction. While all DSB recombination repair models include 5'-3' resection, there are no studies that directly assess the resection needed for repair between sister chromatids in G-2 arrested cells of random, radiation-induced 'dirty' DSBs. Using our Pulse Field Gel Electrophoresis-shift approach, we determined resection at IR-DSBs in WT and mutants lacking exonuclease1 or Sgs1 helicase. Lack of either reduced resection length by half, without decreased DSB repair or survival. In the exo1 Delta sgs1 Delta double mutant, resection was barely detectable, yet it only took an additional hour to achieve a level of repair comparable toWT and there was only a 2-fold dose-modifying effect on survival. Results with a Dnl4 deletion strain showed that remaining repair was not due to endjoining. Thus, similar to what has been shown for a single, clean HO-induced DSB, a severe reduction in resection tract length has only a modest effect on repair of multiple, dirty DSBs in G2-arrested cells. Significantly, this study provides the first opportunity to directly relate resection length at DSBs to the capability for global recombination repair between sister chromatids. C1 [Westmoreland, James W.; Resnick, Michael A.] NIEHS, Chromosome Stabil Sect, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Chromosome Stabil Sect, Genome Integr & Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov FU Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, Department of Health and Human Services) [1 Z01 ES065073]; NIH FX Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, Department of Health and Human Services) [Project 1 Z01 ES065073 to M.A.R.]. Funding for open access charge: NIH in-house funds. NR 52 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 29 PY 2016 VL 44 IS 2 BP 695 EP 704 DI 10.1093/nar/gkv1109 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF3RY UT WOS:000371266000027 PM 26503252 ER PT J AU Cali, F Bharti, SK Di Perna, R Brosh, RM Pisani, FM AF Cali, Federica Bharti, Sanjay Kumar Di Perna, Roberta Brosh, Robert M., Jr. Pisani, Francesca M. TI Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SISTER-CHROMATID COHESION; TIM-TIPIN COMPLEX; XENOPUS EGG EXTRACTS; IRON-SULFUR CLUSTER; S-PHASE; BIOCHEMICAL-CHARACTERIZATION; INTERACTING PROTEIN; EUKARYOTIC DNA; G-QUADRUPLEX; TIMELESS AB We present evidence that Tim establishes a physical and functional interaction with DDX11, a superfamily 2 iron-sulfur cluster DNA helicase genetically linked to the chromosomal instability disorder Warsaw breakage syndrome. Tim stimulates DDX11 unwinding activity on forked DNA substrates up to 10fold and on bimolecular anti-parallel G-quadruplex DNA structures and three-stranded D-loop approximately 4-5-fold. Electrophoretic mobility shift assays revealed that Tim enhances DDX11 binding to DNA, suggesting that the observed stimulation derives from an improved ability of DDX11 to interact with the nucleic acid substrate. Surface plasmon resonance measurements indicate that DDX11 directly interacts with Tim. DNA fiber track assays with HeLa cells exposed to hydroxyurea demonstrated that Tim or DDX11 depletion significantly reduced replication fork progression compared to control cells; whereas no additive effect was observed by co-depletion of both proteins. Moreover, Tim and DDX11 are epistatic in promoting efficient resumption of stalled DNA replication forks in hydroxyurea-treated cells. This is consistent with the finding that association of the two endogenous proteins in the cell extract chromatin fraction is considerably increased following hydroxyurea exposure. Overall, our studies provide evidence that Tim and DDX11 physically and functionally interact and act in concert to preserve replication fork progression in perturbed conditions. C1 [Cali, Federica; Di Perna, Roberta; Pisani, Francesca M.] CNR, Ist Biochim Prot, Via Pietro Castellino 111, I-80131 Naples, Italy. [Bharti, Sanjay Kumar; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. RP Pisani, FM (reprint author), CNR, Ist Biochim Prot, Via Pietro Castellino 111, I-80131 Naples, Italy. EM fm.pisani@ibp.cnr.it FU Italian 'Ministero dell'Istruzione, Universita e Ricerca' (MIUR) [PON01_00862, PON01_00117, PON01_01585]; Project 'FaReBio di Qualita' from Italian 'Ministero della Economia'; 'Progetto CREME' from Regione Campania; Intramural Research Program of the National Institutes of Health, National Institute on Aging; Italian MIUR FX PON projects from Italian 'Ministero dell'Istruzione, Universita e Ricerca' (MIUR) [PON01_00862; PON01_00117 and PON01_01585 to F. M. P.]; Project 'FaReBio di Qualita' from Italian 'Ministero della Economia' [PhD grant to F. C.]; 'Progetto CREME' from Regione Campania [to R. D. P.]; Intramural Research Program of the National Institutes of Health, National Institute on Aging [to R. B. in part]. Funding for open access charge: The publication fee will be charged on grant from Italian MIUR. NR 53 TC 5 Z9 5 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 29 PY 2016 VL 44 IS 2 BP 705 EP 717 DI 10.1093/nar/gkv1112 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DF3RY UT WOS:000371266000028 PM 26503245 ER PT J AU Guerrieri, GM Wakim, PG Keenan, PA Schenkel, LA Berlin, K Gibson, CJ Rubinow, DR Schmidt, PJ AF Guerrieri, Gioia M. Wakim, Paul G. Keenan, P. A. Schenkel, Linda A. Berlin, Kate Gibson, Carolyn J. Rubinow, David R. Schmidt, Peter J. TI Sex differences in visuospatial abilities persist during induced hypogonadism SO NEUROPSYCHOLOGIA LA English DT Article DE Sex differences; Sex steroids; Hypogonadism; Mental rotation; Visuospatial ID HEALTHY-YOUNG WOMEN; PHARMACOLOGICALLY INDUCED HYPOGONADISM; CORTICAL ACTIVATION PATTERNS; ESTROGEN REPLACEMENT THERAPY; MENTAL ROTATION; MENSTRUAL-CYCLE; POSTMENOPAUSAL WOMEN; WORKING-MEMORY; VERBAL MEMORY; COGNITIVE FUNCTION AB Background: Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates. Objective: To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism. Methods: Men (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonistinduced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models. Results: During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects). Conclusion: The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus sex differences in visuospatial performance in adulthood could reflect early developmental effects of sex steroid exposure or other environmental exposures differing across the sexes as our data confirm that these differences are independent of circulating estradiol or testosterone levels in men and women. Published by Elsevier Ltd. C1 [Guerrieri, Gioia M.; Schenkel, Linda A.; Berlin, Kate; Gibson, Carolyn J.; Schmidt, Peter J.] NIMH, Sect Behav Endocrinol, NIH, Dept Hlth & Human Serv, Bldg 10 CRC,Room 25330,10 Ctr Dr,MSC 1277, Bethesda, MD 20892 USA. [Wakim, Paul G.] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Keenan, P. A.] Cronos Clin Consulting, 22 Tanglewood Dr, Titusville, NJ 08560 USA. [Rubinow, David R.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), NIMH, 10 CRC,Room 25330,10 Ctr Dr,MSC 1277, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX This work was funded by the National Institute of Mental Health Intramural Research Program and was written as part of Dr. Schmidt's official duties as a Government employee. Dr. Schmidt had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 107 TC 0 Z9 0 U1 4 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD JAN 29 PY 2016 VL 81 BP 219 EP 229 DI 10.1016/j.neuropsychologia.2015.12.021 PG 11 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA DE2LS UT WOS:000370459400020 PM 26719236 ER PT J AU Taichman, DB Backus, J Baethge, C Bauchner, H de Leeuw, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T Haileamlak, A James, A Laine, C Peiperl, L Pinborg, A Sahni, P Wu, SN AF Taichman, Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuw, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish Haileamlak, Abraham James, Astrid Laine, Christine Peiperl, Larry Pinborg, Anja Sahni, Peush Wu, Sinan TI Sharing Clinical Trial Data SO DEUTSCHES ARZTEBLATT INTERNATIONAL LA English DT Editorial Material C1 [Taichman, Darren B.] ICMJE, London, England. [Backus, Joyce] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. [Baethge, Christopher] Deutsch Arzteblatt, Amharic, Germany. RP Taichman, DB (reprint author), ICMJE, London, England. NR 1 TC 0 Z9 0 U1 0 U2 1 PU DEUTSCHER AERZTE-VERLAG GMBH PI COLOGNE PA DIESELSTRABE 2, POSTFACH 400265, D-50859 COLOGNE, GERMANY SN 1866-0452 J9 DTSCH ARZTEBL INT JI Dtsch. Arztebl. Int. PD JAN 29 PY 2016 VL 113 IS 4 BP 41 EP 43 DI 10.3238/arztebl.2016.0041 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DD6XZ UT WOS:000370069300001 PM 26883412 ER PT J AU Woodfolk, JA Glesner, J Wright, PW Kepley, CL Li, M Himly, M Muehling, LM Gustchina, A Wlodawer, A Chapman, MD Pomes, A AF Woodfolk, Judith A. Glesner, Jill Wright, Paul W. Kepley, Christopher L. Li, Mi Himly, Martin Muehling, Lyndsey M. Gustchina, Alla Wlodawer, Alexander Chapman, Martin D. Pomes, Anna TI Antigenic Determinants of the Bilobal Cockroach Allergen Bla g 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HOUSE-DUST MITE; FLUORESCENT MULTIPLEX ARRAY; SITE-DIRECTED MUTAGENESIS; HUMAN IGE ANTIBODIES; AMINO-ACID-RESIDUES; B-CELL EPITOPES; RECOMBINANT ALLERGENS; CRYSTAL-STRUCTURE; IMMUNOGLOBULIN-E; GRASS-POLLEN AB Bla g 2 is a major indoor cockroach allergen associated with the development of asthma. Antigenic determinants on Bla g 2 were analyzed by mutagenesis based on the structure of the allergen alone and in complex with monoclonal antibodies that interfere with IgE antibody binding. The structural analysis revealed mechanisms of allergen-antibody recognition through cation-pi interactions. Single and multiple Bla g 2 mutants were expressed in Pichia pastoris and purified. The triple mutant K132A/K251A/F162Y showed an similar to 100-fold reduced capacity to bind IgE, while preserving the native molecular fold, as proven by x-ray crystallography. This mutant was still able to induce mast cell release. T-cell responses were assessed by analyzing Th1/Th2 cytokine production and the CD4(+) T-cell phenotype in peripheral blood mononuclear cell cultures. Although T-cell activating capacity was similar for the KKF mutant and Bla g 2 based on CD25 expression, the KKF mutant was a weaker inducer of the Th2 cytokine IL-13. Furthermore, this mutant induced IL-10 from a non-T-cell source at higher levels that those induced by Bla g 2. Our findings demonstrate that a rational design of site-directed mutagenesis was effective in producing a mutant with only 3 amino acid substitutions that maintained the same fold as wild type Bla g 2. These residues, which were involved in IgE antibody binding, endowed Bla g 2 with a T-cell modulatory capacity. The antigenic analysis of Bla g 2 will be useful for the subsequent development of recombinant allergen vaccines. C1 [Woodfolk, Judith A.; Wright, Paul W.; Muehling, Lyndsey M.] Univ Virginia, Dept Med, Div Allergy, Charlottesville, VA 22903 USA. [Glesner, Jill; Chapman, Martin D.; Pomes, Anna] INDOOR Biotechnol Inc, 700 Harris St, Charlottesville, VA 22908 USA. [Kepley, Christopher L.] Univ N Carolina, Joint Sch Nanosci & Nanoengn, Greensboro, NC 27401 USA. [Li, Mi; Gustchina, Alla; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. [Li, Mi] Leidos Biomed Res Inc, Frederick Natl Lab, Basic Sci Program, Frederick, MD 21702 USA. [Himly, Martin] Salzburg Univ, Dept Mol Biol, A-5020 Salzburg, Austria. RP Pomes, A (reprint author), INDOOR Biotechnol Inc, 700 Harris St, Charlottesville, VA 22908 USA. EM apomes@inbio.com RI Himly, Martin/D-1568-2015; OI Himly, Martin/0000-0001-5416-085X; Pomes, Anna/0000-0002-8729-1829 FU National Institutes of Health from NIAID [R01AI077653, R01AI77653-01A2S1]; Intramural Research Program of the National Institutes of Health, NCI Center for Cancer Research; National Institutes of Health from NCI [HHSN26120080001E] FX This work was supported by National Institutes of Health Grants R01AI077653 and R01AI77653-01A2S1 from NIAID, in part by the Intramural Research Program of the National Institutes of Health, NCI Center for Cancer Research, and in part by National Institutes of Health Contract HHSN26120080001E from NCI. M. D. C is a co-owner and has a financial interest in Indoor Biotechnologies, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Health and Human Services. NR 56 TC 3 Z9 3 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 29 PY 2016 VL 291 IS 5 BP 2288 EP 2301 DI 10.1074/jbc.M115.702324 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD0LB UT WOS:000369610400019 PM 26644466 ER PT J AU Sharma, NR Wang, XH Majerciak, V Ajiro, M Kruhlak, M Meyers, C Zheng, ZM AF Sharma, Nishi R. Wang, Xiaohong Majerciak, Vladimir Ajiro, Masahiko Kruhlak, Michael Meyers, Craig Zheng, Zhi-Ming TI Cell Type- and Tissue Context-dependent Nuclear Distribution of Human Ago2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ARGONAUTE PROTEINS; HERPESVIRUS ORF57; GENE-EXPRESSION; RNA; LOCALIZATION; STRESS; ONCOPROTEIN; MICRORNAS; CLEAVAGE AB Argonaute-2 protein (Ago2), a major component of RNA-induced silencing complex (RISC), has been viewed as a cytoplasmic protein. In this study, we demonstrated by immunofluorescence confocal microscopy that Ago2 is distributed mainly as a nuclear protein in primary human foreskin keratinocytes in monolayer cultures and their derived organotypic (raft) cultures, although it exhibits only a minimal level of nuclear distribution in continuous cell lines such as HeLa and HaCaT cells. Oncogenic human papillomavirus type 16 (HPV16) or type 18 (HPV18) infection of the keratinocytes does not affect the nuclear Ago2 distribution. Examination of human tissues reveals that Ago2 exhibits primarily as a nuclear protein in skin, normal cervix, and cervical cancer tissues, but not in larynx. Together, our data provide the first convincing evidence that the subcellular distribution of Ago2 occurs in a cell type-and tissue context-dependent manner and may correlate with its various functions in regulation of gene expression. C1 [Sharma, Nishi R.; Wang, Xiaohong; Majerciak, Vladimir; Zheng, Zhi-Ming] NCI, Tumor Virus RNA Biol Sect,Gene Regulat & Chromoso, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Kruhlak, Michael] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Meyers, Craig] Penn State Univ, Sch Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. RP Zheng, ZM (reprint author), NCI, Tumor Virus RNA Biol Sect,Gene Regulat & Chromoso, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM zhengt@exchange.nih.gov FU NCI Investigator-initiated Intramural Research Project [1ZIASC010357-15]; Center for Cancer Research, NCI, National Institutes of Health; National Institutes of Health [U01 CA179724] FX This study was supported by the NCI Investigator-initiated Intramural Research Project 1ZIASC010357-15, the Center for Cancer Research, NCI, National Institutes of Health (to Z. M. Z.). This work was also supported partially by National Institutes of Health Grant U01 CA179724 (to C. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. NR 21 TC 1 Z9 1 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 29 PY 2016 VL 291 IS 5 BP 2302 EP 2309 DI 10.1074/jbc.C115.695049 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD0LB UT WOS:000369610400020 PM 26699195 ER PT J AU Dearborn, AD Wall, JS Cheng, NQ Heymann, JB Kajava, AV Varkey, J Langen, R Steven, AC AF Dearborn, Altaira D. Wall, Joseph S. Cheng, Naiqian Heymann, J. Bernard Kajava, Andrey V. Varkey, Jobin Langen, Ralf Steven, Alasdair C. TI alpha-Synuclein Amyloid Fibrils with Two Entwined, Asymmetrically Associated Protofibrils SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSMISSION ELECTRON-MICROSCOPY; ATOMIC-FORCE MICROSCOPY; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; LEWY BODIES; IN-VITRO; CORE STRUCTURE; MASS ANALYSIS; FILAMENTS; PROTEIN AB Parkinson disease and other progressive neurodegenerative conditions are characterized by the intracerebral presence of Lewy bodies, containing amyloid fibrils of alpha-synuclein. We used cryo-electron microscopy and scanning transmission electron microscopy (STEM) to study in vitro-assembled fibrils. These fibrils are highly polymorphic. Focusing on twisting fibrils with an inter-crossover spacing of 77 nm, our reconstructions showed them to consist of paired protofibrils. STEM mass per length data gave one subunit per 0.47 nm axial rise per protofibril, consistent with a superpleated beta-structure. The STEM images show two thread-like densities running along each of these fibrils, which we interpret as ladders of metal ions. These threads confirmed the two-protofibril architecture of the 77-nm twisting fibrils and allowed us to identify this morphotype in STEM micrographs. Some other, but not all, fibril morphotypes also exhibit dense threads, implying that they also present a putative metal binding site. We propose a molecular model for the protofibril and suggest that polymorphic variant fibrils have different numbers of protofibrils that are associated differently. C1 [Dearborn, Altaira D.; Cheng, Naiqian; Heymann, J. Bernard; Steven, Alasdair C.] Natl Inst Hlth, Struct Biol Res Lab, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD 20892 USA. [Wall, Joseph S.] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Kajava, Andrey V.] Univ Montpellier, Ctr Rech Biochim Macromol, CNRS, F-34172 Montpellier, France. [Kajava, Andrey V.] Univ ITMO, Inst Bioengn, St Petersburg 197101, Russia. [Varkey, Jobin; Langen, Ralf] Univ So Calif, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Varkey, Jobin] Karunya Univ, Coimbatore 641114, Tamil Nadu, India. Natl Inst Hlth, NIAMS, Struct Biol Res Lab, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), Natl Inst Hlth, NIAMS, Struct Biol Res Lab, Bldg 50,Rm 1517,50 South Dr, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 FU NIAMS/National Institutes of Health; National Institutes of Health [1R01NS084345]; DBT-Ramalingaswami fellowship FX This research was supported by the intramural research program of NIAMS/National Institutes of Health (to A. C. S.) and National Institutes of Health Grant 1R01NS084345 (to R. L.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Supported by a DBT-Ramalingaswami fellowship. NR 43 TC 3 Z9 3 U1 4 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 29 PY 2016 VL 291 IS 5 BP 2310 EP 2318 DI 10.1074/jbc.M115.698787 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DD0LB UT WOS:000369610400021 PM 26644467 ER PT J AU Ciesla, L Okine, M Rosenberg, A Dossou, KSS Toll, L Wainer, IW Moaddel, R AF Ciesla, L. Okine, M. Rosenberg, A. Dossou, K. S. S. Toll, L. Wainer, I. W. Moaddel, R. TI Development and characterization of the alpha 3 beta 4 alpha 5 nicotinic receptor cellular membrane affinity chromatography column and its application for on line screening of plant extracts SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Frontal affinity chromatography; Alkaloids; Anabasine; Subtype selectivity ID COATED MAGNETIC BEADS; OPEN-TUBULAR COLUMN; ACETYLCHOLINE-RECEPTORS; STATIONARY PHASES; IDENTIFICATION; SUBUNITS; LIGANDS; FLOW AB The alpha 3 beta 4 alpha 5 nAChR has been recently shown to be a useful target for smoking cessation pharmacotherapies. Herein, we report on the development and characterization of the alpha 3 beta 4 alpha 5 nicotinic receptor column by frontal displacement chromatography. The binding affinity of the nicotine and minor alkaloids found in tobacco smoke condensates were determined for both the OM and alpha 3 beta 4 alpha 5 nicotinic receptors. It was demonstrated that while no subtype selectivity was observed for nicotine and nornicotine, anabasine was selective for the alpha 3 beta 4 alpha 5 nicotinic receptor. The non-competitive inhibitor binding site was also studied and it was demonstrated while mecamylarnine was not selective between subtypes, buproprion showed subtype selectivity for the alpha 3 beta 4 nicotinic receptor. The application of this methodology to complex mixtures was then carried out by screening aqueous-alcoholic solutions of targeted plant extracts, including Lycopodium clavatum L. (Lycopodiaceae) and Trigonella foenum graecum L. (Fabaceae) against both the OM and alpha 3 beta 4 alpha 5 nAChRs. Published by Elsevier B.V. C1 [Ciesla, L.; Okine, M.; Rosenberg, A.; Dossou, K. S. S.; Wainer, I. W.; Moaddel, R.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Ciesla, L.] Med Univ Lublin, Dept Inorgan Chem, Chodzki 4A, PL-20093 Lublin, Poland. [Toll, L.] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34990 USA. RP Moaddel, R (reprint author), NIA, Bioanalyt Chem & Drug Screening Ctr, Clin Invest Lab, NIH,Biomed Res Ctr, Suite 100,251 Bayview Blvd, Baltimore, MD 21224 USA. EM moaddelru@mail.nih.gov FU NIA; IACTRS FDA/NIH Collaborative Grant; NIH; FDA under the Family Smoking Prevention and Tobacco Control Act FX This work was supported in part by funds from the NIA Intramural Research Program and from the IACTRS FDA/NIH Collaborative Grant. Research reported in this publication was supported by the NIH intramural research program and the FDA through funds obtained under the Family Smoking Prevention and Tobacco Control Act. The content was not reviewed by the Food and Drug Administration, but underwent the standard manuscript clearance process for scientific papers published from the NIH intramural research program. NR 25 TC 3 Z9 3 U1 6 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JAN 29 PY 2016 VL 1431 BP 138 EP 144 DI 10.1016/j.chroma.2015.12.065 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA DC4ND UT WOS:000369196700016 PM 26774122 ER PT J AU Guo, JQ Zhang, W Zhang, LL Ding, HX Zhang, JJ Song, C Zhang, YF Xia, NM Li, MF Liang, YM Hu, XZ Luan, HJ Wang, H AF Guo, Jiqiang Zhang, Wen Zhang, Lili Ding, Huaxia Zhang, Jingjing Song, Chen Zhang, Yanfei Xia, Namei Li, Mingfang Liang, Yinming Hu, Xianzhang Luan, Haojiang Wang, Hui TI Probable involvement of p11 with interferon alpha induced depression SO SCIENTIFIC REPORTS LA English DT Article ID CHRONIC HEPATITIS-C; 5-HT4 RECEPTOR; RAT-BRAIN; SEROTONIN RECEPTOR; GENE POLYMORPHISMS; CELLS; MICE; HIPPOCAMPUS; MODULATION; EXPRESSION AB Depression is one of the major side effects of interferon alpha (IFN-alpha) treatment, but the molecular mechanism underlying IFN-alpha-induced depression remains unclear. Several studies have shown that the serotonin receptors 5-HTR1b and 5-HTR4 play key roles in the anti-depression effects associated with p11 (S100A10). We investigated the effects of IFN-alpha on the regulation of p11, 5-HTR1b and 5-HTR4 in mice and human neuroblastoma cells (SH-sy5y). We found that intraperitoneal injection with IFN-alpha in Balb/c mice resulted in an increased immobility in FST and TST, and potently lowered the protein levels of p11, 5-HTR1b and 5-HTR4 in the hippocampus or cingulate gyrus. IFN-alpha significantly down-regulated the protein levels of p11, 5-HTR1b and 5-HTR4 in SH-sy5y cells, in a time-and dose-dependent manner. Our study revealed that over-expression of p11 could prevent the IFN-alpha-induced down-regulation of 5-HTR1b and 5-HTR4. The results indicated that IFN-a treatment resulted in p11 down-regulation, which subsequently decreased 5-HTR1b and 5-HTR4 in vitro or in vivo. Our findings suggested that p11 might be a potential regulator on 5-HTR1b and 5-HTR4 as well as a predictor of or a therapeutic target for IFN-alpha-induced depression. C1 [Guo, Jiqiang; Zhang, Wen; Zhang, Lili; Wang, Hui] Xinxiang Med Univ, Sch Basic Med Sci, Immunol Res Ctr, Xinxiang, Peoples R China. [Guo, Jiqiang; Zhang, Wen; Ding, Huaxia; Zhang, Jingjing; Song, Chen; Zhang, Yanfei; Xia, Namei; Li, Mingfang; Liang, Yinming; Hu, Xianzhang; Wang, Hui] Xinxiang Med Univ, Sch Lab Med, Collaborat Innovat Ctr Mol Diag & Lab Med Henan P, Xinxiang, Peoples R China. [Luan, Haojiang] NIMH, Mol Biol Lab, Bethesda, MD USA. RP Wang, H (reprint author), Xinxiang Med Univ, Sch Basic Med Sci, Immunol Res Ctr, Xinxiang, Peoples R China. EM wanghui@xxmu.edu.cn FU National Natural Science Foundation of China [81241095, 81471559] FX We appreciate Jingyi Bai from the Duke University for proofreading to improve our English writing. This work was supported by the National Natural Science Foundation of China (81241095 & 81471559 to Hui Wang). NR 69 TC 3 Z9 3 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 29 PY 2016 VL 6 AR 17029 DI 10.1038/srep17029 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC0QX UT WOS:000368923900001 PM 26821757 ER PT J AU Ghirlando, R Mutskova, R Schwartz, C AF Ghirlando, Rodolfo Mutskova, Radina Schwartz, Chad TI Enrichment and characterization of ferritin for nanomaterial applications SO NANOTECHNOLOGY LA English DT Article DE nanomaterial; analytical ultracentrifugation; sedimentation velocity ID IRON-STORAGE; ANALYTICAL ULTRACENTRIFUGATION; SEDIMENTATION-VELOCITY; MOLECULAR-WEIGHT; APOFERRITIN; NANOPARTICLE; CORE; DISSOCIATION; METABOLISM; SCATTERING AB Ferritin is a ubiquitous iron storage protein utilized as a nanomaterial for labeling biomolecules and nanoparticle construction. Commercially available preparations of horse spleen ferritin, widely used as a starting material, contain a distribution of ferritins with different iron loads. We describe a detailed approach to the enrichment of differentially loaded ferritin molecules by common biophysical techniques such as size exclusion chromatography and preparative ultracentrifugation, and characterize these preparations by dynamic light scattering, and analytical ultracentrifugation. We demonstrate a combination of methods to standardize an approach for determining the chemical load of nearly any particle, including nanoparticles and metal colloids. Purification and characterization of iron content in monodisperse ferritin species is particularly critical for several applications in nanomaterial science. C1 [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mutskova, Radina] Univ Maryland, Honors Coll, Integrated Life Sci, College Pk, MD 20742 USA. [Schwartz, Chad] Beckman Coulter Inc, Indianapolis, IN 46268 USA. RP Ghirlando, R (reprint author), NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bldg 5,Room 208,5 Mem Dr,MSC 0540, Bethesda, MD 20892 USA. EM rodolfo.ghirlando@nih.gov; cschwartz@beckman.com FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (RG). The authors thank Dr Marie-Paule Strub and Dr Duck-Yeon Lee (Biochemistry Core Facility, NHLBI) of the National Heart, Lung and Blood Institute for assistance with the atomic absorption spectrometry. NR 43 TC 0 Z9 0 U1 8 U2 26 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD JAN 29 PY 2016 VL 27 IS 4 AR 045102 DI 10.1088/0957-4484/27/4/045102 PG 10 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA CZ0VU UT WOS:000366825000004 PM 26656976 ER PT J AU Baram, M Atsmon-Raz, Y Ma, BY Nussinov, R Miller, Y AF Baram, Michal Atsmon-Raz, Yoav Ma, Buyong Nussinov, Ruth Miller, Yifat TI Amylin-A beta oligomers at atomic resolution using molecular dynamics simulations: a link between Type 2 diabetes and Alzheimer's disease SO PHYSICAL CHEMISTRY CHEMICAL PHYSICS LA English DT Article ID ISLET AMYLOID POLYPEPTIDE; PARTICLE MESH EWALD; CONFORMATIONAL SELECTION; SYNERGISTIC INTERACTIONS; POTENTIAL FUNCTIONS; CONSTANT-PRESSURE; ENERGY LANDSCAPE; PHYSIOLOGICAL PH; ALPHA-SYNUCLEIN; LIQUID WATER AB Clinical studies have identified Type 2 diabetes (T2D) as a risk factor of Alzheimer's disease (AD). One of the potential mechanisms that link T2D and AD is the loss of cells associated with degenerative changes. Amylin(1-37) aggregates (the pathological species in T2D) were found to be co-localized with those of A beta(1-42) (the pathological species in AD) to form the Amylin(1-37)-A beta(1-42) plaques, promoting aggregation and thus contributing to the etiology of AD. However, the mechanisms by which Amylin(1-37) co-aggregates with A beta(1-42) are still elusive. This work presents the interactions between Amylin(1-37) oligomers and A beta(1-42) oligomers at atomic resolution applying extensive molecular dynamics simulations for relatively large ensemble of cross-seeding Amylin(1-37)-A beta(1-42) oligomers. The main conclusions of this study are first, A beta(1-42) oligomers prefer to interact with Amylin(1-37) oligomers to form single layer conformations (in-register interactions) rather than double layer conformations; and second, in some double layer conformations of the cross-seeding Amylin(1-37)-A beta(1-42) oligomers, the Amylin(1-37) oligomers destabilize the A beta(1-42) oligomers and thus inhibit A beta(1-42) aggregation, while in other double layer conformations, the Amylin(1-37) oligomers stabilize A beta(1-42) oligomers and thus promote A beta(1-42) aggregation. C1 [Baram, Michal; Atsmon-Raz, Yoav; Miller, Yifat] Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel. [Baram, Michal; Atsmon-Raz, Yoav; Miller, Yifat] Ben Gurion Univ Negev, Ilse Katz Inst Nanoscale Sci & Technol, IL-84105 Beer Sheva, Israel. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Miller, Y (reprint author), Ben Gurion Univ Negev, Dept Chem, IL-84105 Beer Sheva, Israel.; Miller, Y (reprint author), Ben Gurion Univ Negev, Ilse Katz Inst Nanoscale Sci & Technol, IL-84105 Beer Sheva, Israel.; Nussinov, R (reprint author), NCI, Basic Sci Program, Leidos Biomed Res Inc, Canc & Inflammat Program, Frederick, MD 21702 USA.; Nussinov, R (reprint author), Tel Aviv Univ, Sackler Inst Mol Med, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM NussinoR@helix.nih.gov; ymiller@bgu.ac.il RI Ma, Buyong/F-9491-2011; Atsmon-Raz, Yoav/H-1763-2013 OI Ma, Buyong/0000-0002-7383-719X; Atsmon-Raz, Yoav/0000-0001-6476-9845 FU FP7-PEOPLE-CIG [303741]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project was supported by the FP7-PEOPLE-2011-CIG, research grant no. 303741, and in whole or in part by Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 69 TC 10 Z9 10 U1 4 U2 25 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1463-9076 EI 1463-9084 J9 PHYS CHEM CHEM PHYS JI Phys. Chem. Chem. Phys. PD JAN 28 PY 2016 VL 18 IS 4 BP 2330 EP 2338 DI 10.1039/c5cp03338a PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA DC8YI UT WOS:000369506000009 PM 26349542 ER PT J AU Depp, TB McGinnis, KA Kraemer, K Akgun, KM Edelman, EJ Fiellin, DA Butt, AA Crystal, S Gordon, AJ Freiberg, M Gibert, CL Rimland, D Bryant, KJ Crothers, K AF Depp, Timothy B. McGinnis, Kathleen A. Kraemer, Kevin Akguen, Kathleen M. Edelman, E. Jennifer Fiellin, David A. Butt, Adeel A. Crystal, Stephen Gordon, Adam J. Freiberg, Matthew Gibert, Cynthia L. Rimland, David Bryant, Kendall J. Crothers, Kristina TI Risk factors associated with acute exacerbation of chronic obstructive pulmonary disease in HIV-infected and uninfected patients SO AIDS LA English DT Article DE acute exacerbation; AECOPD; AIDS/HIV; chronic obstructive pulmonary disease; cigarette smoking; COPD; tobacco use; unhealthy alcohol use ID ANTIRETROVIRAL THERAPY ERA; COPD EXACERBATIONS; UNITED-STATES; LUNG-DISEASE; ALCOHOL-USE; CARE; HEALTH; VETERANS; EPIDEMIOLOGY; MORTALITY AB Objective:To determine the association between HIV infection and other risk factors for acute exacerbation of chronic obstructive pulmonary disease (AECOPD).Design:Longitudinal, national Veterans Aging Cohort Study including 43 618 HIV-infected and 86 492 uninfected veterans.Methods:AECOPD was defined as an inpatient or outpatient COPD ICD-9 diagnosis accompanied by steroid and/or antibiotic prescription within 5 days. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) for first AECOPD over 2 years and used Poisson regression models to adjust for risk factors.Results:Over 234099 person-years of follow-up, 1428 HIV-infected and 2104 uninfected patients had at least one AECOPD. HIV-infected patients had an increased rate of AECOPD compared with uninfected (18.8 vs. 13.3 per 1000 person-years, P<0.001). In adjusted models, AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4(+) cell count (cells/l) compared with uninfected (HIV-infected CD4(+)<200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4(+) 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4(+)350: IRR 0.99, 95% CI 0.88-1.10). HIV infection also modified the association between current smoking and alcohol-related diagnoses with risk for AECOPD such that interaction terms for HIV and current smoking or HIV and alcohol-related diagnoses were each significantly associated with AECOPD.Conclusion:HIV infection, especially with lower CD4(+) cell count, is an independent risk factor for AECOPD. Enhanced susceptibility to harm from current smoking or unhealthy alcohol use in HIV-infected patients may also contribute to the greater rate of AECOPD. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved. C1 [Depp, Timothy B.] Univ S Carolina, Columbia, SC 29208 USA. [Depp, Timothy B.; McGinnis, Kathleen A.; Kraemer, Kevin; Butt, Adeel A.; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Kraemer, Kevin; Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Akguen, Kathleen M.] VA Connecticut Healthcare Syst, West Haven, CT USA. [Akguen, Kathleen M.; Edelman, E. Jennifer; Fiellin, David A.] Yale Univ, Sch Med, New Haven, CT USA. [Butt, Adeel A.] Hamad Healthcare Qual Inst, Doha, Qatar. [Butt, Adeel A.] Hamad Med Corp, Doha, Qatar. [Crystal, Stephen] Rutgers State Univ, New Brunswick, NJ 08903 USA. [Freiberg, Matthew] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Gibert, Cynthia L.] Washington DC VA Med Ctr, Washington, DC USA. [Rimland, David] VA Med Ctr, Atlanta, GA USA. [Rimland, David] Emory Univ, Sch Med, Atlanta, GA USA. [Bryant, Kendall J.] NIAAA, NIH, Bethesda, MD USA. [Crothers, Kristina] Univ Washington, Seattle, WA 98195 USA. RP Crothers, K (reprint author), Univ Washington, Harborview Med Ctr, 325 9th Ave,POB 359762, Seattle, WA 98104 USA. EM crothk@uw.edu OI Edelman, E. Jennifer/0000-0002-9375-0489; Fiellin, David/0000-0002-4006-010X; Crothers, Kristina/0000-0001-9702-0371 FU NIH/NHLBI [R01 HL090342]; NIAAA [U24-AA020794]; AHRQ [U19HS021, R18HS023258, U10 AA013566] FX NIH/NHLBI R01 HL090342, NIAAA U24-AA020794, AHRQ U19HS021, R18HS023258 and U10 AA013566. NR 69 TC 5 Z9 5 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD JAN 28 PY 2016 VL 30 IS 3 BP 455 EP 463 DI 10.1097/QAD.0000000000000940 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA DC6CB UT WOS:000369306300003 PM 26765938 ER PT J AU Clapham, KR Chu, AY Wessel, J Natarajan, P Flannick, J Rivas, MA Sartori, S Mehran, R Baber, U Fuster, V Scott, RA Rader, DJ Boehnke, M McCarthy, MI Altshuler, DM Kathiresan, S Peloso, GM AF Clapham, Katharine R. Chu, Audrey Y. Wessel, Jennifer Natarajan, Pradeep Flannick, Jason Rivas, Manuel A. Sartori, Samantha Mehran, Roxana Baber, Usman Fuster, Valentin Scott, Robert A. Rader, Daniel J. Boehnke, Michael McCarthy, Mark I. Altshuler, David M. Kathiresan, Sekar Peloso, Gina M. TI A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans SO BMC ENDOCRINE DISORDERS LA English DT Article DE Betatrophin; Angiopoietin-like 8; rs145464906 ID LOW-FREQUENCY; VARIANTS; ANGPTL8/BETATROPHIN; SUSCEPTIBILITY; BETATROPHIN; PROTEIN; DISEASE; DESIGN AB Background: Experiments in mice initially suggested a role for the protein angiopoietin-like 8 (ANGPTL8) in glucose homeostasis. However, subsequent experiments in model systems have challenged this proposed role. We sought to better understand the importance of ANGPTL8 in human glucose homeostasis by examining the association of a null mutation in ANGPTL8 with fasting glucose levels and risk for type 2 diabetes. Methods: A naturally-occurring null mutation in human ANGPTL8 (rs145464906; c.361C > T; p.Q121X) is carried by similar to 1 in 1000 individuals of European ancestry and is associated with higher levels of plasma high-density lipoprotein cholesterol, suggesting that this mutation has functional significance. We examined the association of p.Q121X with fasting glucose levels and risk for type 2 diabetes in up to 95,558 individuals (14,824 type 2 diabetics and 80,734 controls). Results: We found no significant association of p.Q121X with either fasting glucose or type 2 diabetes (p-value = 0.90 and 0.65, respectively). Given our sample sizes, we had >98 % power to detect at least a 0.23 mmol/L effect on plasma glucose and >95 % power to detect a 70 % increase in risk for type 2 diabetes. Conclusion: Disruption of ANGPTL8 function in humans does not seem to have a large effect on measures of glucose tolerance. C1 [Clapham, Katharine R.; Natarajan, Pradeep; Rivas, Manuel A.; Kathiresan, Sekar; Peloso, Gina M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Chu, Audrey Y.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chu, Audrey Y.] Natl Heart Lung & Blood Inst NHLBI Framingham Hea, Framingham, MA 01702 USA. [Wessel, Jennifer] Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA. [Wessel, Jennifer] Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Natarajan, Pradeep; Kathiresan, Sekar; Peloso, Gina M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Natarajan, Pradeep; Kathiresan, Sekar; Peloso, Gina M.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Natarajan, Pradeep; Flannick, Jason; Rivas, Manuel A.; Altshuler, David M.; Kathiresan, Sekar; Peloso, Gina M.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Flannick, Jason; Altshuler, David M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sartori, Samantha; Mehran, Roxana; Baber, Usman; Fuster, Valentin] Icahn Sch Med Mt Sinai, Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Scott, Robert A.] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0SL, England. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Altshuler, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Peloso, Gina M.] Crosstown Ctr, 801 Massachusetts Ave,Third Floor, Boston, MA 02118 USA. RP Peloso, GM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA.; Peloso, GM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Peloso, GM (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.; Peloso, GM (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Peloso, GM (reprint author), Crosstown Ctr, 801 Massachusetts Ave,Third Floor, Boston, MA 02118 USA. EM gpeloso@bu.edu RI Fuster, Valentin/H-4319-2015; OI Fuster, Valentin/0000-0002-9043-9986; Natarajan, Pradeep/0000-0001-8402-7435; Wessel, Jennifer/0000-0002-7031-0085 FU National Heart, Lung, and Blood Institute of National Institutes of Health [K01HL125751]; Research Scholar award from Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq FX GMP is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL125751. SK is supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. 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 do not report any conflict of interest. NR 15 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6823 J9 BMC ENDOCR DISORD JI BMC Endocr. Disord. PD JAN 28 PY 2016 VL 16 AR 7 DI 10.1186/s12902-016-0088-8 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DC4UO UT WOS:000369216000001 PM 26822414 ER PT J AU Chowdhury, B Seetharam, A Wang, ZP Liu, YL Lossie, AC Thimmapuram, J Irudayaraj, J AF Chowdhury, Basudev Seetharam, Arun Wang, Zhiping Liu, Yunlong Lossie, Amy C. Thimmapuram, Jyothi Irudayaraj, Joseph TI A Study of Alterations in DNA Epigenetic Modifications (5mC and 5hmC) and Gene Expression Influenced by Simulated Microgravity in Human Lymphoblastoid Cells SO PLOS ONE LA English DT Article ID UBIQUITIN LIGASES; HUMAN-LYMPHOCYTES; STRESS-RESPONSE; SPACE-FLIGHT; METHYLATION; SEQ; GENOME; 5-HYDROXYMETHYLCYTOSINE; LINES; SPACEFLIGHT AB Cells alter their gene expression in response to exposure to various environmental changes. Epigenetic mechanisms such as DNA methylation are believed to regulate the alterations in gene expression patterns. In vitro and in vivo studies have documented changes in cellular proliferation, cytoskeletal remodeling, signal transduction, bone mineralization and immune deficiency under the influence of microgravity conditions experienced in space. However microgravity induced changes in the epigenome have not been well characterized. In this study we have used Next-generation Sequencing (NGS) to profile ground-based "simulated" microgravity induced changes on DNA methylation (5-methylcytosine or 5mC), hydroxymethylation (5-hydroxymethylcytosine or 5hmC), and simultaneous gene expression in cultured human lymphoblastoid cells. Our results indicate that simulated microgravity induced alterations in the methylome (similar to 60% of the differentially methylated regions or DMRs are hypomethylated and similar to 92% of the differentially hydroxymethylated regions or DHMRs are hyperhydroxymethylated). Simulated microgravity also induced differential expression in 370 transcripts that were associated with crucial biological processes such as oxidative stress response, carbohydrate metabolism and regulation of transcription. While we were not able to obtain any global trend correlating the changes of methylation/hydroxylation with gene expression, we have been able to profile the simulated microgravity induced changes of 5mC over some of the differentially expressed genes that includes five genes undergoing differential methylation over their promoters and twenty five genes undergoing differential methylation over their gene-bodies. To the best of our knowledge, this is the first NGS-based study to profile epigenomic patterns induced by short time exposure of simulated microgravity and we believe that our findings can be a valuable resource for future explorations. C1 [Chowdhury, Basudev] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Chowdhury, Basudev; Lossie, Amy C.; Irudayaraj, Joseph] Purdue Univ, Bindley Biosci Ctr, Discovery Pk, W Lafayette, IN 47907 USA. [Wang, Zhiping; Liu, Yunlong] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Wang, Zhiping; Liu, Yunlong] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA. [Thimmapuram, Jyothi] Purdue Univ, Bioinformat Core, W Lafayette, IN 47907 USA. [Lossie, Amy C.] Purdue Univ, Dept Anim Sci, W Lafayette, IN 47907 USA. [Irudayaraj, Joseph] Purdue Univ, Dept Agr & Biol Engn, W Lafayette, IN 47907 USA. [Lossie, Amy C.] NIH, Off Behav & Social Sci Res, Bldg 10, Bethesda, MD 20892 USA. RP Irudayaraj, J (reprint author), Purdue Univ, Bindley Biosci Ctr, Discovery Pk, W Lafayette, IN 47907 USA.; Thimmapuram, J (reprint author), Purdue Univ, Bioinformat Core, W Lafayette, IN 47907 USA.; Irudayaraj, J (reprint author), Purdue Univ, Dept Agr & Biol Engn, W Lafayette, IN 47907 USA. EM jyothit@purdue.edu; josephi@purdue.edu FU NASA [NNX12AN09G]; NIH, NCI, Cancer Prevention Internship Program [R25CA128770]; Indiana CTSI [TR000006]; W.M. Keck Foundation; Purdue Center for Cancer Research [P30CA023168]; National Aeronautics and Space Administration (NASA) [NNX12AN09G]; National Institute of Health (NIH), National Cancer Institute (NCI), Cancer Prevention Internship Program [R25CA128770]; Indiana Clinical and Translational Sciences Institute (CTSI) [TR000006] FX The authors would like to acknowledge the following agencies for their support in funding this study: a) NASA (NNX12AN09G); b) NIH, NCI R25CA128770 Cancer Prevention Internship Program; c) Indiana CTSI (TR000006); d) W.M. Keck Foundation; e) Purdue Center for Cancer Research (P30CA023168). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We would like to thank the National Aeronautics and Space Administration (NASA) task "Defining Epigenetic Programming During Flight Expeditions in Differentiating Embryonic Stem Cells" (NNX12AN09G) for the funding. Partial support provided by the W. M. Keck Foundation; National Institute of Health (NIH), National Cancer Institute (NCI) R25CA128770 Cancer Prevention Internship Program; Indiana Clinical and Translational Sciences Institute (CTSI) (TR000006) and Purdue Center for Cancer Research (P30CA023168) is appreciated. We thank Dr. Phillip Miguel for generating the NGS data and Dr. Hongyu Gao for submitting the Sequencing data in NCBI GEO. NR 74 TC 2 Z9 2 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 28 PY 2016 VL 11 IS 1 AR e0147514 DI 10.1371/journal.pone.0147514 PG 29 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9GF UT WOS:000369528400031 PM 26820575 ER PT J AU Tamura, MK Vittinghoff, E Yang, JR Go, AS Seliger, SL Kusek, JW Lash, J Cohen, DL Simon, J Batuman, V Ordonez, J Makos, G Yaffe, K AF Tamura, Manjula Kurella Vittinghoff, Eric Yang, Jingrong Go, Alan S. Seliger, Stephen L. Kusek, John W. Lash, James Cohen, Debbie L. Simon, James Batuman, Vecihi Ordonez, Juan Makos, Gail Yaffe, Kristine TI Anemia and risk for cognitive decline in chronic kidney disease SO BMC NEPHROLOGY LA English DT Article DE Cognitive decline; CKD; Anemia ID CHRONIC RENAL-INSUFFICIENCY; NUTRITION EXAMINATION SURVEY; OLDER-ADULTS FINDINGS; 3RD NATIONAL-HEALTH; DEMENTIA; IMPAIRMENT AB Background: Anemia is common among patients with chronic kidney disease (CKD) but its health consequences are poorly defined. The aim of this study was to determine the relationship between anemia and cognitive decline in older adults with CKD. Methods: We studied a subgroup of 762 adults age >= 55 years with CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) study. Anemia was defined according to the World Health Organization criteria (hemoglobin <13 g/dL for men and <12 g/dL for women). Cognitive function was assessed annually with a battery of six tests. We used logistic regression to determine the association between anemia and baseline cognitive impairment on each test, defined as a cognitive score more than one standard deviation from the mean, and mixed effects models to determine the relation between anemia and change in cognitive function during follow-up after adjustment for demographic and clinical characteristics. Results: Of 762 participants with mean estimated glomerular filtration rate of 42.7 +/- 16.4 ml/min/1.73 m(2), 349 (46 %) had anemia. Anemia was not independently associated with baseline cognitive impairment on any test after adjustment for demographic and clinical characteristics. Over a median 2.9 (IQR 2.6-3.0) years of follow-up, there was no independent association between anemia and change in cognitive function on any of the six cognitive tests. Conclusions: Among older adults with CKD, anemia was not independently associated with baseline cognitive function or decline. C1 [Tamura, Manjula Kurella] VA Palo Alto Geriatr Res & Educ Clin Ctr, 3801 Miranda Ave, Palo Alto, CA 94304 USA. [Tamura, Manjula Kurella] Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. [Vittinghoff, Eric; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yang, Jingrong; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Seliger, Stephen L.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Kusek, John W.] NIDDK, Bethesda, MD 20892 USA. [Lash, James] Univ Illinois, Dept Med, Chicago, IL USA. [Cohen, Debbie L.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Simon, James] Cleveland Clin, Glickman Urol & Kidney Inst, Dept Nephrol & Hypertens, Cleveland, OH 44106 USA. [Batuman, Vecihi] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Ordonez, Juan] Kaiser Permanente No Calif, Div Nephrol, Oakland, CA USA. [Makos, Gail] St John Providence Med Ctr, Detroit, MI USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Go, Alan S.; Kusek, John W.; Lash, James] CRIC Study Investigators, Philadelphia, PA USA. RP Tamura, MK (reprint author), VA Palo Alto Geriatr Res & Educ Clin Ctr, 3801 Miranda Ave, Palo Alto, CA 94304 USA.; Tamura, MK (reprint author), Stanford Univ, Sch Med, Div Nephrol, Palo Alto, CA 94304 USA. EM mktamura@stanford.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902]; University of Pennsylvania [CTRC CTSA UL1 RR-024134]; Johns Hopkins University [UL1 RR-025005]; University of Maryland [GCRC M01 RR-16500]; Clinical and Translational Science Collaborative of Cleveland; National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health [UL1TR000439]; NIH roadmap for Medical Research; Michigan Institute for Clinical and Health Research (MICHR) [UL1RR024986]; University of Illinois at Chicago [CTSA UL1RR029879]; Tulane University Translational Research in Hypertension and Renal Biology [P30GM103337]; Kaiser NIH/NCRR UCSF-CTSI [UL1 RR-024131]; NIDDK [R01DK069406] FX Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, and U01DK060902). In addition, this work was supported in part by: the University of Pennsylvania CTRC CTSA UL1 RR-024134, Johns Hopkins University UL1 RR-025005, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1RR024986, University of Illinois at Chicago CTSA UL1RR029879, Tulane University Translational Research in Hypertension and Renal Biology P30GM103337, Kaiser NIH/NCRR UCSF-CTSI UL1 RR-024131. The CRIC COG study is supported by R01DK069406 from the NIDDK. NR 24 TC 2 Z9 2 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JAN 28 PY 2016 VL 17 AR 13 DI 10.1186/s12882-016-0226-6 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA DC3XQ UT WOS:000369153500001 ER PT J AU Roseberry, TK Lee, AM Lalive, AL Wilbrecht, L Bonci, A Kreitzer, AC AF Roseberry, Thomas K. Lee, A. Moses Lalive, Arnaud L. Wilbrecht, Linda Bonci, Antonello Kreitzer, Anatol C. TI Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia SO CELL LA English DT Article ID PEDUNCULOPONTINE TEGMENTAL NUCLEUS; SUPERIOR COLLICULUS; PROJECTION NEURONS; RETICULAR-FORMATION; INDIRECT PATHWAYS; BEHAVIORAL STATE; MOTOR BEHAVIORS; RAT; ACTIVATION; STIMULATION AB The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions. C1 [Roseberry, Thomas K.; Lee, A. Moses; Lalive, Arnaud L.; Kreitzer, Anatol C.] Gladstone Inst, San Francisco, CA 94158 USA. [Roseberry, Thomas K.; Lee, A. Moses; Kreitzer, Anatol C.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA. [Lee, A. Moses; Kreitzer, Anatol C.] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94158 USA. [Wilbrecht, Linda] Univ Calif Berkeley, Dept Psychol, 3210 Tolman Hall, Berkeley, CA 94720 USA. [Bonci, Antonello] NIDA, Intramural Res Program, Synapt Plast Sect, Baltimore, MD 21224 USA. [Bonci, Antonello] Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Bonci, Antonello] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. [Kreitzer, Anatol C.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA. [Kreitzer, Anatol C.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. RP Kreitzer, AC (reprint author), Gladstone Inst, San Francisco, CA 94158 USA.; Kreitzer, AC (reprint author), Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA.; Kreitzer, AC (reprint author), Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94158 USA.; Kreitzer, AC (reprint author), Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA.; Kreitzer, AC (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. EM akreitzer@gladstone.ucsf.edu FU NIH [NS064984, P01 DA010154, F31 NS092253, 5T32GM007618-38, RR018928]; Swiss National Science Foundation; State of California; NIDA intramural program FX We thank Delanie Schulte for assistance with genotyping, histology, and microscopy and the A.C.K. laboratory for comments on the manuscript. This work was funded by NIH R01 NS064984 and P01 DA010154 (to A.C.K.), F31 NS092253 (to T.K.R.), 5T32GM007618-38 (to A.M.L.), RR018928 (to the Gladstone Institutes), a grant from the Swiss National Science Foundation (to A.L.L.), funds from the State of California (to L.W.), and an NIDA intramural program (to A.B.). NR 58 TC 15 Z9 15 U1 4 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD JAN 28 PY 2016 VL 164 IS 3 BP 526 EP 537 DI 10.1016/j.cell.2015.12.037 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DC0KU UT WOS:000368906800021 PM 26824660 ER PT J AU Cheng, JJ Giguere, PM Schmerberg, CM Pogorelov, VM Rodriguiz, RM Huang, XP Zhu, H McCorvy, JD Wetsel, WC Roth, BL Kozikowski, AP AF Cheng, Jianjun Giguere, Patrick M. Schmerberg, Claire M. Pogorelov, Vladimir M. Rodriguiz, Ramona M. Huang, Xi-Ping Zhu, Hu McCorvy, John D. Wetsel, William C. Roth, Bryan L. Kozikowski, Alan P. TI Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ATYPICAL ANTIPSYCHOTIC-DRUGS; RECEPTOR AGONISTS; MEDICINAL CHEMISTRY; WEIGHT-GAIN; SCHIZOPHRENIA; LIGANDS; DESIGN; POTENT; IDENTIFICATION; MEDICATIONS AB A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia. C1 [Cheng, Jianjun; Kozikowski, Alan P.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Drug Discovery Program, Chicago, IL 60612 USA. [Giguere, Patrick M.; Huang, Xi-Ping; Zhu, Hu; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Dept Pharmacol, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Giguere, Patrick M.; Huang, Xi-Ping; Zhu, Hu; McCorvy, John D.; Roth, Bryan L.] Univ N Carolina, Chapel Hill Med Sch, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA. [Schmerberg, Claire M.; Pogorelov, Vladimir M.; Rodriguiz, Ramona M.; Wetsel, William C.] Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Giguere, Patrick M.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1H 8M5, Canada. [Schmerberg, Claire M.] Catalent Pharma Solut, 160N Pharma Dr, Morrisville, NC 27560 USA. RP Kozikowski, AP (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Drug Discovery Program, Chicago, IL 60612 USA. EM kozikowa@uic.edu FU National Institute of Mental Health (NIMH) [R01MH99993]; Psychoactive Drug Screening Program (PDSP) [HHSN-271-2013-00017-C] FX Financial support from the National Institute of Mental Health (NIMH) (no. R01MH99993) and Psychoactive Drug Screening Program (PDSP, Contract no. HHSN-271-2013-00017-C) is gratefully acknowledged. We thank Dr. Werner Tueckmantel for proofreading the manuscript and providing valuable suggestions. NR 45 TC 2 Z9 2 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JAN 28 PY 2016 VL 59 IS 2 BP 578 EP 591 DI 10.1021/acs.jmedchem.5b01153 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DC3JN UT WOS:000369115700007 PM 26704965 ER PT J AU Zhou, Y Ma, J Lin, XY Huang, XP Wu, KC Huang, N AF Zhou, Yu Ma, Jing Lin, Xingyu Huang, Xi-Ping Wu, Kaichun Huang, Niu TI Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MOLECULAR DOCKING; VISCERAL HYPERSENSITIVITY; 5-HT2B RECEPTORS; LIGAND DISCOVERY; FORCE-FIELD; SEROTONIN RECEPTORS; DRUG DISCOVERY; BINDING-SITE; MODEL; PREDICTION AB Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC50 value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure-activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT2B antagonists for the treatment of IBS. C1 [Zhou, Yu; Lin, Xingyu; Huang, Niu] Natl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China. [Zhou, Yu] Tsinghua Univ, Sch Med, Dept Pharmacol & Pharmaceut Sci, Beijing 100084, Peoples R China. [Ma, Jing; Wu, Kaichun] Fourth Mil Med Univ, State Key Lab Canc Biol, 127 West Changle Rd, Xian 710032, Shaanxi Provinc, Peoples R China. [Ma, Jing; Wu, Kaichun] Fourth Mil Med Univ, Xijing Hosp Digest Dis, 127 West Changle Rd, Xian 710032, Shaanxi Provinc, Peoples R China. [Huang, Xi-Ping] Univ N Carolina, NIMH PDSP, Dept Pharmacol, Chapel Hill, NC 27759 USA. RP Huang, N (reprint author), Natl Inst Biol Sci, 7 Sci Pk Rd,Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China.; Wu, KC (reprint author), Fourth Mil Med Univ, State Key Lab Canc Biol, 127 West Changle Rd, Xian 710032, Shaanxi Provinc, Peoples R China.; Wu, KC (reprint author), Fourth Mil Med Univ, Xijing Hosp Digest Dis, 127 West Changle Rd, Xian 710032, Shaanxi Provinc, Peoples R China. EM kaicwu@fmmu.edu.cn; huangniu@nibs.ac.cn FU Chinese Ministry of Science and Technology "973" Grant [2014CB849802]; National Natural Science Foundation of China [81470862]; AstraZeneca Open Innovation Postdoctoral Research Fellowship; China Postdoctoral Science Foundation [2015M570948]; Beijing Postdoctoral Research Foundation [2015ZZ-118]; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) [HHSN-271-2013-00017-C] FX Financial support from the Chinese Ministry of Science and Technology "973" Grant (2014CB849802) and the National Natural Science Foundation of China (81470862) (to N.H.) is gratefully acknowledged. Y.Z. was supported by the AstraZeneca Open Innovation Postdoctoral Research Fellowship, the China Postdoctoral Science Foundation (2015M570948), and the Beijing Postdoctoral Research Foundation (2015ZZ-118). X-P.H. was supported by the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP, HHSN-271-2013-00017-C) directed by Bryan L. Roth (MD, Ph.D.) at the University of North Carolina at Chapel Hill and Program Officer Jamie Driscoll at NIMH (Bethesda, MD). Computational support was provided by the Supercomputing Center of the Chinese Academy of Sciences (SCCAS). We also thank the Chemical Center at NIBS for providing the in-house screening compounds. NR 68 TC 4 Z9 4 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD JAN 28 PY 2016 VL 59 IS 2 BP 707 EP 720 DI 10.1021/acs.jmedchem.5b01631 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DC3JN UT WOS:000369115700015 PM 26700945 ER PT J AU Goldstein, D Moskowitz, AJ Gelijns, AC Ailawadi, G Parides, MK Perrault, LP Hung, JW Voisine, P Dagenais, F Gillinov, AM Thourani, V Argenziano, M Gammie, JS Mack, M Demers, P Atluri, P Rose, EA O'Sullivan, K Williams, DL Bagiella, E Michler, RE Weisel, RD Miller, MA Geller, NL Taddei-Peters, WC Smith, PK Moquete, E Overbey, JR Kron, IL O'Gara, PT Acker, MA AF Goldstein, D. Moskowitz, A. J. Gelijns, A. C. Ailawadi, G. Parides, M. K. Perrault, L. P. Hung, J. W. Voisine, P. Dagenais, F. Gillinov, A. M. Thourani, V. Argenziano, M. Gammie, J. S. Mack, M. Demers, P. Atluri, P. Rose, E. A. O'Sullivan, K. Williams, D. L. Bagiella, E. Michler, R. E. Weisel, R. D. Miller, M. A. Geller, N. L. Taddei-Peters, W. C. Smith, P. K. Moquete, E. Overbey, J. R. Kron, I. L. O'Gara, P. T. Acker, M. A. CA CTSN TI Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEART-FAILURE; VALVE ANNULOPLASTY; DILATED CARDIOMYOPATHY; MYOCARDIAL-INFARCTION; RING ANNULOPLASTY; REPAIR; REPLACEMENT; PREDICTORS; RECURRENCE; MECHANISM AB BACKGROUND In a randomized trial comparing mitral-valve repair with mitral-valve replacement in patients with severe ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI), survival, or adverse events at 1 year after surgery. However, patients in the repair group had significantly more recurrences of moderate or severe mitral regurgitation. We now report the 2-year outcomes of this trial. METHODS We randomly assigned 251 patients to mitral-valve repair or replacement. Patients were followed for 2 years, and clinical and echocardiographic outcomes were assessed. RESULTS Among surviving patients, the mean (+/- SD) 2-year LVESVI was 52.6 +/- 27.7 ml per square meter of body-surface area with mitral-valve repair and 60.6 +/- 39.0 ml per square meter with mitral-valve replacement (mean changes from baseline, -9.0 ml per square meter and -6.5 ml per square meter, respectively). Two-year mortality was 19.0% in the repair group and 23.2% in the replacement group (hazard ratio in the repair group, 0.79; 95% confidence interval, 0.46 to 1.35; P=0.39). The rank-based assessment of LVESVI at 2 years (incorporating deaths) showed no significant between-group difference (z score = -1.32, P=0.19). The rate of recurrence of moderate or severe mitral regurgitation over 2 years was higher in the repair group than in the replacement group (58.8% vs. 3.8%, P < 0.001). There were no significant between-group differences in rates of serious adverse events and overall readmissions, but patients in the repair group had more serious adverse events related to heart failure (P=0.05) and cardiovascular readmissions (P=0.01). On the Minnesota Living with Heart Failure questionnaire, there was a trend toward greater improvement in the replacement group (P=0.07). CONCLUSIONS In patients undergoing mitral-valve repair or replacement for severe ischemic mitral regurgitation, we observed no significant between-group difference in left ventricular reverse remodeling or survival at 2 years. Mitral regurgitation recurred more frequently in the repair group, resulting in more heart-failure-related adverse events and cardiovascular admissions. C1 [Goldstein, D.; Michler, R. E.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Cardiothorac Surg, New York, NY USA. [Moskowitz, A. J.; Gelijns, A. C.; Parides, M. K.; O'Sullivan, K.; Williams, D. L.; Bagiella, E.; Moquete, E.; Overbey, J. R.] Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, Int Ctr Hlth Outcomes & Innovat Res, New York, NY 10029 USA. [Rose, E. A.] Icahn Sch Med Mt Sinai, Cardiovasc Inst, New York, NY USA. [Argenziano, M.] Columbia Univ, Coll Phys & Surg, Dept Surg, Div Cardiothorac Surg, New York, NY USA. [Ailawadi, G.; Kron, I. L.] Univ Virginia, Sch Med, Div Thorac & Cardiovasc Surg, Charlottesville, VA 22908 USA. [Perrault, L. P.; Demers, P.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Voisine, P.; Dagenais, F.] Inst Univ Cardiol Quebec, Hop Laval, Quebec City, PQ, Canada. [Weisel, R. D.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Weisel, R. D.] Univ Toronto, Div Cardiovasc Surg, Toronto Gen Hosp, Univ Hlth Network, Toronto, ON, Canada. [Weisel, R. D.] Univ Toronto, Div Cardiac Surg, Toronto, ON, Canada. [Hung, J. W.] Massachusetts Gen Hosp, Echocardiog Core Lab, Boston, MA 02114 USA. [O'Gara, P. T.] Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. [Gillinov, A. M.] Cleveland Clin Fdn, Dept Thorac & Cardiovasc Surg, Cleveland, OH USA. [Thourani, V.] Emory Univ, Sch Med, Div Cardiothorac Surg, Clin Res Unit, Atlanta, GA 30322 USA. [Gammie, J. S.] Univ Maryland, Baltimore, MD 21201 USA. [Miller, M. A.; Taddei-Peters, W. C.] NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA. [Geller, N. L.] NHLBI, Off Biostat Res, Bldg 10, Bethesda, MD 20892 USA. [Mack, M.] Baylor Res Inst, Dallas, TX USA. [Atluri, P.; Acker, M. A.] Univ Penn, Sch Med, Div Cardiovasc Surg, Dept Surg, Philadelphia, PA 19104 USA. [Smith, P. K.] Duke Univ, Med Ctr, Dept Surg, Div Cardiovasc & Thorac Surg, Durham, NC 27710 USA. RP Gelijns, AC (reprint author), Icahn Sch Med Mt Sinai, Dept Populat Hlth Sci & Policy, 1 Gustave L Levy Pl,Box 1077, New York, NY 10029 USA. EM annetine.gelijns@mssm.edu OI Moskowitz, Alan/0000-0002-4412-9450; Browndyke, Jeffrey/0000-0002-8573-7073 FU National Institutes of Health and Canadian Institutes of Health Research FX Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00807040. NR 43 TC 49 Z9 50 U1 3 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 28 PY 2016 VL 374 IS 4 BP 344 EP 353 DI 10.1056/NEJMoa1512913 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DB8IJ UT WOS:000368760100008 PM 26550689 ER PT J AU Volkow, ND Koob, GF McLellan, AT AF Volkow, Nora D. Koob, George F. McLellan, A. Thomas TI Neurobiologic Advances from the Brain Disease Model of Addiction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SUBSTANCE USE; NUCLEUS-ACCUMBENS; COCAINE ADDICTION; SENSATION SEEKING; MENTAL-HEALTH; UNITED-STATES; PRIMARY-CARE; ALCOHOL-USE; DOPAMINE; REWARD C1 [Volkow, Nora D.] NIDA, 6001 Execut Bldg,Rm 5274, Bethesda, MD 20892 USA. [Koob, George F.] NIAAA, Bethesda, MD USA. [McLellan, A. Thomas] Treatment Res Inst, Philadelphia, PA USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Bldg,Rm 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov RI koob, george/P-8791-2016 NR 58 TC 29 Z9 29 U1 12 U2 46 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 28 PY 2016 VL 374 IS 4 BP 363 EP 371 DI 10.1056/NEJMra1511480 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DB8IJ UT WOS:000368760100010 PM 26816013 ER PT J AU Taichman, DB Backus, J Baethge, C Bauchner, H de Leeuw, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T Haileamlak, A James, A Laine, C Peiperl, L Pinborg, A Sahni, P Wu, SN AF Taichman, Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuw, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish Haileamlak, Abraham James, Astrid Laine, Christine Peiperl, Larry Pinborg, Anja Sahni, Peush Wu, Sinan TI Sharing Clinical Trial Data - A Proposal from the International Committee of Medical Journal Editors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Backus, Joyce] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. OI Groves, Trish/0000-0001-7915-6419 NR 1 TC 44 Z9 44 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 28 PY 2016 VL 374 IS 4 BP 384 EP 386 DI 10.1056/NEJMe1515172 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DB8IJ UT WOS:000368760100014 PM 26786954 ER PT J AU Elkahloun, AG Hafko, R Saavedra, JM AF Elkahloun, Abdel G. Hafko, Roman Saavedra, Juan M. TI An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease SO ALZHEIMERS RESEARCH & THERAPY LA English DT Article DE Alzheimer's disease; Neurodegenerative disorders; Glutamate excitotoxicity; Neuroprotection; Angiotensin II receptor blockers; IPA analysis; GEO database; GSEA ID ANGIOTENSIN RECEPTOR BLOCKERS; FACTOR-KAPPA-B; SPONTANEOUSLY HYPERTENSIVE-RATS; APOLIPOPROTEIN-E PROTECTS; INNATE IMMUNE-RESPONSE; TRAUMATIC BRAIN-INJURY; METHYL-D-ASPARTATE; AMYLOID-BETA; AT(1) RECEPTOR; INFLAMMATORY RESPONSE AB Background: Alzheimer's disease is the most frequent age-related dementia, and is currently without treatment. To identify possible targets for early therapeutic intervention we focused on glutamate excitotoxicity, a major early pathogenic factor, and the effects of candesartan, an angiotensin receptor blocker of neuroprotective efficacy in cell cultures and rodent models of Alzheimer's disease. The overall goal of the study was to determine whether gene analysis of drug effects in a primary neuronal culture correlate with alterations in gene expression in Alzheimer's disease, thus providing further preclinical evidence of beneficial therapeutic effects. Methods: Primary neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. We performed genome-wide expression profile analysis and data evaluation by ingenuity pathway analysis and gene set enrichment analysis, compared with alterations in gene expression from two independent published datasets identified by microarray analysis of postmortem hippocampus from Alzheimer's disease patients. Preferential expression in cerebrovascular endothelial cells or neurons was analyzed by comparison to published gene expression in these cells isolated from human cortex by laser capture microdissection. Results: Candesartan prevented glutamate upregulation or downregulation of several hundred genes in our cultures. Ingenuity pathway analysis and gene set enrichment analysis revealed that inflammation, cardiovascular disease and diabetes signal transduction pathways and amyloid beta metabolism were major components of the neuronal response to glutamate excitotoxicity. Further analysis showed associations of glutamate-induced changes in the expression of several hundred genes, normalized by candesartan, with similar alterations observed in hippocampus from Alzheimer's disease patients. Gene analysis of neurons and cerebrovascular endothelial cells obtained by laser capture microdissection revealed that genes up- and downregulated by glutamate were preferentially expressed in endothelial cells and neurons, respectively. Conclusions: Our data may be interpreted as evidence of direct candesartan neuroprotection beyond its effects on blood pressure, revealing common and novel disease mechanisms that may underlie the in vitro gene alterations reported here and glutamate-induced cell injury in Alzheimer's disease. Our observations provide novel evidence for candesartan neuroprotection through early molecular mechanisms of injury in Alzheimer's disease, supporting testing this compound in controlled clinical studies in the early stages of the illness. C1 [Elkahloun, Abdel G.] NHGRI, Comparat Genom & Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Hafko, Roman; Saavedra, Juan M.] NIMH, Sect Pharmacol, NIH, Bethesda, MD 20892 USA. [Saavedra, Juan M.] Georgetown Univ, Med Ctr, Dept Pharmacol & Physiol, Med Dent SE402, 3900 Reservoir Rd, Washington, DC 20057 USA. RP Saavedra, JM (reprint author), NIMH, Sect Pharmacol, NIH, Bethesda, MD 20892 USA.; Saavedra, JM (reprint author), Georgetown Univ, Med Ctr, Dept Pharmacol & Physiol, Med Dent SE402, 3900 Reservoir Rd, Washington, DC 20057 USA. EM jms522@georgetown.edu FU National Human Genome Research Institute, National Institutes of Health, Bethesda [MD 20892]; National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA [MH 002762-16]; Division of Intramural Research Programs FX AGE was supported by the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892. RH and JMS were supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA (MH 002762-16). NR 115 TC 2 Z9 2 U1 6 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1758-9193 J9 ALZHEIMERS RES THER JI Alzheimers Res. Ther. PD JAN 28 PY 2016 VL 8 AR 5 DI 10.1186/s13195-015-0167-5 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA DB8HV UT WOS:000368758700001 PM 26822027 ER PT J AU Machner, MP Storz, G AF Machner, Matthias P. Storz, Gisela TI Small RNA with a large impact SO NATURE LA English DT Editorial Material ID EPITHELIAL-CELLS; GENE-EXPRESSION; INFECTION C1 [Machner, Matthias P.; Storz, Gisela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. RP Machner, MP; Storz, G (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Mol & Cellular Biol, Bethesda, MD 20892 USA. EM machnerm@mail.nih.gov; storzg@mail.nih.gov NR 9 TC 0 Z9 0 U1 5 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 28 PY 2016 VL 529 IS 7587 BP 472 EP 473 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB7DD UT WOS:000368673800023 PM 26789251 ER PT J AU Tang, WK Xia, D AF Tang, Wai Kwan Xia, Di TI Role of the D1-D2 Linker of Human VCP/p97 in the Asymmetry and ATPase Activity of the D1-domain SO SCIENTIFIC REPORTS LA English DT Article ID AAA ATPASE; P97/VALOSIN-CONTAINING PROTEIN; CRYSTAL-STRUCTURE; P97 MUTANTS; P97/VCP; COMMUNICATION; HYDROLYSIS; MECHANISM; CHAPERONE; HOMOLOGY AB Human AAA(+) protein p97 consists of an N-domain and two tandem ATPase domains D1 and D2, which are connected by the N-D1 and the D1-D2 linkers. Inclusion of the D1-D2 linker, a 22-amino acid peptide, at the end of p97 N-D1 truncate has been shown to activate ATP hydrolysis of its D1-domain, although the mechanism of activation remains unclear. Here, we identify the N-terminal half of this linker, highly conserved from human to fungi, is essential for the ATPase activation. By analyzing available crystal structures, we observed that the D1-D2 linker is capable of inducing asymmetry in subunit association into a p97 hexamer. This observation is reinforced by two new crystal structures, determined in the present work. The effect of D1-D2 linker on the ATPase activity of the D1-domain is correlated to the side-chain conformation of residue R359, a trans-acting arginine-finger residue essential for ATP hydrolysis of the D1-domain. The activation in D1-domain ATPase activity by breaking perfect six-fold symmetry implies functional importance of asymmetric association of p97 subunits, the extent of which can be determined quantitatively by the metric Asymmetric Index. C1 [Tang, Wai Kwan; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM xiad@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX The authors wish to thank George Leiman for editorial assistance. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 33 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 28 PY 2016 VL 6 AR 20037 DI 10.1038/srep20037 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB8RV UT WOS:000368785200001 PM 26818443 ER PT J AU Kumar, JS Jenkins, LMM Gottesman, MM Hall, MD AF Kumar, Jeyan S. Jenkins, Lisa M. Miller Gottesman, Michael M. Hall, Matthew D. TI The Drug Excipient Cyclodextrin Interacts With D-Luciferin and Interferes With Bioluminescence Imaging SO MOLECULAR IMAGING LA English DT Article DE cyclodextrin; D-luciferin; bioluminescence; drug carriers; drug transporters ID BETA-CYCLODEXTRIN; P-GLYCOPROTEIN; EFFLUX; BIOAVAILABILITY; ENHANCEMENT; COMPLEXES; FUTURE; ABCG2 AB Cyclodextrins are well-characterized, barrel-shaped molecules that can solubilize organic small molecules in aqueous solution via host-guest interactions. As such, cyclodextrins are used as excipients for experimental therapeutics in vivo. We observed unanticipated modifications to bioluminescence imaging (BLI) signal intensity when 2-hydroxy-propyl-beta-cyclodextrin (HPCD) was coinjected as an excipient. We hypothesized that HPCD binds D-luciferin and interferes with the BLI signal. Using luciferase-expressing cell lines, we showed that HPCD lowers the BLI signal in a concentration-dependent manner. Flow cytometry revealed that HPCD resulted in reduced cellular accumulation of D-luciferin, and mass spectrometry revealed D-luciferin HPCD species, confirming a direct interaction. In vivo imaging using a luciferase mouse model demonstrated that HPCD reduced luciferin-mediated BLI compared to luciferin alone. The implications of using HPCD as an excipient in BLI studies are discussed. C1 [Kumar, Jeyan S.; Jenkins, Lisa M. Miller; Gottesman, Michael M.; Hall, Matthew D.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. [Hall, Matthew D.] NIH, NCATS Chem Genom Ctr, Rockville, MD USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU National Institutes of Health, National Cancer Institute FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. NR 24 TC 0 Z9 0 U1 2 U2 2 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 EI 1536-0121 J9 MOL IMAGING JI Mol. Imaging PD JAN 27 PY 2016 VL 15 DI 10.1177/1536012115625225 PG 7 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA DN0AN UT WOS:000376726900001 ER PT J AU Wasson, JA Simon, AK Myrick, DA Wolf, G Driscoll, S Pfaff, SL Macfarlan, TS Katz, DJ AF Wasson, Jadiel A. Simon, Ashley K. Myrick, Dexter A. Wolf, Gernot Driscoll, Shawn Pfaff, Samuel L. Macfarlan, Todd S. Katz, David J. TI Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally SO ELIFE LA English DT Article ID PREIMPLANTATION MOUSE EMBRYO; DE-NOVO METHYLATION; EPIGENETIC MEMORY; GENOME ACTIVATION; DNA METHYLATION; GENE-EXPRESSION; NUCLEAR TRANSFER; CRE RECOMBINASE; LSD1; TRANSCRIPTION AB Somatic cell nuclear transfer has established that the oocyte contains maternal factors with epigenetic reprogramming capacity. Yet the identity and function of these maternal factors during the gamete to embryo transition remains poorly understood. In C. elegans, LSD1/KDM1A enables this transition by removing H3K4me2 and preventing the transgenerational inheritance of transcription patterns. Here we show that loss of maternal LSD1/KDM1A in mice results in embryonic arrest at the 1-2 cell stage, with arrested embryos failing to undergo the maternal-to zygotic transition. This suggests that LSD1/KDM1A maternal reprogramming is conserved. Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults. These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes. These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development. C1 [Wasson, Jadiel A.; Myrick, Dexter A.; Katz, David J.] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA USA. [Wasson, Jadiel A.; Myrick, Dexter A.] Emory Univ, Grad Div Biol & Biomed Sci, Atlanta, GA 30322 USA. [Simon, Ashley K.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Wolf, Gernot; Macfarlan, Todd S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Driscoll, Shawn; Pfaff, Samuel L.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Driscoll, Shawn; Pfaff, Samuel L.] Salk Inst Biol Studies, Gene Express Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. RP Katz, DJ (reprint author), Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA USA.; Macfarlan, TS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM macfarlan@nih.gov; djkatz@emory.edu FU National Science Foundation [IOS 1354998] FX National Science Foundation IOS 1354998 Jadiel A Wasson David J Katz; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. NR 52 TC 8 Z9 8 U1 2 U2 5 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 27 PY 2016 VL 5 AR e08848 DI 10.7554/eLife.08848 PG 25 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DI8YE UT WOS:000373787600001 ER PT J AU Muterko, A Kalendar, R Salina, E AF Muterko, Alexandr Kalendar, Ruslan Salina, Elena TI Novel alleles of the VERNALIZATION1 genes in wheat are associated with modulation of DNA curvature and flexibility in the promoter region SO BMC PLANT BIOLOGY LA English DT Article DE Cereal; Genetic variation; Flowering time; Vernalization requirement; Wheat; DNA curvature; VRN-box; VRN1 genes; Promoter; New alleles; Anomalous migration ID SPRING GROWTH HABIT; TRITICUM-AESTIVUM L.; GENOME-WIDE ANALYSIS; TATA-BOX; TETRAPLOID WHEAT; WINTER-WHEAT; MOLECULAR CHARACTERIZATION; GEOGRAPHICAL VARIATION; REGULATORY ELEMENTS; POLYACRYLAMIDE-GELS AB Background: In wheat, the vernalization requirement is mainly controlled by the VRN genes. Different species of hexaploid and tetraploid wheat are widely used as genetic source for new mutant variants and alleles for fundamental investigations and practical breeding programs. In this study, VRN-A1 and VRN-B1 were analysed for 178 accessions representing six tetraploid wheat species (Triticum dicoccoides, T. dicoccum, T. turgidum, T. polonicum, T. carthlicum, T. durum) and five hexaploid species (T. compactum, T. sphaerococcum, T. spelta, T. macha, T. vavilovii). Results: Novel allelic variants in the promoter region of VRN-A1 and VRN-B1 were identified based on the change in curvature and flexibility of the DNA molecules. The new variants of VRN-A1 (designated as Vrn-A1a.2, Vrn-A1b. 2 - Vrn-A1b. 6 and Vrn-A1i) were found to be widely distributed in hexaploid and tetraploid wheat, and in fact were predominant over the known VRN-A1 alleles. The greatest diversity of the new variants of VRN-B1 (designated as VRN-B1.f, VRN-B1.s and VRN-B1.m) was found in the tetraploid and some hexaploid wheat species. For the first time, minor differences within the sequence motif known as the VRN-box of VRN1 were correlated with wheat growth habit. Thus, vrn-A1b.3 and vrn-A1b.4 were revealed in winter wheat in contrast to Vrn-A1b. 2, Vrn-A1b. 5, Vrn-A1b.6 and Vrn-A1i. It was found that single nucleotide mutation in the VRN-box can influence the vernalization requirement and growth habit of wheat. Our data suggest that both the A-tract and C-rich segment within the VRN-box contribute to its functionality, and provide a new view of the hypothesised role of the VRN-box in regulating transcription of the VRN1 genes. Specifically, it is proposed that combination of mutations in this region can modulate vernalization sensitivity and flowering time of wheat. Conclusions: New allelic variants of the VRN-A1 and VRN-B1 genes were identified in hexaploid and tetraploid wheat. Mutations in A-tract and C-rich segments within the VRN-box of VRN-A1 are associated with modulation of the vernalization requirement and flowering time. New allelic variants will be useful in fundamental investigations into the regulation of VRN1 expression, and provide a valuable genetic resource for practical breeding of wheat. C1 [Muterko, Alexandr; Salina, Elena] Russian Acad Sci, Inst Cytol & Genet, Lab Plant Mol Genet & Cytogenet, Fed Res Ctr, Lavrentyeva Ave 10, Novosibirsk 630090, Russia. [Muterko, Alexandr] Natl Ctr Seed & Cultivar Invest, Dept Common & Mol Genet, Plant Breeding & Genet Inst, Ovidiopolskaya Rd 3, UA-65036 Odessa, Ukraine. [Kalendar, Ruslan] RSE Natl Ctr Biotechnol, Lab Plant Genom & Bioinformat, Sh Valikhanov 13-1, Astana 010000, Kazakhstan. [Kalendar, Ruslan] Univ Helsinki, Inst Biotechnol, MTT Plant Genom Lab, Bioctr 3, POB 65,Viikinkaari 1, Helsinki 00014, Finland. RP Muterko, A (reprint author), Russian Acad Sci, Inst Cytol & Genet, Lab Plant Mol Genet & Cytogenet, Fed Res Ctr, Lavrentyeva Ave 10, Novosibirsk 630090, Russia.; Muterko, A (reprint author), Natl Ctr Seed & Cultivar Invest, Dept Common & Mol Genet, Plant Breeding & Genet Inst, Ovidiopolskaya Rd 3, UA-65036 Odessa, Ukraine. EM muterko@gmail.com RI Kalendar, Ruslan/D-9751-2012; OI Kalendar, Ruslan/0000-0003-3986-2460; Muterko, Alexandr/0000-0002-9083-9162 FU Russian Scientific Foundation [14-14-00161] FX We are grateful to Carly Schramm for comments and English polishing in the manuscript. The analysis of the VRN-B1 promoter region in hexaploid and tetraploid wheat species and sequencing of the Vrn-A1b.6 and VRN-B1.m variants were supported by the Russian Scientific Foundation (Project No. 14-14-00161). NR 78 TC 4 Z9 4 U1 6 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2229 J9 BMC PLANT BIOL JI BMC Plant Biol. PD JAN 27 PY 2016 VL 16 SU 1 DI 10.1186/s12870-015-0691-2 PG 17 WC Plant Sciences SC Plant Sciences GA DD3IY UT WOS:000369816800007 PM 26822192 ER PT J AU Romagnoli, R Baraldi, PG Prencipe, F Lopez-Cara, C Rondanin, R Simoni, D Hamel, E Grimaudo, S Pipitone, RM Meli, M Tolomeo, M AF Romagnoli, Romeo Baraldi, Pier Giovanni Prencipe, Filippo Lopez-Cara, Carlota Rondanin, Riccardo Simoni, Daniele Hamel, Ernest Grimaudo, Stefania Pipitone, Rosaria Maria Meli, Maria Tolomeo, Manlio TI Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE STAT5 inhibitors; BCR/ABL expressing leukemia; Apoptosis; Structure-activity relationship; In vitro antiproliferative activity ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITORS; CONSTITUTIVE ACTIVATION; HEMATOPOIETIC-CELLS; BIOLOGICAL EVALUATION; ANTIMITOTIC AGENTS; TRANSCRIPTIONAL CONTROL; MOLECULAR TARGETS; CANCER-THERAPY AB Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative I as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation. (C) 2015 Elsevier Masson SAS. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Lopez-Cara, Carlota; Rondanin, Riccardo; Simoni, Daniele] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Grimaudo, Stefania; Pipitone, Rosaria Maria] Univ Palermo, Dipartimento Biomed Med Interna & Specialist, I-90125 Palermo, Italy. [Meli, Maria] Univ Palermo, Dipartimento Sci Promoz Salute & Materno Infantil, Area Farmacol, I-90125 Palermo, Italy. [Tolomeo, Manlio] Univ Palermo, Ctr Interdipartimentale Ric Oncol Clin, I-90125 Palermo, Italy. [Tolomeo, Manlio] Univ Palermo, Dipartimento Biomed Med Interna & Specialist, Sez Malattie Infett, I-90125 Palermo, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy. EM rmr@unife.it RI LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Baraldi, Pier Giovanni/B-7933-2017 OI LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; FU Intramural NIH HHS [Z99 CA999999] NR 58 TC 0 Z9 0 U1 9 U2 22 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD JAN 27 PY 2016 VL 108 BP 39 EP 52 DI 10.1016/j.ejmech.2015.11.022 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DC4LG UT WOS:000369191800005 PM 26629859 ER PT J AU Bailey, JA Bazavov, A Bernard, C Bouchard, CM Detar, C Du, DP El-Khadra, AX Foley, J Freeland, ED Gamiz, E Gottlieb, S Heller, UM Jain, RD Komijani, J Kronfeld, AS Laiho, J Levkova, L Liu, YZ Mackenzie, PB Meurice, Y Neil, ET Qiu, SW Simone, JN Sugar, R Toussaint, D Van de Water, RS Zhou, R AF Bailey, Jon A. Bazavov, A. Bernard, C. Bouchard, C. M. DeTar, C. Du, Daping El-Khadra, A. X. Foley, J. Freeland, E. D. Gamiz, E. Gottlieb, Steven Heller, U. M. Jain, R. D. Komijani, J. Kronfeld, A. S. Laiho, J. Levkova, L. Liu, Yuzhi Mackenzie, P. B. Meurice, Y. Neil, E. T. Qiu, Si-Wei Simone, J. N. Sugar, R. Toussaint, D. Van de Water, R. S. Zhou, Ran CA Fermilab Lattice & MILC TI B -> Kl(+)l(-) decay form factors from three-flavor lattice QCD SO PHYSICAL REVIEW D LA English DT Article ID CHIRAL PERTURBATION-THEORY; HEAVY-QUARK; GAUGE-THEORIES; MESON DECAYS; COMPUTATION; FERMIONS; SYMMETRY; PHYSICS; SCALE; SCET AB We compute the form factors for the B --> Kl(+)l(-) semileptonic decay process in lattice QCD using gauge-field ensembles with 2 + 1 flavors of sea quark, generated by the MILC Collaboration. The ensembles span lattice spacings from 0.12 to 0.045 fm and have multiple sea-quark masses to help control the chiral extrapolation. The asqtad improved staggered action is used for the light valence and sea quarks, and the clover action with the Fermilab interpretation is used for the heavy b quark. We present results for the form factors f(+)(q(2)), f(0)(q2), and f(T)(q2), where q(2) is the momentum transfer, together with a comprehensive examination of systematic errors. Lattice QCD determines the form factors for a limited range of q(2), and we use the model-independent z expansion to cover the whole kinematically allowed range. We present our final form-factor results as coefficients of the z expansion and the correlations between them, where the errors on the coefficients include statistical and all systematic uncertainties. We use this complete description of the form factors to test QCD predictions of the form factors at high and low q(2). C1 [Bailey, Jon A.] Seoul Natl Univ, Dept Phys & Astron, Seoul, South Korea. [Bazavov, A.] Brookhaven Natl Lab, Dept Phys, Upton, NY 11973 USA. [Bernard, C.; Komijani, J.] Washington Univ, Dept Phys, St Louis, MO 63110 USA. [Bouchard, C. M.] Ohio State Univ, Dept Phys, Columbus, OH 43210 USA. [DeTar, C.; Foley, J.; Levkova, L.; Qiu, Si-Wei] Univ Utah, Dept Phys & Astron, Salt Lake City, UT 84112 USA. [Du, Daping; Laiho, J.] Syracuse Univ, Dept Phys, Syracuse, NY 13244 USA. [El-Khadra, A. X.; Jain, R. D.] Univ Illinois, Dept Phys, Urbana, IL 61801 USA. [Freeland, E. D.] Art Inst Chicago, Sch Art Inst Chicago, Chicago, IL 60603 USA. [Gamiz, E.] Univ Granada, CAFPE, Granada, Spain. [Gamiz, E.] Univ Granada, Dept Fis Teor & Cosmos, Granada, Spain. [Gottlieb, Steven] Indiana Univ, Dept Phys, Bloomington, IN 47405 USA. [Heller, U. M.] Amer Phys Soc, New York, NY 11961 USA. [Kronfeld, A. S.; Mackenzie, P. B.; Simone, J. N.; Van de Water, R. S.; Zhou, Ran] Fermilab Natl Accelerator Lab, Batavia, IL 60510 USA. [Kronfeld, A. S.] Tech Univ Munich, Inst Adv Study, Garching, Germany. [Liu, Yuzhi; Neil, E. T.] Univ Colorado, Dept Phys, Boulder, CO 80309 USA. [Meurice, Y.] Univ Iowa, Dept Phys & Astron, Iowa City, IA 52242 USA. [Neil, E. T.] Brookhaven Natl Lab, RIKEN, BNL Res Ctr, Upton, NY 11973 USA. [Sugar, R.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Toussaint, D.] Univ Arizona, Dept Phys, Tucson, AZ 85721 USA. [Bouchard, C. M.] Coll William & Mary, Dept Phys, Williamsburg, VA 23185 USA. [Qiu, Si-Wei] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Zhou, R (reprint author), Fermilab Natl Accelerator Lab, Batavia, IL 60510 USA. EM zhouran@fnal.gov RI Gamiz, Elvira/E-8009-2016; Bouchard, Christopher/N-3723-2016; OI Gamiz, Elvira/0000-0001-5125-2687; Bouchard, Christopher/0000-0003-1639-7164; DeTar, Carleton/0000-0002-0216-6771 FU Office of Science of the U.S. Department of Energy; National Science Foundation's Teragrid/XSEDE Program; U.S. Department of Energy [DE-FG02-91ER40628, DE-FC02-12ER41879, DE-FG02-91ER40661, DE-SC0010120, DE-FC02-06ER41443, DE-FG02-91ER40677, DE-FG02-13ER42001, DE-FG02-ER41976, DE-SC0010114, DE-AC02-98CH10886]; National Science Foundation [PHY-10034278, PHY10-67881, PHY-1316748, PHY-1212389, PHY-1417805]; URA Visiting Scholars program; MICINN (Spain) [FPA2010-16696]; Ramon y Cajal program; Junta de Andalucia (Spain) [FQM-101, FQM-6552]; European Commission (EC) [PCIG10-GA-2011-303781]; German Excellence Initiative; European Union Seventh Framework Programme [291763]; European Union's Marie Curie COFUND program; Basic Science Research Program of the National ResearchFoundation of Korea (NRF) - Ministry of Education [2014027937, 2015024974]; Creative Research Initiatives Program of the NRF - Korean government (MEST) [2014001852, 2015001776]; United States Department of Energy [DE-AC02-07CH11359] FX We thank Wolfgang Altmannshofer, Martin Beneke, and Enrico Lunghi for useful conversations about the form factors and phenomenology of b -> s processes. We thank Heechang Na for useful conversations about correlator fit techniques. We thank Richard J. Hill for clarifying discussions about the unitarity constraints in the z expansion. Computations for this work were carried out with resources provided by the USQCD Collaboration, the Argonne Leadership Computing Facility, the National Energy Research Scientific Computing Center, and the Los Alamos National Laboratory, which are funded by the Office of Science of the U.S. Department of Energy; and with resources provided by the National Institute for Computational Science, the Pittsburgh Supercomputer Center, the San Diego Supercomputer Center, and the Texas Advanced Computing Center, which are funded through the National Science Foundation's Teragrid/XSEDE Program. This work was supported in part by the U.S. Department of Energy under Awards No. DE-FG02-91ER40628 (C. B. and J. K.), No. DE-FC02-12ER41879 (C. D., J. F., and L. L.), No. DE-FG02-91ER40661 (S. G. and R. Z.), No. DE-SC0010120 (S. G.), No. DE-FC02-06ER41443 (R. Z.), No. DE-FG02-91ER40677 (A. X. K., C. M. B., D. D., E. D. F., and R. D. J.), No. DE-FG02-13ER42001 (A. X. K. and D. D.), No. DE-FG02-ER41976 (D. T.), and No. DE-SC0010114 (Y. L. and Y. M.); by the National Science Foundation under Grants No. PHY-10034278, No. PHY10-67881 (C. D. and L. L.), No. PHY-1316748 (R. S.), No. PHY-1212389 (R. Z.), and No. PHY-1417805 (J. L. and D. D.); by the URA Visiting Scholars program, (Y. L., Y. M., A. X. K., D. D., and C. M. B.); by the MICINN (Spain) under Grant No. FPA2010-16696 and the Ramon y Cajal program (E. G.); by the Junta de Andalucia (Spain) under Grants No. FQM-101 and No. FQM-6552 (E. G.); by European Commission (EC) under Grant No. PCIG10-GA-2011-303781 (E. G.); by the German Excellence Initiative and the European Union Seventh Framework Programme under grant agreement No. 291763 as well as the European Union's Marie Curie COFUND program (A. S. K.); and by the Basic Science Research Program of the National ResearchFoundation of Korea (NRF) funded by the Ministry of Education (Grants No. 2014027937 and No. 2015024974) and the Creative Research Initiatives Program (Grants No. 2014001852 and No. 2015001776) of the NRF grant funded by the Korean government (MEST; J. A. B.). This manuscript has been coauthored by an employee of Brookhaven Science Associates, LLC, under Contract No. DE-AC02-98CH10886 with the U.S. Department of Energy. Fermilab is operated by Fermi Research Alliance, LLC, under Contract No. DE-AC02-07CH11359 with the United States Department of Energy. NR 140 TC 11 Z9 11 U1 0 U2 1 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0010 EI 2470-0029 J9 PHYS REV D JI Phys. Rev. D PD JAN 27 PY 2016 VL 93 IS 2 AR 025026 DI 10.1103/PhysRevD.93.025026 PG 34 WC Astronomy & Astrophysics; Physics, Particles & Fields SC Astronomy & Astrophysics; Physics GA DC6KL UT WOS:000369328700009 ER PT J AU MacDonald, K Thomas, ML Sciolla, AF Schneider, B Pappas, K Bleijenberg, G Bohus, M Bekh, B Carpenter, L Carr, A Dannlowski, U Dorahy, M Fahlke, C Finzi-Dottan, R Karu, T Gerdner, A Glaesmer, H Grabe, HJ Heins, M Kenny, DT Kim, D Knoop, H Lobbestael, J Lochner, C Lauritzen, G Ravndal, E Riggs, S Sar, V Schafer, I Schlosser, N Schwandt, ML Stein, MB Subic-Wrana, C Vogel, M Wingenfeld, K AF MacDonald, Kai Thomas, Michael L. Sciolla, Andres F. Schneider, Beacher Pappas, Katherine Bleijenberg, Gijs Bohus, Martin Bekh, Bradley Carpenter, Linda Carr, Alan Dannlowski, Udo Dorahy, Martin Fahlke, Claudia Finzi-Dottan, Ricky Karu, Tobi Gerdner, Arne Glaesmer, Heide Grabe, Hans Joergen Heins, Marianne Kenny, Dianna T. Kim, Daeho Knoop, Hans Lobbestael, Jill Lochner, Christine Lauritzen, Grethe Ravndal, Edle Riggs, Shelley Sar, Vedat Schaefer, Ingo Schlosser, Nicole Schwandt, Melanie L. Stein, Murray B. Subic-Wrana, Claudia Vogel, Mark Wingenfeld, Katja TI Minimization of Childhood Maltreatment Is Common and Consequential: Results from a Large, Multinational Sample Using the Childhood Trauma Questionnaire SO PLOS ONE LA English DT Article ID NATIONAL COMORBIDITY SURVEY; ADULT PSYCHIATRIC-DISORDERS; FORM CTQ-SF; PSYCHOMETRIC PROPERTIES; HOUSEHOLD DYSFUNCTION; GERMAN VERSION; LIFE STRESS; ABUSE; RELIABILITY; VALIDITY AB Childhood maltreatment has diverse, lifelong impact on morbidity and mortality. The Childhood Trauma Questionnaire (CTQ) is one of the most commonly used scales to assess and quantify these experiences and their impact. Curiously, despite very widespread use of the CTQ, scores on its Minimization-Denial (MD) subscale-originally designed to assess a positive response bias-are rarely reported. Hence, little is known about this measure. If response biases are either common or consequential, current practices of ignoring the MD scale deserve revision. Therewith, we designed a study to investigate 3 aspects of minimization, as defined by the CTQ's MD scale: 1) its prevalence; 2) its latent structure; and finally 3) whether minimization moderates the CTQ's discriminative validity in terms of distinguishing between psychiatric patients and community volunteers. Archival, item-level CTQ data from 24 multinational samples were combined for a total of 19,652 participants. Analyses indicated: 1) minimization is common; 2) minimization functions as a continuous construct; and 3) high MD scores attenuate the ability of the CTQ to distinguish between psychiatric patients and community volunteers. Overall, results suggest that a minimizing response bias-as detected by the MD subscale-has a small but significant moderating effect on the CTQ's discriminative validity. Results also may suggest that some prior analyses of maltreatment rates or the effects of early maltreatment that have used the CTQ may have underestimated its incidence and impact. We caution researchers and clinicians about the widespread practice of using the CTQ without the MD or collecting MD data but failing to assess and control for its effects on outcomes or dependent variables. C1 [MacDonald, Kai; Thomas, Michael L.; Schneider, Beacher; Pappas, Katherine; Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Sciolla, Andres F.] Univ Calif Davis, Dept Psychiat & Behav Sci, Davis, CA 95616 USA. [Bleijenberg, Gijs; Heins, Marianne; Knoop, Hans] Radboud Univ Nijmegen, Med Ctr, Expert Ctr Chron Fatigue, NL-6525 ED Nijmegen, Netherlands. [Bohus, Martin] Heidelberg Univ, Cent Inst Mental Hlth, Heidelberg, Germany. [Bekh, Bradley] Atlanta VA Med Ctr, Atlanta, GA USA. [Bekh, Bradley] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Carpenter, Linda] Brown Univ, Providence, RI 02912 USA. [Carr, Alan] Univ Coll Dublin, Dublin 2, Ireland. [Dannlowski, Udo] Univ Munster, Dept Psychiat, D-48149 Munster, Germany. [Dorahy, Martin] Univ Canterbury, Dept Psychol, Christchurch 1, New Zealand. [Fahlke, Claudia] Univ Gothenburg, Dept Psychol, Box 14158, S-40020 Gothenburg, Sweden. [Finzi-Dottan, Ricky; Karu, Tobi] Bar Ilan Univ, Ramat Gan, Israel. [Gerdner, Arne] Jonkoping Univ, Sch Hlth Sci, Jonkoping, Sweden. [Glaesmer, Heide] Univ Leipzig, Dept Med Psychol & Med, D-04109 Leipzig, Germany. [Grabe, Hans Joergen] Helios Hosp Stralsund, Dept Psychiat & Psychotherapy, Stralsund, Germany. [Grabe, Hans Joergen] Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany. [Kenny, Dianna T.] Univ Sydney, Sydney, NSW 2006, Australia. [Kim, Daeho] Hanyang Univ, Sch Med, Dept Psychiat, Seoul 133791, South Korea. [Lobbestael, Jill] Maastricht Univ, Fac Psychol & Neurosci, Dept Clin Psychol, NL-6200 MD Maastricht, Netherlands. [Lochner, Christine] Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South Africa. [Lauritzen, Grethe; Ravndal, Edle] Univ Oslo, Norwegian Inst Alcohol & Drug Res SIRUS, Oslo, Norway. [Lauritzen, Grethe; Ravndal, Edle] Univ Oslo, Norwegian Ctr Addict Res SERAF, Oslo, Norway. [Riggs, Shelley] Univ N Texas, Denton, TX 76203 USA. [Sar, Vedat] Koc Univ, Sch Med, Istanbul, Turkey. [Schaefer, Ingo] Univ Med Ctr Hamburg Eppendorf, Dept Psychiat & Psychotherapy, Hamburg, Germany. [Schlosser, Nicole] Evangel Hosp Bielefeld, Res Dept, Bielefeld, Germany. [Schwandt, Melanie L.] NIAAA, Bethesda, MD USA. [Subic-Wrana, Claudia] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Psychosomat Med & Psychotherapy, D-55122 Mainz, Germany. [Vogel, Mark] Univ Basel, Hosp Psychiat, Div Subst Use Disorders, Basel, Switzerland. [Wingenfeld, Katja] Charite, Dept Psychiat, Campus Benjamin Franklin, Berlin, Germany. RP MacDonald, K (reprint author), Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. EM kai@kaimacdonald.com RI Sar, Vedat/B-9832-2009; Schwandt, Melanie/L-9866-2016; Knoop, Hans/D-3264-2009; OI Sar, Vedat/0000-0002-5392-9644; Knoop, Hans/0000-0001-7763-3517; Fahlke, Claudia/0000-0002-8059-5491; Dannlowski, Udo/0000-0002-0623-3759 FU National Institutes Health [MH071537, HD071982]; Australia Research Council; New South Wales Dept of Juvenile Justice, Australia FX The work from BB's lab was supported by National Institutes Health Grants MH071537 and HD071982. The work from DK's lab was supported by the Australia Research Council and New South Wales Dept of Juvenile Justice, Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 7 Z9 7 U1 4 U2 9 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 JAN 27 PY 2016 VL 11 IS 1 AR e0146058 DI 10.1371/journal.pone.0146058 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9GD UT WOS:000369528200007 PM 26815788 ER PT J AU Gore, AV Athans, B Iben, JR Johnson, K Russanova, V Castranova, D Pham, VN Butler, MG Williams-Simons, L Nichols, JT Besciani, E Feldman, B Kimmel, CB Liu, PP Weinstein, BM AF Gore, Aniket V. Athans, Brett Iben, James R. Johnson, Kristin Russanova, Valya Castranova, Daniel Pham, Van N. Butler, Matthew G. Williams-Simons, Lisa Nichols, James T. Besciani, Erica Feldman, Bejamin Kimmel, Charles B. Liu, Paul P. Weinstein, Brant M. TI Epigenetic regulation of hematopoiesis by DNA methylation SO ELIFE LA English DT Article ID X-CHROMOSOME INACTIVATION; STEM-CELLS; AORTIC ENDOTHELIUM; PROGENITOR CELLS; DEFINITIVE HEMATOPOIESIS; TRANSGENIC ZEBRAFISH; ADULT HEMATOPOIESIS; METHYLTRANSFERASE 1; BLOOD PROGENITORS; RUNX1 EXPRESSION AB During embryonic development, cell type-specific transcription factors promote cell identities, while epigenetic modifications are thought to contribute to maintain these cell fates. Our understanding of how genetic and epigenetic modes of regulation work together to establish and maintain cellular identity is still limited, however. Here, we show that DNA methyltransferase 3bb.1 (dnmt3bb.1) is essential for maintenance of hematopoietic stem and progenitor cell (HSPC) fate as part of an early Notch-runx1-cmyb HSPC specification pathway in the zebrafish. Dnmt3bb.1 is expressed in HSPC downstream from Notch1 and runx1, and loss of Dnmt3bb.1 activity leads to reduced cmyb locus methylation, reduced cmyb expression, and gradual reduction in HSPCs. Ectopic overexpression of dnmt3bb.1 in non-hematopoietic cells is sufficient to methylate the cmyb locus, promote cmyb expression, and promote hematopoietic development. Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs. C1 [Gore, Aniket V.; Athans, Brett; Johnson, Kristin; Russanova, Valya; Castranova, Daniel; Pham, Van N.; Butler, Matthew G.; Williams-Simons, Lisa; Feldman, Bejamin; Weinstein, Brant M.] NICHHD, Div Dev Biol, NIH, Bethesda, MD 20892 USA. [Iben, James R.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Nichols, James T.; Kimmel, Charles B.] Univ Oregon, Inst Neurosci, Eugene, OR 97403 USA. [Besciani, Erica; Liu, Paul P.] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHHD, Div Dev Biol, NIH, Bethesda, MD 20892 USA. EM WeinsteB@mail.nih.gov FU National Institute of Child Health and Human Development [ZIA-HD001011, P01HD22486]; National Human Genome Research Institute; Fondation Leducq; National Institute of Dental and Craniofacial Research [DE13834, K99DE024190] FX National Institute of Child Health and Human Development ZIA-HD001011 Aniket V Gore Brett Athans Kristin Johnson Daniel Castranova Van N Pham Matthew G Butler Brant M Weinstein; National Human Genome Research Institute Erica Bresciani Paul P Liu; Fondation Leducq Aniket V Gore Brett Athans Kristin Johnson Daniel Castranova Van N Pham Matthew G Butler Brant M Weinstein; National Institute of Child Health and Human Development James R Iben Valya Russanova Lisa Williams-Simons Bejamin Feldman; National Institute of Dental and Craniofacial Research DE13834 Charles B Kimmel; National Institute of Dental and Craniofacial Research K99DE024190 James T Nichols; National Institute of Child Health and Human Development P01HD22486 Charles B Kimmel NR 87 TC 2 Z9 2 U1 2 U2 12 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 27 PY 2016 VL 5 AR e11813 DI 10.7554/eLife.11813 PG 25 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DC2QF UT WOS:000369060700001 PM 26814702 ER PT J AU Sare, RM AF Sare, R. Michelle TI Diaschisis: An Old Concept Brought to New Life SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material C1 [Sare, R. Michelle] NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Room 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. RP Sare, RM (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Room 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. EM Rachel.Sare@nih.gov NR 6 TC 0 Z9 0 U1 2 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 27 PY 2016 VL 36 IS 4 BP 1051 EP 1052 DI 10.1523/JNEUROSCI.4014-15.2016 PG 2 WC Neurosciences SC Neurosciences & Neurology GA DC4GX UT WOS:000369180000001 PM 26818495 ER PT J AU Morsci, NS Hall, DH Driscoll, M Sheng, ZH AF Morsci, Natalia S. Hall, David H. Driscoll, Monica Sheng, Zu-Hang TI Age-Related Phasic Patterns of Mitochondrial Maintenance in Adult Caenorhabditis elegans Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE age-related changes; Caenorhabditis elegans; in vivo microscopy; mitochondrial trafficking; neuronal mitochondria ID LIFE-SPAN; C-ELEGANS; IN-VIVO; AXONAL-TRANSPORT; OXIDATIVE STRESS; GENETIC-ANALYSIS; NERVOUS-SYSTEM; LONGEVITY; RECEPTOR; DISEASE AB Aging is associated with cognitive decline and increasing risk of neurodegeneration. Perturbation of mitochondrial function, dynamics, and trafficking are implicated in the pathogenesis of several age-associated neurodegenerative diseases. Despite this fundamental importance, the critical understanding of how organismal aging affects lifetime neuronal mitochondrial maintenance remains unknown, particularly in a physiologically relevant context. To address this issue, we performed a comprehensive in vivo analysis of age-associated changes in mitochondrial morphology, density, trafficking, and stress resistance in individual Caenorhabditis elegans neurons throughout adult life. Adult neurons display three distinct stages of increase, maintenance, and decrease in mitochondrial size and density during adulthood. Mitochondrial trafficking in the distal neuronal processes declines progressively with age starting from early adulthood. In contrast, long-lived daf-2 mutants exhibit delayed age-associated changes in mitochondrial morphology, constant mitochondrial density, and maintained trafficking rates during adulthood. Reduced mitochondrial load at late adulthood correlates with decreased mitochondrial resistance to oxidative stress. Revealing aging-associated changes in neuronal mitochondria in vivo is an essential precedent that will allow future elucidation of the mechanistic causes of mitochondrial aging. Thus, our study establishes the critical foundation for the future analysis of cellular pathways and genetic and pharmacological factors regulating mitochondrial maintenance in aging-and disease-relevant conditions. C1 [Morsci, Natalia S.; Sheng, Zu-Hang] NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Hall, David H.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10461 USA. [Driscoll, Monica] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA.; Driscoll, M (reprint author), Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. EM driscoll@dls.rutgers.edu; shengz@ninds.nih.gov FU Intramural Research Program of NINDS through NIH [NS003029, NS002946, R01AG046358, OD010943]; NIH Office of Research Infrastructure Programs [P40 OD010440] FX This work was supported by the Intramural Research Program of NINDS through NIH Grants NS003029 and NS002946 (Z.-H.S.), R01AG046358 (M.D.), and OD010943 (D.H.H.). We thank S. Koushika (National Centre for Biological Sciences (NCBS), Bangalore, India) for sharing the Pmec-7::mitoGFP strain and C. Rongo (Rutgers University, Piscataway, NJ) for sharing the Pglr-1::mitoROGFP2 strain. We thank L. Herndon, A. Jevince, and G. Stephney for technical help with TEM, N. R. Hall for help with statistics, and H. Ushakov for some transgenic constructions. We also thank members of the Sheng lab for constructive discussion and Marina Nogueira (NIH summer intern) for assistance in animal maintenance and imaging. Some strains were provided by the Caenorhabditis Genetics Center, funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). NR 63 TC 3 Z9 3 U1 2 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 27 PY 2016 VL 36 IS 4 BP 1373 EP 1385 DI 10.1523/JNEUROSCI.2799-15.2016 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DC4GX UT WOS:000369180000029 PM 26818523 ER PT J AU Easton, AV Oliveira, RG O'Connell, EM Kepha, S Mwandawiro, CS Njenga, SM Kihara, JH Mwatele, C Odiere, MR Brooker, SJ Webster, JP Anderson, RM Nutman, TB AF Easton, Alice V. Oliveira, Rita G. O'Connell, Elise M. Kepha, Stella Mwandawiro, Charles S. Njenga, Sammy M. Kihara, Jimmy H. Mwatele, Cassian Odiere, Maurice R. Brooker, Simon J. Webster, Joanne P. Anderson, Roy M. Nutman, Thomas B. TI Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming SO PARASITES & VECTORS LA English DT Article DE qPCR; Diagnostics; Soil-transmitted helminths; Deworming; Impact evaluation; Gastrointestinal parasites; Co-infection; Ascaris lumbricoides ID SOIL-TRANSMITTED HELMINTHS; POLYMERASE-CHAIN-REACTION; REAL-TIME PCR; ASCARIS-LUMBRICOIDES INFECTION; NEGLECTED TROPICAL DISEASES; FECAL EGG COUNTS; KATZ THICK SMEAR; SCHISTOSOMA-MANSONI; RESEARCH AGENDA; ANCYLOSTOMA-DUODENALE AB Background: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. Methods: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. Results: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15 % for Entamoeba histolytica. The prevalence was <1 % for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98 % for A. lumbricoides and N. americanus, whereas KK sensitivity was 70 % and 32 %, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). Conclusions: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information. C1 [Easton, Alice V.; O'Connell, Elise M.; Nutman, Thomas B.] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Easton, Alice V.; Oliveira, Rita G.; Anderson, Roy M.] Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, London, England. [Kepha, Stella] Makerere Univ, Coll Hlth Sci, Sch Publ Hlth, Kampala, Uganda. [Mwandawiro, Charles S.; Njenga, Sammy M.; Kihara, Jimmy H.; Mwatele, Cassian] Kenya Govt Med Res Ctr, Eastern & Southern Africa Ctr Int Parasite Contro, Nairobi, Kenya. [Odiere, Maurice R.] Kenya Govt Med Res Ctr, Ctr Global Hlth Res, Neglected Trop Dis Res Unit, Kisumu, Kenya. [Brooker, Simon J.] London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England. [Webster, Joanne P.] Univ London Royal Vet Coll, London, Herts, England. RP Easton, AV (reprint author), NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.; Easton, AV (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Infect Dis Epidemiol, London, England. EM alice.easton@nih.gov OI Easton, Alice/0000-0002-4476-9415 FU Bill and Melinda Gates Foundation; KEMRI Wellcome Trust; Marshall Commission (Foreign and Commonwealth Office, UK); NIH Oxford-Cambridge Scholars Program; THRiVE (Training Health Researchers into Vocational Excellence in East Africa) consortium - Wellcome Trust [087540]; Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases, NIH FX We would like to thank the school children, schoolteachers, and Bungoma administrators for their support. We would like to extend special thanks to all the members of the study team: Bungoma County Hospital, Siangwe, Siaka, Sang'alo, Nasimbo and Ranje village administrators and Community Health Workers. We thank Birgit Nikolay, Andria Stylianou, James Truscott, and Michael Fay for their consultation on statistical questions. Thanks to Sasisekhar Bennuru for help with the egg spiking experiment, and Joseph Kubofcik for help in the lab. The fieldwork was supported by a grant from the Bill and Melinda Gates Foundation to the London Centre for Neglected Tropical Disease Research and the KEMRI Wellcome Trust. AVE is supported by a PhD training fellowship from the Marshall Commission (Foreign and Commonwealth Office, UK) and the NIH Oxford-Cambridge Scholars Program. SK is supported by a PhD training fellowship from THRiVE (Training Health Researchers into Vocational Excellence in East Africa) consortium, which is funded by the Wellcome Trust (087540). This work was supported in part by the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 11 Z9 12 U1 4 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JAN 27 PY 2016 VL 9 AR 38 DI 10.1186/s13071-016-1314-y PG 12 WC Parasitology SC Parasitology GA DC0KK UT WOS:000368905700001 PM 26813411 ER PT J AU Stein, EV Miller, TW Ivins-O'Keefe, K Kaur, S Roberts, DD AF Stein, Erica V. Miller, Thomas W. Ivins-O'Keefe, Kelly Kaur, Sukhbir Roberts, David D. TI Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1 beta Production and Activation through CD47 SO SCIENTIFIC REPORTS LA English DT Article ID NLRP3 INFLAMMASOME ACTIVATION; HUMAN DENDRITIC CELLS; GROWTH-FACTOR-BETA; IMMUNE-RESPONSE; HUMAN MONOCYTES; CUTTING EDGE; PLASMA THROMBOSPONDIN; HYDROGEN-SULFIDE; GENE-EXPRESSION; LUNG INJURY AB Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1 beta by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1 beta mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NF kappa B/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1 beta in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1 beta in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1 beta, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro- and anti-inflammatory effects on the IL-1 beta pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia. C1 [Stein, Erica V.; Miller, Thomas W.; Ivins-O'Keefe, Kelly; Kaur, Sukhbir; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stein, Erica V.] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Microbiol, Washington, DC 20037 USA. [Stein, Erica V.] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Immunol, Washington, DC 20037 USA. [Stein, Erica V.] George Washington Univ, Microbiol & Immunol Program, Inst Biomed Sci, Dept Trop Med, Washington, DC 20037 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Dr. Alan Sher, Dr. Dragana Jankovic, Dr. Kevin Shenderov, Dr. Nicolas Riteau, and Dr. Roshanak Semnani for advice on experimental procedures and scientific discussions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 79 TC 0 Z9 0 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 27 PY 2016 VL 6 AR 19684 DI 10.1038/srep19684 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB8AD UT WOS:000368737900001 PM 26813769 ER PT J AU Kamal, AK Khoja, A Usmani, B Muqeet, A Zaidi, F Ahmed, M Shakeel, S Soomro, N Gowani, A Asad, N Ahmed, A Sayani, S Azam, I Saleem, S AF Kamal, Ayeesha Kamran Khoja, Adeel Usmani, Bushra Muqeet, Abdul Zaidi, Fabiha Ahmed, Masood Shakeel, Saadia Soomro, Nabila Gowani, Ambreen Asad, Nargis Ahmed, Asma Sayani, Saleem Azam, Iqbal Saleem, Sarah TI Translating knowledge for action against stroke - using 5-minute videos for stroke survivors and caregivers to improve post-stroke outcomes: study protocol for a randomized controlled trial (Movies4Stroke) SO TRIALS LA English DT Article DE Stroke; Educational intervention; Behavior change; Mobile health; Implementation; Information and communication technology; Prevention; Non-communicable disease; Low and middle income countries; Adherence ID MIDDLE-INCOME COUNTRIES; NONCOMMUNICABLE DISEASES; BLOOD-PRESSURE; HEALTH; PAKISTAN; MODEL; PREVENTION; MANAGEMENT AB Background: Two thirds of the global mortality of stroke is borne by low and middle income countries (LMICs). Pakistan is the world's sixth most populous country with a stroke-vulnerable population and is without a single dedicated chronic care center. In order to provide evidence for a viable solution responsive to this health care gap, and leveraging the existing >70 % mobile phone density, we thought it rational to test the effectiveness of a mobile phone-based video intervention of short 5-minute movies to educate and support stroke survivors and their primary caregivers. Methods: Movies4Stroke will be a randomized control, outcome assessor blinded, parallel group, single center superiority trial. Participants with an acute stroke, medically stable, with mild to moderate disability and having a stable primary caregiver will be included. After obtaining informed consent the stroke survivor-caregiver dyad will be randomized. Intervention participants will have the movie program software installed in their phone, desktop, or Android device which will allow them to receive, view and repeat 5-minute videos on stroke-related topics at admission, discharge and first and third months after enrollment. The control arm will receive standard of care at an internationally accredited center with defined protocols. The primary outcome measure is medication adherence as ascertained by a locally validated Morisky Medication Adherence Scale and control of major risk factors such as blood pressure, blood sugar and blood cholesterol at 12 months post discharge. Secondary outcome measures are post-stroke complications and mortality, caregiver knowledge and change in functional outcomes after acute stroke at 1, 3, 6, 9 and 12 months. Movies4Stroke is designed to enroll 300 participant dyads after inflating 10 % to incorporate attrition and noncompliance and has been powered at 95 % to detect a 15 % difference between intervention and usual care arm. Analysis will be done by the intention-to-treat principle. Discussion: Movies4Stroke is a randomized trial testing an application aimed at supporting caregivers and stroke survivors in a LMIC with no rehabilitation or chronic support systems. C1 [Kamal, Ayeesha Kamran] Aga Khan Univ, Neurol Sect, Dept Med, Stadium Rd, Karachi 74800, Pakistan. [Khoja, Adeel] Aga Khan Univ, Int Cerebrovasc Translat Clin Res Training Progra, Natl Inst Hlth, Stroke Serv,Fogarty Int Ctr, Karachi 74800, Pakistan. [Usmani, Bushra] Aga Khan Univ, Karachi 74800, Pakistan. [Muqeet, Abdul; Zaidi, Fabiha; Sayani, Saleem] eHlth Resource Ctr, Aga Khan Dev Network, Karachi, Pakistan. [Ahmed, Masood; Shakeel, Saadia] Natl Inst Hlth, Fogarty Int Ctr, Int Cerebrovasc Translat Clin Res Training Progra, Movies Stroke Study, Karachi, Pakistan. [Ahmed, Masood; Shakeel, Saadia] Aga Khan Univ, Karachi 74800, Pakistan. [Soomro, Nabila] Aga Khan Univ, Dept Med, Sect Neurol, Karachi 74800, Pakistan. [Soomro, Nabila] Dow Univ Hlth Sci, Inst Phys Med & Rehabil, Karachi, Pakistan. [Gowani, Ambreen] Aga Khan Univ, Dept Med, Stroke Serv, Karachi 74800, Pakistan. [Asad, Nargis] Aga Khan Univ, Dept Psychiat, Karachi 74800, Pakistan. [Ahmed, Asma] Aga Khan Univ, Dept Med, Sect Diabet Endocrinol & Metab, Karachi 74800, Pakistan. [Azam, Iqbal; Saleem, Sarah] Aga Khan Univ, Dept Community Hlth Sci, Karachi 74800, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ, Neurol Sect, Dept Med, Stadium Rd, Karachi 74800, Pakistan. EM ayeesha.kamal@aku.edu RI Emchi, Karma/Q-1952-2016 FU University Research Council (URC); Aga Khan University [132001MED, D43TW008660]; Fogarty International Center [D43TW008660]; National Institute of Neurologic Disorders and Stroke (NIH) FX Dr. Ayeesha Kamran Kamal has received funding from the University Research Council (URC), Aga Khan University, Project ID: 132001MED for this project entitled "Translating knowledge for action against stroke - using 5-minute videos for numeracy and literacy challenged stroke survivors and caregivers to improve outcomes." She is also the co-director and recipient of a grant entitled "The International Cerebrovascular Translational Clinical Research Training Program" (Fogarty International Center, National Institutes of Health), Award ID: D43TW008660.; Dr. Adeel Khoja is a neurovascular research fellow whose mentored research practicum training is currently being funded by Award Number D43TW008660 from the Fogarty International Center and the National Institute of Neurologic Disorders and Stroke (NIH) and involves ascertainment of outcomes in this study. NR 36 TC 0 Z9 0 U1 5 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD JAN 27 PY 2016 VL 17 AR 52 DI 10.1186/s13063-016-1175-x PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DB8ME UT WOS:000368770000003 PM 26818913 ER PT J AU Zhu, R Sinwel, D Hasenhuetl, PS Saha, K Kumar, V Zhang, P Rankl, C Holy, M Sucic, S Kudlacek, O Karner, A Sandtner, W Stockner, T Gruber, HJ Freissmuth, M Newman, AH Sitte, HH Hinterdorfer, P AF Zhu, Rong Sinwel, Doris Hasenhuetl, Peter S. Saha, Kusumika Kumar, Vivek Zhang, Peng Rankl, Christian Holy, Marion Sucic, Sonja Kudlacek, Oliver Karner, Andreas Sandtner, Walter Stockner, Thomas Gruber, Hermann J. Freissmuth, Michael Newman, Amy Hauck Sitte, Harald H. Hinterdorfer, Peter TI Nanopharmacological Force Sensing to Reveal Allosteric Coupling in Transporter Binding Sites SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE allostery; binding sites; citalopram; nanopharmacology; serotonin transporter ID SEROTONIN TRANSPORTER; NEUROTRANSMITTER TRANSPORTERS; DOPAMINE TRANSPORTER; SUBSTRATE-BINDING; ANTIDEPRESSANTS; CITALOPRAM; LEUT; RECOGNITION; SYMPORTER; VESTIBULE AB Controversy regarding the number and function of ligand binding sites in neurotransmitter/sodium symporters arose from conflicting data in crystal structures and molecular pharmacology. Here, we have designed novel tools for atomic force microscopy that directly measure the interaction forces between the serotonin transporter (SERT) and the S- and R-enantiomers of citalopram on the single molecule level. This approach is based on force spectroscopy, which allows for the extraction of dynamic information under physiological conditions thus inaccessible via X-ray crystallography. Two distinct populations of characteristic binding strengths of citalopram to SERT were revealed in Na+-containing buffer. In contrast, in Li+-containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT-G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT when accessed in a physiological context. Competition experiments revealed that these two sites are allosterically coupled and exert reciprocal modulation. C1 [Zhu, Rong; Sinwel, Doris; Karner, Andreas; Gruber, Hermann J.; Hinterdorfer, Peter] Johannes Kepler Univ Linz, Inst Biophys, Gruberstr 40, A-4020 Linz, Austria. [Hasenhuetl, Peter S.; Saha, Kusumika; Holy, Marion; Sucic, Sonja; Kudlacek, Oliver; Sandtner, Walter; Stockner, Thomas; Freissmuth, Michael; Sitte, Harald H.] Med Univ Vienna, Ctr Physiol & Pharmacol, Waehringerstr 13a, A-1090 Vienna, Austria. [Kumar, Vivek; Zhang, Peng; Newman, Amy Hauck] NIDA, Med Chem Sect, Mol Targets & Medicat Discovery Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Rankl, Christian] Keysight Technol Austria GmbH, Mooslackengasse 17, A-1190 Vienna, Austria. [Sinwel, Doris; Hinterdorfer, Peter] Johannes Kepler Univ Linz, Christian Doppler Lab Nanoscop Methods Biophys, Gruberstr 40, A-4020 Linz, Austria. [Karner, Andreas; Hinterdorfer, Peter] Ctr Adv Bioanal, Gruberstr 40, A-4020 Linz, Austria. RP Hinterdorfer, P (reprint author), Johannes Kepler Univ Linz, Inst Biophys, Gruberstr 40, A-4020 Linz, Austria.; Hinterdorfer, P (reprint author), Johannes Kepler Univ Linz, Christian Doppler Lab Nanoscop Methods Biophys, Gruberstr 40, A-4020 Linz, Austria.; Hinterdorfer, P (reprint author), Ctr Adv Bioanal, Gruberstr 40, A-4020 Linz, Austria. EM peter.hinterdorfer@jku.at RI Kumar, Vivek/F-6183-2016; Stockner, Thomas/A-9509-2014; Gruber, Hermann/C-4234-2013; OI Stockner, Thomas/0000-0002-7071-8283; Sucic, Sonja/0000-0001-5136-8022; Sitte, Harald/0000-0002-1339-7444 FU Austrian Science Fund [F35]; National Institute on Drug Abuse-Intramural Research Program, NIH FX We thank L. Wildling, D. Vater, M. Kastner, M. Leitner, and Q. Beatty for assistance, C. J. Loland and A. Ebner for discussion, and N. Muller for NMR facilities. This work was supported by Austrian Science Fund Grant F35 and the National Institute on Drug Abuse-Intramural Research Program, NIH. NR 22 TC 3 Z9 3 U1 2 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD JAN 26 PY 2016 VL 55 IS 5 BP 1719 EP 1722 DI 10.1002/anie.201508755 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA DD3WM UT WOS:000369854000019 PM 26695726 ER PT J AU Ma, JT McKeown, NM Hwang, SJ Hoffmann, U Jacques, PF Fox, CS AF Ma, Jiantao McKeown, Nicola M. Hwang, Shih-Jen Hoffmann, Udo Jacques, Paul F. Fox, Caroline S. TI Sugar-Sweetened Beverage Consumption Is Associated With Change of Visceral Adipose Tissue Over 6 Years of Follow-Up SO CIRCULATION LA English DT Article DE obesity; subcutaneous adipose tissue; visceral adipose tissue ID FOOD-FREQUENCY QUESTIONNAIRE; LIPOPROTEIN-LIPASE; METABOLIC SYNDROME; UNITED-STATES; FRUCTOSE; DISEASE; FAT; REPRODUCIBILITY; VALIDITY; INSULIN AB Background Sugar-sweetened beverage (SSB) intake has been linked to abnormal abdominal adipose tissue. We examined the prospective association of habitual SSB intake and change in visceral adipose tissue (VAT) and subcutaneous adipose tissue. Methods and Results The quantity (volume, cm(3)) and quality (attenuation, Hounsfield Unit) of abdominal adipose tissue were measured using computed tomography in 1003 participants (mean age 45.3 years, 45.0% women) at examination 1 and 2 in the Framingham's Third Generation cohort. The 2 exams were approximate to 6 years apart. At baseline, SSB and diet soda intake were assessed using a valid food frequency questionnaire. Participants were categorized into 4 groups: none to <1 serving/mo (nonconsumers), 1 serving/mo to <1 serving/week, 1 serving/week to 1 serving/d, and 1 serving/d (daily consumers) of either SSB or diet soda. After adjustment for multiple confounders including change in body weight, higher SSB intake was associated with greater change in VAT volume (P trend<0.001). VAT volume increased by 658 cm(3) (95% confidence interval [CI], 602 to 713), 649 cm(3) (95% CI, 582 to 716), 707 cm(3) (95% CI, 657 to 757), and 852 cm(3) (95% CI, 760 to 943) from nonconsumers to daily consumers. Higher SSB intake was also associated with greater decline of VAT attenuation (P trend=0.007); however, the association became nonsignificant after additional adjustment for VAT volume change. In contrast, diet soda consumption was not associated with change in abdominal adipose tissue. Conclusions Regular SSB intake was associated with adverse change in both VAT quality and quantity, whereas we observed no such association for diet soda. C1 [Ma, Jiantao; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study & Populat Sci Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. [McKeown, Nicola M.; Jacques, Paul F.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Nutr Epidemiol Program, Boston, MA 02111 USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study & Populat Sci Branch, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxa@nhlbi.nih.gov FU Framingham Heart Study (FHS) of National Heart, Lung, and Blood Institute (NHLBI) of National Institute of Health; Boston University School of Medicine; NHLBI FHS [N01-HC-25195] FX This work was conducted in part using resources and data from the Framingham Heart Study (FHS) of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health and Boston University School of Medicine. This work was supported by the NHLBI FHS (N01-HC-25195). NR 35 TC 2 Z9 2 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 26 PY 2016 VL 133 IS 4 BP 370 EP 377 DI 10.1161/CIRCULATIONAHA.115.018704 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DC5KE UT WOS:000369259100005 PM 26755505 ER PT J AU Williams, SR Hsu, FC Keene, KL Chen, WM Nelson, S Southerland, AM Madden, EB Coull, B Gogarten, SM Furie, KL Dzhivhuho, G Rowles, JL Mehndiratta, P Malik, R Dupuis, J Lin, HH Seshadri, S Rich, SS Sale, MM Worrall, BB AF Williams, Stephen R. Hsu, Fang-Chi Keene, Keith L. Chen, Wei-Min Nelson, Sarah Southerland, Andrew M. Madden, Ebony B. Coull, Bruce Gogarten, Stephanie M. Furie, Karen L. Dzhivhuho, Godfrey Rowles, Joe L. Mehndiratta, Prachi Malik, Rainer Dupuis, Josee Lin, Honghuang Seshadri, Sudha Rich, Stephen S. Sale, Michele M. Worrall, Bradford B. CA METASTROKE Genomics & Randomized Trials Netwo TI Shared genetic susceptibility of vascular-related biomarkers with ischemic and recurrent stroke SO NEUROLOGY LA English DT Article ID C-REACTIVE-PROTEIN; GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; DELTA(4)-3-OXOSTEROID 5-BETA-REDUCTASE; CIRCULATING FIBRINOGEN; AFRICAN-AMERICANS; SRD5B1 AKR1D1; POPULATION; INFLAMMATION; METAANALYSIS AB Objective:To investigate the genetic contributors to cerebrovascular disease and variation in biomarkers of ischemic stroke.Methods:The Vitamin Intervention for Stroke Prevention Trial (VISP) was a randomized, controlled clinical trial of B vitamin supplementation to prevent recurrent stroke, myocardial infarction, or death. VISP collected baseline measures of C-reactive protein (CRP), fibrinogen, creatinine, prothrombin fragments F1+2, thrombin-antithrombin complex, and thrombomodulin prior to treatment initiation. Genome-wide association scans were conducted for these traits and follow-up replication analyses were performed.Results:We detected an association between CRP single nucleotide polymorphisms (SNPs) and circulating CRP levels (most associated SNP, rs2592902, p = 1.14 x 10(-9)) in 2,100 VISP participants. We discovered a novel association for CRP level in the AKR1D1 locus (rs2589998, p = 7.3 x 10(-8), approaching genome-wide significance) that also is an expression quantitative trait locus for CRP gene expression. We replicated previously identified associations of fibrinogen with SNPs in the FGB and LEPR loci. CRP-associated SNPs and CRP levels were significantly associated with risk of ischemic stroke and recurrent stroke in VISP as well as specific stroke subtypes in METASTROKE. Fibrinogen levels but not fibrinogen-associated SNPs were also found to be associated with recurrent stroke in VISP.Conclusions:Our data identify a genetic contribution to inflammatory and hemostatic biomarkers in a stroke population. Additionally, our results suggest shared genetic contributions to circulating CRP levels measured poststroke and risk for incident and recurrent ischemic stroke. These data broaden our understanding of genetic contributors to biomarker variation and ischemic stroke risk, which should be useful in clinical risk evaluation. C1 [Williams, Stephen R.; Keene, Keith L.; Chen, Wei-Min; Rich, Stephen S.; Sale, Michele M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Williams, Stephen R.] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA. [Southerland, Andrew M.; Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Mehndiratta, Prachi; Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Hsu, Fang-Chi] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Madden, Ebony B.] NHGRI, Bethesda, MD 20892 USA. [Southerland, Andrew M.; Furie, Karen L.] Brown Univ, Dept Neurol, Providence, RI 02912 USA. [Furie, Karen L.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Coull, Bruce] Univ Arizona, Dept Neurol, Tucson, AZ USA. [Keene, Keith L.] E Carolina Univ, Dept Biol, Greenville, NC USA. [Keene, Keith L.] E Carolina Univ, Ctr Hlth Dispar, Greenville, NC USA. [Nelson, Sarah; Gogarten, Stephanie M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Dzhivhuho, Godfrey] Univ Cape Town, Dept Clin Lab Sci, ZA-7700 Rondebosch, South Africa. [Rowles, Joe L.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Malik, Rainer] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Worrall, BB (reprint author), Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. EM bbw9r@virginia.edu RI Boncoraglio, Giorgio/B-8647-2011; OI Rowles, Joe/0000-0002-0716-4759; Gogarten, Stephanie/0000-0002-7231-9745; Chen, Wei-Min/0000-0002-2643-2333 FU National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS34447]; National Human Genome Research Institute [U01 HG004438l]; Genomics and Randomized Trials (GARNET) Network [U01HG00516-03]; National Heart, Lung and Blood Institute (NHLBI) [N01-HC-25195]; NINDS [NS17950]; NHLBI [U01HL 096917]; National Institute on Aging (NIA) [AG08122, AG033193] FX Study recruitment and collection of datasets for the VISP trial were supported by a grant (R01 NS34447; PI James Toole) from the National Institute of Neurological Disorders and Stroke (NINDS). GWAS genotyping performed at the Center for Inherited Disease Research (CIDR) (U01 HG004438l; PI David Valle) was funded by the National Human Genome Research Institute and the Genomics and Randomized Trials (GARNET) Network (U01HG00516-03; co-PI Michele M. Sale and Bradford B. Worrall) and genetic data cleaning was provided by the GARNET Coordinating Center (U01HG005157; PI Bruce S. Weir). Given that all VISP participants were stroke cases, we obtained GWAS data (dbGAP) for external controls from the High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation (study accession: phs000187.v1.p1); they were also genotyped on the Illumina Human-Omni1-Quad by CIDR. The Framingham Heart Study is funded by the National Heart, Lung and Blood Institute (NHLBI) (contract no. N01-HC-25195; http://www.framinghamheartstudy.org/) and by grants from NINDS (NS17950, www.ninds.nih.gov/), the NHLBI (U01HL 096917; www.nhlbi.nih.gov), and the National Institute on Aging (NIA) (AG08122, AG033193; www.nia.nih.gov). All links are current as of August 4, 2015. METASTROKE is an unfunded consortium of large case-control and cohort GWAS studies of stroke. NR 38 TC 3 Z9 3 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD JAN 26 PY 2016 VL 86 IS 4 BP 351 EP 359 DI 10.1212/WNL.0000000000002319 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA DC5LV UT WOS:000369263400002 PM 26718567 ER PT J AU Gu, XL Zhou, L Lu, W AF Gu, Xinglong Zhou, Liang Lu, Wei TI An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development SO CELL REPORTS LA English DT Article ID METHYL-D-ASPARTATE; GABAERGIC SYNAPSES; ALPHA-ACTININ; NEURONAL-ACTIVITY; NR1 SUBUNIT; CALMODULIN; HIPPOCAMPUS; PLASTICITY; PROTEIN; INACTIVATION AB In the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs) in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABA(A) receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain. C1 [Gu, Xinglong; Zhou, Liang; Lu, Wei] NINDS, Synapse & Neural Circuit Res Unit, NIH, 35 Convent Dr,3C1000, Bethesda, MD 20892 USA. RP Lu, W (reprint author), NINDS, Synapse & Neural Circuit Res Unit, NIH, 35 Convent Dr,3C1000, Bethesda, MD 20892 USA. EM luw4@mail.nih.gov RI gu, xinglong/A-3054-2011 OI gu, xinglong/0000-0002-0437-5606 FU Intramural Research Program of NIH, NINDS FX We appreciate Xia Mao for mouse colony management. We are grateful to Chris McBain, Jeffrey Diamond, Katherine Roche, Claire Le Pichon, Mary Anne Hutchison, and Jun Li for critical comments on the manuscript. The authors also thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. This research was supported by the Intramural Research Program of NIH, NINDS (to W.L.). NR 54 TC 5 Z9 5 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 26 PY 2016 VL 14 IS 3 BP 471 EP 478 DI 10.1016/j.celrep.2015.12.061 PG 8 WC Cell Biology SC Cell Biology GA DB7NF UT WOS:000368701600009 PM 26774487 ER PT J AU Grohar, PJ Kim, S Rivera, GOR Sen, N Haddock, S Harlow, ML Maloney, NK Zhu, J O'Neill, M Jones, TL Huppi, K Grandin, M Gehlhaus, K Klumpp-Thomas, CA Buehler, E Helman, LJ Martin, SE Caplen, NJ AF Grohar, Patrick J. Kim, Suntae Rivera, Guillermo O. Rangel Sen, Nirmalya Haddock, Sara Harlow, Matt L. Maloney, Nichole K. Zhu, Jack O'Neill, Maura Jones, Tamara L. Huppi, Konrad Grandin, Magdalena Gehlhaus, Kristen Klumpp-Thomas, Carleen A. Buehler, Eugen Helman, Lee J. Martin, Scott E. Caplen, Natasha J. TI Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma SO CELL REPORTS LA English DT Article ID CHROMOSOME-TRANSLOCATION; EWS/FLI-1 FUSION; SOLID TUMORS; DNA-BINDING; TARGET; GENE; PLADIENOLIDE; FAMILY; CANCER; SF3B AB Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show that Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss of function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1-driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells. C1 [Grohar, Patrick J.; Maloney, Nichole K.] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. [Grohar, Patrick J.] Vanderbilt Univ, Sch Med, Dept pharmacol, Nashville, TN 37232 USA. [Grohar, Patrick J.; Harlow, Matt L.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA. [Kim, Suntae; Rivera, Guillermo O. Rangel; Sen, Nirmalya; Haddock, Sara; Jones, Tamara L.; Huppi, Konrad; Grandin, Magdalena; Gehlhaus, Kristen; Caplen, Natasha J.] NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zhu, Jack] NCI, Mol Genet Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Rivera, Guillermo O. Rangel] NIH Acad, Off Intramural Training & Educ, NIH, Bethesda, MD 20892 USA. [O'Neill, Maura] Frederick Natl Lab Canc Res, Leidos Biomed Res Inc, Protein Characterizat Lab, Frederick, MD 21702 USA. [Klumpp-Thomas, Carleen A.; Buehler, Eugen; Martin, Scott E.] Natl Ctr Adv Translat Sci, Trans NIH RNAi Screening Facil, Div Preclin Innovat, NIH, Rockville, MD 20850 USA. [Helman, Lee J.] NCI, Mol Oncol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Caplen, NJ (reprint author), NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM ncaplen@mail.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural Research Program of the National Cancer Institute (NCI); Center for Cancer Research (CCR) NIH; DHHS; National Cancer Institute; NIH [HHSN261200800001E]; Lily's Garden Foundation; Sarcoma Alliance for Research Through Collaboration; Turner-Hazinski Award; Vanderbilt University FX This research was supported by the Intramural Research Program of the National Cancer Institute (NCI), Center for Cancer Research (CCR) NIH; DHHS; federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E; and funding to P.J.G. from the Lily's Garden Foundation, the Sarcoma Alliance for Research Through Collaboration, and the Turner-Hazinski Award, Vanderbilt University. We thank Christiane Olivero (Colgate University, Hamilton, NY), Zhili Zheng (Surgery Branch, CCR, NCI), Amy McCalla (Pediatric Oncology Branch, CCR, NCI), and Thorkell Andersson (Protein Characterization Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD) for technical assistance and Javed Khan for SKNMC cells. We also thank members of the Genetics Branch, CCR, NCI, in particular, Javed Khan, Ashish Lal, Shile Zhang, John Shern, Young Song, Sean Davies, and Josh Waterfall for helpful discussion. NR 35 TC 0 Z9 0 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JAN 26 PY 2016 VL 14 IS 3 BP 598 EP 610 DI 10.1016/j.celrep.2015.12.063 PG 13 WC Cell Biology SC Cell Biology GA DB7NF UT WOS:000368701600019 PM 26776507 ER PT J AU Ma, JSY Kim, JY Kazane, SA Choi, SH Yun, HY Kim, MS Rodgers, DT Pugh, HM Singer, O Sun, SB Fonslow, BR Kochenderfer, JN Wright, TM Schultz, PG Young, TS Kim, CH Cao, Y AF Ma, Jennifer S. Y. Kim, Ji Young Kazane, Stephanie A. Choi, Sei-hyun Yun, Hwa Young Kim, Min Soo Rodgers, David T. Pugh, Holly M. Singer, Oded Sun, Sophie B. Fonslow, Bryan R. Kochenderfer, James N. Wright, Timothy M. Schultz, Peter G. Young, Travis S. Kim, Chan Hyuk Cao, Yu TI Versatile strategy for controlling the specificity and activity of engineered T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer immunotherapy; chimeric antigen receptor T cell; noncanonical amino acids; cytokine release syndrome; B-cell aplasia ID CHIMERIC-ANTIGEN-RECEPTOR; UNNATURAL AMINO-ACIDS; ACUTE MYELOID-LEUKEMIA; BINDING AFFINITY; CANCER; ANTIBODIES; TOXICITY; THERAPY; COSTIMULATION; RECOGNITION AB The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T-cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy. C1 [Ma, Jennifer S. Y.; Kim, Ji Young; Kazane, Stephanie A.; Kim, Min Soo; Rodgers, David T.; Pugh, Holly M.; Singer, Oded; Sun, Sophie B.; Wright, Timothy M.; Schultz, Peter G.; Young, Travis S.; Kim, Chan Hyuk] Calif Inst Biomed Res, Dept Biol, La Jolla, CA 92037 USA. [Choi, Sei-hyun; Yun, Hwa Young; Schultz, Peter G.; Cao, Yu] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Choi, Sei-hyun; Yun, Hwa Young; Schultz, Peter G.; Cao, Yu] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Fonslow, Bryan R.] Scripps Res Inst, Dept Chem Physiol, La Jolla, CA 92037 USA. [Fonslow, Bryan R.] SCIEX Separat, Brea, CA 92821 USA. [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Kazane, Stephanie A.] Pfizer Inc, Ctr Therapeut Innovat, Dept Prot Chem, San Diego, CA 92121 USA. [Yun, Hwa Young] Pusan Natl Univ, Coll Pharm, Busan 609735, South Korea. [Kim, Min Soo] Sorrento Therapeut Inc, Dept Res & Dev, San Diego, CA 92121 USA. RP Schultz, PG; Young, TS; Kim, CH (reprint author), Calif Inst Biomed Res, Dept Biol, La Jolla, CA 92037 USA. EM schultz@scripps.edu; tyoung@calibr.org; chkim@calibr.org FU NIGMS NIH HHS [R01 GM062159] NR 50 TC 13 Z9 13 U1 7 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 26 PY 2016 VL 113 IS 4 BP E450 EP E458 DI 10.1073/pnas.1524193113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB6IJ UT WOS:000368617900009 PM 26759368 ER PT J AU Lu, W Sun, JH Yoon, JS Zhang, Y Zheng, LX Murphy, E Mattson, MP Lenardo, MJ AF Lu, Wei Sun, Junhui Yoon, Jeong Seon Zhang, Yan Zheng, Lixin Murphy, Elizabeth Mattson, Mark P. Lenardo, Michael J. TI Mitochondrial Protein PGAM5 Regulates Mitophagic Protection against Cell Necroptosis SO PLOS ONE LA English DT Article ID RECEPTOR-INTERACTING PROTEIN; MIXED LINEAGE KINASE; PROGRAMMED NECROSIS; MEDIATED MITOPHAGY; MOVEMENT-DISORDER; DEATH PATHWAYS; RIP3; PHOSPHATASE; APOPTOSIS; HEART AB Necroptosis as a molecular program, rather than simply incidental cell death, was established by elucidating the roles of receptor interacting protein (RIP) kinases 1 and 3, along with their downstream partner, mixed lineage kinase/like domain protein (MLKL). Previous studies suggested that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein that associates with RIP1/RIP3/MLKL complex, promotes necroptosis. We have generated mice deficient in the pgam5 gene and surprisingly found PGAM5-deficiency exacerbated rather than reduced necroptosis in response to multiple in vitro and in vivo necroptotic stimuli, including ischemic reperfusion injury (I/R) in the heart and brain. Electron microscopy, biochemical, and confocal analysis revealed that PGAM5 is indispensable for the process of PINK1 dependent mitophagy which antagonizes necroptosis. The loss of PGAM5/PINK1 mediated mitophagy causes the accumulation of abnormal mitochondria, leading to the overproduction of reactive oxygen species (ROS) that worsen necroptosis. Our results revise the former proposal that PGAM5 acts downstream of RIP1/RIP3 to mediate necroptosis. Instead, PGAM5 protects cells from necroptosis by independently promoting mitophagy. PGAM5 promotion of mitophagy may represent a therapeutic target for stroke, myocardial infarction and other diseases caused by oxidative damage and necroptosis. C1 [Lu, Wei; Zheng, Lixin; Lenardo, Michael J.] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Sun, Junhui; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Yoon, Jeong Seon; Mattson, Mark P.] NIA, Cellular & Mol Neurosci Sect, Lab Neurosci, NIH, Baltimore, MD 21224 USA. [Zhang, Yan] NCI, Mol Mech Apoptosis Sect, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lenardo@nih.gov FU Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Heart Lung and Blood Institute; National Institute on Aging, National Institutes of Health FX This work was supported in part by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases, National Heart Lung and Blood Institute and the National Institute on Aging, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 6 Z9 7 U1 4 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2016 VL 11 IS 1 AR e0147792 DI 10.1371/journal.pone.0147792 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9FZ UT WOS:000369527800211 PM 26807733 ER PT J AU Wood, R Morrow, C Barry, CE Bryden, WA Call, CJ Hickey, AJ Rodes, CE Scriba, TJ Blackburn, J Issarow, C Mulder, N Woodward, J Moosa, A Singh, V Mizrahi, V Warner, DF AF Wood, Robin Morrow, Carl Barry, Clifton E., III Bryden, Wayne A. Call, Charles J. Hickey, Anthony J. Rodes, Charles E. Scriba, Thomas J. Blackburn, Jonathan Issarow, Chacha Mulder, Nicola Woodward, Jeremy Moosa, Atica Singh, Vinayak Mizrahi, Valerie Warner, Digby F. TI Real-Time Investigation of Tuberculosis Transmission: Developing the Respiratory Aerosol Sampling Chamber (RASC) SO PLOS ONE LA English DT Article ID AIRBORNE MYCOBACTERIUM-TUBERCULOSIS; POLYMERASE-CHAIN-REACTION; AIR; INFECTION; TB; ADOLESCENTS; COMPLEX; CYCLE AB Knowledge of the airborne nature of respiratory disease transmission owes much to the pioneering experiments of Wells and Riley over half a century ago. However, the mechanical, physiological, and immunopathological processes which drive the production of infectious aerosols by a diseased host remain poorly understood. Similarly, very little is known about the specific physiological, metabolic and morphological adaptations which enable pathogens such as Mycobacterium tuberculosis (Mtb) to exit the infected host, survive exposure to the external environment during airborne carriage, and adopt a form that is able to enter the respiratory tract of a new host, avoiding innate immune and physical defenses to establish a nascent infection. As a first step towards addressing these fundamental knowledge gaps which are central to any efforts to interrupt disease transmission, we developed and characterized a small personal clean room comprising an array of sampling devices which enable isolation and representative sampling of airborne particles and organic matter from tuberculosis (TB) patients. The complete unit, termed the Respiratory Aerosol Sampling Chamber (RASC), is instrumented to provide real-time information about the particulate output of a single patient, and to capture samples via a suite of particulate impingers, impactors and filters. Applying the RASC in a clinical setting, we demonstrate that a combination of molecular and microbiological assays, as well as imaging by fluorescence and scanning electron microscopy, can be applied to investigate the identity, viability, and morphology of isolated aerosolized particles. Importantly, from a preliminary panel of active TB patients, we observed the real-time production of large numbers of airborne particles including Mtb, as confirmed by microbiological culture and polymerase chain reaction (PCR) genotyping. Moreover, direct imaging of captured samples revealed the presence of multiple rod-like Mtb organisms whose physical dimensions suggested the capacity for travel deep into the alveolar spaces of the human lung. C1 [Wood, Robin; Morrow, Carl; Barry, Clifton E., III; Scriba, Thomas J.; Blackburn, Jonathan; Issarow, Chacha; Mulder, Nicola; Moosa, Atica; Singh, Vinayak; Mizrahi, Valerie; Warner, Digby F.] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med IDM, ZA-7925 Cape Town, South Africa. [Wood, Robin; Morrow, Carl] Univ Cape Town, IDM, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Barry, Clifton E., III] NIAID, Lab Clin Infect Dis, US Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Bryden, Wayne A.; Call, Charles J.] Zeteo Tech LLC, Ellicott City, MD USA. [Hickey, Anthony J.] RTI Int, Res Triangle Pk, NC USA. [Rodes, Charles E.] Aerosol Exposure Dimens, Cary, NC USA. [Scriba, Thomas J.] Univ Cape Town, Dept Paediat & Child Hlth, South African TB Vaccine Initiat, Cape Town, South Africa. [Blackburn, Jonathan; Issarow, Chacha; Mulder, Nicola; Woodward, Jeremy] Univ Cape Town, Fac Hlth Sci, Dept Integrat Biomed Sci, Struct Biol Res Unit, ZA-7925 Cape Town, South Africa. [Moosa, Atica; Singh, Vinayak; Mizrahi, Valerie; Warner, Digby F.] Univ Cape Town, Fac Hlth Sci, MRC NHLS UCT Mol Mycobacteriol Res Unit, Cape Town, South Africa. [Moosa, Atica; Singh, Vinayak; Mizrahi, Valerie; Warner, Digby F.] Univ Cape Town, Fac Hlth Sci, DST NRF Ctr Excellence Biomed TB Res, Dept Pathol, Cape Town, South Africa. RP Morrow, C (reprint author), Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med IDM, ZA-7925 Cape Town, South Africa.; Morrow, C (reprint author), Univ Cape Town, IDM, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. EM Carl.Morrow@hiv-research.org.za RI Barry, III, Clifton/H-3839-2012; SINGH, VINAYAK/L-8442-2016 OI SINGH, VINAYAK/0000-0001-9002-2489 FU Bill & Melinda Gates Foundation [OPP1116641, 26123]; National Treasury under Economic Competitiveness and Support Package [MRC-RFA-UFSP-01-2013/CCAMP]; Intramural Research Program of the NIAID, NIH; South African Medical Research Council (MRC) FX This work is funded by grants from the Bill & Melinda Gates Foundation (OPP1116641), and the South African Medical Research Council (MRC) with funds from National Treasury under the Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013/CCAMP) (RW CM TJS JB CI NM JW AM VS VM DFW); the Intramural Research Program of the NIAID, NIH (CEB); and Bill & Melinda Gates Foundation Investment ID 26123 (WAB CJC AJH CER).; Academic and technical support was provided from The Tuberculosis Aerobiology Advisory Group (TAAG) funded by the Bill and Melinda Gates Foundation. NR 29 TC 2 Z9 2 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 25 PY 2016 VL 11 IS 1 AR e0146658 DI 10.1371/journal.pone.0146658 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DC9FZ UT WOS:000369527800030 PM 26807816 ER PT J AU Kong, LJ Tang, JY Cui, M AF Kong, Lingjie Tang, Jianyong Cui, Meng TI In vivo volumetric imaging of biological dynamics in deep tissue via wavefront engineering SO OPTICS EXPRESS LA English DT Article ID ADAPTIVE COMPENSATION TECHNIQUE; 2-PHOTON MICROSCOPY; NEURONAL-ACTIVITY; CONFOCAL MICROSCOPY; OPTICAL MICROSCOPY; MOUSE-BRAIN; LIGHT; SYSTEM; CELLS AB Biological systems undergo dynamical changes continuously which span multiple spatial and temporal scales. To study these complex biological dynamics in vivo, high-speed volumetric imaging that can work at large imaging depth is highly desired. However, deep tissue imaging suffers from wavefront distortion, resulting in reduced Strehl ratio and image quality. Here we combine the two wavefront engineering methods developed in our lab, namely the optical phase-locked ultrasound lens based volumetric imaging and the iterative multiphoton adaptive compensation technique, and demonstrate in vivo volumetric imaging of microglial and mitochondrial dynamics at large depth in mouse brain cortex and lymph node, respectively. (C) 2016 Optical Society of America C1 [Kong, Lingjie; Cui, Meng] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Tang, Jianyong] NIAID, Lab Syst Biol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Cui, Meng] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Cui, Meng] Purdue Univ, Integrated Imaging Cluster, W Lafayette, IN 47907 USA. [Cui, Meng] Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. RP Cui, M (reprint author), Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Integrated Imaging Cluster, W Lafayette, IN 47907 USA.; Cui, M (reprint author), Purdue Univ, Bindley Biosci Ctr, W Lafayette, IN 47907 USA. EM mengcui@purdue.edu RI kong, lingjie/G-5822-2012 OI kong, lingjie/0000-0003-1974-3245 FU NIH [1U01NS094341-01]; Purdue University; Howard Hughes Medical Institute; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX L.K. and M.C. thank the support from NIH (1U01NS094341-01), Purdue University, and Howard Hughes Medical Institute. This research was also supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 47 TC 3 Z9 3 U1 6 U2 22 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JAN 25 PY 2016 VL 24 IS 2 BP 1214 EP 1221 DI 10.1364/OE.24.001214 PG 8 WC Optics SC Optics GA DC2SJ UT WOS:000369066300087 PM 26832504 ER PT J AU Blackstone, C AF Blackstone, Craig TI KIF1B beta and Neuroblastoma: Failure to Divide and Cull SO DEVELOPMENTAL CELL LA English DT Editorial Material ID MITOCHONDRIA; DRP1; 1P36; GENE AB Neuroblastomas are associated with KIF1B beta mutations within tumor suppressor region 1p36. In this issue of Developmental Cell, Li et al. (2016) show that KIF1B beta binding releases calcineurin autoinhibition, leading to dephosphorylation of the DRP1 GTPase and subsequent mitochondria! fragmentation. KIF1B beta impairment causes mitochondrial hyperfusion, impairing developmental apoptosis and promoting tumorigenesis. C1 [Blackstone, Craig] NINDS, Neurogenet Branch, NIH, Bldg 35,Room 2A-201,9000 Rockville Pike, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 35,Room 2A-201,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov NR 10 TC 0 Z9 0 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD JAN 25 PY 2016 VL 36 IS 2 BP 127 EP 128 DI 10.1016/j.devcel.2016.01.005 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA DC6TV UT WOS:000369353400001 PM 26812010 ER PT J AU Ito, K Mitsunaga, M Arihiro, S Saruta, M Matsuoka, M Kobayashi, H Tajiri, H AF Ito, Kimihiro Mitsunaga, Makoto Arihiro, Seiji Saruta, Masayuki Matsuoka, Mika Kobayashi, Hisataka Tajiri, Hisao TI Molecular targeted photoimmunotherapy for HER2-positive human gastric cancer in combination with chemotherapy results in improved treatment outcomes through different cytotoxic mechanisms SO BMC CANCER LA English DT Article DE Molecular targeted therapy; Photoimmunotherapy; HER2; Gastric cancer; 5-fluorouracil ID NEAR-INFRARED PHOTOIMMUNOTHERAPY; THYMIDYLATE SYNTHETASE; MONOCLONAL-ANTIBODIES; GENE AMPLIFICATION; HER2; IMMUNOTHERAPY; TRASTUZUMAB; THERAPY; FUTURE; TUMORS AB Background: Photoimmunotherapy (PIT) is a novel type of molecular optical imaging-guided cancer phototherapy based on a monoclonal antibody conjugated to a photosensitizer, IR700, in combination with near-infrared (NIR) light. PIT rapidly causes target-specific cell death by inducing cell membrane damages and appears to be highly effective; however, we have previously demonstrated that tumor recurrences were eventually seen in PIT-treated mice, likely owing to inhomogeneous mAb-IR700 conjugate distribution in the tumor, thus limiting the effectiveness of PIT as a monotherapy. Here, we examined the effects of human epidermal growth factor-2 (HER2)-targeted PIT in combination with 5-fluorouracil (5-FU) compared to PIT alone for HER2-expressing human gastric cancer cells. Methods: NCI-N87 cells, HER2-positive human gastric cancer cells, were used for the experiments. Trastuzumab, a monoclonal antibody directed against HER2, was conjugated to IR700. To assess the short-term cytotoxicity and examine the apoptotic effects upon addition of 5-FU in vitro, we performed LIVE/DEAD and caspase-3 activity assays. Additionally, to explore the effects on long-term growth inhibition, trypan blue dye exclusion assay was performed. NCI-N87 tumor xenograft models were prepared for in vivo treatment studies and the tumor-bearing mice were randomized into various treatment groups. Results: Compared to PIT alone, the combination of HER2-targeted PIT and 5-FU rapidly induced significant cytotoxicity in both the short-term and long-term cytotoxicity assays. While both 5-FU and/or trastuzumab-IR700 conjugate treatment induced an increase in caspase-3 activity, there was no additional increase in caspase-3 activity upon NIR light irradiation after incubation with 5-FU and/or trastuzumab-IR700. The combination of HER2-targeted PIT and 5-FU resulted in greater and longer tumor growth inhibition than PIT monotherapy in vivo. This combined effect of PIT and 5-FU is likely owing to their different mechanisms of inducing tumor cell death, namely necrotic membrane damage by PIT and apoptotic cell death by 5-FU and trastuzumab. Conclusions: PIT in combination with 5-FU resulted in enhanced antitumor effects compared to PIT alone for HER2-expressing human gastric cancer in vitro and in vivo. This combination photoimmunochemotherapy represents a practical method for treating human gastric cancer and should be investigated further in the clinical setting. C1 [Ito, Kimihiro; Mitsunaga, Makoto; Arihiro, Seiji; Saruta, Masayuki; Matsuoka, Mika; Tajiri, Hisao] Jikei Univ, Div Gastroenterol & Hepatol, Dept Internal Med, Sch Med,Minato Ku, 3-25-8 Nishishinbashi, Tokyo 1058461, Japan. [Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,RoomB3B69,MSC1088, Bethesda, MD 20892 USA. RP Mitsunaga, M (reprint author), Jikei Univ, Div Gastroenterol & Hepatol, Dept Internal Med, Sch Med,Minato Ku, 3-25-8 Nishishinbashi, Tokyo 1058461, Japan. EM mit@jikei.ac.jp FU JSPS [26710010]; Uehara Memorial Foundation; Kato Memorial Bioscience Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; Kowa Life Science Foundation; Nakayama Cancer Research Institute; Jikei University Research Fund FX We thank Yuko Kamata for providing technical support and Dr. Toru Harada for tissue processing. Grant supports: Grant-in-Aid for Young Scientists (A) (JSPS KAKENHI 26710010 to M. Mitsunaga), Uehara Memorial Foundation to M. Mitsunaga, Kato Memorial Bioscience Foundation to M. Mitsunaga, Mochida Memorial Foundation for Medical and Pharmaceutical Research to M. Mitsunaga, Takeda Science Foundation to M. Mitsunaga, Kowa Life Science Foundation to M. Mitsunaga, Nakayama Cancer Research Institute to M. Mitsunaga, and The Jikei University Research Fund to K.I. and M. Mitsunaga. NR 29 TC 1 Z9 1 U1 3 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 25 PY 2016 VL 16 AR 37 DI 10.1186/s12885-016-2072-0 PG 10 WC Oncology SC Oncology GA DC0FM UT WOS:000368892600001 PM 26810644 ER PT J AU Bogoch, II Brady, OJ Kraemer, MUG German, M Creatore, MI Kulkarni, MA Brownstein, JS Mekaru, SR Hay, SI Groot, E Watts, A Khan, K AF Bogoch, Isaac I. Brady, Oliver J. Kraemer, Moritz U. G. German, Matthew Creatore, Marisa I. Kulkarni, Manisha A. Brownstein, John S. Mekaru, Sumiko R. Hay, Simon I. Groot, Emily Watts, Alexander Khan, Kamran TI Anticipating the international spread of Zika virus from Brazil SO LANCET LA English DT Letter C1 [Bogoch, Isaac I.; Khan, Kamran] Univ Toronto, Dept Med, Div Infect Dis, Toronto, ON, Canada. [Bogoch, Isaac I.] Univ Hlth Network, Div Internal Med, Toronto, ON, Canada. [Bogoch, Isaac I.] Univ Hlth Network, Div Infect Dis, Toronto, ON, Canada. [Creatore, Marisa I.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Kraemer, Moritz U. G.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford, England. [German, Matthew; Creatore, Marisa I.; Watts, Alexander; Khan, Kamran] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Kulkarni, Manisha A.] Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada. [Brownstein, John S.; Mekaru, Sumiko R.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Brady, Oliver J.; Hay, Simon I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Hay, Simon I.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Hay, Simon I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Khan, K (reprint author), Univ Toronto, Dept Med, Div Infect Dis, Toronto, ON, Canada. EM khank@smh.ca RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Brady, Oliver/0000-0002-3235-2129 FU NLM NIH HHS [R01 LM010812]; Wellcome Trust [095066] NR 5 TC 89 Z9 98 U1 8 U2 214 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 23 PY 2016 VL 387 IS 10016 BP 335 EP 336 DI 10.1016/S0140-6736(16)00080-5 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DB4XI UT WOS:000368516500019 PM 26777915 ER PT J AU Taichman, DB Backus, J Baethge, C Bauchner, H de Leeuw, PW Drazen, JM Fletcher, J Frizelle, FA Groves, T AF Taichman, Darren B. Backus, Joyce Baethge, Christopher Bauchner, Howard de Leeuw, Peter W. Drazen, Jeffrey M. Fletcher, John Frizelle, Frank A. Groves, Trish TI Sharing clinical trial data: a proposal from the International Committee of Medical Journal Editors SO LANCET LA English DT Editorial Material C1 [Taichman, Darren B.] Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. [Frizelle, Frank A.] World Assoc Med Editors, New Delhi, India. RP Taichman, DB (reprint author), Natl Lib Med, Lib Operat, Bethesda, MD 20894 USA. EM dtaichman@acponline.org OI Groves, Trish/0000-0001-7915-6419 NR 1 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JAN 23 PY 2016 VL 387 IS 10016 BP E9 EP E11 DI 10.1016/S0140-6736(15)01279-9 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DB4XI UT WOS:000368516500001 PM 26803441 ER PT J AU Agol, V Cello, J Chumakov, K Ehrenfeld, E Wimmer, E AF Agol, Vadim Cello, Jeronimo Chumakov, Konstantin Ehrenfeld, Ellie Wimmer, Eckard TI Eradicating polio: A balancing act SO SCIENCE LA English DT Letter C1 [Agol, Vadim; Chumakov, Konstantin] MP Chumakov Inst Poliomyelitis & Viral Encephalit, Moscow 142782, Russia. [Agol, Vadim] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physical Chem Biol, Moscow 119899, Russia. [Cello, Jeronimo; Wimmer, Eckard] SUNY Stony Brook, Dept Mol Genet & Microbiol, Sch Med, Stony Brook, NY 11794 USA. [Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. [Ehrenfeld, Ellie] NIAID, NIH, Bethesda, MD 20892 USA. RP Chumakov, K (reprint author), US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD 20903 USA. EM Konstantin.Chumakov@fda.hhs.gov NR 4 TC 0 Z9 0 U1 2 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JAN 22 PY 2016 VL 351 IS 6271 BP 348 EP 348 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB3VH UT WOS:000368440500028 PM 26798005 ER PT J AU Sinha, P Aarnisalo, P Chubb, R Poulton, IJ Guo, J Nachtrab, G Kimura, T Swami, S Saeed, H Chen, M Weinstein, LS Schipani, E Sims, NA Kronenberg, HM Wu, JY AF Sinha, Partha Aarnisalo, Piia Chubb, Rhiannon Poulton, Ingrid J. Guo, Jun Nachtrab, Gregory Kimura, Takaharu Swami, Srilatha Saeed, Hamid Chen, Min Weinstein, Lee S. Schipani, Ernestina Sims, Natalie A. Kronenberg, Henry M. Wu, Joy Y. TI Loss of G(s)alpha in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OSTEOBLASTIC CELLS; MESENCHYMAL PROGENITORS; POSTMENOPAUSAL WOMEN; INTERMITTENT PTH; PHOSPHOLIPASE-C; MINERAL DENSITY; PROTEIN-KINASE; IN-VIVO; DIFFERENTIATION; RECEPTOR AB Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including G(s)alpha. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of G(s)alpha in the osteoblast lineage. Postnatal removal of G(s)alpha in the osteoblast lineage (P-G(s)alpha(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 mu g/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-G(s)alpha(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-G(s)alpha(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via G(s)alpha but not phospholipase C via G(q/11) (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of G(s)alpha in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond G(s)alpha and G(q/11) act downstream of PTH on osteoblast differentiation. C1 [Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon; Guo, Jun; Nachtrab, Gregory; Kronenberg, Henry M.; Wu, Joy Y.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Aarnisalo, Piia] Univ Helsinki, Dept Clin Chem, Helsinki 00029, Finland. [Aarnisalo, Piia] Univ Helsinki, Cent Hosp, HUSLAB, Lab Serv, Helsinki 00029, Finland. [Poulton, Ingrid J.; Sims, Natalie A.] Univ Melbourne, St Vincents Inst, Fitzroy, Vic 3065, Australia. [Poulton, Ingrid J.; Sims, Natalie A.] Univ Melbourne, St Vincents Hosp, Dept Med, Fitzroy, Vic 3065, Australia. [Kimura, Takaharu; Swami, Srilatha; Saeed, Hamid; Wu, Joy Y.] Stanford Univ, Sch Med, Div Endocrinol, 300 Pasteur Dr,S-025, Stanford, CA 94305 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, NIH, Metab Dis Branch, Bethesda, MD 20892 USA. [Schipani, Ernestina] Univ Michigan, Dept Orthoped Surg, Ann Arbor, MI 48109 USA. [Schipani, Ernestina] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. RP Wu, JY (reprint author), Stanford Univ, Sch Med, Div Endocrinol, 300 Pasteur Dr,S-025, Stanford, CA 94305 USA. EM jywu1@stanford.edu FU National Institutes of Health [AR054741, AR059942, AR061228, DK011794]; NIDDK Intramural Research Program FX This work was supported by National Institutes of Health Grants AR054741 and AR059942 (to J. Y. W.), AR061228 (to P. S.), and DK011794 (to H. M. K.) and the NIDDK Intramural Research Program (to M. C. and L. S. W.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 50 TC 4 Z9 4 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 22 PY 2016 VL 291 IS 4 BP 1631 EP 1642 DI 10.1074/jbc.M115.679753 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB6JI UT WOS:000368620700008 PM 26598522 ER PT J AU Strickfaden, H McDonald, D Kruhlak, MJ Haince, JF Th'ng, JPH Rouleau, M Ishibashi, T Corry, GN Ausio, J Underhill, DA Pokier, GG Hendzel, MJ AF Strickfaden, Hilmar McDonald, Darin Kruhlak, Michael J. Haince, Jean-Francois Th'ng, John P. H. Rouleau, Michele Ishibashi, Toytaka Corry, Gareth N. Ausio, Juan Underhill, D. Alan Pokier, Guy G. Hendzel, Michael J. TI Poly(ADP-ribosyl)ation-dependent Transient Chromatin Decondensation and Histone Displacement following Laser Microirradiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; BINDING-PROPERTIES; ADP-RIBOSYLATION; LIVING CELLS; REPAIR; POLY(ADP-RIBOSE); RECRUITMENT; PARP-1; ATM AB Chromatin undergoes a rapid ATP-dependent, ATM and H2AX-independent decondensation when DNA damage is introduced by laser microirradiation. Although the detailed mechanism of this decondensation remains to be determined, the kinetics of decondensation are similar to the kinetics of poly(ADP-ribosyl)ation. We used laser microirradiation to introduce DNA strand breaks into living cells expressing a photoactivatable GFP-tagged histone H2B. We find that poly(ADPribosyl)ation mediated primarily by poly(ADP-ribose) polymerase 1 (PARP1) is responsible for the rapid decondensation of chromatin at sites of DNA damage. This decondensation of chromatin correlates temporally with the displacement of histones, which is sensitive to PARP inhibition and is transient in nature. Contrary to the predictions of the histone shuttle hypothesis, we did not find that histone H1 accumulated on poly(ADP-ribose) (PAR) in vivo. Rather, histone H1, and to a lessor extent, histones H2A and H2B were rapidly depleted from the sites of PAR accumulation. However, histone H1 returns to chromatin and the chromatin recondenses. Thus, the PARP-dependent relaxation of chromatin closely correlates with histone displacement. C1 [Strickfaden, Hilmar; McDonald, Darin; Corry, Gareth N.; Underhill, D. Alan; Pokier, Guy G.; Hendzel, Michael J.] Univ Alberta, Fac Dent & Med, Dept Oncol, Edmonton, AB T6G IZ2, Canada. [Kruhlak, Michael J.] NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Th'ng, John P. H.] Northern Ontario Sch Med, Thunder Bay, ON P7B 5E1, Canada. [Ishibashi, Toytaka; Ausio, Juan] Univ Victoria, Dept Biochem & Microbiol, POB 3055, Victoria, BC V8W 3P6, Canada. [Ishibashi, Toytaka] Hong Kong Univ Sci & Technol, Div Life Sci, Kowloon, Hong Kong, Peoples R China. [Haince, Jean-Francois; Rouleau, Michele] Univ Laval, Fac Med, CHUQ, Oncol Axis,Laval Univ Hosp,Res Ctr, Quebec City, PQ G1V 4G2, Canada. RP Hendzel, MJ (reprint author), Univ Alberta, Dept Oncol, 11560 Univ Ave NW, Edmonton, AB T6G 1Z2, Canada. EM mhendzel@ualberta.ca FU Canadian Institutes of Health Research; Canadian Cancer Society; Alberta Cancer Research Institute; Alberta Cancer foundation; Bayrische Forschungsallianz FX This work was supported in part by grants from the Canadian Institutes of Health Research, the Canadian Cancer Society, and the Alberta Cancer Research Institute. The authors declare that they have no conflicts of interest with the contents of this article.; Holds a postdoctoral fellowship by the Alberta Cancer foundation and supported by the Bayrische Forschungsallianz. NR 47 TC 3 Z9 3 U1 3 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 22 PY 2016 VL 291 IS 4 BP 1789 EP 1802 DI 10.1074/jbc.M115.694992 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DB6JI UT WOS:000368620700020 PM 26559976 ER PT J AU Corona, A Meleddu, R Esposito, F Distinto, S Bianco, G Masaoka, T Maccioni, E Menendez-Arias, L Alcaro, S Le Grice, SFJ Tramontano, E AF Corona, Angela Meleddu, Rita Esposito, Francesca Distinto, Simona Bianco, Giulia Masaoka, Takashi Maccioni, Elias Menendez-Arias, Luis Alcaro, Stefano Le Grice, Stuart F. J. Tramontano, Enzo TI Ribonuclease H/DNA Polymerase HIV-1 Reverse Transcriptase Dual Inhibitor: Mechanistic Studies on the Allosteric Mode of Action of Isatin-Based Compound RMNC6 SO PLOS ONE LA English DT Article ID HIGH-RESOLUTION STRUCTURES; RNASE-H ACTIVITIES; DNA-SYNTHESIS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; FORCE-FIELD; PRIMER GRIP; RESISTANCE; MUTATIONS; SITE AB The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC50 values of 1.4 and 9.8 mu M on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibitor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT. C1 [Corona, Angela; Meleddu, Rita; Esposito, Francesca; Distinto, Simona; Bianco, Giulia; Maccioni, Elias; Tramontano, Enzo] Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy. [Masaoka, Takashi; Le Grice, Stuart F. J.] NCI, Frederick, MD 21701 USA. [Menendez-Arias, Luis] CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain. [Menendez-Arias, Luis] Univ Autonoma Madrid, Madrid, Spain. [Alcaro, Stefano] Magna Graecia Univ Catanzaro, Dipartimento Sci Salute, Campus S Venuta,Viale Europa, I-88100 Catanzaro, Italy. [Tramontano, Enzo] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. RP Tramontano, E (reprint author), Univ Cagliari, Dept Life & Environm Sci, Cagliari, Italy. EM tramon@unica.it RI Corona, Angela/G-7327-2014; Menendez Arias, Luis /G-2436-2016; Tramontano, Enzo/B-4919-2012; Menendez Arias, Luis/N-7447-2016; Esposito, Francesca/I-8879-2012 OI Corona, Angela/0000-0002-6630-8636; Tramontano, Enzo/0000-0002-4849-0980; Menendez Arias, Luis/0000-0002-1251-6640; Esposito, Francesca/0000-0001-9725-7977 FU RAS [LR 7/2007CRP-24915]; Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; Spanish Ministry of Economy and Competitiveness [BIO2013-48788-C2-1-R]; Fundacion Ramon Areces FX This work was supported by RAS grant LR 7/2007CRP-24915. T.M. and S.L.G. are supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Work in Madrid was supported by grant BIO2013-48788-C2-1-R (Spanish Ministry of Economy and Competitiveness) and an institutional grant of Fundacion Ramon Areces. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 3 Z9 3 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 22 PY 2016 VL 11 IS 1 AR e0147225 DI 10.1371/journal.pone.0147225 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB6WB UT WOS:000368655300075 PM 26800261 ER PT J AU Jandu, H Aluzaite, K Fogh, L Thrane, SW Noer, JB Proszek, J Do, KN Hansen, SN Damsgaard, B Nielsen, SL Stougaard, M Knudsen, BR Moreira, J Hamerlik, P Gajjar, M Smid, M Martens, J Foekens, J Pommier, Y Brunner, N Schrohl, AS Stenvang, J AF Jandu, Haatisha Aluzaite, Kristina Fogh, Louise Thrane, Sebastian Wingaard Noer, Julie B. Proszek, Joanna Khoa Nguyen Do Hansen, Stine Ninel Damsgaard, Britt Nielsen, Signe Lykke Stougaard, Magnus Knudsen, Birgitta R. Moreira, Jose Hamerlik, Petra Gajjar, Madhavsai Smid, Marcel Martens, John Foekens, John Pommier, Yves Brunner, Nils Schrohl, Anne-Sofie Stenvang, Jan TI Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines SO BMC CANCER LA English DT Article DE Breast cancer; Topoisomerase I; Irinotecan; SN-38; Resistance; ABCG2/BCRP ID HUMAN TOPOISOMERASE-I; COLORECTAL-CANCER; DRUG-SENSITIVITY; LUNG-CANCER; CAMPTOTHECIN; CHEMOTHERAPY; VITRO; PHOSPHORYLATION; OVEREXPRESSION; ANTHRACYCLINE AB Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF 7 and MDA MB 231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan. C1 [Jandu, Haatisha; Aluzaite, Kristina; Fogh, Louise; Thrane, Sebastian Wingaard; Noer, Julie B.; Hansen, Stine Ninel; Damsgaard, Britt; Nielsen, Signe Lykke; Moreira, Jose; Brunner, Nils; Schrohl, Anne-Sofie; Stenvang, Jan] Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Dis Biol, Sect Mol Dis Biol, Strandblvd 49, DK-2100 Copenhagen, Denmark. [Jandu, Haatisha; Aluzaite, Kristina; Fogh, Louise; Thrane, Sebastian Wingaard; Noer, Julie B.; Hansen, Stine Ninel; Damsgaard, Britt; Nielsen, Signe Lykke; Moreira, Jose; Brunner, Nils; Schrohl, Anne-Sofie; Stenvang, Jan] Univ Copenhagen, Sinodanish Breast Canc Res Ctr, Strandblvd 49, DK-2100 Copenhagen, Denmark. [Proszek, Joanna; Stougaard, Magnus] Aarhus Univ Hosp, Dept Pathol, Noerrebrogade 44,Bldg 18B, DK-8000 Aarhus C, Denmark. [Khoa Nguyen Do] Tech Univ Denmark, DTU Multiassay Core DMAC, Kemitorvet Bldg 208, DK-2800 Lyngby, Denmark. [Knudsen, Birgitta R.] Aarhus Univ, Dept Mol Biol & Genet, CF Mollers Alle 3, DK-8000 Aarhus C, Denmark. [Hamerlik, Petra; Gajjar, Madhavsai] Danish Canc Soc, Res Ctr, Brain Tumor Biol, Strandblvd 49, DK-2100 Copenhagen, Denmark. [Smid, Marcel; Martens, John; Foekens, John] Erasmus MC, Inst Canc, Dept Med Oncol & Canc Genom Netherlands, Rotterdam, Netherlands. [Pommier, Yves] NCI, NIH, Ctr Canc Res, Dev Therapeut Branch, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. [Pommier, Yves] NCI, NIH, Lab Mol, Pharmacol, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. RP Stenvang, J (reprint author), Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Dis Biol, Sect Mol Dis Biol, Strandblvd 49, DK-2100 Copenhagen, Denmark.; Stenvang, J (reprint author), Univ Copenhagen, Sinodanish Breast Canc Res Ctr, Strandblvd 49, DK-2100 Copenhagen, Denmark. EM stenvang@sund.ku.dk FU IMK foundation; Danish National Research Foundation [26-331-86-2]; Sino-Danish Breast Cancer Research Centre; Race Against Breast Cancer; Danish Center for Translational Breast Cancer Research; John and Birthe Meyer Foundation; Netherlands Genomics Initiative (NGI)/the Netherlands Organization for Scientific Research FX We acknowledge DAKO A/S, Denmark for providing the TOP1 probe mix. This work was supported by The IMK foundation; Danish National Research Foundation (26-331-86-2): Sino-Danish Breast Cancer Research Centre; A Race Against Breast Cancer; Danish Center for Translational Breast Cancer Research; The John and Birthe Meyer Foundation; and the Netherlands Genomics Initiative (NGI)/the Netherlands Organization for Scientific Research. NR 50 TC 3 Z9 3 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JAN 22 PY 2016 VL 16 AR 34 DI 10.1186/s12885-016-2071-1 PG 13 WC Oncology SC Oncology GA DB4ME UT WOS:000368486300001 PM 26801902 ER PT J AU Simpson, EA Nicolini, Y Shetler, M Suomi, SJ Ferrari, PF Paukner, A AF Simpson, Elizabeth A. Nicolini, Ylenia Shetler, Melissa Suomi, Stephen J. Ferrari, Pier F. Paukner, Annika TI Experience-independent sex differences in newborn macaques: Females are more social than males SO SCIENTIFIC REPORTS LA English DT Article ID GENDER-DIFFERENCES; NEONATAL IMITATION; RHESUS-MONKEY; YOUNG INFANTS; BEHAVIOR; MOTHER; AUTISM; SOCIALIZATION; LIFE; EYE AB Human females exhibit greater social interest and skills relative to males, appearing in infancy, suggesting biological roots; however, male and female infants may be treated differently, potentially causing or amplifying sex differences. Here, we tested whether sex differences in social motivation emerge in infant monkeys (n = 48) reared in a controlled postnatal environment. Compared to males, females at 2-3 weeks looked more at conspecifics' faces (d = 0.65), especially the eyes (d = 1.09), and at 4-5 weeks exhibited more affiliative behaviors (d = 0.64), including gesturing, looking, and proximity to familiar and unfamiliar human caretakers. In sum, converging evidence from humans and monkeys suggests that female infants are more social than males in the first weeks of life, and that such differences may arise independent of postnatal experience. Individual differences in social interest have wide-ranging developmental consequences, impacting infants' social interaction quality and opportunities for learning. Understanding the evolution of sex differences and their developmental emergence is necessary to best support infants with varying levels of sociality. C1 [Simpson, Elizabeth A.] Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. [Simpson, Elizabeth A.; Suomi, Stephen J.; Paukner, Annika] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Dept Hlth & Human Serv, Poolesville, MD USA. [Simpson, Elizabeth A.; Nicolini, Ylenia; Ferrari, Pier F.] Univ Parma, Dipartimento Neurosci, I-4300 Parma, Italy. [Shetler, Melissa] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Comp Support Serv, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Simpson, EA (reprint author), Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA.; Simpson, EA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Dept Hlth & Human Serv, Poolesville, MD USA.; Simpson, EA (reprint author), Univ Parma, Dipartimento Neurosci, I-4300 Parma, Italy. EM simpsone@miami.edu FU Division of Intramural Research, NICHD; NICHD [P01HD064653] FX This work was supported by the Division of Intramural Research, NICHD, and NICHD P01HD064653 (to PFF). We thank Timothy Mrozek for stimulus creation, Grace Maloney and Sheila Sutti for collecting eye tracking data, Michelle Miller, Anna Casey, Mandy Riddle, Ryan McNeil, Neal Marquez, and Kristen Byers for serving as the models for the human interaction test, Stefano Kaburu for caregiver interaction observations, and Kielee Jennings for data entry. NR 64 TC 4 Z9 4 U1 4 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 22 PY 2016 VL 6 AR 19669 DI 10.1038/srep19669 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB7HI UT WOS:000368685000001 PM 26794858 ER PT J AU Zhu, WZ Tsang, S Browe, DM Woo, AYH Huang, Y Xu, CJ Liu, JF Lv, FX Zhang, Y Xiao, RP AF Zhu, Weizhong Tsang, Sharon Browe, David M. Woo, Anthony Y. H. Huang, Ying Xu, Chanjuan Liu, Jian-Feng Lv, Fengxiang Zhang, Yan Xiao, Rui-ping TI Interaction of beta 1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling SO JCI INSIGHT LA English DT Article ID GLYCATION END-PRODUCTS; ACUTE MYOCARDIAL-INFARCTION; HEART-ATTACK TRIAL; DIABETES-MELLITUS; PROTEIN-KINASE; NONDIABETIC PATIENTS; DILATED CARDIOMYOPATHY; INDEPENDENT ACTIVATION; ACUTE HYPERGLYCEMIA; NEURITE OUTGROWTH AB Stimulation of beta 1-adrenergic receptor (beta 1AR), a GPCR, and the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor (PRR), have been independently implicated in the pathogenesis of cardiomyopathy caused by various etiologies, including myocardial infarction, ischemia/reperfusion injury, and metabolic stress. Here, we show that the two distinctly different receptors, beta 1AR and RAGE, are mutually dependent in mediating myocardial injury and the sequelae of cardiomyopathy. Deficiency or inhibition of RAGE blocks beta 1AR- and RAGE-mediated myocardial cell death and maladaptive remodeling. Ablation or blockade of beta 1AR fully abolishes RAGE-induced detrimental effects. Mechanistically, RAGE and beta 1AR form a complex, which in turn activates Ca2+/calmodulin-dependent kinase II (CaMKII), resulting in loss of cardiomyocytes and myocardial remodeling. These results indicate that RAGE and beta 1AR not only physically crosstalk at the receptor level, but also functionally converge at the common mediator, CaMKII, highlighting a combined inhibition of RAGE and beta 1AR as a more effective therapy to treat diverse cardiovascular diseases, such as myocardial infarction, ischemia/reperfusion injury, and diabetic cardiovascular complications. C1 [Zhu, Weizhong] Nantong Univ, Sch Pharm, Nantong, Peoples R China. [Tsang, Sharon; Browe, David M.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Woo, Anthony Y. H.; Huang, Ying; Lv, Fengxiang; Zhang, Yan; Xiao, Rui-ping] Peking Univ, Inst Mol Med, State Key Lab Membrane Biol, Beijing, Peoples R China. [Woo, Anthony Y. H.] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang, Peoples R China. [Xu, Chanjuan; Liu, Jian-Feng] Huazhong Univ Sci & Technol, Sch Life Sci & Technol, Wuhan, Peoples R China. [Xiao, Rui-ping] Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China. [Xiao, Rui-ping] Beijing City Key Lab Cardiometab Mol Med, Beijing, Peoples R China. RP Zhang, Y; Xiao, RP (reprint author), Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. EM zhangyan9876@pku.edu.cn; xiaor@pku.edu.cn FU Intramural NIH HHS [Z01 AG000287-10, Z01 AG000287-11] NR 58 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JAN 21 PY 2016 VL 1 IS 1 AR e84969 DI 10.1172/jci.insight.84969 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1IK UT WOS:000387103000002 PM 26966719 ER PT J AU Martinez-Reyes, I Diebold, LP Kong, H Schieber, M Huang, H Hensley, CT Mehta, MM Wang, TY Santos, JH Woychik, R Dufour, E Spelbrink, JN Weinberg, SE Zhao, YM DeBerardinis, RJ Chandel, NS AF Martinez-Reyes, Inmaculada Diebold, Lauren P. Kong, Hyewon Schieber, Michael Huang, He Hensley, Christopher T. Mehta, Manan M. Wang, Tianyuan Santos, Janine H. Woychik, Richard Dufour, Eric Spelbrink, Johannes N. Weinberg, Samuel E. Zhao, Yingming DeBerardinis, Ralph J. Chandel, Navdeep S. TI TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions SO MOLECULAR CELL LA English DT Article ID REDUCTIVE CARBOXYLATION; HISTONE ACETYLATION; ALPHA-KETOGLUTARATE; ELECTRON-TRANSPORT; CELLS; METABOLISM; DYSFUNCTION; GROWTH; DNA; GENERATION AB Mitochondrial metabolism is necessary for the maintenance of oxidative TCA cycle function and mitochondrial membrane potential. Previous attempts to decipher whether mitochondria are necessary for biological outcomes have been hampered by genetic and pharmacologic methods that simultaneously disrupt multiple functions linked to mitochondrial metabolism. Here, we report that inducible depletion of mitochondrial DNA (rho degrees cells) diminished respiration, oxidative TCA cycle function, and the mitochondrial membrane potential, resulting in diminished cell proliferation, hypoxic activation of HIF-1, and specific histone acetylation marks. Genetic reconstitution only of the oxidative TCA cycle function specifically in these inducible rho degrees cells restored metabolites, resulting in re-establishment of histone acetylation. In contrast, genetic reconstitution of the mitochondrial membrane potential restored ROS, which were necessary for hypoxic activation of HIF-1 and cell proliferation. These results indicate that distinct mitochondrial functions associated with respiration are necessary for cell proliferation, epigenetics, and HIF-1 activation. C1 [Martinez-Reyes, Inmaculada; Diebold, Lauren P.; Kong, Hyewon; Schieber, Michael; Mehta, Manan M.; Weinberg, Samuel E.; Chandel, Navdeep S.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Huang, He; Zhao, Yingming] Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. [Hensley, Christopher T.; DeBerardinis, Ralph J.] Univ Texas SW Med Ctr Dallas, Res Inst, Childrens Med Ctr, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. [Wang, Tianyuan; Santos, Janine H.; Woychik, Richard] NIEHS, Div Extramural Res & Training, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. [Dufour, Eric] Univ Tampere, BioMediTech, Biokatu 8, Tampere 33520, Finland. [Dufour, Eric] Univ Tampere, Tampere Univ Hosp, Biokatu 8, Tampere 33520, Finland. [Spelbrink, Johannes N.] Radboud Univ Nijmegen, Nijmegen Ctr Mitochondrial Disorders, Dept Pediat, Med Ctr, Geert Grootepl 10,POB 9101, NL-6500 HB Nijmegen, Netherlands. RP Chandel, NS (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. EM nav@northwestern.edu RI Spelbrink, Johannes/L-4661-2015; OI Spelbrink, Johannes/0000-0002-9756-2602; Dufour, Eric/0000-0001-6690-5329 FU NIH [RO1 CA12306708, PO1AG049665, RO1 HL122062, T32 CA009560, T32 GM008061, T32 T32HL076139, T32 HL076139]; Ramon Areces Foundation of Spain; Netherlands Organization for Scientific Research [865.10.004]; Robert A. Welch Foundation [I17733]; [RO1 CA157996] FX This work was supported by NIH (RO1 CA12306708, PO1AG049665, and RO1 HL122062) to N.S.C., a postdoctoral fellowship by Ramon Areces Foundation of Spain (to I.M.-R.), NIH (T32 CA009560 to M.M.M.), NIH (T32 GM008061 to L.P.D.), NIH (T32 T32HL076139 to S.E.W.), and NIH (T32 HL076139 to M.S.). J.N.S. is supported by Netherlands Organization for Scientific Research (865.10.004). R.J.D. was supported by RO1 CA157996 and Robert A. Welch Foundation grant I17733. We thank Robert H. Lurie Cancer Center Flow Cytometry facility for their invaluable assistance. We thank the members of the Chandel lab for thoughtful discussion. NR 31 TC 18 Z9 19 U1 8 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD JAN 21 PY 2016 VL 61 IS 2 BP 199 EP 209 DI 10.1016/j.molcel.2015.12.002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DG8HX UT WOS:000372325400004 PM 26725009 ER PT J AU Min, KW Liggett, JL Silva, G Wu, WW Wang, R Shen, RF Eling, TE Baek, SJ AF Min, K-W Liggett, J. L. Silva, G. Wu, W. W. Wang, R. Shen, R-F Eling, T. E. Baek, S. J. TI NAG-1/GDF15 accumulates in the nucleus and modulates transcriptional regulation of the Smad pathway SO ONCOGENE LA English DT Article ID DRUG-ACTIVATED GENE-1; BETA SUPERFAMILY MEMBER; GROWTH-FACTOR-BETA; COLORECTAL-CANCER CELLS; MORPHOGENETIC PROTEIN; PROSTATE CARCINOMA; SIGNALING PATHWAY; TRANSGENIC MICE; MOUSE MODEL; EXPRESSION AB Protein dynamics, modifications and trafficking are all processes that can modulate protein activity. Accumulating evidence strongly suggests that many proteins have distinctive roles dependent on cellular location. Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a transforming growth factor-beta (TGF-beta) superfamily protein that has a role in cancer, obesity and inflammation. NAG-1 is synthesized and cleaved into a mature peptide, which is ultimately secreted into the extracellular matrix (ECM). In this study, we have found that full-length NAG-1 is expressed in not only the cytoplasm and ECM, but also in the nucleus. NAG-1 is dynamically moved to the nucleus, exported into cytoplasm and further transported into the ECM. We have also found that nuclear NAG-1 contributes to inhibition of the Smad pathway by interrupting the Smad complex. Overall, our study indicates that NAG-1 is localized in the nucleus and provides new evidence that NAG-1 controls transcriptional regulation in the Smad pathway. C1 [Min, K-W; Liggett, J. L.; Silva, G.; Baek, S. J.] Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, 2407 River Dr, Knoxville, TN 37996 USA. [Wu, W. W.; Wang, R.; Shen, R-F] US FDA, CBER, Facil Biotechnol Resources, Bethesda, MD 20014 USA. [Eling, T. E.] NIEHS, Mol Carcinogenesis Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Min, K-W] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA. RP Baek, SJ (reprint author), Univ Tennessee, Coll Vet Med, Dept Biomed & Diagnost Sci, 2407 River Dr, Knoxville, TN 37996 USA. EM sbaek2@utk.edu RI Silva, Gabriel/D-7731-2017; OI Silva, Gabriel/0000-0002-5660-9769; Min, Kyung-Won/0000-0002-8718-3588 FU National Institutes of Health [R01CA108975]; Center of Excellence in Livestock Diseases and Human Health, University of Tennessee; CAPES Foundation, Brazil [BEX 3159/14-0]; NIH, NIEHS Intramural Research Program [Z01-ES010016-14] FX We thank Dr Xingya Wang (College of Pharmaceutical Science, Zhejiang Chinese Medical University, China) and Ms Misty Bailey (University of Tennessee) for their critical reading of the manuscript. We also thank Dr John Dunlap (Advanced Microscopy and Imaging Center at The University of Tennessee) for providing technical help on confocal microscopy. This work was supported by the National Institutes of Health (R01CA108975), and the Center of Excellence in Livestock Diseases and Human Health, University of Tennessee, to SJB and a grant (BEX 3159/14-0) from the CAPES Foundation, Brazil (GS). This research was also supported, in part, by the NIH, NIEHS Intramural Research Program (TEE) Z01-ES010016-14. NR 68 TC 5 Z9 5 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD JAN 21 PY 2016 VL 35 IS 3 BP 377 EP 388 DI 10.1038/onc.2015.95 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DC2OF UT WOS:000369055300011 PM 25893289 ER PT J AU Soslow, JH Damon, SM Crum, K Lawson, MA Slaughter, JC Xu, M Arai, AE Sawyer, DB Parra, DA Damon, BM Markham, LW AF Soslow, Jonathan H. Damon, Stephen M. Crum, Kimberly Lawson, Mark A. Slaughter, James C. Xu, Meng Arai, Andrew E. Sawyer, Douglas B. Parra, David A. Damon, Bruce M. Markham, Larry W. TI Increased myocardial native T1 and extracellular volume in patients with Duchenne muscular dystrophy SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Duchenne muscular dystrophy; Cardiomyopathy; Cardiovascular magnetic resonance; Extracellular volume fraction; T1 mapping ID CARDIOVASCULAR MAGNETIC-RESONANCE; HISTOLOGICAL VALIDATION; HEART-DISEASE; FIBROSIS; FRACTION; QUANTIFICATION; CARDIOMYOPATHY; ENHANCEMENT; ASSOCIATION; DYSFUNCTION AB Background: Duchenne muscular dystrophy (DMD) cardiomyopathy is a progressive disease for which there is no cure. Disease-specific therapies are needed that can be initiated before irreversible myocardial damage ensues. In order to evaluate therapeutic efficacy, surrogate endpoints other than ejection fraction must be found. The hypothesis of this study is that T1 and extracellular volume fraction (ECV) mapping using cardiovascular magnetic resonance (CMR) can detect diffuse extracellular matrix expansion in DMD patients with normal left ventricular ejection fraction (LVEF) and without myocardial late gadolinium enhancement (LGE). Methods: Thirty-one DMD and 11 healthy control participants were prospectively enrolled. CMR using a modified Look-Locker (MOLLI) sequence was performed in all participants before and after contrast administration. T1 and ECV maps of the mid left ventricular myocardium were generated and regions of interest were contoured using the standard 6-segment AHA model. Global and segmental values were compared between DMD and controls using a Wilcoxon rank-sum test. Results: The DMD participants had significantly higher mean native T1 compared with controls (1045 ms vs 988 ms, p = 0.001). DMD participants with normal LVEF and without evidence of LGE also demonstrated elevated mean native T1 (1039 ms vs 988 ms, p = 0.002, and 1038 ms vs 988 ms, p = 0.011). DMD participants had a significantly greater mean ECV than controls (0.31 vs 0.24, p < 0.001), even in the settings of normal LVEF (0.28 vs 0.24, p < 0.001) and negative LGE (0.29 vs 0.24, p = 0.001). Conclusions: DMD participants have elevated LV myocardial native T1 and ECV, even in the setting of normal LVEF and in the absence of LGE. T1 and ECV mapping in DMD have potential to serve as surrogate cardiomyopathy outcome measures for clinical trials. C1 [Soslow, Jonathan H.; Crum, Kimberly; Parra, David A.; Markham, Larry W.] Vanderbilt Univ, Med Ctr, Monroe Carell Jr Childrens Hosp, Thomas P Graham Jr Div Pediat Cardiol,Dept Pediat, 2200 Childrens Way Suite 5230,Doctors Off Tower, Nashville, TN 37232 USA. [Damon, Stephen M.] Vanderbilt Univ, Dept Elect Engn & Comp Sci, Nashville, TN 37232 USA. [Lawson, Mark A.] Vanderbilt Univ, Med Ctr, Dept Med, Div Cardiovasc Med, Nashville, TN 37232 USA. [Slaughter, James C.; Xu, Meng] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN 37232 USA. [Arai, Andrew E.] NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. [Sawyer, Douglas B.] Maine Med Ctr, Dept Cardiac Serv, Portland, ME 04102 USA. [Damon, Bruce M.] Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Damon, Bruce M.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Damon, Bruce M.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37232 USA. RP Soslow, JH (reprint author), Vanderbilt Univ, Med Ctr, Monroe Carell Jr Childrens Hosp, Thomas P Graham Jr Div Pediat Cardiol,Dept Pediat, 2200 Childrens Way Suite 5230,Doctors Off Tower, Nashville, TN 37232 USA. EM Jonathan.h.soslow@vanderbit.edu OI Slaughter, James/0000-0002-8770-980X FU American Heart Association (Dallas, TX) [13CRP14530007]; National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, MD) [K23HL123938]; National Center for Research Resources [UL1 RR024975-01]; National Center for Advancing Translational Sciences (Bethesda, MD) [2 UL1 TR000445-06]; Fighting Duchenne Foundation; Fight DMD/Jonah & Emory Discovery Grant (Nashville, TN) FX This work was supported by American Heart Association Grant 13CRP14530007 (Soslow) (Dallas, TX).; Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL123938 (Bethesda, MD) (Soslow). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; The project was supported by the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06 (Bethesda, MD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; This project was supported by the Fighting Duchenne Foundation and the Fight DMD/Jonah & Emory Discovery Grant (Nashville, TN) (Markham). NR 36 TC 6 Z9 7 U1 4 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD JAN 21 PY 2016 VL 18 AR 5 DI 10.1186/s12968-016-0224-7 PG 13 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DB8XL UT WOS:000368800400001 PM 26795569 ER PT J AU Bontemps-Gallo, S Madec, E Robbe-Masselot, C Souche, E Dondeyne, J Lacroix, JM AF Bontemps-Gallo, Sebastien Madec, Edwige Robbe-Masselot, Catherine Souche, Erika Dondeyne, Jacqueline Lacroix, Jean-Marie TI The opgC gene is required for OPGs succinylation and is osmoregulated through RcsCDB and EnvZ/OmpR in the phytopathogen Dickeya dadantii SO SCIENTIFIC REPORTS LA English DT Article ID PERIPLASMIC GLUCANS; ERWINIA-CHRYSANTHEMI; ESCHERICHIA-COLI; INSERTION MUTAGENESIS; RCSB PHOSPHORELAY; BACTERIA; PROTEIN; SYSTEM; BIOSYNTHESIS; VIRULENCE AB Osmoregulated periplasmic glucans (OPGs) are a family of periplasmic oligosaccharides found in the envelope of most Proteobacteria. They are required for virulence of zoo-and phyto-pathogens. The glucose backbone of OPGs is substituted by various kinds of molecules depending on the species, O-succinyl residues being the most widely distributed. In our model, Dickeya dadantii, a phytopathogenic bacteria causing soft rot disease in a wide range of plant species, the backbone of OPGs is substituted by O-succinyl residues in media of high osmolarity and by O-acetyl residues whatever the osmolarity. The opgC gene encoding a transmembrane protein required for the succinylation of the OPGs in D. dadantii was found after an in silico search of a gene encoding a protein with the main characteristics recovered in the two previously characterized OpgC of E. coli and R. sphaeroides, i.e. 10 transmembrane segments and one acyl-transferase domain. Characterization of the opgC gene revealed that high osmolarity expression of the succinyl transferase is controlled by both the EnvZ-OmpR and RcsCDB phosphorelay systems. The loss of O-succinyl residue did not affect the virulence of D. dadantii, suggesting that only the glucose backbone of OPGs is required for virulence. C1 [Bontemps-Gallo, Sebastien; Madec, Edwige; Robbe-Masselot, Catherine; Dondeyne, Jacqueline; Lacroix, Jean-Marie] Univ Lille, UMR CNRS Lille1 8576, Struct & Funct Glycobiol Unit, F-59655 Villeneuve Dascq, France. [Souche, Erika] Univ Leuven, Ctr Human Genet, Herestr 49, B-3000 Leuven, Belgium. [Bontemps-Gallo, Sebastien] NIAID, Lab Zoonot Pathogens, NIH, Hamilton, MT USA. RP Lacroix, JM (reprint author), Univ Lille, UMR CNRS Lille1 8576, Struct & Funct Glycobiol Unit, F-59655 Villeneuve Dascq, France. EM jean-marie.lacroix@univ-lille1.fr OI bontemps-gallo, sebastien/0000-0002-1834-5416 FU Centre National de la Recherche Scientifique; Ministere de l'Enseignement Superieur et de la Recherche; University of Lille FX The authors would like to thank Dominique Lecoeur and Anne-France Boussemart for their technical assistances. We are grateful to Martha Thayer for the manuscript improvements. This work was supported by grants from the Centre National de la Recherche Scientifique, from the Ministere de l'Enseignement Superieur et de la Recherche and from the University of Lille. SBG was funded by post-doctoral fellowship of the University of Lille. The funders were not involved in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 0 Z9 0 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 21 PY 2016 VL 6 AR 19619 DI 10.1038/srep19619 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB8LT UT WOS:000368768900004 PM 26790533 ER PT J AU Wang, ZF Leng, Y Wang, JY Liao, HM Bergman, J Leeds, P Kozikowski, A Chuang, DM AF Wang, Zhifei Leng, Yan Wang, Junyu Liao, Hsiao-Mei Bergman, Joel Leeds, Peter Kozikowski, Alan Chuang, De-Maw TI Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: potential roles of alpha-tubulin acetylation and FGF-21 up-regulation SO SCIENTIFIC REPORTS LA English DT Article ID MOOD STABILIZERS LITHIUM; TRANSIENT ISCHEMIA; CEREBRAL-ISCHEMIA; AXONAL-TRANSPORT; MOUSE MODEL; RAT MODEL; DISEASE; DAMAGE; REGENERATION; DEACETYLASE AB Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as alpha-tubulin. HDAC6 dysfunction is associated with several pathological conditions in the central nervous system. This study investigated the beneficial effects of tubastatin A (TubA), a novel specific HDAC6 inhibitor, in a rat model of transient middle cerebral artery occlusion (MCAO) and an in vitro model of excitotoxicity. Post-ischemic TubA treatment robustly improved functional outcomes, reduced brain infarction, and ameliorated neuronal cell death in MCAO rats. These beneficial effects lasted at least three days after MCAO. Notably, when given at 24 hours after MCAO, TubA still exhibited significant protection. Levels of acetylated alpha-tubulin were decreased in the ischemic hemisphere on Days 1 and 3 after MCAO, and were significantly restored by TubA. MCAO markedly downregulated fibroblast growth factor-21 (FGF-21) and TubA significantly reversed this downregulation. TubA also mitigated impaired FGF-21 signaling in the ischemic hemisphere, including up-regulating beta-Klotho, and activating ERK and Akt/GSK-3 beta signaling pathways. In addition, both TubA and exogenous FGF-21 conferred neuroprotection and restored mitochondrial trafficking in rat cortical neurons against glutamate-induced excitotoxicity. Our findings suggest that the neuroprotective effects of TubA likely involve HDAC6 inhibition and the subsequent up-regulation of acetylated alpha-tubulin and FGF-21. C1 [Wang, Zhifei] Shanghai Univ Tradit Chinese Med, Sch Basic Med, Shanghai 201203, Peoples R China. [Wang, Zhifei; Leng, Yan; Wang, Junyu; Liao, Hsiao-Mei; Leeds, Peter; Chuang, De-Maw] NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Bergman, Joel; Leeds, Peter] Univ Illinois, Drug Discovery Program, Chicago, IL 60612 USA. RP Wang, ZF (reprint author), Shanghai Univ Tradit Chinese Med, Sch Basic Med, Shanghai 201203, Peoples R China.; Wang, ZF; Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM zfwang4911@163.com; chuang@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; National Natural Science Foundation of China [81503055]; Shanghai Pujiang Program [15PJ1407700] FX This study was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, the National Natural Science Foundation of China (81503055), and Shanghai Pujiang Program (15PJ1407700). The authors thank Dr. Vincent Schram for technical assistance in live cell imaging, Lisa Scheuing for assistance in data analysis on mitochondria trafficking, Drs. Chi-Tso Chiu and Gabriel Linares for their comments and advice, and Ioline Henter for expert editorial work. This work was written as part of Zhifei Wang, Yan Leng, Junyu Wang, Hsiao-Mei Liao, Peter Leeds, and De-Maw Chuang's official duties as Government employees (affiliated with Annual Report MH002468). The views expressed in this article do not necessarily represent the views of the NIMH, NIH, HHS, nor the United States Government. NR 36 TC 3 Z9 3 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 21 PY 2016 VL 6 AR 19626 DI 10.1038/srep19626 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB8QC UT WOS:000368780600001 PM 26790818 ER PT J AU Balla, T AF Balla, Tamas TI Lipid code for membrane recycling SO NATURE LA English DT Editorial Material ID PHOSPHATIDYLINOSITOL 4-PHOSPHATE C1 [Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov OI Balla, Tamas/0000-0002-9077-3335 NR 13 TC 0 Z9 0 U1 5 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JAN 21 PY 2016 VL 529 IS 7586 BP 292 EP 293 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB2QT UT WOS:000368354800028 PM 26760211 ER PT J AU Dalerba, P Sahoo, D Paik, S Guo, XQ Yothers, G Song, N Wilcox-Fogel, N Forgo, E Rajendran, PS Miranda, SP Hisamori, S Hutchison, J Kalisky, T Qian, DL Wolmark, N Fisher, GA van de Rijn, M Clarke, MF AF Dalerba, Piero Sahoo, Debashis Paik, Soonmyung Guo, Xiangqian Yothers, Greg Song, Nan Wilcox-Fogel, Nate Forgo, Erna Rajendran, Pradeep S. Miranda, Stephen P. Hisamori, Shigeo Hutchison, Jacqueline Kalisky, Tomer Qian, Dalong Wolmark, Norman Fisher, George A. van de Rijn, Matt Clarke, Michael F. TI CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COLORECTAL-CANCER; ADJUVANT CHEMOTHERAPY; STEM-CELLS; EXPRESSION; FLUOROURACIL; MARKER; LEUCOVORIN; RECURRENCE; SIGNATURE; FEATURES AB BACKGROUND The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. METHODS We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. RESULTS The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P = 0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P = 0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P = 0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P = 0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P = 0.006). CONCLUSIONS Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.) C1 [Dalerba, Piero] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Dalerba, Piero] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Dalerba, Piero] Columbia Univ, Dept Med, New York, NY 10032 USA. [Dalerba, Piero; Sahoo, Debashis; Rajendran, Pradeep S.; Miranda, Stephen P.; Hisamori, Shigeo; Hutchison, Jacqueline; Qian, Dalong; Clarke, Michael F.] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Guo, Xiangqian; Forgo, Erna; van de Rijn, Matt] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Wilcox-Fogel, Nate; Fisher, George A.; Clarke, Michael F.] Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA. [Sahoo, Debashis] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Sahoo, Debashis] Univ Calif San Diego, Dept Comp Sci & Engn, San Diego, CA 92103 USA. [Kalisky, Tomer] Bar Ilan Univ, Fac Engn, Ramat Gan, Israel. [Paik, Soonmyung; Yothers, Greg; Song, Nan; Wolmark, Norman] NRG Oncol, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. [Paik, Soonmyung] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Seoul 120749, South Korea. [Guo, Xiangqian] Henan Univ, Sch Med, Dept Biochem & Mol Biol, Kaifeng, Peoples R China. RP Dalerba, P (reprint author), Columbia Univ, Irving Canc Res Ctr, Herbert Irving Comprehens Canc Ctr, 1130 St Nicholas Ave,Rm 505A, New York, NY 10032 USA. EM pdd2109@columbia.edu; mfclarke@stanford.edu OI Dalerba, Piero/0000-0002-8815-4981 FU National Comprehensive Cancer Network, the National Institutes of Health FX Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others. NR 40 TC 42 Z9 43 U1 11 U2 23 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2016 VL 374 IS 3 BP 211 EP 222 DI 10.1056/NEJMoa1506597 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DB3IS UT WOS:000368404800006 PM 26789870 ER PT J AU Dean, J AF Dean, Jurrien TI Exacting Requirements for Development of the Egg SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Dean, Jurrien] NIDDK, Lab Cellular & Dev Biol, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, Bethesda, MD 20892 USA. NR 9 TC 1 Z9 1 U1 2 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 21 PY 2016 VL 374 IS 3 BP 279 EP 280 DI 10.1056/NEJMe1515512 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DB3IS UT WOS:000368404800015 PM 26789878 ER PT J AU Islam, MN Iqbal, S Katebi, AR Hogue, MT AF Islam, Md. Nasrul Iqbal, Sumaiya Katebi, Ataur R. Hogue, Md. Tamjidul TI A balanced secondary structure predictor SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Secondary structure prediction; Support vector machine; Meta predictor; Balanced accuracy ID ACCESSIBLE SURFACE-AREA; CODE RELATING SEQUENCE; AMINO-ACID-COMPOSITION; HIDDEN MARKOV MODEL; BACKBONE TORSION ANGLES; SUPPORT VECTOR MACHINE; GLOBULAR-PROTEINS; NEURAL-NETWORKS; CONFORMATION; RECOGNITION AB Secondary structure (SS) refers to the local spatial organization of a polypeptide backbone atoms of a protein. Accurate prediction of SS can provide crucial features to form the next higher level of 3D structure of a protein accurately. SS has three different major components, helix (H), beta (E) and coil (C). Most of the SS predictors express imbalanced accuracies by claiming higher prediction performances in predicting H and C, and on the contrary having low accuracy in E predictions. E component being in low count, a predictor may show very good overall performance by over-predicting H and C and under predicting E, which can make such predictors biologically inapplicable. In this work we are motivated to develop a balanced SS predictor by incorporating 33 physicochemical properties into 15-tuble peptides via Chou's general PseAAC, which allowed obtaining higher accuracies in predicting all three SS components. Our approach uses three different support vector machines for binary classification of the major classes and then form optimized multiclass predictor using genetic algorithm (GA). The trained three binary SVMs are E versus non-E (i.e., E/-E), C/-C and H/-H. This GA based optimized and combined three class predictor, called cSVM, is further combined with SPINE X to form the proposed final balanced predictor, called MetaSSPred. This novel paradigm assists us in optimizing the precision and recall. We prepared two independent test datasets (CB471 and N295) to compare the performance of our predictors with SPINE X. MetaSSPred significantly increases beta accuracy (Q(E)) for both the datasets. Q(E) score of MetaSSPred on CB471 and N295 were 71.7% and 74.4% respectively. These scores are 20.9% and 19.0% improvement over the QE scores given by SPINE X alone on CB471 and N295 datasets respectively. Standard deviations of the accuracies across three SS classes of MetaSSPred on CB471 and N295 datasets were 4.2% and 2.3% respectively. On the other hand, for SPINE X, these values are 12.9% and 10.9% respectively. These findings suggest that the proposed MetaSSPred is a well-balanced SS predictor compared to the state-of-the-art SPINE X predictor. Published by Elsevier Ltd. C1 [Islam, Md. Nasrul; Iqbal, Sumaiya; Hogue, Md. Tamjidul] Univ New Orleans, Comp Sci, New Orleans, LA 70148 USA. [Katebi, Ataur R.] NCI, NIH, Bethesda, MD 20892 USA. RP Hogue, MT (reprint author), Univ New Orleans, Comp Sci, New Orleans, LA 70148 USA. EM thoque@uno.edu FU Louisiana Board of Regents, United States, through the Board of Regents Support Fund [LEQSF (2013-16)-RD-A-19] FX MNI, SI and MTH gratefully acknowledge the Louisiana Board of Regents, United States, through the Board of Regents Support Fund, LEQSF (2013-16)-RD-A-19. NR 70 TC 1 Z9 1 U1 3 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD JAN 21 PY 2016 VL 389 BP 60 EP 71 DI 10.1016/j.jtbi.2015.10.015 PG 12 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA CZ6LR UT WOS:000367213300007 ER PT J AU Cheng, MCJ Smith, BD Hourigan, CS Gojo, I Pratz, KW Blackford, A Smith, TJ AF Cheng, Mok-Chung Jennifer Smith, B. Douglas Hourigan, Christopher Simon Gojo, Ivana Pratz, Keith William Blackford, Amanda Smith, Thomas J. TI A single-center survey of health-related quality of life among acute myeloid leukemia survivors in first complete remission. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Cancer Survivorship Symposium on Advancing Care and Research CY JAN 15-16, 2016 CL San Francisco, CA C1 NIH, Bldg 10, Bethesda, MD 20892 USA. Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RI Hourigan, Christopher/S-2476-2016 OI Hourigan, Christopher/0000-0002-6189-8067 NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 SU S MA 223 PG 1 WC Oncology SC Oncology GA DO9MA UT WOS:000378109500213 PM 27185839 ER PT J AU Gomez, SL Gonzales, FA Shariff-Marco, S Dwyer, LA Nuru-Jeter, A AF Gomez, Scarlett Lin Gonzales, Felisa A. Shariff-Marco, Salma Dwyer, Laura A. Nuru-Jeter, Amani TI Discrimination and quality of life among breast cancer survivors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Cancer Survivorship Symposium on Advancing Care and Research CY JAN 15-16, 2016 CL San Francisco, CA C1 Canc Prevent Inst Calif, Fremont, CA USA. NIH, Bldg 10, Bethesda, MD 20892 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 SU S MA 250 PG 1 WC Oncology SC Oncology GA DO9MA UT WOS:000378109500237 ER PT J AU Halley, M Beryl, L Gillespie, K Rendle, K May, SG Frosch, DL AF Halley, Meghan Beryl, Louise Gillespie, Katherine Rendle, Katharine May, Suepattra Grace Frosch, Domnick L. TI "Hot Girls Pearls" and other coping strategies for women experiencing adverse effects from endocrine therapy in the treatment of breast cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Cancer Survivorship Symposium on Advancing Care and Research CY JAN 15-16, 2016 CL San Francisco, CA C1 Palo Alto Med Fdn, Res Inst, Palo Alto, CA 94301 USA. Chegg Inc, Palo Alto, CA USA. NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. Precis Hlth Econ, Austin, TX USA. Gordon & Betty Moore Fdn, Palo Alto, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 SU S MA 197 PG 1 WC Oncology SC Oncology GA DO9MA UT WOS:000378109500187 ER PT J AU Halpern, MT Urato, M Kent, EE AF Halpern, Michael T. Urato, Matthew Kent, Erin E. TI Health care satisfaction among older cancer survivors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT Cancer Survivorship Symposium on Advancing Care and Research CY JAN 15-16, 2016 CL San Francisco, CA C1 Univ Arizona, Coll Publ Hlth, Tucson, AZ USA. RTI Int, Res Triangle Pk, NC USA. NCI, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 SU S MA 18 PG 1 WC Oncology SC Oncology GA DO9MA UT WOS:000378109500019 ER PT J AU Yabroff, KR Dowling, EC Guy, GP Banegas, MP Davidoff, A Han, XS Virgo, KS McNeel, TS Chawla, N Blanch-Hartigan, D Kent, EE Li, CY Rodriguez, JL de Moor, JS Zheng, ZY Jemal, A Ekwueme, DU AF Yabroff, K. Robin Dowling, Emily C. Guy, Gery P., Jr. Banegas, Matthew P. Davidoff, Amy Han, Xuesong Virgo, Katherine S. McNeel, Timothy S. Chawla, Neetu Blanch-Hartigan, Danielle Kent, Erin E. Li, Chunyu Rodriguez, Juan L. de Moor, Janet S. Zheng, Zhiyuan Jemal, Ahmedin Ekwueme, Donatus U. TI Financial Hardship Associated With Cancer in the United States: Findings From a Population-Based Sample of Adult Cancer Survivors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; MEDICAL-CARE; INSURANCE STATUS; ECONOMIC BURDEN; COST; DIAGNOSIS; TOXICITY; STAGE; CHEMOTHERAPY; ONCOLOGISTS AB Purpose To estimate the prevalence of financial hardship associated with cancer in the United States and identify characteristics of cancer survivors associated with financial hardship. Methods We identified 1,202 adult cancer survivors diagnosed or treated at >= 18 years of age from the 2011 Medical Expenditure Panel Survey Experiences With Cancer questionnaire. Material financial hardship was measured by ever (1) borrowing money or going into debt, (2) filing for bankruptcy, (3) being unable to cover one's share of medical care costs, or (4) making other financial sacrifices because of cancer, its treatment, and lasting effects of treatment. Psychological financial hardship was measured as ever worrying about paying large medical bills. We examined factors associated with any material or psychological financial hardship using separate multivariable logistic regression models stratified by age group (18 to 64 and >= 65 years). Results Material financial hardship was more common in cancer survivors age 18 to 64 years than in those >= 65 years of age (28.4% v 13.8%; P < .001), as was psychological financial hardship (31.9% v 14.7%, P < .001). In adjusted analyses, cancer survivors age 18 to 64 years who were younger, female, nonwhite, and treated more recently and who had changed employment because of cancer were significantly more likely to report any material financial hardship. Cancer survivors who were uninsured, had lower family income, and were treated more recently were more likely to report psychological financial hardship. Among cancer survivors >= 65 years of age, those who were younger were more likely to report any financial hardship. Conclusion Cancer survivors, especially the working-age population, commonly experience material and psychological financial hardship. (C) 2015 by American Society of Clinical Oncology C1 [Yabroff, K. Robin; Banegas, Matthew P.; Chawla, Neetu; Blanch-Hartigan, Danielle; Kent, Erin E.; de Moor, Janet S.] NCI, Bethesda, MD 20892 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Calverton, MD USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Blanch-Hartigan, Danielle] Bentley Univ, Waltham, MA USA. [Guy, Gery P., Jr.; Li, Chunyu; Rodriguez, Juan L.; Ekwueme, Donatus U.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Han, Xuesong; Zheng, Zhiyuan; Jemal, Ahmedin] Amer Canc Soc, Atlanta, GA 30329 USA. [Virgo, Katherine S.] Emory Univ, Atlanta, GA 30322 USA. [Davidoff, Amy] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Chawla, Neetu] Kaiser Permanente No Calif, Oakland, CA USA. RP Yabroff, KR (reprint author), NCI, Div Canc Control & Populat Sci, 9609 Med Ctr Dr, Rockville, MD 20892 USA. EM robin.yabroff@hhs.gov FU Celgene FX Celgene (I) NR 55 TC 9 Z9 9 U1 2 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 BP 259 EP U125 DI 10.1200/JCO.2015.62.0468 PG 16 WC Oncology SC Oncology GA DJ6NV UT WOS:000374331100014 PM 26644532 ER PT J AU Hwang, JP Somerfield, MR Alston-Johnson, DE Cryer, DR Feld, JJ Kramer, BS Sabichi, AL Wong, SL Artz, AS AF Hwang, Jessica P. Somerfield, Mark R. Alston-Johnson, Devena E. Cryer, Donna R. Feld, Jordan J. Kramer, Barnett S. Sabichi, Anita L. Wong, Sandra L. Artz, Andrew S. TI Computerized Physician Order Entry-Based System Improves Hepatitis B Virus Screening in Patients Undergoing Chemotherapy Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID INFECTION C1 [Hwang, Jessica P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Somerfield, Mark R.] Amer Soc Clin Oncol, Alexandria, VA USA. [Alston-Johnson, Devena E.] Upstate Oncol Associates, Greenville, SC USA. [Cryer, Donna R.] Global Liver Inst, Washington, DC USA. [Feld, Jordan J.] Toronto Western Hosp, Ctr Liver, Toronto, ON M5T 2S8, Canada. [Kramer, Barnett S.] NCI, Bethesda, MD 20892 USA. [Sabichi, Anita L.] Baylor Coll Med, Houston, TX 77030 USA. [Wong, Sandra L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Artz, Andrew S.] Univ Chicago, Chicago, IL 60637 USA. NR 9 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 20 PY 2016 VL 34 IS 3 DI 10.1200/JCO.2015.64.3064 PG 2 WC Oncology SC Oncology GA DJ6NV UT WOS:000374331100022 ER PT J AU Economon, MN Clack, NG Levis, LD Gerfen, CR Svoboda, K Myers, EW Chandrashekar, J AF Economon, Michael N. Clack, Nathan G. Levis, Luke D. Gerfen, Charles R. Svoboda, Karel Myers, Eugene W. Chandrashekar, Jayaram TI A platform for brain-wide imaging and reconstruction of individual neurons SO ELIFE LA English DT Article ID OPTICAL SECTIONING TOMOGRAPHY; PRIMARY MOTOR CORTEX; MOUSE-BRAIN; IN-VIVO; FLUORESCENT PROTEINS; AXONAL PROJECTIONS; CORTICAL-NEURONS; THALAMIC NUCLEI; NERVOUS-SYSTEM; VIRAL VECTORS AB The structure of axonal arbors controls how signals from individual neurons are routed within the mammalian brain. However, the arbors of very few long-range projection neurons have been reconstructed in their entirety, as axons with diameters as small as 100 nm arborize in target regions dispersed over many millimeters of tissue. We introduce a platform for high-resolution, three-dimensional fluorescence imaging of complete tissue volumes that enables the visualization and reconstruction of long-range axonal arbors. This platform relies on a high-speed two-photon microscope integrated with a tissue vibratome and a suite of computational tools for large-scale image data. We demonstrate the power of this approach by reconstructing the axonal arbors of multiple neurons in the motor cortex across a single mouse brain. C1 [Economon, Michael N.; Clack, Nathan G.; Levis, Luke D.; Gerfen, Charles R.; Svoboda, Karel; Myers, Eugene W.; Chandrashekar, Jayaram] Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA. [Gerfen, Charles R.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. [Myers, Eugene W.] Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany. RP Myers, EW; Chandrashekar, J (reprint author), Howard Hughes Med Inst, Janelia Res Campus, Ashburn, VA USA.; Myers, EW (reprint author), Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany. EM myers@mpi-cbg.de; chandrashekarj@janelia.hhmi.org OI Lavis, Luke/0000-0002-0789-6343 FU Howard Hughes Medical Institute FX Howard Hughes Medical Institute Michael N Economo Nathan G Clack Luke D Lavis Karel Svoboda Jayaram Chandrashekar NR 70 TC 20 Z9 21 U1 7 U2 14 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD JAN 20 PY 2016 VL 5 AR e10566 DI 10.7554/eLife.10566 PG 22 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DI8ZK UT WOS:000373790900001 PM 26796534 ER PT J AU Broadbent, AJ Santos, CP Anafu, A Wimmer, E Mueller, S Subbarao, K AF Broadbent, Andrew J. Santos, Celia P. Anafu, Amanda Wimmer, Eckard Mueller, Steffen Subbarao, Kanta TI Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic H1N1 influenza virus, in ferrets SO VACCINE LA English DT Article DE Influenza; Vaccine; Codon pair bias de-optimization ID CONTROLLED-TRIAL; PREVENTION; HEMAGGLUTININ; RECOMBINANTS; EXPRESSION; FUTURE AB Codon-pair bias de-optimization (CPBD) of viruses involves re-writing viral genes using statistically underrepresented codon pairs, without any changes to the amino acid sequence or codon usage. Previously, this technology has been used to attenuate the influenza A/Puerto Rico/8/34 (HINT) virus. The de-optimized virus was immunogenic and protected inbred mice from challenge. In order to assess whether CPBD could be used to produce a live vaccine against a clinically relevant influenza virus, we generated an influenza A/California/07/2009 pandemic H1N1 (2009 pH1N1) virus with de-optimized HA and NA gene segments (2009 pH1N1-(HA+NA)(Min)), and evaluated viral replication and protein expression in MDCK cells, and attenuation, immunogenicity, and efficacy in outbred ferrets. The 2009 pH1N1-(HA + NA)(Min) virus grew to a similar titer as the 2009 pH1N1 wild type (wt) virus in MDCK cells (similar to 10(6) TCID50/ml), despite reduced HA and NA protein expression on western blot. In ferrets, intranasal inoculation of 2009 pH1N1-(HA+NA)(Min) virus at doses ranging from 10(3) to 10(5) TCID50 led to seroconversion in all animals and protection from challenge with the 2009 pH1N1 wt virus 28 days later. The 2009 pH1N1-(HA+NA)(Min) virus did not cause clinical illness in ferrets, but replicated to a similar titer as the wt virus in the upper and lower respiratory tract, suggesting that de-optimization of additional gene segments may be warranted for improved attenuation. Taken together, our data demonstrate the potential of using CPBD technology for the development of a live influenza virus vaccine if the level of attenuation is optimized. Published by Elsevier Ltd. C1 [Broadbent, Andrew J.; Santos, Celia P.; Anafu, Amanda; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Wimmer, Eckard; Mueller, Steffen] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. [Broadbent, Andrew J.] Pirbright Inst, Woking GU24 0NF, Surrey, England. [Mueller, Steffen] Codagenix Inc, Stony Brook, NY 11790 USA. RP Subbarao, K (reprint author), Room 3E13C-1,Bldg 33,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM ksubbarao@niaid.nih.gov OI Broadbent, Andrew/0000-0002-4716-1835 FU Intramural Research Program of the NIH; NIAID FX This research was supported in part by the Intramural Research Program of the NIH and NIAID. We thank the NIAID Comparative Medical Branch and Heather Kenney for technical assistance during animal studies. NR 31 TC 1 Z9 1 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN 20 PY 2016 VL 34 IS 4 BP 563 EP 570 DI 10.1016/j.vaccine.2015.11.054 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA DB9WJ UT WOS:000368868100025 PM 26655630 ER PT J AU Jaacks, LM Barr, DB Sundaram, R Maisog, JM Zhang, CL Louis, GMB AF Jaacks, Lindsay M. Barr, Dana Boyd Sundaram, Rajeshwari Maisog, Jose M. Zhang, Cuilin Louis, Germaine M. Buck TI Pre-pregnancy maternal exposure to polybrominated and polychlorinated biphenyls and gestational diabetes: a prospective cohort study SO ENVIRONMENTAL HEALTH LA English DT Article DE Persistent organic pollutants; Lipids; Diabetes; Pregnancy ID PERSISTENT ORGANIC POLLUTANTS; SUBCUTANEOUS ADIPOSE-TISSUE; INSULIN-RESISTANCE; CIRCULATING LEVELS; METABOLIC SYNDROME; HEALTH-RISKS; SERUM-LIPIDS; MELLITUS; OBESITY; POPULATION AB Background: While several studies have shown an association between environmental pollutants and diabetes among non-pregnant adults, few studies have prospectively assessed the association among pregnant women. We estimated the association between maternal pre-pregnancy levels of a polybrominated biphenyl (PBB 153) and 36 polychlorinated biphenyls (PCBs) with gestational diabetes (GDM). Methods: Data are from women (18-40 years) participating in a prospective cohort who achieved pregnancy lasting >= 24 weeks gestation and completed monthly pregnancy journals (n = 258). Women were recruited between 2005 and 2007 from 16 counties in Michigan and Texas. Women who ever reported a physician diagnosis of high blood glucose in monthly pregnancy journals were categorized as having gestational diabetes (n = 28; 10.9 %). Multivariable binary logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CIs). Results: There was no association between PBB 153 and GDM or any of the PCB congeners and GDM in unadjusted models. All associations remained non-significant with stepwise adjustment for age and waist-to-height ratio. Only with further adjustment for total serum lipids did the associations become significant, with lower levels of nine PCB congeners associated with GDM: 138, 153, 156, 167, 170, 172, 178, 180, and 194. The adjusted ORs for PCBs 170 and 180 were the strongest: 0.40 (0.18, 0.88) and 0.41 (0.19, 0.87), respectively. Conclusions: Pre-pregnancy levels of PCBs were not consistently associated with development of GDM in this prospective cohort of U.S. women. Interestingly, we found that although women with GDM had higher mean pre-pregnancy circulating lipid levels compared to women without GDM, they had lower wet weight circulating levels of many PCBs. More research is needed to understand the dynamic fluctuations of PCBs and other persistent organic pollutants between lipid compartments in women preparing to conceive and throughout pregnancy. C1 [Jaacks, Lindsay M.] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Claudia Nance Rollins Bldg 7040-1,1518 Clifton Rd, Atlanta, GA 30322 USA. [Barr, Dana Boyd] Emory Univ, Rollins Sch Publ Hlth, Dept Environm Hlth, Atlanta, GA 30322 USA. [Sundaram, Rajeshwari] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Intramural Populat Hlth Res, Rockville, MD USA. [Maisog, Jose M.] Glotech Inc, Rockville, MD USA. [Zhang, Cuilin; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, Rockville, MD USA. RP Jaacks, LM (reprint author), Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Claudia Nance Rollins Bldg 7040-1,1518 Clifton Rd, Atlanta, GA 30322 USA. EM ljaacks@emory.edu OI Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-3-3355, N01-HD-3-3356, N01-HD-3-3358]; Rollins School of Public Health Hubert Chair Fund; Emory Health and Exposome Research Center: Understanding Lifetime Exposures (HERCULES) - National Institute of Environmental Health Sciences [P30 ES019776] FX The LIFE Study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts #N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358). LMJ is supported by the Rollins School of Public Health Hubert Chair Fund. DBB is partially supported by the Emory Health and Exposome Research Center: Understanding Lifetime Exposures (HERCULES), funded by the National Institute of Environmental Health Sciences (P30 ES019776). None of the aforementioned funding sources had a role in the design, analysis, or writing of this article. NR 59 TC 2 Z9 2 U1 4 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JAN 20 PY 2016 VL 15 AR 11 DI 10.1186/s12940-016-0092-5 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA DB5SJ UT WOS:000368573600001 PM 26792546 ER PT J AU Yoshimura, T Imamichi, T Weiss, JM Sato, M Li, LZ Matsukawa, A Wang, JM AF Yoshimura, Teizo Imamichi, Tomozumi Weiss, Jonathan M. Sato, Miwa Li, Liangzhu Matsukawa, Akihiro Wang, Ji Ming TI Induction of Monocyte Chemoattractant Proteins in Macrophages via the Production of Granulocyte/Macrophage ColonyStimulating Factor by Breast Cancer Cells SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE monocytes/macrophages; chemokines; inflammation; tumor microenvironment; breast cancer ID COLONY-STIMULATING FACTOR; GENE-EXPRESSION; MAMMARY-TUMORS; CDNA CLONING; METASTASIS; CSF-1; MCP-1; PURIFICATION; INFLAMMATION; CCL2 AB Monocyte chemoattractant protein-1 (MCP-1)/CCL2 plays an important role in the initiation and progression of cancer. We previously reported that in 4T1 murine breast cancer, non-tumor stromal cells, including macrophages, were the major source of MCP-1. In the present study, we analyzed the potential mechanisms by which MCP-1 is upregulated in macrophages infiltrating 4T1 tumors. We found that cell free culture supernatants of 4T1 cells (4T1-sup) markedly upregulated MCP-1 production by peritoneal inflammatory macrophages. 4T1-sup also upregulated other MCPs, such as MCP-3/CCL7 and MCP-5/CCL12, but modestly upregulated neutrophil chemotactic chemokines, such as KC/CXCL1 or MIP-2/CXCL2. Physicochemical analysis indicated that an approximately 2-3 kDa 4T1 cell product was responsible for the capacity of 4T1-sup to upregulate MCP-1 expression by macrophages. A neutralizing antibody against granulocyte/macrophage colony stimulating factor (GM-CSF), but not macrophage CSF, almost completely abrogated MCP-1-inducing activity of 4T1-sup, and recombinant GM-CSF potently upregulated MCP-1 production by macrophages. The expression levels of GM-CSF in 4T1 tumors in vivo were higher than other tumors, such as Lewis lung carcinoma. Treatment of mice with anti-GM-CSF antibody significantly reduced the growth of 4T1 tumors at the injection sites but did not reduce MCP-1 production or lung metastasis in tumor-bearing mice. These results indicate that 4T1 cells have the capacity to directly upregulate MCP-1 production by macrophages by releasing GM-CSF; however, other mechanisms are also involved in increased MCP-1 levels in the 4T1 tumor microenvironment. C1 [Yoshimura, Teizo; Weiss, Jonathan M.; Wang, Ji Ming] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Yoshimura, Teizo; Sato, Miwa; Matsukawa, Akihiro] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Pathol & Expt Med, Okayama, Japan. [Imamichi, Tomozumi] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Lab Human Retrovirol & Immunoinformat, Frederick, MD USA. [Li, Liangzhu] Shanghai Jiao Tong Univ, Sch Pharm, Minist Educ, Engn Res Ctr Cell & Therapeut Antibody, Shanghai 200030, Peoples R China. RP Yoshimura, T (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM yoshimut@okayama-u.ac.jp FU Intramural Research Program of the NIH, NCI; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Natural Science Foundation of China [81470073] FX We are grateful to Dr. Oleg Chertov, Ms. Megan W Karwan, Ms. Loretta Smith, Mr. Timothy Back, and staff of LASP, Leidos Biomedical Research, Inc., for their assistance in HPLC and animal studies. We are also grateful to Dr. Joost J. Oppenheim for his critical comments. This research was supported by the Intramural Research Program of the NIH, NCI, and National Cancer Institute, National Institutes of Health 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 organization imply endorsement by the U.S. Government. LL was supported by National Natural Science Foundation of China (81470073). NR 48 TC 2 Z9 2 U1 0 U2 7 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JAN 20 PY 2016 VL 7 AR 2 DI 10.3389/fimmu.2016.00002 PG 13 WC Immunology SC Immunology GA DB3TC UT WOS:000368433600001 PM 26834744 ER PT J AU Li, J Cai, BW Qi, YW Zhao, WT Liu, JW Xu, RX Pang, Q Tao, ZY Hong, LX Liu, SF Leerkes, M Quinones, M Su, XZ AF Li, Jian Cai, Baowei Qi, Yanwei Zhao, Wenting Liu, Jianwen Xu, Ruixue Pang, Qin Tao, Zhiyong Hong, Lingxian Liu, Shengfa Leerkes, Maarten Quinones, Mariam Su, Xin-zhuan TI UTR introns, antisense RNA and differentially spliced transcripts between Plasmodium yoelii subspecies SO MALARIA JOURNAL LA English DT Article DE Malaria; RNA-seq; Gene expression; Single nucleotide polymorphism (SNP); Alternative splicing ID RODENT MALARIA PARASITE; GENE-EXPRESSION; IMMUNE-RESPONSES; SEQ; GENOME; FALCIPARUM; BLOOD; SEQUENCE; MODEL; MICROSATELLITES AB Background: The rodent malaria parasite Plasmodium yoelii is an important animal model for studying host-parasite interaction and molecular basis of malaria pathogenesis. Although a draft genome of P. yoelii yoelii YM is available, and RNA sequencing (RNA-seq) data for several rodent malaria species (RMP) were reported recently, variations in coding regions and structure of mRNA transcript are likely present between different parasite strains or subspecies. Sequencing of cDNA libraries from additional parasite strains/subspecies will help improve the gene models and genome annotation. Methods: Here two directional cDNA libraries from mixed blood stages of a subspecies of P. yoelii (P. y. nigeriensis NSM) with or without mefloquine (MQ) treatment were sequenced, and the sequence reads were compared to the genome and cDNA sequences of P. y. yoelii YM in public databases to investigate single nucleotide polymorphisms (SNPs) in coding regions, variations in intron-exon structure and differential splicing between P. yoelii subspecies, and variations in gene expression under MQ pressure. Results: Approximately 56 million of 100 bp paired-end reads were obtained, providing an average of similar to 225-fold coverage for the coding regions. Comparison of the sequence reads to the YM genome revealed introns in 5' and 3' untranslated regions (UTRs), altered intron/exon boundaries, alternative splicing, overlapping sense-antisense reads, and potentially new transcripts. Interestingly, comparison of the NSM RNA-seq reads obtained here with those of YM discovered differentially spliced introns; e.g., spliced introns in one subspecies but not the other. Alignment of the NSM cDNA sequences to the YM genome sequence also identified similar to 84,000 SNPs between the two parasites. Conclusion: The discoveries of UTR introns and differentially spliced introns between P. yoelii subspecies raise interesting questions on the potential role of these introns in regulating gene expression and evolution of malaria parasites. C1 [Li, Jian; Cai, Baowei; Qi, Yanwei; Zhao, Wenting; Liu, Jianwen; Xu, Ruixue; Pang, Qin; Hong, Lingxian; Liu, Shengfa; Su, Xin-zhuan] Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China. [Qi, Yanwei; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Tao, Zhiyong] Bengbu Med Coll, Dept Parasitol, Bengbu 233030, Peoples R China. [Leerkes, Maarten; Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, NIH, Bethesda, MD 20892 USA. RP Li, J (reprint author), Xiamen Univ, State Key Lab Cellular Stress Biol, Innovat Ctr Cell Signaling Network, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China. EM jianli_204@xmu.edu.cn; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248 FU National Natural Science Foundation of China [81220108019, 81271858, 81201324]; Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China [B06016]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH) FX This work was supported by the National Natural Science Foundation of China #81220108019, #81271858, and #81201324, by Project 111 of the State Bureau of Foreign Experts and Ministry of Education of China (B06016), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). The authors thank Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. This study used the Office of Cyber Infrastructure and Computational Biology (OCICB) High Performance Computing (HPC) cluster at NIAID and the high-performance computational capabilities of the Helix Systems (http://helix.nih.gov) at the NIH, Bethesda, MD. NR 41 TC 1 Z9 1 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JAN 20 PY 2016 VL 15 AR 30 DI 10.1186/s12936-015-1081-9 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DB3GM UT WOS:000368398300001 PM 26791272 ER PT J AU Borucki, MK Lao, V Hwang, M Gardner, S Adney, D Munster, V Bowen, R Allen, JE AF Borucki, Monica K. Lao, Victoria Hwang, Mona Gardner, Shea Adney, Danielle Munster, Vincent Bowen, Richard Allen, Jonathan E. TI Middle East Respiratory Syndrome Coronavirus Intra-Host Populations Are Characterized by Numerous High Frequency Variants SO PLOS ONE LA English DT Article ID DROMEDARY CAMELS; NUCLEOCAPSID PROTEIN; MERS-COV; ANTIBODIES; EMERGENCE; EVOLUTION AB Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen related to SARS virus. In vitro studies indicate this virus may have a broad host range suggesting an increased pandemic potential. Genetic and epidemiological evidence indicate camels serve as a reservoir for MERS virus but the mechanism of cross species transmission is unclear and many questions remain regarding the susceptibility of humans to infection. Deep sequencing data was obtained from the nasal samples of three camels that had been experimentally infected with a human MERS-CoV isolate. A majority of the genome was covered and average coverage was greater than 12,000x depth. Although only 5 mutations were detected in the consensus sequences, 473 intrahost single nucleotide variants were identified. Many of these variants were present at high frequencies and could potentially influence viral phenotype and the sensitivity of detection assays that target these regions for primer or probe binding. C1 [Borucki, Monica K.; Lao, Victoria; Hwang, Mona; Gardner, Shea; Allen, Jonathan E.] Lawrence Livermore Natl Lab, Livermore, CA USA. [Adney, Danielle; Bowen, Richard] Colorado State Univ, Ft Collins, CO 80523 USA. [Munster, Vincent] NIH, Rocky Mt Labs, Hamilton, MT USA. RP Borucki, MK (reprint author), Lawrence Livermore Natl Lab, Livermore, CA USA. EM borucki2@llnl.gov OI Munster, Vincent/0000-0002-2288-3196 FU U.S. Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344]; NIH S10 Instrumentation Grants [S10RR029668, S10RR027303] FX This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344. This work used the Vincent J. Coates Genomics Sequencing Laboratory at UC Berkeley, supported by NIH S10 Instrumentation Grants S10RR029668 and S10RR027303. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 20 PY 2016 VL 11 IS 1 AR e0146251 DI 10.1371/journal.pone.0146251 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5BW UT WOS:000368529100029 PM 26790002 ER PT J AU Swamydas, M Gao, JL Break, TJ Johnson, MD Jaeger, M Rodriguez, CA Lim, JK Green, NM Collar, AL Fischer, BG Lee, CCR Perfect, JR Alexander, BD Kullberg, BJ Netea, MG Murphy, PM Lionakis, MS AF Swamydas, Muthulekha Gao, Ji-Liang Break, Timothy J. Johnson, Melissa D. Jaeger, Martin Rodriguez, Carlos A. Lim, Jean K. Green, Nathaniel M. Collar, Amanda L. Fischer, Brett G. Lee, Chyi-Chia Richard Perfect, John R. Alexander, Barbara D. Kullberg, Bart-Jan Netea, Mihai G. Murphy, Philip M. Lionakis, Michail S. TI CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID SYSTEMIC CANDIDIASIS; INTERLEUKIN-8 RECEPTOR; ACUTE PYELONEPHRITIS; MOUSE NEUTROPHILS; UNITED-STATES; MICE; CXCR1; SUSCEPTIBILITY; CHEMOTAXIS; MECHANISMS AB Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the United States. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1(-/-) mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Increased susceptibility of Cxcr1(-/-) mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis. C1 [Swamydas, Muthulekha; Break, Timothy J.; Green, Nathaniel M.; Collar, Amanda L.; Fischer, Brett G.; Lionakis, Michail S.] NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Gao, Ji-Liang; Fischer, Brett G.; Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Johnson, Melissa D.; Perfect, John R.; Alexander, Barbara D.] Duke Univ, Sch Med, Durham, NC 27708 USA. [Jaeger, Martin; Kullberg, Bart-Jan; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. [Jaeger, Martin; Kullberg, Bart-Jan; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis, NL-6500 HB Nijmegen, Netherlands. [Rodriguez, Carlos A.; Lim, Jean K.] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA. [Lee, Chyi-Chia Richard] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lionakis, MS (reprint author), NIAID, Fungal Pathogenesis Unit, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lionakism@niaid.nih.gov RI Jaeger, Martin/H-3359-2015 FU Division of Intramural Research, NIAID, NIH; European Research Council (ERC) [310372] FX This work was supported by the Division of Intramural Research, NIAID, NIH. M.G.N. was supported by a European Research Council (ERC) Consolidator Grant (no. 310372). The funding sources had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 3 Z9 3 U1 2 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD JAN 20 PY 2016 VL 8 IS 322 AR 322ra10 DI 10.1126/scitranslmed.aac7718 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DB4VI UT WOS:000368511300003 PM 26791948 ER PT J AU Quiroz, C Orru, M Rea, W Ciudad-Roberts, A Yepes, G Britt, JP Ferre, S AF Quiroz, Cesar Orru, Marco Rea, William Ciudad-Roberts, Andres Yepes, Gabriel Britt, Jonathan P. Ferre, Sergi TI Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; glutamate; infralimbic cortex; nucleus accumbens; optogenetics; ventral tegmental area ID ADENOSINE A(2A) RECEPTORS; VENTRAL TEGMENTAL AREA; PREFRONTAL CORTEX; IN-VIVO; ELECTRICAL-STIMULATION; STRIATAL DOPAMINE; REWARD CIRCUITRY; RELEASE; RAT; FEAR AB It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivo microdialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A(2)A receptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA. C1 [Quiroz, Cesar; Orru, Marco; Rea, William; Ciudad-Roberts, Andres; Yepes, Gabriel; Ferre, Sergi] Natl Inst Drug Abuse, Integrat Neurobiol Sect, Intramural Res Program, Baltimore, MD 21224 USA. [Britt, Jonathan P.] Natl Inst Drug Abuse, Synapt Plast Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), Natl Inst Drug Abuse, Integrat Neurobiol Sect, Intramural Res Program, Triad Technol Bldg,333 Cassell Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Britt, Jonathan/D-8877-2011; Ferre, Sergi/K-6115-2014 OI Britt, Jonathan/0000-0003-3044-9565; Ferre, Sergi/0000-0002-1747-1779 FU National Institute on Drug Abuse FX This work supported by the intramural funds of the National Institute on Drug Abuse. We thank Dr Roy A. Wise for his critical review of the paper. NR 36 TC 6 Z9 6 U1 2 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 20 PY 2016 VL 36 IS 3 BP 851 EP 859 DI 10.1523/JNEUROSCI.2850-15.2016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DB2QW UT WOS:000368355100020 PM 26791215 ER PT J AU Hara, Y Yuk, F Puri, R Janssen, WGM Rapp, PR Morrison, JH AF Hara, Yuko Yuk, Frank Puri, Rishi Janssen, William G. M. Rapp, Peter R. Morrison, John H. TI Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys SO JOURNAL OF NEUROSCIENCE LA English DT Article DE area 46; delayed response; estradiol; menopause; mitochondria; MSB ID MULTIPLE-SYNAPSE BOUTONS; DENTATE GYRUS; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; POSTMENOPAUSAL WOMEN; LUTEINIZING-HORMONE; MENOPAUSE; TRANSITION; INCREASES; DECLINE AB Humans and nonhuman primates are vulnerable to age-and menopause-related decline in working memory, a cognitive function reliant on area 46 of the dorsolateral prefrontal cortex (dlPFC). We showed previously that presynaptic mitochondrial number and morphology in monkey dlPFC neurons correlate with working memory performance. The current study tested the hypothesis that the types of synaptic connections these boutons form are altered with aging and menopause in rhesus monkeys and that these metrics may be coupled with mitochondrial measures and working memory. Using serial section electron microscopy, we examined the frequencies and characteristics of nonsynaptic, single-synaptic, and multisynaptic boutons (MSBs) in the dlPFC. In contrast to our previous observations in the monkey hippocampal dentate gyrus, where MSBs comprised similar to 40% of boutons, the vast majority of dlPFC boutons were single-synaptic, whereas MSBs constituted a mere 10%. The frequency of MSBs was not altered by normal aging, but decreased by over 50% with surgical menopause induced by ovariectomy in aged monkeys. Cyclic estradiol treatment in aged ovariectomized animals restored MSB frequencies to levels comparable to young and aged premenopausal monkeys. Notably, the frequency of MSBs positively correlated with working memory scores, as measured by the average accuracy on the delayed response (DR) test. Furthermore, MSB incidence positively correlated with the number of healthy straight mitochondria in dlPFC boutons and inversely correlated with the number of pathological donut-shaped mitochondria. Together, our data suggest that MSBs are coupled to cognitive function and mitochondrial health and are sensitive to estrogen. C1 [Hara, Yuko; Yuk, Frank; Puri, Rishi; Janssen, William G. M.; Morrison, John H.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hara, Yuko; Yuk, Frank; Puri, Rishi; Janssen, William G. M.; Morrison, John H.] Icahn Sch Med Mt Sinai, Kastor Neurobiol Aging Labs, New York, NY 10029 USA. [Morrison, John H.] Icahn Sch Med Mt Sinai, Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Morrison, John H.] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA. [Rapp, Peter R.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Morrison, John H.] Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Morrison, John H.] Univ Calif Davis, Sch Med, Dept Neurol, Davis, CA 95616 USA. RP Morrison, JH (reprint author), Univ Calif Davis, Calif Natl Primate Res Ctr, 1 Shields Ave, Davis, CA 95616 USA. EM jhmorrison@ucdavis.edu FU National Institute on Aging [P01 AG06647, R37 AG06647, R01 AG010606] FX This work was supported by National Institute on Aging Grants P01 AG06647, R37 AG06647, and R01 AG010606 (J.H.M.) and in part by the Intramural Research Program of the National Institute on Aging. We thank Mary Roberts, Sania Fong, Deborah Kent, Katie Hartley, Sona Santos, Heather McKay, Carmel Stanko, and Anne Canfield at the California National Primate Research Center for their expert technical assistance involving the rhesus monkeys and Dr. Donald Canfield for assistance in veterinary work. We also thank Susan Fink, Ginelle Andrews, and Shannon Wadsworth for expert technical assistance in tissue processing and Dr. Johanna Crimins for critical discussion on this manuscript. NR 56 TC 3 Z9 3 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 20 PY 2016 VL 36 IS 3 BP 901 EP 910 DI 10.1523/JNEUROSCI.3480-13.2016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA DB2QW UT WOS:000368355100024 PM 26791219 ER PT J AU Kim, AR Kim, HS Kim, DK Nam, ST Kim, HW Park, YH Lee, D Lee, MB Lee, JH Kim, B Beaven, MA Kim, HS Kim, YM Choi, WS AF Kim, A-Ram Kim, Hyuk Soon Kim, Do Kyun Nam, Seung Taek Kim, Hyun Woo Park, Young Hwan Lee, Dajeong Lee, Min Bum Lee, Jun Ho Kim, Bokyung Beaven, Michael A. Kim, Hyung Sik Kim, Young Mi Choi, Wahn Soo TI Mesenteric IL-10-producing CD5(+) regulatory B cells suppress cow's milk casein-induced allergic responses in mice SO SCIENTIFIC REPORTS LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; T-CELLS; FOOD ALLERGY; B10 CELLS; MURINE MODEL; ORAL TOLERANCE; LYMPH-NODES; INDUCED ANAPHYLAXIS; IMMUNE-RESPONSES; MOUSE MODEL AB Food allergy is a hypersensitive immune reaction to food proteins. We have previously demonstrated the presence of IL-10-producing CD5(+) B cells and suggested their potential role in regulating cow's milk casein allergy in humans and IgE-mediated anaphylaxis in mice. In this study, we determined whether IL-10-producing CD5(+) regulatory B cells control casein-induced food allergic responses in mice and, if so, the underlying mechanisms. The induction of oral tolerance (OT) by casein suppressed casein-induced allergic responses including the decrease of body temperature, symptom score, diarrhea, recruitment of mast cells and eosinophils into jejunum, and other biological parameters in mice. Notably, the population of IL-10-producing CD5(+) B cells was increased in mesenteric lymph node (MLN), but not in spleen or peritoneal cavity (PeC) in OT mice. The adoptive transfer of CD5(+) B cells from MLN, but not those from spleen and PeC, suppressed the casein-induced allergic responses in an allergen-specific and IL-10-dependent manner. The inhibitory effect of IL-10-producing CD5(+) B cells on casein-induced allergic response was dependent on Foxp3(+) regulatory T cells. Taken together, mesenteric IL-10-producing regulatory B cells control food allergy via Foxp3(+) regulatory T cells and could potentially act as a therapeutic regulator for food allergy. C1 [Kim, A-Ram; Kim, Hyuk Soon; Kim, Do Kyun; Nam, Seung Taek; Kim, Hyun Woo; Park, Young Hwan; Lee, Dajeong; Lee, Min Bum; Lee, Jun Ho; Kim, Bokyung; Choi, Wahn Soo] Konkuk Univ, Sch Med, Chungju 380701, South Korea. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Kim, Hyung Sik] Sungkyunkwan Univ, Sch Pharm, Suwon 440746, South Korea. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul 132714, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Sch Med, Chungju 380701, South Korea. EM kym123@duksung.ac.kr; wahnchoi@kku.ac.kr FU National Research Foundation of Korea (NRF) grant (MSIP) [2012R1A2A1A03670516]; National Research Foundation of Korea (NRF) grant (MSIP) - Korea government [NRF-2013R1A4A1069575]; Intramural Program of the National Heart, Lung, and Blood Institute, NIH FX This work was supported by the National Research Foundation of Korea (NRF) grant (MSIP, No. 2012R1A2A1A03670516) and in part by a National Research Foundation of Korea (NRF) grant (MSIP, NRF-2013R1A4A1069575) funded by the Korea government. Dr. Michael A. Beaven was supported by the Intramural Program of the National Heart, Lung, and Blood Institute, NIH. NR 60 TC 3 Z9 4 U1 3 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 20 PY 2016 VL 6 AR 19685 DI 10.1038/srep19685 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB2US UT WOS:000368366000001 PM 26785945 ER PT J AU Song, NJ Yun, UJ Yang, S Wu, C Seo, CR Gwon, AR Baik, SH Choi, Y Choi, BY Bahn, G Kim, S Kwon, SM Park, JS Baek, SH Park, TJ Yoon, K Kim, BJ Mattson, MP Lee, SJ Jo, DG Park, KW AF Song, No-Joon Yun, Ui Jeong Yang, Sunghee Wu, Chunyan Seo, Cho-Rong Gwon, A-Ryeong Baik, Sang-Ha Choi, Yuri Choi, Bo Youn Bahn, Gahee Kim, Suji Kwon, So-Mi Park, Jin Su Baek, Seung Hyun Park, Tae Joo Yoon, Keejung Kim, Byung-Joon Mattson, Mark P. Lee, Sung-Joon Jo, Dong-Gyu Park, Kye Won TI Notch1 deficiency decreases hepatic lipid accumulation by induction of fatty acid oxidation SO SCIENTIFIC REPORTS LA English DT Article ID ADIPOCYTE DIFFERENTIATION; TRANSCRIPTION FACTORS; INSULIN-RESISTANCE; ADIPOSE-TISSUE; PPAR-GAMMA; INHIBITION; OBESITY; STEATOSIS; PATHWAY; DISEASE AB Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet-fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosis. C1 [Song, No-Joon; Seo, Cho-Rong; Kim, Suji; Kwon, So-Mi; Park, Kye Won] Sungkyunkwan Univ, Dept Food Sci & Biotechnol, Seoul, South Korea. [Yun, Ui Jeong; Yang, Sunghee; Gwon, A-Ryeong; Baik, Sang-Ha; Choi, Yuri; Choi, Bo Youn; Bahn, Gahee; Park, Jin Su; Baek, Seung Hyun; Jo, Dong-Gyu] Sungkyunkwan Univ, Sch Pharm, Seoul, South Korea. [Wu, Chunyan; Lee, Sung-Joon] Korea Univ, Dept Biotechnol, Grad Sch Life Sci & Biotechnol, PLUS Program BK21, Seoul 136713, South Korea. [Gwon, A-Ryeong; Kim, Byung-Joon] Gachon Univ Med & Sci, Grad Sch Med, Dept Internal Med, Gachon, South Korea. [Park, Tae Joo] Ulsan Natl Inst Sci & Technol, Sch Nanobiosci & Chem Engn, Ulsan, South Korea. [Yoon, Keejung] Sungkyunkwan Univ, Dept Genet Engn, Seoul, South Korea. [Mattson, Mark P.] NIA, Lab Neurosci, Intramural Res Program, Baltimore, MD 21224 USA. RP Jo, DG (reprint author), Sungkyunkwan Univ, Sch Pharm, Seoul, South Korea. EM jodg@skku.edu; kwpark@skku.edu RI Park, Tae Joo/G-1460-2011 OI Park, Tae Joo/0000-0003-3176-177X FU Korea Health21 R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea [A101711, HI14C2539]; Basic Science Research Program through the National Research Foundation of Korea (NRF) [20110014302, 2013R1A1A2060447, 2012S1A2A1A01031782, 2015R1A2A1A01003530]; Ministry of Education, Science and Technology, Republic of Korea; Intramural Research Program of the National Institute on Aging, NIH FX This study was supported by a grant (A101711, HI14C2539) from the Korea Health21 R&D Project, Ministry for Health, Welfare, and Family Affairs, Republic of Korea. This study was also supported by grants (20110014302, 2013R1A1A2060447, 2012S1A2A1A01031782, 2015R1A2A1A01003530) funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF), the Ministry of Education, Science and Technology, Republic of Korea. This research was supported, in part, by the Intramural Research Program of the National Institute on Aging, NIH. NR 32 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 20 PY 2016 VL 6 AR 19377 DI 10.1038/srep19377 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB2PG UT WOS:000368350900002 PM 26786165 ER PT J AU Nogales, V Reinhold, WC Varma, S Martinez-Cardus, A Moutinho, C Moran, S Heyn, H Sebio, A Barnadas, A Pommier, Y Esteller, M AF Nogales, Vanesa Reinhold, William C. Varma, Sudhir Martinez-Cardus, Anna Moutinho, Catia Moran, Sebastian Heyn, Holger Sebio, Ana Barnadas, Agusti Pommier, Yves Esteller, Manel TI Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs SO ONCOTARGET LA English DT Article DE SLFN11; CpG island methylation; epigenetics; chemoresistance; DNA-damaging agents ID RNA HELICASE; OVARIAN-CANCER; DNA-REPAIR; CELLS; CHEMOTHERAPY; CISPLATIN; PROTEIN; HYPERMETHYLATION; SENSITIVITY; INHIBITION AB Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers predicting differential sensitivity to these agents in a given tumor type have been clearly identified. Epigenetic gene silencing is increasingly being recognized as a factor conferring distinct tumoral drug sensitivity, so we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines with respect to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have found promoter CpG island hypermethylation-associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) to be associated with increased resistance to platinum compounds. We have also experimentally validated these findings in vitro. In this setting, we also identified the BRCA1 interacting DHX9 RNA helicase (also known as RHA) as a protein partner for SLFN11, suggesting a mechanistic pathway for the observed chemoresistance effect. Most importantly, we have been able to extend these findings clinically, following the observation that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation had a poor response to both cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platinum drugs in human cancer. C1 [Nogales, Vanesa; Martinez-Cardus, Anna; Moutinho, Catia; Moran, Sebastian; Heyn, Holger; Esteller, Manel] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Catalonia, Spain. [Reinhold, William C.] NCI, Genom & Bioinformat Grp, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Varma, Sudhir; Pommier, Yves] NCI, Dev Therapeut Branch, Bethesda, MD 20892 USA. [Varma, Sudhir; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Sebio, Ana; Barnadas, Agusti] Univ Autonoma Barcelona, Hosp Santa Ceu & St Pau, Dept Med Oncol, Barcelona, Catalonia, Spain. [Esteller, Manel] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain. [Esteller, Manel] Inst Catalana Rec & Estud Avancats, Barcelona, Catalonia, Spain. RP Esteller, M (reprint author), Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Catalonia, Spain.; Esteller, M (reprint author), Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain.; Esteller, M (reprint author), Inst Catalana Rec & Estud Avancats, Barcelona, Catalonia, Spain. EM mesteller@idibell.cat RI Moran, Sebastian /G-5293-2013; OI Moran, Sebastian /0000-0003-4192-8983; Heyn, Holger/0000-0002-3276-1889 FU European Community [HEALTH-F2-2010-258677]; Instituto de Salud Carlos III (ISCIII); ERDF [PIE13/00022]; Spanish Cancer Research Network (RTICC) [RD12/0036/0039]; Ministerio de Educacion, Ciencia e Innovacion [SAF2010-14935, 13FIS037, PT13/0001/0033]; Cellex Foundation; Health and Science Departments of the Catalan Government (Generalitat de Catalunya, AGAUR) [2009SGR1315, 2014SGR633]; Center for Cancer Research, Intramural Program of the National Cancer Institute [Z01 BC 006150] FX This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no HEALTH-F2-2010-258677 - CURELUNG project, the Instituto de Salud Carlos III (ISCIII), co-financed by the ERDF Fund, 'A way to achieve Europe', under the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE) and the Spanish Cancer Research Network (RTICC) no. RD12/0036/0039, Ministerio de Educacion, Ciencia e Innovacion Grant SAF2010-14935, 13FIS037 and PT13/0001/0033 (Proteomics Unit, ProteoRed, PRB2-ISCIII), Cellex Foundation, and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya, AGAUR no. 2009SGR1315 and 2014SGR633). ME is an ICREA Research Professor. The studies performed by the NCI team (YP, SV, WR) are supported by the Center for Cancer Research, Intramural Program of the National Cancer Institute (Z01 BC 006150). NR 31 TC 13 Z9 14 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JAN 19 PY 2016 VL 7 IS 3 BP 3084 EP 3097 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DD5GV UT WOS:000369951800068 PM 26625211 ER PT J AU Verner, MA Ngueta, G Jensen, ET Fromme, H Volkel, W Nygaard, UC Granum, B Longnecker, MP AF Verner, Marc-Andre Ngueta, Gerard Jensen, Elizabeth T. Fromme, Hermann Voelkel, Wolfgang Nygaard, Unni Cecilie Granum, Berit Longnecker, Matthew P. TI A Simple Pharmacokinetic Model of Prenatal and Postnatal Exposure to Perfluoroalkyl Substances (PFASs) SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID HUMAN BREAST-MILK; PERFLUORINATED COMPOUNDS; TEMPORAL TREND; LACTATION; SERUM; PERFLUOROOCTANOATE; PFOA; PERFLUOROHEXANESULFONATE; CHEMICALS; MONKEYS AB Most children are exposed to perfluoroalkyl substances (PFASs) through placental transfer, breastfeeding, and other environmental sources. To date, there are no validated tools to estimate exposure and body burden during infancy and childhood. In this study, we aimed to (i) develop a two-generation pharmacokinetic model of prenatal and postnatal exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), and perfluorohexanesulfonate (PFHxS); and to (ii) evaluate it against measured childrens levels in two studies. We developed a pharmacokinetic model consisting of a maternal and a child compartment to simulate lifetime exposure in women and transfer to the child across the placenta and through breastfeeding. To evaluate the model, we performed simulations for each motherchild dyad from two studies in which maternal PFAS levels at delivery and childrens PFAS levels were available. Model predictions based on maternal PFAS levels, sex of child, body weight, and duration of breastfeeding explained between 52% and 60% of the variability in measured childrens levels at 6 months of age and between 52% and 62% at 36 months. Monte Carlo simulations showed that the daily intake through breastfeeding and resulting internal PFAS levels can be much higher in nursing infants than in mothers. This pharmacokinetic model shows potential for postnatal exposure assessment in the context of epidemiological studies and risk assessment. C1 [Verner, Marc-Andre; Ngueta, Gerard] Univ Montreal, Sch Publ Hlth, Dept Occupat & Environm Hlth, Montreal, PQ H3T 1A8, Canada. [Verner, Marc-Andre] Univ Montreal, Univ Montreal Publ Hlth Res Inst IRSPUM, Montreal, PQ H3T 1A8, Canada. [Jensen, Elizabeth T.; Longnecker, Matthew P.] NIEHS, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Jensen, Elizabeth T.] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Fromme, Hermann; Voelkel, Wolfgang] Bavarian Hlth & Food Safety Author, Dept Chem Safety & Toxicol, D-80538 Munich, Germany. [Nygaard, Unni Cecilie; Granum, Berit] Norwegian Inst Publ Hlth, Div Environm Med, POB 4404 Nydalen, N-0403 Oslo, Norway. RP Verner, MA (reprint author), Univ Montreal, Sch Publ Hlth, Dept Occupat & Environm Hlth, Montreal, PQ H3T 1A8, Canada.; Verner, MA (reprint author), Univ Montreal, Univ Montreal Publ Hlth Res Inst IRSPUM, Montreal, PQ H3T 1A8, Canada. EM marc-andre.verner.1@umontreal.ca RI Jensen, Elizabeth/L-1466-2016; OI Granum, Berit/0000-0002-3401-8132; Volkel, Wolfgang/0000-0002-2292-6168; Longnecker, Matthew/0000-0001-6073-5322 FU NIH, National Institute of Environmental Health Sciences; Emerging Researcher Fellowship from the Universite de Montreal Public Health Research Institute (IRSPUM); Norwegian Ministry of Health; Ministry of Education and Research; National Institutes of Health (NIEHS) [NO-ES- 75558]; National Institutes of Health (NINDS) [1 UO1 NS 047537-01]; Norwegian Research Council/FUGE [151918/S10] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. M.A.V. is the recipient of an Emerging Researcher Fellowship from the Universite de Montreal Public Health Research Institute (IRSPUM). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, the National Institutes of Health (NIEHS) (contract no. NO-ES- 75558), the National Institutes of Health (NINDS) (grant no. 1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). NR 48 TC 3 Z9 3 U1 14 U2 32 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD JAN 19 PY 2016 VL 50 IS 2 BP 978 EP 986 DI 10.1021/acs.est.5b04399 PG 9 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA DB5OL UT WOS:000368563400051 PM 26691063 ER PT J AU Iskakova, AN Romanova, AA Aitkulova, AM Sikhayeva, NS Zholdybayeva, EV Ramanculov, EM AF Iskakova, Aisha N. Romanova, Aliya A. Aitkulova, Akbota M. Sikhayeva, Nurgul S. Zholdybayeva, Elena V. Ramanculov, Erlan M. TI Polymorphisms in genes involved in the absorption, distribution, metabolism, and excretion of drugs in the Kazakhs of Kazakhstan SO BMC GENETICS LA English DT Article DE Kazakhstan; Single nucleotide polymorphism; Adsorption; Distribution; Metabolism; Excretion; OpenArray ID WARFARIN; POPULATION; CHINESE; GENOTYPE; ALLELES; CYP2C19 AB Background: Studies of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are crucial to the development of therapeutics in clinical medicine. Such data provide information that may improve our understanding of individual differences in sensitivity or resistance to certain drugs, thereby helping to avoid adverse drug reactions (ADRs) in patients and improve the quality of therapies. Here, we aimed to analyse single nucleotide polymorphisms (SNPs) involved in the ADME of multiple drugs in Kazakhs from Kazakhstan. Results: A total of 158 SNPs involved in the ADME of various drugs were studied. We analysed 320 Kazakh DNA samples using OpenArray genotyping. Of the 158 SNPs, 75 were not found in heterozygous or homozygous variants. Comparative analysis among Kazakhs and world populations showed a fairly high percentage of population differentiation. Conclusion: These results provide further information for pharmacogenetic databases and may contribute to the development of personalized approaches and safer therapies for the Kazakh population. Moreover, these data provide insights into the different racial groups that may have contributed to the Kazakh population. C1 [Iskakova, Aisha N.; Romanova, Aliya A.; Aitkulova, Akbota M.; Sikhayeva, Nurgul S.; Zholdybayeva, Elena V.; Ramanculov, Erlan M.] Natl Biotechnol Ctr, Natl Sci Lab Biotechnol, Alma Ata, Kazakhstan. [Iskakova, Aisha N.] Al Farabi Kazakh Natl Univ, Biol & Biotechnol Dept, Alma Ata, Kazakhstan. [Sikhayeva, Nurgul S.] LN Gumilyov Eurasian Natl Univ, Fac Nat Sci, Astana, Kazakhstan. [Ramanculov, Erlan M.] Nazarbayev Univ, Sch Sci & Technol, Astana, Kazakhstan. RP Iskakova, AN (reprint author), Natl Biotechnol Ctr, Natl Sci Lab Biotechnol, Alma Ata, Kazakhstan.; Iskakova, AN (reprint author), Al Farabi Kazakh Natl Univ, Biol & Biotechnol Dept, Alma Ata, Kazakhstan. EM aishaisk1@gmail.com RI Iskakova, Aisha/C-7136-2015 OI Iskakova, Aisha/0000-0002-0631-062X FU Ministry of Education and Science of the Republic of Kazakhstan [O.0584] FX This work was supported by program No O.0584, funded by the Ministry of Education and Science of the Republic of Kazakhstan. NR 20 TC 1 Z9 1 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD JAN 19 PY 2016 VL 17 AR 23 DI 10.1186/s12863-016-0329-x PG 22 WC Genetics & Heredity SC Genetics & Heredity GA DB4PS UT WOS:000368496100003 PM 26785747 ER PT J AU Kim, SA Inamura, K Yamauchi, M Nishihara, R Mima, K Sukawa, Y Li, TT Yasunari, M Morikawa, T Fitzgerald, KC Fuchs, CS Wu, KN Chan, AT Zhang, XH Ogino, S Qian, ZR AF Kim, Sun A. Inamura, Kentaro Yamauchi, Mai Nishihara, Reiko Mima, Kosuke Sukawa, Yasutaka Li, Tingting Yasunari, Mika Morikawa, Teppei Fitzgerald, Kathryn C. Fuchs, Charles S. Wu, Kana Chan, Andrew T. Zhang, Xuehong Ogino, Shuji Qian, Zhi Rong TI Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis SO BRITISH JOURNAL OF CANCER LA English DT Article DE colorectum; epithelial-mesenchymal transition; neoplasm invasiveness ID ISLAND METHYLATOR PHENOTYPE; ADVANCED COLORECTAL-CANCER; POPULATION-BASED SAMPLE; MICROSATELLITE INSTABILITY; BETA-CATENIN; PROGNOSTIC-SIGNIFICANCE; BORDER CONFIGURATION; RECTAL-CANCER; BRAF MUTATION; COLON-CANCER AB Background: Loss of CDH1 (E-cadherin) expression in cancer cells may promote cell migration and invasion. Therefore, we hypothesised that loss of CDH1 expression in colorectal carcinoma might be associated with aggressive features and clinical outcome. Methods: Utilising molecular pathological epidemiology database of 689 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed tumour CDH1 expression by immunohistochemistry. Multivariate logistic regression analysis was conducted to assess association of CDH1 loss with tumour growth pattern (expansile-intermediate vs infiltrative) and lymph node metastasis and distant metastasis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and PIK3CA, BRAF and KRAS mutations. Mortality according to CDH1 status was assessed using Cox proportional hazards model. Results: Loss of tumour CDH1 expression was observed in 356 cases (52%), and associated with infiltrative tumour growth pattern (odds ratio (OR), 2.02; 95% confidence interval (CI), 1.23-3.34; P = 0.006) and higher pN stage (OR, 1.73; 95% CI, 1.23-2.43; P = 0.001). Tumour CDH1 expression was not significantly associated with distant metastasis or prognosis. Conclusions: Loss of CDH1 expression in colorectal cancer is associated with infiltrative tumour growth pattern and lymph node metastasis. C1 [Kim, Sun A.; Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko; Mima, Kosuke; Sukawa, Yasutaka; Li, Tingting; Yasunari, Mika; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave M420, Boston, MA 02215 USA. [Kim, Sun A.; Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko; Mima, Kosuke; Sukawa, Yasutaka; Li, Tingting; Yasunari, Mika; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Harvard Univ, Sch Med, 450 Brookline Ave M420, Boston, MA 02215 USA. [Inamura, Kentaro] NCI, Lab Human Carcinogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Nishihara, Reiko; Wu, Kana] Harvard Univ, Dept Nutr, TH Chan Sch Publ Hlth, 655 Huntington Ave Bldg 2,Room 213, Boston, MA 02115 USA. [Li, Tingting] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Gastroenterol, 28 Fuxing Rd, Beijing 100853, Peoples R China. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. [Fitzgerald, Kathryn C.; Ogino, Shuji] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, 655 Huntington Ave, Boston, MA 02115 USA. [Fuchs, Charles S.; Chan, Andrew T.; Zhang, Xuehong] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 29 Wigglesworth St, Boston, MA 02120 USA. [Fuchs, Charles S.; Chan, Andrew T.; Zhang, Xuehong] Harvard Univ, Sch Med, 29 Wigglesworth St, Boston, MA 02120 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St,GRJ-722, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, 55 Fruit St,GRJ-722, Boston, MA 02114 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, 29 Wigglesworth St, Boston, MA 02120 USA. [Ogino, Shuji] Harvard Univ, Sch Med, 29 Wigglesworth St, Boston, MA 02120 USA. RP Ogino, S; Qian, ZR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave M420, Boston, MA 02215 USA.; Ogino, S; Qian, ZR (reprint author), Harvard Univ, Sch Med, 450 Brookline Ave M420, Boston, MA 02215 USA.; Ogino, S (reprint author), Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, 655 Huntington Ave, Boston, MA 02115 USA.; Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, 29 Wigglesworth St, Boston, MA 02120 USA.; Ogino, S (reprint author), Harvard Univ, Sch Med, 29 Wigglesworth St, Boston, MA 02120 USA. EM shuji_ogino@dfci.harvard.edu; zhirong_qian@dfci.harvard.edu FU U.S. National Institutes of Health (NIH) [K07 CA190673, R01 CA137178, K24 DK098311, P50 CA127003, R01 CA151993, R35 CA197735, P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552]; Paula and Russell Agrusa Fund for Colorectal Cancer Research; Friends of the Dana-Farber Cancer Institute; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Asan Medical Center, Korea; Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad; Takashi Tsuruo Memorial Fund, Japan; Uehara Memorial Foundation, Japan FX This work was supported by U.S. National Institutes of Health (NIH) grants (K07 CA190673 to RN; R01 CA137178 and K24 DK098311 to ATC; P50 CA127003 to CSF; R01 CA151993 and R35 CA197735 to SO; P01 CA87969 and UM1 CA186107 to Meir J Stampfer, Nurse's Health Study; P01 CA55075 and UM1 CA167552 to Walter C Willett, Health Professional's Follow-up Study); grants from the Paula and Russell Agrusa Fund for Colorectal Cancer Research, the Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. SAK was supported by an early exchange postdoctoral fellowship grant from Asan Medical Center, Korea. KI was supported by a Japan Society for the Promotion of Science Postdoctoral Fellowship for Research Abroad and by Takashi Tsuruo Memorial Fund, Japan. KM was supported by a fellowship grant from the Uehara Memorial Foundation, Japan. ATC is a Damon Runyon Clinical Investigator. We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Use of standardised official symbols: We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including BRAF; CDH1 (so-called E-cadherin); CTNNB1 (catenin (cadherin-associated protein), beta 1, 88kDa; so-called beta-catenin); KRAS; and PIK3CA; all of which are described at www.genenames.org. NR 38 TC 2 Z9 3 U1 5 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 19 PY 2016 VL 114 IS 2 BP 199 EP 206 DI 10.1038/bjc.2015.347 PG 8 WC Oncology SC Oncology GA DB5NV UT WOS:000368561800010 PM 26742007 ER PT J AU Garcia-Albeniz, X Rudolph, A Hutter, C White, E Lin, Y Rosse, SA Figueiredo, JC Harrison, TA Jiao, S Brenner, H Casey, G Hudson, TJ Thornquist, M Le Marchand, L Potter, J Slattery, ML Zanke, B Baron, JA Caan, BJ Chanock, SJ Berndt, SI Stelling, D Fuchs, CS Hoffmeister, M Butterbach, K Du, MM Gauderman, WJ Gunter, MJ Lemire, M Ogino, S Lin, J Hayes, RB Haile, RW Schoen, RE SWarnick, G Jenkins, MA Thibodeau, SN Schumacher, FR Lindor, NM Kolonel, LN Hopper, JL Gong, J Seminara, D Pflugeisen, BM Ulrich, CM Qu, CH Duggan, D Cotterchio, M Campbell, PT Carlson, CS Newcomb, PA Giovannucci, E Hsu, L Chan, AT Peters, U Chang-Claude, J AF Garcia-Albeniz, Xabier Rudolph, Anja Hutter, Carolyn White, Emily Lin, Yi Rosse, Stephanie A. Figueiredo, Jane C. Harrison, Tabitha A. Jiao, Shuo Brenner, Hermann Casey, Graham Hudson, Thomas J. Thornquist, Mark Le Marchand, Loic Potter, John Slattery, Martha L. Zanke, Brent Baron, John A. Caan, Bette J. Chanock, Stephen J. Berndt, Sonja I. Stelling, Deanna Fuchs, Charles S. Hoffmeister, Michael Butterbach, Katja Du, Mengmeng Gauderman, W. James Gunter, Marc J. Lemire, Mathieu Ogino, Shuji Lin, Jennifer Hayes, Richard B. Haile, Robert W. Schoen, Robert E. SWarnick, Greg Jenkins, Mark A. Thibodeau, Stephen N. Schumacher, Fredrick R. Lindor, Noralane M. Kolonel, Laurence N. Hopper, John L. Gong, Jian Seminara, Daniela Pflugeisen, Bethann M. Ulrich, Cornelia M. Qu, Conghui Duggan, David Cotterchio, Michelle Campbell, Peter T. Carlson, Christopher S. Newcomb, Polly A. Giovannucci, Edward Hsu, Li Chan, Andrew T. Peters, Ulrike Chang-Claude, Jenny TI CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE GWAS; colorectal cancer; menopausal hormone therapy; polymorphisms; gene-environment interaction; cytochrome P450 ID GENOME-WIDE ASSOCIATION; GENE-ENVIRONMENT INTERACTION; POSTMENOPAUSAL HORMONE-THERAPY; COLON-CANCER; SUSCEPTIBILITY LOCI; REPLACEMENT THERAPY; RECTAL-CANCER; WOMEN; HEALTH; METAANALYSIS AB Background: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. Methods: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. Results: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs) = 0.61 (0.52-0.72), P = 4.8 x 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR = 0.64 (0.52-0.78), P = 1.2 x 10(-5) (alpha threshold = 3.1 x 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. Conclusions: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis. C1 [Garcia-Albeniz, Xabier; Fuchs, Charles S.; Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Garcia-Albeniz, Xabier; Lin, Jennifer; Giovannucci, Edward; Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Rudolph, Anja; Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Hutter, Carolyn; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [White, Emily; Lin, Yi; Rosse, Stephanie A.; Harrison, Tabitha A.; Jiao, Shuo; Thornquist, Mark; Potter, John; Stelling, Deanna; Du, Mengmeng; SWarnick, Greg; Gong, Jian; Ulrich, Cornelia M.; Carlson, Christopher S.; Newcomb, Polly A.; Hsu, Li; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [White, Emily; Lin, Yi; Rosse, Stephanie A.; Harrison, Tabitha A.; Jiao, Shuo; Thornquist, Mark; Potter, John; Stelling, Deanna; Du, Mengmeng; SWarnick, Greg; Gong, Jian; Carlson, Christopher S.; Newcomb, Polly A.; Hsu, Li; Peters, Ulrike] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. [Figueiredo, Jane C.; Casey, Graham; Schumacher, Fredrick R.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Brenner, Hermann; Hoffmeister, Michael; Butterbach, Katja] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany. [Brenner, Hermann; Ulrich, Cornelia M.] German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany. [Brenner, Hermann; Ulrich, Cornelia M.] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, D-69120 Heidelberg, Germany. [Hudson, Thomas J.; Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Epidemiol Program, Ctr Canc, Honolulu, HI 96813 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT 84132 USA. [Zanke, Brent] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON K1Y 4E9, Canada. [Baron, John A.] Univ N Carolina, Sch Med, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Caan, Bette J.] Kaiser Permanente, Div Res, Med Care Program, Oakland, CA 94612 USA. [Chanock, Stephen J.; Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Fuchs, Charles S.; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Gauderman, W. James] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Gunter, Marc J.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY 10016 USA. [Haile, Robert W.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA 15213 USA. [Jenkins, Mark A.; Hopper, John L.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic 3010, Australia. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med, Scottsdale, AZ 85259 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Pathol, Scottsdale, AZ 85259 USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Genet, Scottsdale, AZ 85259 USA. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ 85259 USA. [Pflugeisen, Bethann M.; Qu, Conghui] Fred Hutchinson Canc Res Ctr, Dept Canc Prevent, Seattle, WA 98109 USA. [Ulrich, Cornelia M.] Univ Utah, Dept Populat Sci, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Duggan, David] Translat Genom Res Inst Tgen, Phoenix, AZ 85004 USA. [Cotterchio, Michelle] Canc Care Ontario, Prevent & Canc Control, Toronto, ON M5G 2L7, Canada. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Chang-Claude, Jenny] Univ Med Ctr Hamburg Eppendorf, UCCH, D-20246 Hamburg, Germany. RP Chan, AT (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.; Chang-Claude, J (reprint author), German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany.; Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA.; Peters, U (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10017 USA. EM achan@partners.org; upeters@fhcrc.org; j.chang-claude@dkfz.de RI Jenkins, Mark/P-7803-2015; Brenner, Hermann/B-4627-2017; OI Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X; Hoffmeister, Michael/0000-0002-8307-3197 FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045]; NCI [R25 CA094880, P30 CA008748]; National Institutes of Health (RFA) [CA-95-011]; National Cancer Institute, National Institutes of Health [U01 CA122839]; National Institutes of Health: Australasian Colorectal Cancer Family Registry [U01 CA097735]; National Institutes of Health: Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; National Institutes of Health: Seattle Colorectal Cancer Family Registry [U01 CA074794]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; National Institutes of Health [U01 CA074783, R01 CA48998, R01 CA137178, P01 CA 087969, P50 CA 127003, R37 CA54281, P01 CA033619, R01 CA63464]; GL2 grant from the Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research, through Ontario Ministry of Research and Innovation; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) [Z01 CP 010200, U01 HG004446, U01 HG 004438]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C, HHSN271201100004C]; ASISA Fellowship; SEOM (Sociedad Espanola de Oncologia Medica) grant; NIDDK [K24DK098311]; [HL115606]; [R35 CA197735] FX DACHS: we thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. GECCO: we would like to thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. NHS: we would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS. We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. PLCO: we thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute; the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial; Mr Tom Riley and staff, Information Management Services, Inc.; Ms Barbara O'Brien and staff, Westat, Inc.; and Drs Bill Kopp, Wen Shao and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. PMH: we would like to thank the study participants and staff of the Hormones and Colon Cancer study. WHI: we thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Short%20List.pdf. Funding details are as follows: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045). Mengmeng Du is supported by grants R25 CA094880 and P30 CA008748 from NCI. CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The following Colon CFR centres contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); NHS is supported by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003). MEC: National Institutes of Health (R37 CA54281, P01 CA033619 and R01 CA63464).; OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS, Colon CGEMS pancreatic cancer scan (PanScan) and the Lung Cancer and Smoking study. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093 v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PAN). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201 100046C, HHSN268201100001C, HHSN268201100002C, HHSN2 68201100003C, HHSN268201100004C and HHSN271201100004C. XG-A is a recipient of an ASISA Fellowship and SEOM (Sociedad Espanola de Oncologia Medica) grant. ATC is a Damon Runyon Clinical Investigator and is also supported by NIDDK K24DK098311. WJG is supported by grant #HL115606. SO is supported by grant R35 CA197735. NR 54 TC 2 Z9 2 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 19 PY 2016 VL 114 IS 2 BP 221 EP 229 DI 10.1038/bjc.2015.443 PG 9 WC Oncology SC Oncology GA DB5NV UT WOS:000368561800013 PM 26766742 ER PT J AU Cheung, HH Yang, YZ Lee, TL Rennert, O Chan, WY AF Cheung, Hoi-Hung Yang, Yanzhou Lee, Tin-Lap Rennert, Owen Chan, Wai-Yee TI Hypermethylation of genes in testicular embryonal carcinomas SO BRITISH JOURNAL OF CANCER LA English DT Article DE Embryonal carcinoma; DNA methylation; sex-linked genes; USP13; RBMY1A ID GERM-CELL TUMORS; TESTIS-SPECIFIC PROTEIN; DNA METHYLATION; PROSTATE-CANCER; IN-SITU; EXPRESSION; PTEN; LOCALIZATION; FEATURES; MARKER AB Background: Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation. Methods: To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages (stage I and stage III) of divergent invasiveness. Non-cancerous testicular tissues were included. Expression of a number of hypermethylated genes were examined by quantitative RT-PCR and immunohistochemistry (IHC). Results: A total of 1167 tumour-hypermethylated differentially methylated regions (DMRs) were identified across the genome. Among them, 40 genes/ncRNAs were found to have hypermethylated promoters. Quantitative RT-PCR confirmed downregulation of 8 out of 9 of the genes. Among the confirmed genes, five were sex-linked genes, including X-linked genes STAG2, SPANXD/E and MIR1184, and Y-linked genes RBMY1A1/1B/1D and FAM197Y2P. RBMY1A is a testis-specific gene for spermatogenesis. RNF168 and USP13 are potential tumour suppressors. Expression of RBMY1A was lost in EC and seminoma as documented in the Protein Atlas. We confirmed downregulation of USP13 in EC by IHC. Conclusions: Our genome-wide analysis of testicular EC identified methylation changes in several previously unknown genes. This may provide insight of crosstalk between normal germ cell development and carcinogenesis. C1 [Cheung, Hoi-Hung; Chan, Wai-Yee] Chinese Univ Hong Kong, Chinese Univ Hong Kong Shandong Univ Joint Lab Re, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. [Yang, Yanzhou] Ningxia Med Univ, Key Lab Fertil Preservat & Maintenance, Minist Educ, Key Lab Reprod & Genet Ningxia, Ningxia 750004, Peoples R China. [Lee, Tin-Lap; Chan, Wai-Yee] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Reprod Dev & Endocrinol Theme, Shatin, Hong Kong, Peoples R China. [Rennert, Owen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Cheung, HH; Chan, WY (reprint author), Chinese Univ Hong Kong, Chinese Univ Hong Kong Shandong Univ Joint Lab Re, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China.; Chan, WY (reprint author), Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Reprod Dev & Endocrinol Theme, Shatin, Hong Kong, Peoples R China. EM cheunghh@cuhk.edu.hk; chanwy@cuhk.edu.hk RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Chinese University of Hong Kong; CUHK-Shandong University Joint Laboratory FX This work was supported by funds provided by the Chinese University of Hong Kong and the CUHK-Shandong University Joint Laboratory. NR 40 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 19 PY 2016 VL 114 IS 2 BP 230 EP 236 DI 10.1038/bjc.2015.408 PG 7 WC Oncology SC Oncology GA DB5NV UT WOS:000368561800014 PM 26625006 ER PT J AU Elagha, AA Weissman, G AF Elagha, Abdalla A. Weissman, Gaby TI Pacemaker Malfunction Attributed to Multidetector Cardiac Computed Tomography SO CIRCULATION LA English DT Editorial Material C1 [Elagha, Abdalla A.] Cairo Univ Hosp, Dept Cardiol, Cairo, Egypt. [Elagha, Abdalla A.] NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Weissman, Gaby] Medstar Heart & Vasc Inst, Washington, DC USA. [Weissman, Gaby] Georgetown Univ, Washington, DC USA. RP Elagha, AA (reprint author), Kasr Alaini Hosp, Dept Cardiol, 1 Saraya St,Third Floor, Cairo 11211, Egypt. EM abdalla.elagha@kasralainy.edu.eg NR 2 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JAN 19 PY 2016 VL 133 IS 3 BP 342 EP 343 DI 10.1161/CIRCULATIONAHA.115.019412 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DB5FV UT WOS:000368540900016 PM 26783279 ER PT J AU Yuan, JD Hegde, PS Clynes, R Foukas, PG Harari, A Kleen, TO Kvistborg, P Maccalli, C Maecker, HT Page, DB Robins, H Song, WR Stack, EC Wang, E Whiteside, TL Zhao, YD Zwierzina, H Butterfield, LH Fox, BA AF Yuan, Jianda Hegde, Priti S. Clynes, Raphael Foukas, Periklis G. Harari, Alexandre Kleen, Thomas O. Kvistborg, Pia Maccalli, Cristina Maecker, Holden T. Page, David B. Robins, Harlan Song, Wenru Stack, Edward C. Wang, Ena Whiteside, Theresa L. Zhao, Yingdong Zwierzina, Heinz Butterfield, Lisa H. Fox, Bernard A. TI Novel technologies and emerging biomarkers for personalized cancer immunotherapy SO JOURNAL FOR IMMUNOTHERAPY OF CANCER LA English DT Review DE Immune checkpoint blockade; Cancer immunotherapy; Biomarkers; Task Force; Immune monitoring; Technology; Bioinformatics ID REGULATORY T-CELLS; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; ADVANCED MELANOMA PATIENTS; TUMOR-INFILTRATING LYMPHOCYTES; MICROARRAY EXPRESSION DATA; EXOME ANALYSIS REVEALS; EMBRYONIC STEM-CELLS; CTLA-4 BLOCKADE; LUNG-CANCER; METASTATIC MELANOMA AB The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery. C1 [Yuan, Jianda] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Hegde, Priti S.] Genentech Inc, San Francisco, CA 94080 USA. [Clynes, Raphael] Bristol Myers Squibb Co, Princeton, NJ 08648 USA. [Foukas, Periklis G.; Harari, Alexandre] Univ Lausanne Hosp, Ctr Expt Therapeut, CH-1011 Lausanne, Switzerland. [Foukas, Periklis G.; Harari, Alexandre] Univ Lausanne Hosp, Ludwig Inst Canc Res, CH-1011 Lausanne, Switzerland. [Foukas, Periklis G.] Univ Athens, Sch Med, Attikon Univ Hosp, Dept Pathol, Haidari 12462, Greece. [Kleen, Thomas O.] Epiontis GmbH, D-12489 Berlin, Germany. [Kvistborg, Pia] Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands. [Maccalli, Cristina] Univ Hosp Siena, Italian Network Biotherapy Tumors NIBIT Lab, Med Oncol & Immunotherapy, I-53100 Siena, Italy. [Maecker, Holden T.] Stanford Univ, Med Ctr, Stanford, CA 94303 USA. [Page, David B.; Fox, Bernard A.] Providence Canc Ctr, Earle Chiles Res Inst, Portland, OR 97213 USA. [Robins, Harlan] Adapt Technol Inc, Seattle, WA 98102 USA. [Song, Wenru] AstraZeneca, Gaithersburg, MD 20878 USA. [Stack, Edward C.] PerkinElmer, Hopkinton, MA 01784 USA. [Wang, Ena] Sidra Med & Res Ctr, Doha, Qatar. [Whiteside, Theresa L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. [Zhao, Yingdong] NCI, Rockville, MD 20850 USA. [Zwierzina, Heinz] Innsbruck Med Univ, Med Klin, A-6020 Innsbruck, Austria. [Butterfield, Lisa H.] Univ Pittsburgh, Inst Canc, Dept Med Surg & Immunol, Pittsburgh, PA 15213 USA. RP Yuan, JD (reprint author), Mem Sloan Kettering Canc Ctr, 1275 New York Ave Box 386, New York, NY 10065 USA. EM jiandayuanusa@gmail.com; bernard.fox@providence.org OI Harari, Alexandre/0000-0002-1055-2090 FU NCI NIH HHS [P30 CA124435, R01 CA168628] NR 255 TC 26 Z9 26 U1 12 U2 38 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2051-1426 J9 J IMMUNOTHER CANCER JI J. Immunother. Cancer PD JAN 19 PY 2016 VL 4 AR 3 DI 10.1186/s40425-016-0107-3 PG 25 WC Oncology SC Oncology GA DB2YQ UT WOS:000368377000003 PM 26788324 ER PT J AU Andersen, NJ Boguslawski, EA Naidu, AS Szot, C Bromberg-White, JL Kits, K Kuk, CY Holton, LE St Croix, B Chambers, CM Duesbery, NS AF Andersen, N. J. Boguslawski, E. A. Naidu, A. S. Szot, C. Bromberg-White, J. L. Kits, K. Kuk, C. Y. Holton, L. E. St Croix, B. Chambers, C. M. Duesbery, N. S. TI Anthrax Toxin Receptor 1 Is Essential for Arteriogenesis in a Mouse Model of Hindlimb Ischemia SO PLOS ONE LA English DT Article ID TUMOR ANGIOGENESIS; GROWTH; INFLAMMATION; EXPRESSION; PROLIFERATION; VENULES; CELLS AB Anthrax toxin receptor 1/tumor endothelial marker 8 (Antxr1 or TEM8) is up-regulated in tumor vasculature and serves as a receptor for anthrax toxin, but its physiologic function is unclear. The objective of this study was to evaluate the role of Antxr1 in arteriogenesis. The role of Antxr1 in arteriogenesis was tested by measuring gene expression and immunohistochemistry in a mouse model of hindlimb ischemia using wild-type and ANTXR1(-/-)mice. Additional tests were performed by measuring gene expression in in vitro models of fluid shear stress and hypoxia, as well as in human muscle tissues obtained from patients having peripheral artery disease. We observed that Antxr1 expression transiently increased in ischemic tissues following femoral artery ligation and that its expression was necessary for arteriogenesis. In the absence of Antxr1, the mean arterial lumen area in ischemic tissues decreased. Antxr1 mRNA and protein expression was positively regulated by fluid shear stress, but not by hypoxia. Furthermore, Antxr1 expression was elevated in human peripheral artery disease requiring lower extremity bypass surgery. These findings demonstrate an essential physiologic role for Antxr1 in arteriogenesis and peripheral artery disease, with important implications for managing ischemia and other arteriogenesis-dependent vascular diseases. C1 [Andersen, N. J.; Holton, L. E.; Chambers, C. M.] Spectrum Hosp, Frederik Meijer Heart & Vasc Inst, 100 Michigan St NE, Grand Rapids, MI 49503 USA. [Andersen, N. J.; Boguslawski, E. A.; Naidu, A. S.; Bromberg-White, J. L.; Kits, K.; Kuk, C. Y.; Chambers, C. M.; Duesbery, N. S.] Van Andel Res Inst, Ctr Canc Cell Biol, Lab Canc & Dev Cell Biol, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. [Szot, C.; St Croix, B.] NCI, Tumor Angiogenesis Sect, Ctr Canc Res, Bldg 560, Frederick, MD 21702 USA. [Kits, K.] Van Andel Educ Inst, Partners Sci Program, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. RP Duesbery, NS (reprint author), Van Andel Res Inst, Ctr Canc Cell Biol, Lab Canc & Dev Cell Biol, 333 Bostwick Ave NE, Grand Rapids, MI 49503 USA. EM duesbery@vai.org OI DUESBERY, NICK/0000-0002-4258-5655 FU Van Andel Institute; Frederic Meijer Heart and Vascular Institute; intramural research program of the NCI, NIH, Department of Health and Social Services (DHSS) FX Work was funded by the Van Andel Institute, the Frederic Meijer Heart and Vascular Institute, and the intramural research program of the NCI, NIH, Department of Health and Social Services (DHSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 0 Z9 0 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 19 PY 2016 VL 11 IS 1 AR e0146586 DI 10.1371/journal.pone.0146586 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5BP UT WOS:000368528400049 PM 26785120 ER PT J AU Kaileh, M Vazquez, E MacFarlane, AW Campbell, K Kurosaki, T Siebenlist, U Sen, R AF Kaileh, Mary Vazquez, Estefania MacFarlane, Alexander W. Campbell, Kerry Kurosaki, Tomohiro Siebenlist, Ulrich Sen, Ranjan TI mTOR-Dependent and Independent Survival Signaling by PI3K in B Lymphocytes SO PLOS ONE LA English DT Article ID NF-KAPPA-B; CELL DEVELOPMENT; BAFF-R; IKK-ALPHA; RECEPTOR; ACTIVATION; MICE; INHIBITOR; CD19; PATHWAY AB Peripheral B lymphocyte survival requires the B cell receptor (BCR) and B cell activating factor (BAFF) binding to its receptor (BAFF-R). Deletion of the BCR, or its signal transducing chaperone Ig beta, leads to rapid loss of mature B cells, indicating that signals initiated at the BCR are crucial for B cell survival. BAFF or BAFF-R deficiency also significantly reduces the numbers of mature B cells despite normal BCR expression. Together, these observations indicate that continued BCR and BAFF-R signaling are essential for the survival of mature resting B cells in the periphery. Here we demonstrate that tonic BCR signals up-regulate p100 (Nfkb2) as well as Mcl-1 protein expression at a post-transcriptional level via a PI3K-dependent pathway. p100 expression is mTOR-independent, whereas Mcl-1 expression is mTOR-dependent. BAFF treatment further elevated Mcl-1 levels by an mTOR-independent pathway, while consuming p100. Accordingly, Mcl-1 induction by BAFF is abrogated in Nfkb2(-/-) B cells. We propose that the cumulative effects of the BCR and BAFF-R signaling pathways increase Mcl-1 levels beyond the threshold required for B cell survival. C1 [Kaileh, Mary; Sen, Ranjan] NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. [Vazquez, Estefania; Siebenlist, Ulrich] NIAID, Lab Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [MacFarlane, Alexander W.; Campbell, Kerry] Fox Chase Canc Ctr, Inst Canc Res, Div Basic Sci, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Kurosaki, Tomohiro] Osaka Univ, WPI Immunol Frontier Res Ctr, Lab Lymphocyte Differentiat, Suita, Osaka, Japan. RP Sen, R (reprint author), NIA, Gene Regulat Sect, Lab Mol Biol & Immunol, NIH, Baltimore, MD 21224 USA. EM ranjan.sen@nih.gov OI MacFarlane IV, Alexander/0000-0003-1740-4848 FU Intramural research Program of the NIH, National institute on Aging (Baltimore, MD) FX This research was supported entirely by the Intramural research Program of the NIH, National institute on Aging (Baltimore, MD). NR 45 TC 1 Z9 1 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 19 PY 2016 VL 11 IS 1 AR e0146955 DI 10.1371/journal.pone.0146955 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5BP UT WOS:000368528400085 PM 26785352 ER PT J AU Nelson, MI Pollett, S Ghersi, B Silva, M Simons, MP Icochea, E Gonzalez, AE Segovia, K Kasper, MR Montgomery, JM Bausch, DG AF Nelson, Martha I. Pollett, Simon Ghersi, Bruno Silva, Maria Simons, Mark P. Icochea, Eliana Gonzalez, Armando E. Segovia, Karen Kasper, Matthew R. Montgomery, Joel M. Bausch, Daniel G. TI The Genetic Diversity of Influenza A Viruses in Wild Birds in Peru SO PLOS ONE LA English DT Article ID AVIAN INFLUENZA; ARGENTINA; AMERICA AB Our understanding of the global ecology of avian influenza A viruses (AIVs) is impeded by historically low levels of viral surveillance in Latin America. Through sampling and whole-genome sequencing of 31 AIVs from wild birds in Peru, we identified 10 HA subtypes (H1H4, H6-H7, H10-H13) and 8 NA subtypes (N1-N3, N5-N9). The majority of Peruvian AIVs were closely related to AIVs found in North America. However, unusual reassortants, including a H13 virus containing a PA segment related to extremely divergent Argentinian viruses, suggest that substantial AIV diversity circulates undetected throughout South America. C1 [Nelson, Martha I.] NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. [Pollett, Simon; Ghersi, Bruno; Silva, Maria; Simons, Mark P.; Segovia, Karen; Kasper, Matthew R.; Montgomery, Joel M.; Bausch, Daniel G.] US Naval Med Res Unit 6, Virol & Emerging Infect Dept, Callao, Peru. [Pollett, Simon] Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia. [Pollett, Simon] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Icochea, Eliana; Gonzalez, Armando E.] Univ Nacl Mayor San Marcos, Sch Vet Med, Lima, Peru. [Bausch, Daniel G.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Pollett, S (reprint author), US Naval Med Res Unit 6, Virol & Emerging Infect Dept, Callao, Peru.; Pollett, S (reprint author), Univ Sydney, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia.; Pollett, S (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. EM spollett@med.usyd.edu.au FU Global Emerging Infections Surveillance (GEIS) Work unit [847705 82000 25GB B0016] FX This work was supported by Global Emerging Infections Surveillance (GEIS) Work unit no.: 847705 82000 25GB B0016. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 3 Z9 3 U1 1 U2 9 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 JAN 19 PY 2016 VL 11 IS 1 AR e0146059 DI 10.1371/journal.pone.0146059 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB5BP UT WOS:000368528400022 PM 26784331 ER PT J AU Monsivais, D Clementi, C Peng, J Titus, MM Barrish, JP Creighton, CJ Lydon, JP DeMayo, FJ Matzuk, MM AF Monsivais, Diana Clementi, Caterina Peng, Jia Titus, Mary M. Barrish, James P. Creighton, Chad J. Lydon, John P. DeMayo, Francesco J. Matzuk, Martin M. TI Uterine ALK3 is essential during the window of implantation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BMP signaling pathway; endometrium; implantation failure; infertility; progesterone receptor ID EMBRYO IMPLANTATION; BLASTOCYST IMPLANTATION; PROGESTERONE-RECEPTOR; PLACENTAL DEVELOPMENT; EPITHELIAL-CELLS; EARLY-PREGNANCY; CROSS-TALK; UTERUS; MOUSE; ESTROGEN AB The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-beta family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3(flox/flox)-Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor beta (TGF-beta) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity. C1 [Monsivais, Diana; Clementi, Caterina; Peng, Jia; Titus, Mary M.; Matzuk, Martin M.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Monsivais, Diana; Lydon, John P.; Matzuk, Martin M.] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA. [Barrish, James P.] Texas Childrens Hosp, Electron Microscopy Lab, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Creighton, Chad J.; Matzuk, Martin M.] Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA. [Lydon, John P.; Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [DeMayo, Francesco J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA. RP Matzuk, MM (reprint author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. EM mmatzuk@bcm.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD032067, HD042311]; Institutional Research and Academic Career Development [K12-GM084897]; National Cancer Institute [CA125123]; A. I. & Manet Schepps Endowment for Discovery FX We thank Drs. Yuji Mishina and Richard Behringer for their kind gift of the Alk3flox/flox mice. These studies were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development Grants HD032067 (to M.M.M.) and HD042311 (to J.P.L.), Institutional Research and Academic Career Development Award K12-GM084897 (to D.M.), National Cancer Institute Grant CA125123 (to C.J.C.), and the A. I. & Manet Schepps Endowment for Discovery (to D.M. and M.M.M.). NR 57 TC 3 Z9 3 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 19 PY 2016 VL 113 IS 3 BP E387 EP E395 DI 10.1073/pnas.1523758113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB4BX UT WOS:000368458800018 PM 26721398 ER PT J AU Shah, MR Lauer, MS AF Shah, Monica R. Lauer, Michael S. TI Striking the Right Balance in Heart Failure SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ENALAPRIL; MORTALITY; MORBIDITY; SURVIVAL; TRIAL C1 [Shah, Monica R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Shah, MR (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8174, Bethesda, MD 20892 USA. EM shahmr@nhlbi.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 19 PY 2016 VL 164 IS 2 BP 125 EP + DI 10.7326/M15-2587 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DB0CI UT WOS:000368175800018 PM 26720859 ER PT J AU Shen, W Hixon, JA McLean, MH Li, WQ Durum, SK AF Shen, Wei Hixon, Julie A. McLean, Mairi H. Li, Wen Qing Durum, Scott K. TI IL-22-Expressing Murine Lymphocytes Display Plasticity and Pathogenicity in Reporter Mice SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE IL-22; Th17; Th22; T cell plasticity; IL-27 ID INNATE LYMPHOID-CELLS; CD4(+) T-CELLS; ROR-GAMMA-T; ARYL-HYDROCARBON RECEPTOR; FACTOR C-MAF; CUTTING EDGE; TH17 CELLS; INTESTINAL PATHOLOGY; IL-22 PRODUCTION; T(H)17 CELLS AB IL-22 has multiple activities ranging from tissue repair to inflammation. To characterize the pathogenicity and plasticity of cells that produce IL-22, a novel reporter mouse strain was generated. Homeostatic IL-22 reporter expression was observed in intestinal lymphoid cells identified as CD4 T cells and ILC3 cells. In a model of inflammatory bowel disease, CD4 T cells strongly expressed the IL-22 reporter in mesenteric lymph node. To examine plasticity of IL-22(+) T cells, they were purified after generation in vitro or in vivo from inflamed colon, and then cultured under Th1, Th2, or Th17 conditions. In vitro-generated IL-22(+) CD4 T cells showed relatively durable IL-22 expression under Th1 or Th2 conditions, whereas in vivo-generated cells rapidly lost IL-22 expression under these conditions. In vitro-generated cells could not be diverted to express Th1 or Th2 cytokines despite the expression of "master regulators." In vivo generated cells could be diverted, at very low frequency, to express Th1 or Th2 cytokines. Both in vitro- and in vivo-generated cells could be induced in vitro to express high levels of IL-17A and IL-17F, assigning them to a "Th17 biased" class. However, IL-27 potently downregulated IL-22 expression. To examine IL-22(+) T cell pathogenicity, in vitro-generated cells were transferred into Rag1(-/-) mice, retaining the modest reporter expression and inducing moderate colitis. In contrast, IL-22 expressers from colitic mice, transferred into secondary hosts, lost reporter expression, acquired high T-bet and modest IFN gamma and IL-17 expression, and induced severe colitis. These findings are consistent with a model of strong polarization under optimal in vitro conditions, but a plastic state of T cells in vivo. C1 [Shen, Wei; Hixon, Julie A.; McLean, Mairi H.; Li, Wen Qing; Durum, Scott K.] NCI, Canc & Inflammat Program, Mol Immunoregulat Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Durum, SK (reprint author), NCI, Canc & Inflammat Program, Mol Immunoregulat Lab, Ctr Canc Res,NIH, Frederick, MD 21701 USA. EM durums@mail.nih.gov FU Ely and Edythe Broad Foundation; Crohn's and Colitis Foundation of America; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX We thank Drs. Ram Savan and J. Oppenheim for comments on the manuscript. WS was supported by a grant from the Ely and Edythe Broad Foundation (to SD) and MM was supported by a grant from the Crohn's and Colitis Foundation of America (to SD). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (MRA). 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 57 TC 2 Z9 2 U1 2 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD JAN 19 PY 2016 VL 6 AR 662 DI 10.3389/fimmu.2015.00662 PG 14 WC Immunology SC Immunology GA DB3SZ UT WOS:000368433200001 ER PT J AU Jain, R Chen, Y Kanno, Y Joyce-Shaikh, B Vahedi, G Hirahara, K Blumenschein, WM Sukumar, S Haines, CJ Sadekova, S McClanahan, TK McGeachy, MJ O'Shea, JJ Cua, DJ AF Jain, Renu Chen, Yi Kanno, Yuka Joyce-Shaikh, Barbara Vahedi, Golnaz Hirahara, Kiyoshi Blumenschein, Wendy M. Sukumar, Selvakumar Haines, Christopher J. Sadekova, Svetlana McClanahan, Terrill K. McGeachy, Mandy J. O'Shea, John J. Cua, Daniel J. TI Interleukin-23-Induced Transcription Factor Blimp-1 Promotes Pathogenicity of T Helper 17 Cells SO IMMUNITY LA English DT Article ID CYTOKINE GM-CSF; T(H)17 CELLS; TGF-BETA; TH17 CELLS; DIFFERENTIATION; GENERATION; RECEPTOR; IL-23; CONTRIBUTES; HOMEOSTASIS AB Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors ROR gamma t, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORgt to activate the Th17 inflammatory program. C1 [Jain, Renu; Chen, Yi; Joyce-Shaikh, Barbara; Blumenschein, Wendy M.; Sukumar, Selvakumar; Haines, Christopher J.; Sadekova, Svetlana; McClanahan, Terrill K.; McGeachy, Mandy J.; Cua, Daniel J.] Merck Res Labs, Palo Alto, CA 94304 USA. [Kanno, Yuka; Vahedi, Golnaz; Hirahara, Kiyoshi; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Cua, DJ (reprint author), Merck Res Labs, 901 Calif Ave, Palo Alto, CA 94304 USA. EM daniel.cua@merck.com RI Hirahara, Kiyoshi/E-2460-2017 OI Hirahara, Kiyoshi/0000-0002-9128-9449 NR 36 TC 12 Z9 13 U1 3 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD JAN 19 PY 2016 VL 44 IS 1 BP 131 EP 142 DI 10.1016/j.immuni.2015.11.009 PG 12 WC Immunology SC Immunology GA DB2NU UT WOS:000368347000018 PM 26750311 ER PT J AU Blecker, S Johnson, NJ Altekruse, S Horwitz, LI AF Blecker, Saul Johnson, Norman J. Altekruse, Sean Horwitz, Leora I. TI Association of Occupation as a Physician With Likelihood of Dying in a Hospital SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID OF-LIFE CARE; PLACE; DEATH C1 [Blecker, Saul; Horwitz, Leora I.] NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA. [Johnson, Norman J.] US Bur Census, Natl Longitudinal Mortal Study Branch, Suitland, MD USA. [Altekruse, Sean] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Blecker, S (reprint author), NYU, Sch Med, 227 E 30th St,648, New York, NY 10016 USA. EM saul.blecker@nyumc.org FU AHRQ HHS [K08HS23683, K08 HS023683] NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 19 PY 2016 VL 315 IS 3 BP 301 EP 303 DI 10.1001/jama.2015.16976 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA DB2WN UT WOS:000368371400029 PM 26784781 ER PT J AU Muthana, SM Gildersleeve, JC AF Muthana, Saddam M. Gildersleeve, Jeffrey C. TI Factors Affecting Anti-Glycan IgG and IgM Repertoires in Human Serum SO SCIENTIFIC REPORTS LA English DT Article ID BLOOD-GROUP SUBSTANCES; ALPHA-GAL EPITOPE; INCREASED IMMUNOGENICITY; CARBOHYDRATE MICROARRAY; NATURAL ANTIBODIES; IMMUNOGLOBULIN CONCENTRATIONS; BURKHOLDERIA-PSEUDOMALLEI; CANCER-IMMUNOTHERAPY; PANCREATIC-CANCER; IMMUNOREACTIVE T AB Serum anti-glycan antibodies play important roles in many immune processes and are of particular interest as biomarkers for many diseases. Changes in anti-glycan antibodies can occur with the onset of disease or in response to stimuli such as pathogens and vaccination. Understanding relationships between anti-glycan antibody repertoires and genetic and environment factors is critical for basic research and clinical applications, but little information is available. In this study we evaluated the effects of age, race, gender, and blood type on anti-glycan antibody profiles in the serum of 135 healthy subjects. As expected, IgG and IgM antibody signals to blood group antigens correlated strongly with blood type. Interestingly, antibodies to other non-ABH glycans, such as the alpha-Gal antigen, also correlated with blood type. A statistically significant decline in IgM signals with age was observed for many antibody subpopulations, but not for IgG. Moreover, statistically significant correlations between race and IgG levels to certain LacNAc-containing glycans were observed. The results have important implications for designing studies and interpreting results in the area of biomarker discovery and for the development of vaccines. The study also highlights the importance of collecting and reporting patient information that could affect serum anti-glycan antibody levels. C1 [Muthana, Saddam M.; Gildersleeve, Jeffrey C.] NCI, Biol Chem Lab, NIH, Frederick, MD 21702 USA. [Muthana, Saddam M.] Alfaisal Univ, Coll Sci & Gen Studies, Dept Chem, Riyadh, Saudi Arabia. RP Gildersleeve, JC (reprint author), NCI, Biol Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, NCI; Consortium for Functional Glycomics [GM62116] FX We thank the Consortium for Functional Glycomics (GM62116; The Scripps Research Institute), Professor Tom Tolbert (University of Kansas), Professor Lai-Xi Wang (University of Maryland), Professor Xuefei Huang (Michigan State University), and Dr. Joseph Barchi (National Cancer Institute) for contributing glycans for the array. This work was supported by the Intramural Research Program of the National Institutes of Health, NCI. NR 78 TC 5 Z9 5 U1 3 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD JAN 19 PY 2016 VL 6 AR 19509 DI 10.1038/srep19509 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DB1SS UT WOS:000368289800002 PM 26781493 ER PT J AU Martin, B Chadwick, W Janssens, J Premont, RT Schmalzigaug, R Becker, KG Lehrmann, E Wood, WH Zhang, YQ Siddiqui, S Park, SS Cong, WN Daimon, CM Maudsley, S AF Martin, Bronwen Chadwick, Wayne Janssens, Jonathan Premont, Richard T. Schmalzigaug, Robert Becker, Kevin G. Lehrmann, Elin Wood, William H. Zhang, Yongqing Siddiqui, Sana Park, Sung-Soo Cong, Wei-na Daimon, Caitlin M. Maudsley, Stuart TI GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging SO FRONTIERS IN ENDOCRINOLOGY LA English DT Article DE GIT2; metabolism; keystone; aging; dysglycemia; trajectory ID INDUCED INSULIN-RESISTANCE; NF-KAPPA-B; SKELETAL-MUSCLE CELLS; ENDOPLASMIC-RETICULUM STRESS; PROTEIN-INTERACTION NETWORK; TYPE-2 DIABETES-MELLITUS; PANCREATIC BETA-CELLS; AGE-RELATED DISEASE; OXIDATIVE STRESS; DNA-REPAIR AB Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional "keystone" role in regulating the aging process by coordinating somatic responses to energy deficits. C1 [Martin, Bronwen; Cong, Wei-na; Daimon, Caitlin M.] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Chadwick, Wayne; Siddiqui, Sana; Park, Sung-Soo; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Janssens, Jonathan; Maudsley, Stuart] Univ Antwerp, VIB Dept Mol Genet, Translat Neurobiol Grp, B-2020 Antwerp, Belgium. [Janssens, Jonathan; Maudsley, Stuart] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium. [Premont, Richard T.; Schmalzigaug, Robert] Duke Univ, Dept Med, Div Gastroenterol, Durham, NC USA. [Becker, Kevin G.; Lehrmann, Elin; Wood, William H.; Zhang, Yongqing] NIH, Gene Express & Genom Unit, Baltimore, MD USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA.; Maudsley, S (reprint author), Univ Antwerp, VIB Dept Mol Genet, Translat Neurobiol Grp, B-2020 Antwerp, Belgium.; Maudsley, S (reprint author), Univ Antwerp, Inst Born Bunge, Neurogenet Lab, B-2020 Antwerp, Belgium. EM stuart.maudsley@molgen.vib-ua.be FU Intramural Research Programs of the National Institute on Aging [NIH AG000325-05]; Research Foundation of Flanders (FWO) Odysseus Program FX This work was carried out with the support of the Intramural Research Programs of the National Institute on Aging (NIH AG000325-05) and the Research Foundation of Flanders (FWO) Odysseus Program. NR 181 TC 0 Z9 0 U1 2 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-2392 J9 FRONT ENDOCRINOL JI Front. Endocrinol. PD JAN 18 PY 2016 VL 6 AR 191 DI 10.3389/fendo.2015.00191 PG 28 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DP4WN UT WOS:000378498100001 ER PT J AU Dang, DK Shin, EJ Nam, Y Ryoo, S Jeong, JH Jang, CG Nabeshima, T Hong, JS Kim, HC AF Dang, Duy-Khanh Shin, Eun-Joo Nam, Yunsung Ryoo, Sungwoo Jeong, Ji Hoon Jang, Choon-Gon Nabeshima, Toshitaka Hong, Jau-Shyong Kim, Hyoung-Chun TI Apocynin prevents mitochondrial burdens, microglial activation, and pro-apoptosis induced by a toxic dose of methamphetamine in the striatum of mice via inhibition of p47phox activation by ERK SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Methamphetamine toxicity; Phosphorylation of ERK1/2; p47phox knockout mice; Mitochondria; Cleaved PKC delta; Oxidative stress; Microglia of M1 phenotype; Pro-apoptosis; Striatum; Dopamine ID MANGANESE SUPEROXIDE-DISMUTASE; KINASE-C-DELTA; INFLAMMATION-MEDIATED NEURODEGENERATION; IDIOPATHIC PARKINSONS-DISEASE; NADPH OXIDASE ACTIVATION; MUTANT ALPHA-SYNUCLEIN; INDUCED NEUROTOXICITY; OXIDATIVE STRESS; DOPAMINERGIC NEURODEGENERATION; IN-VITRO AB the present study, we investigated the role of PHOX in methamphetamine (MA)-induced neurotoxic and inflammatory changes in mice. Methods: We examined changes in mitogen-activated protein kinases (MAPKs), mitochondrial function [i.e., mitochondrial membrane potential, intramitochondrial Ca2+ accumulation, mitochondrial oxidative burdens, mitochondrial superoxide dismutase expression, and mitochondrial translocation of the cleaved form of protein kinase C delta type (cleaved PKC delta)], microglial activity, and pro-apoptotic changes [i.e., cytosolic cytochrome c release, cleaved caspase 3, and terminal deoxynucleotidyl transferase dUDP nick-end labeling (TUNEL) positive populations] after a neurotoxic dose of MA in the striatum of mice to achieve a better understanding of the effects of apocynin, a non-specific PHOX inhibitor, or genetic inhibition of p47phox (by using p47phox knockout mice or p47phox antisense oligonucleotide) against MA-induced dopaminergic neurotoxicity. Results: Phosphorylation of extracellular signal-regulated kinases (ERK1/2) was most pronounced out of MAPKs after MA. We observed MA-induced phosphorylation and membrane translocation of p47phox in the striatum of mice. The activation of p47phox promoted mitochondrial stresses followed by microglial activation into the M1 phenotype, and pro-apoptotic changes, and led to dopaminergic impairments. ERK activated these signaling pathways. Apocynin or genetic inhibition of p47phox significantly protected these signaling processes induced by MA. ERK inhibitor U0126 did not exhibit any additional positive effects against protective activity mediated by apocynin or p47phox genetic inhibition, suggesting that ERK regulates p47phox activation, and ERK constitutes the crucial target for apocynin-mediated inhibition of PHOX activation. Conclusions: Our results indicate that the neuroprotective mechanism of apocynin against MA insult is via preventing mitochondrial burdens, microglial activation, and pro-apoptotic signaling process by the ERK-dependent activation of p47phox. C1 [Dang, Duy-Khanh; Shin, Eun-Joo; Nam, Yunsung; Kim, Hyoung-Chun] Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon, South Korea. [Ryoo, Sungwoo] Kangwon Natl Univ, Dept Biol Sci, Coll Nat Sci, Chunchon, South Korea. [Jeong, Ji Hoon] Chung Ang Univ, Coll Med, Dept Pharmacol, Seoul 156756, South Korea. [Jang, Choon-Gon] Sungkyunkwan Univ, Sch Pharm, Dept Pharmacol, Suwon, South Korea. [Nabeshima, Toshitaka] Meijo Univ, Dept Reg Pharmaceut Care & Sci, Grad Sch Pharmaceut Sci, Nagoya, Aichi, Japan. [Nabeshima, Toshitaka] Japanese Drug Org Appropriate Use & Res, NPO, Nagoya, Aichi, Japan. [Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, Durham, NC USA. RP Kim, HC (reprint author), Kangwon Natl Univ, Coll Pharm, Neuropsychopharmacol & Toxicol Program, Chunchon, South Korea. EM kimhc@kangwon.ac.kr FU Korea Food and Drug Administration, Republic of Korea [14182MFDS979]; BK21 PLUS program, National Research Foundation of Korea, Republic of Korea FX This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea. Duy-Khanh Dang and Yunsung Nam were supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea. Equipment at the Institute of New Drug Development Research (Kangwon National University) was used for this study. The English language in this document has been checked by at least two professional editors, both native speakers of English (Beverly Hills English, Los Angeles, CA90024, USA). NR 95 TC 3 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD JAN 18 PY 2016 VL 13 AR 12 DI 10.1186/s12974-016-0478-x PG 22 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA DB3NE UT WOS:000368417600002 PM 26780950 ER PT J AU Cyphert, JM McGee, MA Nyska, A Schladweiler, MC Kodavanti, UP Gavett, SH AF Cyphert, Jaime M. McGee, Marie A. Nyska, Abraham Schladweiler, Mette C. Kodavanti, Urmila P. Gavett, Stephen H. TI Long-term toxicity of naturally occurring asbestos in male Fischer 344 rats SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A-CURRENT ISSUES LA English DT Article ID LIBBY AMPHIBOLE ASBESTOS; BRONCHIOLOALVEOLAR CARCINOMA; INTRATRACHEAL INSTILLATION; LUNG-FUNCTION; EXPOSURE; MESOTHELIOMA; DEFINITIONS; ASBESTIFORM; INHALATION; MONTANA AB Naturally occurring asbestos (NOA) fibers are found in geologic deposits that may be disturbed by mining, earthworks, or natural processes, resulting in adverse health risks to exposed individuals. The toxicities of Libby amphibole and NOA samples including Sumas Mountain chrysotile (SM), El Dorado tremolite (ED), and Ontario ferroactinolite cleavage fragments (ON) were compared in male Fischer 344 (F344) rats 15 mo after exposure. Rat-respirable fractions of LA and SM displayed greater mean lengths and aspect ratios than ED and ON. After a single intratracheal (IT) instillation (0.5 or 1.5 mg/rat), persistent changes in ventilatory parameters and a significant increase in lung resistance at baseline and after methacholine aerosol dosing were found only in rats exposed to 1.5 mg SM. High-dose ED significantly elevated bronchoalveolar lavage lactate dehydrogenase (LDH) activity and protein levels, while high-dose SM increased gamma-glutamyl transferase and LDH activities. A moderate degree of lung interstitial fibrosis after exposure to 1.5 mg SM persisted 15 mo after exposure, unchanged from previous findings at 3 mo. LA induced mild fibrosis, while ED and ON produced minimal and no apparent fibrosis, respectively. Bronchioloalveolar carcinoma was observed 15 mo after exposure to LA or ED. Data demonstrated that SM, given by bolus IT dosing on an equivalent mass basis, induced greater pulmonary function deficits, airway hyperresponsiveness, and interstitial fibrosis than other NOA, although unlike LA and ED, no apparent evidence for carcinogenicity was found. All NOA samples except ON cleavage fragments produced some degree of long-term toxicity. C1 [Cyphert, Jaime M.] Univ N Carolina, Sch Med, Curriculum Toxicol, Chapel Hill, NC USA. [McGee, Marie A.] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Nyska, Abraham] NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. [Nyska, Abraham] Tel Aviv Univ, Sackler Sch Med, Timrat, Israel. [Schladweiler, Mette C.; Kodavanti, Urmila P.; Gavett, Stephen H.] US EPA, Environm Publ Hlth Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. RP Gavett, SH (reprint author), US EPA, DABT, Mail Code B105-02,109 TW Alexander Dr, Res Triangle Pk, NC 27711 USA. EM gavett.stephen@epa.gov OI McGee, Marie/0000-0001-8572-1613 FU U.S. Environmental Protection Agency/University of North Carolina Toxicology Research Program Training Agreement [CR83515201-0]; U.S. Environmental Protection Agency (Region 8 and Office of Solid Waste and Emergency Response) FX This work was supported by a U.S. Environmental Protection Agency/University of North Carolina Toxicology Research Program Training Agreement (CR83515201-0) and the U.S. Environmental Protection Agency (Region 8 and Office of Solid Waste and Emergency Response). The authors thank Judy Richards for technical assistance, and Julie Wroble for manuscript review. Jaime M. Cyphert and Marie A. McGee contributed equally to this work. NR 45 TC 3 Z9 3 U1 2 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1528-7394 EI 1087-2620 J9 J TOXICOL ENV HEAL A JI J. Toxicol. Env. Health Part A PD JAN 17 PY 2016 VL 79 IS 2 BP 49 EP 60 DI 10.1080/15287394.2015.1099123 PG 12 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA DF2OP UT WOS:000371183500001 PM 26818398 ER PT J AU Deter, RL Lee, W Sangi-Haghpeykar, H Tarca, AL Li, J Yeo, L Romero, R AF Deter, Russell L. Lee, Wesley Sangi-Haghpeykar, Haleh Tarca, Adi L. Li, Jia Yeo, Lami Romero, Roberto TI Personalized third-trimester fetal growth evaluation: comparisons of individualized growth assessment, percentile line and conditional probability methods SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Fetal size trajectories; Rossavik size model; ultrasound ID BIRTH-WEIGHT PERCENTILES; PERINATAL MORBIDITY; CURVE STANDARDS; AGE INFANTS; PREDICTION; RESTRICTION; CENTILES; SIZE AB Objective: To compare third-trimester size trajectory prediction errors (average transformed percent deviations) for three individualized fetal growth assessment methods.Methods: This study utilized longitudinal measurements of nine directly measured size parameters in 118 fetuses with normal neonatal growth outcomes. Expected value (EV) function coefficients and variance components were obtained using two-level random coefficient modeling. Growth models (IGA) or EV coefficients and variance components (PLM and CPM) were used to calculate predicted values at approximate to 400 third-trimester time points. Percent deviations (%Dev) calculated at these time points using all three methods were expressed as percentages of IGA MA-specific reference ranges [transformed percent deviations (T%Dev)]. Third-trimester T%Dev values were averaged (aT%Dev) for each parameter. Meanstandard deviation's for sets of aT%Dev values derived from each method (IGA, PLM and CPM) were calculated and compared.Results: Mean aT%Dev values for nine parameters were: (i) IGA: -4.3 to 5.2% (9/9 not different from zero); (ii) PLM: -32.7 to 25.6% (4/9 not different from zero) and (iii) CPM: -20.4 to 17.4% (5/9 not different from zero). Seven of nine systematic deviations from zero were statistically significant when IGA values were compared to either PLM or CPM values. Variabilities were smaller for IGA when compared to those for PLM or CPM, with (i) 5/9 being statistically significant (IGA versus PLM), (ii) 2/9 being statistically significant (IGA versus CPM) and (iii) 5/9 being statistically significant (PLM versus CPM).Conclusions: Significant differences in the agreement between predicted third-trimester size parameters and their measured values were found for the three methods tested. With most parameters, IGA gave smaller mean aT%Dev values and smaller variabilities. The CPM method was better than the PLM approach for most but not all parameters. These results suggest that third-trimester size trajectories are best characterized by IGA in fetuses with normal growth outcomes. C1 [Deter, Russell L.; Lee, Wesley; Sangi-Haghpeykar, Haleh] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, Wesley] Oakland Univ, William Beaumont Sch Med, Dept Obstet & Gynecol, Rochester, MI 48063 USA. [Lee, Wesley; Tarca, Adi L.; Yeo, Lami; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Li, Jia] Oakland Univ, Dept Elect & Comp Engn, Rochester, MI 48063 USA. [Yeo, Lami] Wayne State Univ, Hutzel Hosp, Dept Elect & Comp Engn, 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. RP Deter, RL (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, One Baylor Plaza, Houston, TX 77030 USA. EM russelld@bcm.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS FX This research was supported (in-part) by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. R. Romero contributed to this work as part of his official duties as an employee of the United States Federal Government. None of the other authors have disclosed a conflict of interest NR 34 TC 3 Z9 3 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD JAN 17 PY 2016 VL 29 IS 2 BP 177 EP 185 DI 10.3109/14767058.2014.995083 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA CX3VT UT WOS:000365628300002 PM 25491881 ER PT J AU Kim, LY Thompson, PM Lee, HT Pershad, M Campbell, SL Alushin, GM AF Kim, Laura Y. Thompson, Peter M. Lee, Hyunna T. Pershad, Mihir Campbell, Sharon L. Alushin, Gregory M. TI The Structural Basis of Actin Organization by Vinculin and Metavinculin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cryo-EM; cytoskeleton; mechanobiology; adhesion; cell motility ID EM STRUCTURE DETERMINATION; FOCAL ADHESION; F-ACTIN; ELECTRON-MICROSCOPY; DILATED CARDIOMYOPATHY; CRYSTAL-STRUCTURE; INTRAMOLECULAR ASSOCIATION; TALIN-BINDING; CELL-ADHESION; META-VINCULIN AB Vinculin is an essential adhesion protein that links membrane-bound integrin and cadherin receptors through their intracellular binding partners to filamentous actin, facilitating mechanotransduction. Here we present an 8.5-angstrom-resolution cryo-electron microscopy reconstruction and pseudo-atomic model of the vinculin tail (Vt) domain bound to F-actin. Upon actin engagement, the N-terminal "strap" and helix 1 are displaced from the Vt helical bundle to mediate actin bundling. We find that an analogous conformational change also occurs in the H1' helix of the tail domain of metavinculin (MVt) upon actin binding, a muscle-specific splice isoform that suppresses actin bundling by Vt. These data support a model in which metavinculin tunes the actin bundling activity of vinculin in a tissue-specific manner, providing a mechanistic framework for understanding metavinculin mutations associated with hereditary cardiomyopathies. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). C1 [Kim, Laura Y.; Alushin, Gregory M.] NHLBI, Lab Macromol Interact, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. [Thompson, Peter M.; Lee, Hyunna T.; Campbell, Sharon L.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Pershad, Mihir] Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. RP Alushin, GM (reprint author), NHLBI, Lab Macromol Interact, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM alushing@mail.nih.gov OI Thompson, Peter/0000-0001-7562-6049 FU National Institutes of Health [1DP5OD17885-1]; NHLBI Division of Intramural Research FX We gratefully acknowledge Jenny Hinshaw, National Institute of Diabetes and Digestive and Kidney Diseases, for the use of her Tecnai F20 electron microscope; Alisdair Steven, National Institute of Allergy and Infectious Diseases, for use of his vitrification apparatus; and Scott Gradia, University of California, Berkeley, for the generation and deposition of expression vectors in Addgene. We thank Yasuharu Takagi and James Sellers, National Heart, Lung, and Blood Institute (NHLBI), for the gift of rabbit muscle actin. We also acknowledge Eva Nogales, University of California, Berkeley, for use of computational resources during the early stages of this project. This study utilized the high-performance Biowulf Linux cluster . We also gratefully acknowledge Robert Cail, NHLBI, for generating the Vt Delta C5-GFP construct and Pinar Gurel, NHLBI, for critical reading of the manuscript. This work was supported by a National Institutes of Health Director's Early Independence Award (1DP5OD17885-1) to G.M.A. and the NHLBI Division of Intramural Research. NR 72 TC 4 Z9 4 U1 3 U2 13 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 16 PY 2016 VL 428 IS 1 BP 10 EP 25 DI 10.1016/j.jmb.2015.09.031 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DE5NC UT WOS:000370676700003 PM 26493222 ER PT J AU Iyama, T Wilson, DM AF Iyama, Teruaki Wilson, David M., III TI Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Cockayne syndrome; CSA/ERCC8; CSB/ERCC6; DNA damage response; DNA repair ID TRANSCRIPTION-COUPLED REPAIR; NUCLEOTIDE EXCISION-REPAIR; INTERSTRAND CROSS-LINKS; RNA-POLYMERASE-II; GROUP-B GENE; HAMSTER OVARY CELLS; STRAND BREAK REPAIR; XERODERMA-PIGMENTOSUM; IN-VIVO; ATPASE DOMAIN AB Cockayne syndrome (CS) is a premature aging disorder characterized by developmental defects, multisystem progressive degeneration and sensitivity to ultraviolet light. CS is divided into two primary complementation groups, A and B, with the CSA and CSB proteins presumably functioning in DNA repair and transcription. Using laser microirradiation and confocal microscopy, we characterized the nature and regulation of the CS protein response to oxidative DNA damage, double-strand breaks (DSBs), angelicin monoadducts and trioxsalen interstrand crosslinks (ICLs). Our data indicate that CSB recruitment is influenced by the type of DNA damage and is most rapid and robust as follows: ICLs > DSBs > monoadducts > oxidative lesions. Transcription inhibition reduced accumulation of CSB at sites of monoadducts and ICLs, but it did not affect recruitment to (although slightly affected retention at) oxidative damage. Inhibition of histone deacetylation altered the dynamics of CSB assembly, suggesting a role for chromatin status in the response to DNA damage, whereas the proteasome inhibitor MG132 had no effect. The C-terminus of CSB and, in particular, its ubiquitin-binding domain were critical to recruitment, while the N-terminus and a functional ATPase domain played a minor role at best in facilitating protein accumulation. Although the absence of CSA had no effect on CSB recruitment, CSA itself localized at sites of ICLs, DSBs and monoadducts but not at oxidative lesions. Our results reveal molecular components of the CS protein response and point to a major involvement of complex lesions in the pathology of CS. Published by Elsevier Ltd. C1 [Iyama, Teruaki; Wilson, David M., III] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU National Institutes of Health, National Institute on Aging FX We thank Drs. Michael Seidman and Anne Tseng (National Institute on Aging) for their critical reading of the manuscript, Dr. Manikandan Paramasivam (National Institute on Aging) for his helpful advice on the confocal microscopy and laser microirradiation experiments, Dr. Raghavendra Shamanna (National Institute on Aging) for his helpful advice on the immunostaining studies and Dr. Vilhelm Bohr (National Institute on Aging) for his continued support of the ongoing CS investigations. This work was supported by the Intramural Research Program at the National Institutes of Health, National Institute on Aging. NR 67 TC 2 Z9 2 U1 2 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 16 PY 2016 VL 428 IS 1 BP 62 EP 78 DI 10.1016/j.jmb.2015.11.020 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DE5NC UT WOS:000370676700007 PM 26616585 ER PT J AU Shaytan, AK Armeev, GA Goncearenco, A Zhurkin, VB Landsman, D Panchenko, AR AF Shaytan, Alexey K. Armeev, Grigoriy A. Goncearenco, Alexander Zhurkin, Victor B. Landsman, David Panchenko, Anna R. TI Coupling between Histone Conformations and DNA Geometry in Nucleosomes on a Microsecond Timescale: Atomistic Insights into Nucleosome Functions SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE nucleosome dynamics; molecular dynamics simulations; epigenetics; chromatin; protein-DNA interactions ID MOLECULAR-DYNAMICS SIMULATIONS; CORE PARTICLE; CHROMATIN-STRUCTURE; TAIL DOMAINS; LINKER DNA; PROTEIN INTERACTIONS; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; H4; BINDING AB An octamer of histone proteins wraps about 200 bp of DNA into two superhelical turns to form nucleosomes found in chromatin. Although the static structure of the nucleosomal core particle has been solved, details of the dynamic interactions between histones and DNA remain elusive. We performed extensively long unconstrained, all-atom microsecond molecular dynamics simulations of nucleosomes including linker DNA segments and full-length histones in explicit solvent. For the first time, we were able to identify and characterize the rearrangements in nucleosomes on a microsecond timescale including the coupling between the conformation of the histone tails and the DNA geometry. We found that certain histone tail conformations promoted DNA bulging near its entry/exit sites, resulting in the formation of twist defects within the DNA. This led to a reorganization of histone-DNA interactions, suggestive of the formation of initial nucleosome sliding intermediates. We characterized the dynamics of the histone tails upon their condensation on the core and linker DNA and showed that tails may adopt conformationally constrained positions due to the insertion of "anchoring" lysines and arginines into the DNA minor grooves. Potentially, these phenomena affect the accessibility of post-translationally modified histone residues that serve as important sites for epigenetic marks (e.g., at H3K9, H3K27, H4K16), suggesting that interactions of the histone tails with the core and linker DNA modulate the processes of histone tail modifications and binding of the effector proteins. We discuss the implications of the observed results on the nucleosome function and compare our results to different experimental studies. Published by Elsevier Ltd. C1 [Shaytan, Alexey K.; Goncearenco, Alexander; Landsman, David; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Shaytan, Alexey K.; Armeev, Grigoriy A.] Moscow MV Lomonosov State Univ, Fac Biol, Moscow 119991, Russia. [Zhurkin, Victor B.] NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov RI Goncearenco, Alexander/M-3946-2015; Shaytan, Alexey/D-7306-2012 OI Goncearenco, Alexander/0000-0002-9738-7146; Shaytan, Alexey/0000-0003-0312-938X FU Intramural Research Programs of the National Library of Medicine; National Cancer Institute, National Institutes of Health; Russian Science Foundation [14-24-00031]; Intramural Research Program, National Institutes of Health; US Russia Collaboration in the Biomedical Sciences National Institutes of Health; Supercomputing Center of Lomonosov Moscow State University FX This research was supported by the Intramural Research Programs of the National Library of Medicine and the National Cancer Institute, National Institutes of Health, as well as Russian Science Foundation (grant No. 14-24-00031) (development of nucleosome visualization algorithms). Funding for open-access charge is from Intramural Research Program, National Institutes of Health. A.S. was supported by the US Russia Collaboration in the Biomedical Sciences National Institutes of Health visiting fellows' program. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MDdagger. The reported study was supported in part by the Supercomputing Center of Lomonosov Moscow State University and with computational resources of Hexagon Cray XE6m-200 supercomputer, operated by the University of Bergen and the Norwegian Metacenter for High-Performance Computing. NR 89 TC 7 Z9 7 U1 6 U2 16 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 16 PY 2016 VL 428 IS 1 BP 221 EP 237 DI 10.1016/j.jmb.2015.12.004 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DE5NC UT WOS:000370676700018 PM 26699921 ER PT J AU Chang, LC Li, BS Fang, Z Vrieze, S McGue, M Iacono, WG Tseng, GC Chen, W AF Chang, Lun-Ching Li, Bingshan Fang, Zhou Vrieze, Scott McGue, Matt Iacono, William G. Tseng, George C. Chen, Wei TI A computational method for genotype calling in family-based sequencing data SO BMC BIOINFORMATICS LA English DT Article DE Family-based sequencing; Genotype calling; Hidden Markov model ID DE-NOVO MUTATIONS; GENOME-WIDE ASSOCIATION; RARE VARIANTS; AUTISM; INDIVIDUALS; IMPUTATION; DESIGNS; TRIOS; PHASE; MAP AB Background: As sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking. Results: In this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at similar to 10X coverage from the Minnesota Center for Twin and Family Research. Conclusions: The aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/similar to wec47/famldcaller.html. C1 [Chang, Lun-Ching] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Li, Bingshan] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Fang, Zhou; Tseng, George C.; Chen, Wei] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Vrieze, Scott] Univ Colorado, Inst Behav Genet, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [McGue, Matt; Iacono, William G.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Chen, Wei] Childrens Hosp Pittsburgh UPMC, Div Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA. RP Chen, W (reprint author), Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. EM wei.chen@chp.edu FU National Institute of Health [R01HG007358, R01HG006857, R01DA024417] FX This study is supported by the research grants R01HG007358 (W.C.), R01HG006857 (B.L.) and R01DA024417 (W.G.I.) from National Institute of Health. We thank Goncalo Abecasis and Mary Kate in the Department of Biostatistics at the University of Michigan for sharing the C++ libraries for processing VCF files and pedigrees. We also thank Daniel Weeks in the Department of Human Genetics at the University of Pittsburgh for useful comments on the manuscript. NR 30 TC 0 Z9 0 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JAN 16 PY 2016 VL 17 AR 37 DI 10.1186/s12859-016-0880-5 PG 13 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA DB3LY UT WOS:000368414300003 PM 26772743 ER PT J AU Johnson, KE Neta, G Dember, LM Coronado, GD Suls, J Chambers, DA Rundell, S Smith, DH Liu, BM Taplin, S Stoney, CM Farrell, MM Glasgow, RE AF Johnson, Karin E. Neta, Gila Dember, Laura M. Coronado, Gloria D. Suls, Jerry Chambers, David A. Rundell, Sean Smith, David H. Liu, Benmei Taplin, Stephen Stoney, Catherine M. Farrell, Margaret M. Glasgow, Russell E. TI Use of PRECIS ratings in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory SO TRIALS LA English DT Article ID CLINICAL-TRIALS; TOOL; PURPOSE AB Background: The National Institutes of Health (NIH) Health Care Systems Research Collaboratory (NIH Collaboratory) seeks to produce generalizable knowledge about the conduct of pragmatic research in health systems. This analysis applied the PRECIS-2 pragmatic trial criteria to five NIH Collaboratory pragmatic trials to better understand 1) the pragmatic aspects of the design and implementation of treatments delivered in real world settings and 2) the usability of the PRECIS-2 criteria for assessing pragmatic features across studies and across time. Methods/Design: Using the PRECIS-2 criteria, five pragmatic trials were each rated by eight raters. For each trial, we reviewed the original grant application and a required progress report written at the end of a 1-year planning period that included changes to the protocol or implementation approach. We calculated median scores and interrater reliability for each PRECIS domain and for the overall trial at both time points, as well as the differences in scores between the two time points. We also reviewed the rater comments associated with the scores. Results: All five trials were rated to be more pragmatic than explanatory, with comments indicating that raters generally perceived them to closely mirror routine clinical care across multiple domains. The PRECIS-2 domains for which the trials were, on average, rated as most pragmatic on the 1 to 5 scale at the conclusion of the planning period included primary analysis (mean = 4.7 (range = 4.5 to 4.9)), recruitment (4.3 (3.6 to 4.8)), eligibility (4.1 (3.4 to 4.8)), setting (4.1 (4.0 to 4.4)), follow-up (4.1 (3.4 to 4.9)), and primary outcome (4.1 (3.5 to 4.9)). On average, the less pragmatic domains were organization (3.3 (2.6 to 4.4)), flexibility of intervention delivery (3.5 (2.1-4.5)), and flexibility of intervention adherence (3.8 (2.8-4.5)). Interrater agreement was modest but statistically significant for four trials (Gwet's AC1 statistic range 0.23 to 0.40) and the intraclass correlation coefficient ranged from 0.05 to 0.31. Rating challenges included assigning a single score for domains that may relate to both patients and care settings (that is, eligibility or recruitment) and determining to what extent aspects of complex research interventions differ from usual care. Conclusions: These five trials in diverse healthcare settings were rated as highly pragmatic using the PRECIS-2 criteria. Applying the tool generated insightful discussion about real-world design decisions but also highlighted challenges using the tool. PRECIS-2 raters would benefit from additional guidance about how to rate the interwoven patient and practice-level considerations that arise in pragmatic trials. C1 [Johnson, Karin E.] Grp Hlth Res Inst, Seattle, WA USA. [Neta, Gila; Suls, Jerry; Chambers, David A.; Liu, Benmei; Taplin, Stephen; Farrell, Margaret M.] NCI, Bethesda, MD 20892 USA. [Dember, Laura M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Coronado, Gloria D.; Smith, David H.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Rundell, Sean] Univ Washington, Seattle, WA 98195 USA. [Stoney, Catherine M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Glasgow, Russell E.] Univ Colorado, Sch Med, Dept Family Med, Denver, CO USA. RP Neta, G (reprint author), NCI, Bethesda, MD 20892 USA. EM netagil@mail.nih.gov OI Rundell, Sean/0000-0003-0782-5999 FU National Institutes of Health (NIH) Common Fund from the Office of Strategic Coordination within the Office of the NIH Director [U54 AT007748]; NIH [5UH3DK102384-03, 5UH3CA188640-03, 5UH3NS088731-03, 5UH3AR066795-03] FX We are grateful to trial team members other than the authors who reviewed the manuscript and offered valuable feedback. This work is supported by the National Institutes of Health (NIH) Common Fund, through cooperative agreement U54 AT007748 from the Office of Strategic Coordination within the Office of the NIH Director, as well as NIH Awards 5UH3DK102384-03, 5UH3CA188640-03, 5UH3NS088731-03, 5UH3AR066795-03. The views presented here are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 10 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD JAN 16 PY 2016 VL 17 AR 32 DI 10.1186/s13063-016-1158-y PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DA9NS UT WOS:000368136900001 PM 26772801 ER PT J AU Fang, ZZ Zhang, DF Cao, YF Xie, C Lu, D Sun, DX Tanaka, N Jiang, CT Chen, QM Chen, Y Wang, HN Gonzalez, FJ AF Fang, Zhong-Ze Zhang, Dunfang Cao, Yun-Feng Xie, Cen Lu, Dan Sun, Dong-Xue Tanaka, Naoki Jiang, Changtao Chen, Qianming Chen, Yu Wang, Haina Gonzalez, Frank J. TI Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Irinotecan (CPT-11); Metabolomics; Bile acids; Interleukin-10 ID INTESTINAL MUCOSITIS; INDUCED COLITIS; MICE; CHEMOTHERAPY; GLUCURONIDATION; HEPATOTOXICITY; INHIBITION; METABOLISM; TOXICITY; PROTECTS AB Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4(+) naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. Published by Elsevier Inc. C1 [Fang, Zhong-Ze; Xie, Cen; Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fang, Zhong-Ze] Tianjin Med Univ, Sch Publ Hlth, Dept Toxicol, Tianjin, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian, Peoples R China. [Fang, Zhong-Ze; Cao, Yun-Feng] Liaoning Med Univ, Affiliated Hosp 1, Dalian, Peoples R China. [Zhang, Dunfang; Chen, Qianming; Chen, Yu] Sichuan Univ, State Key Lab Oral Dis, West China Hosp Stomatol, Chengdu 610064, Peoples R China. [Lu, Dan] Tianjin Med Univ, Dept Immunol, Tianjin Key Lab Cellular & Mol Immunol, Tianjin, Peoples R China. [Wang, Haina] Shandong Univ, Sch Pharmaceut Sci, Jinan 250100, Peoples R China. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Natural Science Foundation of China [81202586]; Tianjin Project of Thousand Youth Talents; Natural Science Foundation of Shandong Province [BS2013YY054, ZR2010HL023] FX This study was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Natural Science Foundation of China (No. 81202586), Tianjin Project of Thousand Youth Talents, and Natural Science Foundation of Shandong Province (Nos. BS2013YY054 and ZR2010HL023). NR 24 TC 5 Z9 5 U1 5 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JAN 15 PY 2016 VL 291 BP 21 EP 27 DI 10.1016/j.laap.2015.12.003 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA DO9IO UT WOS:000378100100003 PM 26706406 ER PT J AU Numaga-Tomita, T Nishida, M Putney, JW Mori, Y AF Numaga-Tomita, Takuro Nishida, Motohiro Putney, James W., Jr. Mori, Yasuo TI TRPC3 amplifies B-cell receptor-induced ERK signalling via protein kinase D-dependent Rap1 activation SO BIOCHEMICAL JOURNAL LA English DT Article DE B-lymphocytes; Ca2+ signalling; Egr-1; ERK; Rap1; TRP channel ID NERVE GROWTH-FACTOR; ANTIGEN RECEPTOR; PRE-B; CA2+ ENTRY; LYMPHOCYTES; PATHWAY; EXPRESSION; DURATION; EGR-1; PHOSPHORYLATION AB Sustained activation of extracellular-signal-regulated kinase (ERK) has an important role in the decision regarding the cell fate of B-lymphocytes. Recently, we demonstrated that the diacylglycerol-activated non-selective cation channel canonical transient receptor potential 3 (TRPC3) is required for the sustained ERK activation induced by the B-cell receptor. However, the signalling mechanism underlying TRPC3-mediated ERK activation remains elusive. In the present study, we have shown that TRPC3 mediates Ca2+ influx to sustain activation of protein kinase D (PKD) in a protein kinase C-dependent manner in DT40 B-lymphocytes. The later phase of ERK activation depends on the small G-protein Rap1, known as a downstream target of PKD, whereas the earlier phase of ERK activation depends on the Ras protein. It is of interest that sustained ERK phosphorylation is required for the full induction of the immediate early gene Egr-1 (early growth response 1). These results suggest that TRPC3 reorganizes the BCR signalling complex by switching the subtype of small G-proteins to sustain ERK activation in B-lymphocytes. C1 [Numaga-Tomita, Takuro; Nishida, Motohiro] Natl Inst Nat Sci, Natl Inst Physiol Sci, Okazaki Inst Integrat Biosci, Div Cardiocirculatory Signaling, 5-1 Higashiyama,Myodaiji Cho, Okazaki, Aichi 4448787, Japan. [Numaga-Tomita, Takuro; Nishida, Motohiro] Kyushu Univ, Grad Univ Adv Studies, Grad Sch Pharmaceut Sci, SOKENDAI,Sch Life Sci, Fukuoka 8128582, Japan. [Nishida, Motohiro] JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan. [Putney, James W., Jr.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet & Biol Chem, Lab Mol Biol,Nishikyo Ku, Katsura Campus, Kyoto 6158510, Japan. RP Nishida, M (reprint author), Natl Inst Nat Sci, Natl Inst Physiol Sci, Okazaki Inst Integrat Biosci, Div Cardiocirculatory Signaling, 5-1 Higashiyama,Myodaiji Cho, Okazaki, Aichi 4448787, Japan.; Nishida, M (reprint author), Kyushu Univ, Grad Univ Adv Studies, Grad Sch Pharmaceut Sci, SOKENDAI,Sch Life Sci, Fukuoka 8128582, Japan.; Nishida, M (reprint author), JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 3320012, Japan.; Mori, Y (reprint author), Kyoto Univ, Grad Sch Engn, Dept Synthet & Biol Chem, Lab Mol Biol,Nishikyo Ku, Katsura Campus, Kyoto 6158510, Japan. EM nishida@nips.ac.jp; mori@sbchem.kyoto-u.ac.jp RI U-ID, Kyushu/C-5291-2016 FU National Institutes of Health (NIH), National Institute of Environmental Health Sciences; Ministry of Education, Culture, Sports, Science and Technology of Japan [25670031]; Naito Memorial Foundation FX This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (to J.W.P.); Grants-in-Aid for Scientific Research [grant number 25670031] to M.N. from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and grants from Naito Memorial Foundation (to M.N.). NR 35 TC 1 Z9 1 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2016 VL 473 BP 201 EP 210 DI 10.1042/BJ20150596 PN 2 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2ZL UT WOS:000374784300010 PM 26554024 ER PT J AU Ossoli, A Remaley, AT Vaisman, B Calabresi, L Gomaraschi, M AF Ossoli, Alice Remaley, Alan T. Vaisman, Boris Calabresi, Laura Gomaraschi, Monica TI Plasma-derived and synthetic high-density lipoprotein inhibit tissue factor in endothelial cells and monocytes SO BIOCHEMICAL JOURNAL LA English DT Article DE endothelium; high-density lipoprotein; monocytes; protein kinases; scavenger receptors; tissue factor ID APOLIPOPROTEIN-A-I; RANDOMIZED CONTROLLED-TRIAL; CORONARY ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; TRANSGENIC MICE; EXPRESSION; HDL; MILANO; PLAQUE; LIPOPOLYSACCHARIDE AB HDL (high-density lipoproteins) exert anti-thrombotic activities by preventing platelet adhesion and activation and by stimulating the protein C pathway and fibrinolysis. The aim of the present study was to assess the effect of plasma-derived and synthetic HDL on endothelial and monocyte expression of TF (tissue factor), the primary initiator of coagulation. HDL inhibited TF expression and activity in stimulated endothelial cells and monocytes in a dose-dependent way. Synthetic HDL fully retain the ability to inhibit TF expression in a dose-dependent manner; lipid-free apoA-I (apolipoprotein A-I) was not effective and neither was sphingosine 1-phosphate involved. HDL-mediated TF inhibition was due to a modulation of cellular cholesterol content through the interaction with SR-BI (scavenger receptor BI); downstream, HDL inhibited the activation of p38 MAPK (mitogen-activated protein kinase) and the repression of the PI3K (phosphoinositide 3-kinase) pathway responsible for TF expression. In vivo, human apoA-I-transgenic mice displayed a reduced aortic TF expression compared with wild-type animals and TF plasma levels were increased in subjects with low HDL-C (HDL-cholesterol) levels compared with high HDL-C subjects. Thus the anti-thrombotic activity of HDL could also be mediated by the inhibition of TF expression and activity in endothelial cells and monocytes; synthetic HDL retain the inhibitory activity of plasma-derived HDL, supporting the hypothesis that synthetic HDL infusion may be beneficial in the setting of acute coronary syndrome. C1 [Ossoli, Alice; Calabresi, Laura; Gomaraschi, Monica] Univ Milan, Dipartimento Sci Farmacol & Biomol, Ctr Grossi Paoletti, Via Balzaretti 9, I-20133 Milan, Italy. [Ossoli, Alice; Remaley, Alan T.; Vaisman, Boris] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20814 USA. RP Calabresi, L (reprint author), Univ Milan, Dipartimento Sci Farmacol & Biomol, Ctr Grossi Paoletti, Via Balzaretti 9, I-20133 Milan, Italy. EM laura.calabresi@unimi.it RI Ossoli, Alice/K-5917-2016; Gomaraschi, Monica/A-3601-2014 OI Ossoli, Alice/0000-0002-9902-252X; Gomaraschi, Monica/0000-0003-3082-2120 FU University of Milan [17796]; National Heart, Lung and Blood Institute of the National Institutes of Health FX This work was partially supported by the University of Milan within the Development Plan for Young Researchers [grant number 17796 to M.G.]. A.T.R. and B.V. were funded from intramural research funds from the National Heart, Lung and Blood Institute of the National Institutes of Health. NR 35 TC 1 Z9 1 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD JAN 15 PY 2016 VL 473 BP 211 EP 219 DI 10.1042/BJ20151000 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DK2ZL UT WOS:000374784300011 PM 26556891 ER PT J AU Bodelon, C Killian, K Sampson, J Stevenson, H Anderson, W Matsuno, R Brinton, L Lissowska, J Sherman, M Wentzensen, N AF Bodelon, Clara Killian, Keith Sampson, Joshua Stevenson, Holly Anderson, William Matsuno, Rayna Brinton, Louise Lissowska, Jolanta Sherman, Mark Wentzensen, Nicolas TI Methylation profiling of ovarian cancer to study etiologic and prognostic heterogeneity and to develop a molecular classifier. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Ovarian Cancer Research - Exploiting Vulnerabilities CY OCT 17-20, 2015 CL Orlando, FL SP Amer Assoc Canc Res C1 [Bodelon, Clara; Killian, Keith; Sampson, Joshua; Stevenson, Holly; Anderson, William; Brinton, Louise; Sherman, Mark; Wentzensen, Nicolas] NCI, Bethesda, MD 20892 USA. [Matsuno, Rayna] Univ Calif San Diego, San Diego, CA 92103 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. NR 0 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 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2016 VL 22 SU 2 MA B41 PG 2 WC Oncology SC Oncology GA DI2QU UT WOS:000373342300101 ER PT J AU Hernandez, L Kim, MK Lyle, LT Steeg, PS Annunziata, CM AF Hernandez, Lidia Kim, Marianne K. Lyle, L. Tiffany Steeg, Patricia S. Annunziata, Christina M. TI Characterization of ovarian cancer cells as in vivo models for preclinical studies. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR Special Conference on Advances in Ovarian Cancer Research - Exploiting Vulnerabilities CY OCT 17-20, 2015 CL Orlando, FL SP Amer Assoc Canc Res C1 [Hernandez, Lidia; Kim, Marianne K.; Lyle, L. Tiffany; Steeg, Patricia S.; Annunziata, Christina M.] NCI, Bethesda, MD 20892 USA. RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2016 VL 22 SU 2 MA B43 PG 1 WC Oncology SC Oncology GA DI2QU UT WOS:000373342300103 ER EF