FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Pratt, CA Iannotti, RJ Li, KG D'Elio, M Olson, S Lipsky, L Simons-Morton, B Fan, RZ AF Pratt, Charlotte A. Iannotti, Ronald J. Li, Kaigang D'Elio, MaryAnn Olson, Sarah Lipsky, Leah Simons-Morton, Bruce Fan, Ruzong TI Associations among body mass index, waist circumference, dietary factors and cardiometabolic risks in 10th grade students: The NEXT Generation Health Study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Pratt, Charlotte A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Iannotti, Ronald J.; Li, Kaigang; Lipsky, Leah; Simons-Morton, Bruce; Fan, Ruzong] NICHD, NIH, Bethesda, MD USA. [D'Elio, MaryAnn; Olson, Sarah] CDM Grp Inc, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 226.6 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883506232 ER PT J AU Procino, G Milano, S Carmosino, M Nicoletti, MC Wess, J Svelto, M AF Procino, Giuseppe Milano, Serena Carmosino, Monica Nicoletti, Maria Celeste Wess, Juergen Svelto, Maria TI A novel treatment for X-linked nephrogenic diabetes insipidus: the secret in secretin? SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Procino, Giuseppe; Milano, Serena; Carmosino, Monica; Nicoletti, Maria Celeste; Svelto, Maria] Univ Bari, Bari, Italy. [Wess, Juergen] NIDDK, NIH, Bethesda, MD USA. RI Carmosino, Monica/O-2594-2014 OI Carmosino, Monica/0000-0001-7600-8816 NR 0 TC 0 Z9 0 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1115.21 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860505331 ER PT J AU Qin, B Xun, PC Zhu, N Jacobs, D Steffen, L Daviglus, M Van Horn, L Reis, J Loria, C Liu, K He, K AF Qin, Bo Xun, Pengcheng Zhu, Na Jacobs, David Steffen, Lyn Daviglus, Martha Van Horn, Linda Reis, Jared Loria, Catherine Liu, Kiang He, Ka TI B vitamin intake in early adulthood and cognition in late midlife: CARDIA SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Qin, Bo] UNC CH, Dept Nutr, Chapel Hill, NC USA. [Xun, Pengcheng; He, Ka] IU Bloomington, Dept Epid & Bios, Bloomington, IN USA. [Zhu, Na; Jacobs, David; Steffen, Lyn] UMN, Div Epid, Minneapolis, MN USA. [Jacobs, David] U Oslo, Dept Nutr, Oslo, Norway. [Daviglus, Martha] UIC, Dept Med, Chicago, IL USA. [Van Horn, Linda; Liu, Kiang] Northwestern U, Dept Prev Med, Chicago, IL USA. [Reis, Jared; Loria, Catherine] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 840.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860505521 ER PT J AU Qin, YY Freemerman, AJ Li, L Coleman, R Galanko, J Edin, M Zeldin, D Stahl, A Makowski, L AF Qin, Yuanyuan Freemerman, Alex Jay Li, Lei Coleman, Rosalind Galanko, Joesh Edin, Matthew Zeldin, Darryl Stahl, Andreas Makowski, Liza TI Fatty acid transport protein 1 mediates macrophage eicosanoid metabolism SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Qin, Yuanyuan; Freemerman, Alex Jay; Li, Lei; Coleman, Rosalind; Galanko, Joesh; Makowski, Liza] Univ N Carolina, Chapel Hill, NC USA. [Edin, Matthew; Zeldin, Darryl] NIEHS, Res Triangle Pk, NC USA. [Stahl, Andreas] Univ Calif Berkeley, Berkeley, CA 94720 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 373.5 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860503506 ER PT J AU Quick, V Byrd-Bredbenner, C AF Quick, Virginia Byrd-Bredbenner, Carol TI Eating attitudes, behaviors, and associated psychographic characteristics of college students: Are there differences in those with and without nutrition majors? SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Quick, Virginia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, NIH, Bethesda, MD USA. [Byrd-Bredbenner, Carol] Rutgers State Univ, New Brunswick, NJ 08903 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 841.25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883503587 ER PT J AU Quick, V Heller, R Corda, K Martin-Biggers, J Byrd-Bredbenner, C AF Quick, Virginia Heller, Rebecca Corda, Kirsten Martin-Biggers, Jennifer Byrd-Bredbenner, Carol TI Friends Matter: Food safety cognitive and behavioral influences among youth SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Quick, Virginia] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, NIH, Bethesda, MD USA. [Heller, Rebecca; Martin-Biggers, Jennifer; Byrd-Bredbenner, Carol] Rutgers State Univ, New Brunswick, NJ 08903 USA. [Corda, Kirsten] Univ Texas San Antonio, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 626.5 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883501302 ER PT J AU Ramsden, CE Zamora, D Faurot, K Majchrzak, S Hibbeln, J AF Ramsden, Christopher E. Zamora, Daisy Faurot, Kim Majchrzak, Sharon Hibbeln, Joseph TI The Sydney Diet Heart Study: a randomised controlled trial of linoleic acid for secondary prevention of coronary heart disease and death SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Ramsden, Christopher E.; Majchrzak, Sharon; Hibbeln, Joseph] NIAAA, NIH, Bethesda, MD 90034 USA. [Zamora, Daisy; Faurot, Kim] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 8 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 127.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883504334 ER PT J AU Raychoudhuri, A Jana, S Basu, M Basu, NK Owens, IS AF Raychoudhuri, Amit Jana, Sirsendu Basu, Mousumi Basu, Nikhil K. Owens, Ida S. TI Mouse UDP-glucuronosyltransferase Enzymes Capable of Metabolizing Toxic Estrogen Derivatives: Serine Residues Play Crucial Role to Substrate Turnover SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Raychoudhuri, Amit; Jana, Sirsendu; Basu, Mousumi; Basu, Nikhil K.; Owens, Ida S.] NICHD, SGDDM PDEGEN, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 791.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883500303 ER PT J AU Redan, BW Motobar, O Tuzmen, P Guha, R Caplen, N Martin, SE AF Redan, Benjamin W. Motobar, Omid Tuzmen, Pinar Guha, Rajarshi Caplen, Natasha Martin, Scott E. TI RNAi Screen Reveals Candidate miRNAs Associated with the NF-(kappa) B Pathway SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Redan, Benjamin W.] Purdue Univ, W Lafayette, IN 47907 USA. [Motobar, Omid; Tuzmen, Pinar; Guha, Rajarshi; Martin, Scott E.] NIH, NCATS, Rockville, MD USA. [Caplen, Natasha] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 780.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883500691 ER PT J AU Rhee, DK Lim, JC Hockman, SC Ahmad, F Manganiello, VC AF Rhee, Dong Keun Lim, Jung Chae Hockman, Steven C. Ahmad, Faiyaz Manganiello, Vincent C. TI Heterologous expression of human phosphodiesterase 3A enhances oxidative stress resistance in yeast SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Rhee, Dong Keun; Lim, Jung Chae; Hockman, Steven C.; Ahmad, Faiyaz; Manganiello, Vincent C.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1052.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883502101 ER PT J AU Saldanha, LG Dwyer, JT Bailen, RA Chang, FF Andrews, KW Bailey, RL Betz, JM Burt, VL Costello, RB Emenaker, NJ Gahche, JJ Hardy, CJ Pehrsson, PR Roseland, JM AF Saldanha, Leila G. Dwyer, Johanna T. Bailen, Richard A. Chang, Florence F. Andrews, Karen W. Bailey, Regan L. Betz, Joseph M. Burt, Vicki L. Costello, Rebecca B. Emenaker, Nancy J. Gahche, Jaime J. Hardy, Constance J. Pehrsson, Pamela R. Roseland, Janet M. TI Dietary Supplement Label Database (DSLD) Will Capture Information from Dietary Supplement (DS) Labels SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Saldanha, Leila G.; Dwyer, Johanna T.; Bailen, Richard A.; Bailey, Regan L.; Betz, Joseph M.; Costello, Rebecca B.] NIH, ODS, Bethesda, MD 20892 USA. [Chang, Florence F.] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Emenaker, Nancy J.] NCI, NIH, Bethesda, MD 20892 USA. [Andrews, Karen W.; Pehrsson, Pamela R.; Roseland, Janet M.] ARS, USDA, Beltsville, MD USA. [Burt, Vicki L.; Gahche, Jaime J.] CDC, NCHS, Hyattsville, MD USA. [Hardy, Constance J.] US FDA, CFSAN, College Pk, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 848.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883505448 ER PT J AU Salvemini, D Janes, K Finley, A Doyle, T Chen, ZM Bryant, L Tosh, D Jacobson, K AF Salvemini, Daniela Janes, Kali Finley, Amanda Doyle, Timothy Chen, Zhoumou Bryant, Leesa Tosh, Dilip Jacobson, Kenneth TI Adenosine receptor subtype 3 (A3AR) agonists as novel analgesics in chronic neuropathic pain SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Salvemini, Daniela; Janes, Kali; Finley, Amanda; Doyle, Timothy; Chen, Zhoumou; Bryant, Leesa] St Louis Univ, Sch Med, St Louis, MO USA. [Tosh, Dilip; Jacobson, Kenneth] NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 887.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860501315 ER PT J AU Shi, YB AF Shi, Yun-Bo TI Thyroid hormone induction of adult stem cell formation during postembryonic development: An essential role of sonic hedgehog signaling mediated cell-cell interaction SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Shi, Yun-Bo] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 831.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883503585 ER PT J AU Shizukuda, Y Tripodi, D Sachdev, V Brenneman, C Sidenko, S Peter, MS Bolan, C Yau, YY Arai, A Bandettini, P Leitman, S Rosing, D AF Shizukuda, Yukitaka Tripodi, Dorothy Sachdev, Vandana Brenneman, Cynthia Sidenko, Stanislav Peter, Marilyn St. Bolan, Charles Yau, Yu Ying Arai, Andrew Bandettini, Patricia Leitman, Susan Rosing, Douglas TI Is myocardial iron content associated with left atrial systolic function in asymptomatic hereditary hemochromatosis? SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Shizukuda, Yukitaka; Tripodi, Dorothy; Sachdev, Vandana; Brenneman, Cynthia; Sidenko, Stanislav; Peter, Marilyn St.; Bolan, Charles; Arai, Andrew; Bandettini, Patricia; Rosing, Douglas] NHLBI, NIH, Bethesda, MD 20892 USA. [Shizukuda, Yukitaka] Univ Cincinnati, Cincinnati, OH USA. [Yau, Yu Ying; Leitman, Susan] NIH, Cin Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1126.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860503452 ER PT J AU Slezak, JM Mueller, M Ricaurte, GA Cao, JJ Newman, AH Katz, JL AF Slezak, Jonathan M. Mueller, Melanie Ricaurte, George A. Cao, Jianjing Newman, Amy H. Katz, Jonathan L. TI Discriminative-stimulus effects of 3,4-methylenedioxy-N-methylamphetamine (MDMA) and a novel MDMA quatenary analog SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Slezak, Jonathan M.; Katz, Jonathan L.] NIDA, Psychobiol Sect, Intramural Res Program, Baltimore, MD USA. [Cao, Jianjing; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD USA. [Slezak, Jonathan M.; Mueller, Melanie; Ricaurte, George A.] Johns Hopkins Sch Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1098.10 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860502098 ER PT J AU Subramanian, P Becerra, SP AF Subramanian, Preeti Becerra, S. Patricia TI A Novel inhibitor of Lipoxygenase: a Patatin-like Phospholipase Domain-containing 2 (PNPLA2) Protein SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Subramanian, Preeti; Becerra, S. Patricia] NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA lb234 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860506157 ER PT J AU Sylvetsky, AC Greenberg, MJ Rother, KI AF Sylvetsky, Allison Cara Greenberg, Mitchell J. Rother, Kristina I. TI Parental Recognition and Perception of Commercially Available Foods and Beverages Containing Non-nutritive Sweeteners SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Sylvetsky, Allison Cara; Greenberg, Mitchell J.; Rother, Kristina I.] NIDDK, NIH, Bethesda, MD USA. [Sylvetsky, Allison Cara] Emory Univ, Laney Grad Sch, Atlanta, GA 30322 USA. NR 0 TC 1 Z9 1 U1 3 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 232.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883500095 ER PT J AU Tang, WB Guertin, KA Arnold, KB Hartline, JA Minasian, LM Lippman, SM Klein, E Cassano, PA AF Tang, Wenbo Guertin, K. A. Arnold, K. B. Hartline, J. A. Minasian, L. M. Lippman, S. M. Klein, E. Cassano, P. A. TI A prudent diet attenuates lung function decline in cigarette smokers SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Tang, Wenbo; Guertin, K. A.; Cassano, P. A.] Cornell Univ, Ithaca, NY USA. [Arnold, K. B.; Hartline, J. A.] SWOG Stat Ctr, Seattle, WA USA. [Minasian, L. M.] NCI, Bethesda, MD 20892 USA. [Lippman, S. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Klein, E.] Cleveland Clin, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 847.17 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883505274 ER PT J AU Ulane, RE AF Ulane, Rod E. TI NIH Support of Pre- and Postdoctoral Training for a Career as a Research Scientist SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Ulane, Rod E.] NIH, Off Extramural Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 205.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500133 ER PT J AU Valente, AJ Siebenlist, U Chandrasekar, B AF Valente, Anthony J. Siebenlist, Ulrich Chandrasekar, Bysani TI Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Valente, Anthony J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Siebenlist, Ulrich] NIAID, Immunoregulat Lab, B, MD USA. [Chandrasekar, Bysani] Tulane Univ SOM, Inst Heart & Vasc, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 727.13 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860503351 ER PT J AU Vance, TM Wang, Y Su, LJ Fontham, ETH Bensen, JT Mohler, JL Chen, MH Chun, OK AF Vance, Terrence M. Wang, Ying Su, L. Joseph Fontham, Elizabeth T. H. Bensen, Jeannette T. Mohler, James L. Chen, Ming-Hui Chun, Ock K. TI Dietary total antioxidant capacity and prostate cancer tumor stage among African and Caucasian Americans in a population-based study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vance, Terrence M.; Wang, Ying; Chun, Ock K.] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Su, L. Joseph] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1061.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860502608 ER PT J AU Vance, TM Wang, Y Su, LJ Fontham, ETH Bensen, JT Mohler, JL Chen, MH Chun, OK AF Vance, Terrence M. Wang, Ying Su, L. Joseph Fontham, Elizabeth T. H. Bensen, Jeannette T. Mohler, James L. Chen, Ming-Hui Chun, Ock K. TI Sociodemographic, clinical, and lifestyle factors associated with prostate cancer aggressiveness in a population-based study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vance, Terrence M.; Wang, Ying; Chun, Ock K.] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Su, L. Joseph] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1061.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860502353 ER PT J AU Vance, TM Wang, Y Su, LJ Fontham, ETH Bensen, JT Mohler, JL Chen, MH Chun, OK AF Vance, Terrence M. Wang, Ying Su, L. Joseph Fontham, Elizabeth T. H. Bensen, Jeannette T. Mohler, James L. Chen, Ming-Hui Chun, Ock K. TI Association of food intake with prostate cancer aggressiveness of African and Caucasian Americans in a population-based study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vance, Terrence M.; Wang, Ying; Chun, Ock K.] Univ Connecticut, Dept Nutr Sci, Storrs, CT USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Su, L. Joseph] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Sch Publ Hlth, New Orleans, LA USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 366.8 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860501510 ER PT J AU Vandeput, F Szabo-Fresnais, N Dunlop, A Krall, J Manganiello, VC Houslay, MD Movsesian, MA AF Vandeput, Fabrice Szabo-Fresnais, Nicolas Dunlop, Allan Krall, Judith Manganiello, Vincent C. Houslay, Miles D. Movsesian, Matthew A. TI Selective regulation of PDE3A isoforms by differential phosphorylation SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vandeput, Fabrice; Szabo-Fresnais, Nicolas; Krall, Judith; Movsesian, Matthew A.] Univ Utah, Cardiol Sect, VA Salt Lake City HCS, Salt Lake City, UT USA. [Dunlop, Allan] Univ Glasgow, Glasgow, Lanark, Scotland. [Manganiello, Vincent C.] NIH, Bethesda, MD 20892 USA. [Houslay, Miles D.] Kings Coll London, London WC2R 2LS, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1052.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883502361 ER PT J AU Varadarajan, J McWilliams, MJ Hazuda, D Hughes, S AF Varadarajan, Janani McWilliams, Mary Jane Hazuda, Daria Hughes, Stephen TI Analyzing the effects of sub-optimal doses of raltegravir on HIV-1 integration SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Varadarajan, Janani; McWilliams, Mary Jane; Hughes, Stephen] NIH, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Hazuda, Daria] Merck Res Labs, West Point, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 970.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883500367 ER PT J AU Vaz, JD Kac, G Emmett, PM Davis, JM Golding, J Hibbeln, JR AF Vaz, Juliana dos Santos Kac, Gilberto Emmett, Pauline M. Davis, John M. Golding, Jean Hibbeln, Joseph R. TI Dietary patterns, omega-3 fatty acids intake from seafood and high anxiety symptoms during pregnancy: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vaz, Juliana dos Santos; Kac, Gilberto] Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. [Emmett, Pauline M.; Golding, Jean] Univ Bristol, Bristol, Avon, England. [Davis, John M.] Univ Illinois, Chicago, IL USA. [Hibbeln, Joseph R.] NIAAA, Rockville, MD 20852 USA. RI Kac, Gilberto/H-6862-2012 OI Kac, Gilberto/0000-0001-8603-9077 NR 0 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 106.6 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883505292 ER PT J AU Vedin, I Levi, YF Cederholm, T Basun, H Hjorth, E Irving, GF Schultzberg, M Eriksdotter, M Vessby, B Wahlund, LO Salem, N Palmblad, J AF Vedin, Inger Levi, Yvonne Freund Cederholm, Tommy Basun, Hans Hjorth, Erik Irving, Gerd Faxen Schultzberg, Marianne Eriksdotter, Maria Vessby, Bengt Wahlund, Lars-Olof Salem, Norman, Jr. Palmblad, Jan TI Effects of a DHA rich n-3 fatty acid supplementation on fatty acid composition in cerebrospinal fluid in Alzheimer disease. The OmegAD study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Vedin, Inger; Palmblad, Jan] Karolinska Hosp, Dept Med, S-10401 Stockholm, Sweden. [Levi, Yvonne Freund; Hjorth, Erik; Irving, Gerd Faxen; Schultzberg, Marianne; Eriksdotter, Maria; Wahlund, Lars-Olof] Dept Neurobiol & Caring Sci & Soc, Stockholm, Sweden. [Cederholm, Tommy; Vessby, Bengt] Dept Publ Hlth & Caring Sci, Div Nutr & Metab, Uppsala, Sweden. [Basun, Hans] Dept Publ Hlth & Caring Sci, Div Geriatr, Uppsala, Sweden. [Salem, Norman, Jr.] NIAAA, NIH, Rockville, MD 20852 USA. RI Schultzberg, Marianne/E-7076-2014; Eriksdotter, Maria/I-5427-2015 OI Schultzberg, Marianne/0000-0002-8314-0927; Eriksdotter, Maria/0000-0003-2498-4000 NR 0 TC 0 Z9 0 U1 0 U2 7 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA lb343 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883506085 ER PT J AU Verhein, KC High, M Marzec, J McCaw, Z Wiltshire, T Chen, Y Burkholder, A Klimczak, L Fargo, D Kleeberger, SR AF Verhein, Kirsten C. High, Monica Marzec, Jacqui McCaw, Zachary Wiltshire, Tim Chen, Yu Burkholder, Adam Klimczak, Les Fargo, David Kleeberger, Steven R. TI Identification of candidate susceptibility genes in a murine model of respiratory syncytial virus (RSV)-induced bronchiolitis SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Verhein, Kirsten C.; High, Monica; Marzec, Jacqui; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Chen, Yu; Burkholder, Adam; Klimczak, Les; Fargo, David] NIEHS, Res Triangle Pk, NC 27709 USA. [McCaw, Zachary; Wiltshire, Tim] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1212.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860503055 ER PT J AU Wang, HF Quatramoni, P Fox, CS Jacques, PF McKeown, NM AF Wang, Huifen Quatramoni, Paula Fox, Caroline S. Jacques, Paul F. McKeown, Nicola M. TI Association of whole grain intake and longitudinal changes in abdominal adiposity in the Framingham Heart Study SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Wang, Huifen; Jacques, Paul F.; McKeown, Nicola M.] JM USDA HNRCA, Boston, MA USA. [Quatramoni, Paula] Boston Univ, Dept Hlth Sci, Boston, MA 02215 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 126.6 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500486 ER PT J AU Wang, PM Martin, WJ AF Wang, Ping Ming Martin, William J., II TI Evidence of donor epithelial type 2 cell engraftment in bleomycin-injured murine lung after airway delivery SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Wang, Ping Ming; Martin, William J., II] NICHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1166.16 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883504581 ER PT J AU Wang, Y Vance, TM Su, J Fontham, ETH Bensen, JT Mohler, JL Chen, MH Chun, OK AF Wang, Ying Vance, Terrence M. Su, Joseph Fontham, Elizabeth T. H. Bensen, Jeannette T. Mohler, James L. Chen, Ming-Hui Chun, Ock K. TI Proanthocyanidin intake is inversely associated with advanced prostate tumor stages in newly diagnosed prostate cancer patients SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Wang, Ying; Vance, Terrence M.; Chun, Ock K.] Univ Connecticut, Dept Nutr Sci, Storrs Mansfield, CT USA. [Su, Joseph] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fontham, Elizabeth T. H.] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Mohler, James L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 847.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883502018 ER PT J AU Wang, YC Leung, JW Jiang, YJ Lowery, MG Do, HG Vasquez, KM Chen, JJ Wang, WD Li, L AF Wang, Yucai Leung, Justin W. Jiang, Yingjun Lowery, Megan G. Do, Huong G. Vasquez, Karen M. Chen, Junjie Wang, Weidong Li, Lei TI Functional Divergence of Fanconi Anemia Genes SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Wang, Yucai; Leung, Justin W.; Jiang, Yingjun; Do, Huong G.; Chen, Junjie; Li, Lei] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lowery, Megan G.; Vasquez, Karen M.] Univ Texas MD Anderson Canc Ctr, Smithville, TX USA. [Wang, Weidong] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 451.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883502424 ER PT J AU Weaver, JD Wang, HC Shears, SB AF Weaver, Jeremy D. Wang, Huanchen Shears, Stephen B. TI The kinetic properties of a human PPIP5K reveal that its kinase activities are protected against the consequences of a deteriorating cellular bioenergetic environment SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Weaver, Jeremy D.; Wang, Huanchen; Shears, Stephen B.] Natl Inst Environm Hlth Sci, Lab Signal Transduct, NIH, Res Triangle Pk, NC USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1050.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500379 ER PT J AU Wilkinson, D Hiranita, T Mereu, M Tanda, G Newman, AH Katz, JL AF Wilkinson, Derek Hiranita, Takato Mereu, Maddalena Tanda, Gianluigi Newman, Amy H. Katz, Jonathan L. TI In Vivo Binding of N-Substituted Benztropine Analogs and Antagonism of Cocaine Self-Administration SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Wilkinson, Derek; Hiranita, Takato; Mereu, Maddalena; Tanda, Gianluigi; Katz, Jonathan L.] NIDA Intramural Res Program, Psychobiol Sect, Baltimore, MD USA. [Newman, Amy H.] NIDA Intramural Res Program, Med Chem Sect, Baltimore, MD USA. [Hiranita, Takato] Univ Colorado, Boulder, CO 80309 USA. RI Tanda, Gianluigi/B-3318-2009; Hiranita, Takato/G-6567-2011 OI Tanda, Gianluigi/0000-0001-9526-9878; NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 659.8 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500189 ER PT J AU Xiao, L Rao, JN Gorospe, M Wang, JY AF Xiao, Lan Rao, Jaladanki N. Gorospe, Myriam Wang, Jian-Ying TI microRNA-29b Functions as a Repressor of Intestinal Mucosal Growth by Targeting Cyclin-dependent Kinase 2 SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Xiao, Lan; Rao, Jaladanki N.; Wang, Jian-Ying] Univ Maryland, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 946.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860501039 ER PT J AU Yano, H Provasi, D Filizola, M Ferre, S Javitch, JA AF Yano, Hideaki Provasi, Davide Filizola, Marta Ferre, Sergi Javitch, Jonathan A. TI Activation of the G(s) heterotrimer monitored in living cells with novel G(s) biosensors SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Yano, Hideaki; Javitch, Jonathan A.] Columbia Univ, New York, NY USA. [Yano, Hideaki; Ferre, Sergi] NIDA, NIH, Baltimore, MD USA. [Provasi, Davide; Filizola, Marta] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1094.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500018 ER PT J AU Yao, MY Csanyi, G Rodriguez, A Roberts, D Pagano, P Isenberg, J AF Yao, Mingyi Csanyi, Gabor Rodriguez, Andres Roberts, David Pagano, Patrick Isenberg, Jeffrey TI Thrombospondin-1 (TSP1) Impairs Vasorelaxation via Signal Regulatory Protein (SIRP)-alpha-Mediated Activation of NADPH Oxidase 1 (NOX1) SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Yao, Mingyi] Midwestern Univ, Glendale, AZ USA. [Yao, Mingyi; Csanyi, Gabor; Rodriguez, Andres; Pagano, Patrick; Isenberg, Jeffrey] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA USA. [Roberts, David] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1090.5 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860501092 ER PT J AU Yuan, JP Lee, K Graham, S Ahuja, M Ma, R Muallem, S AF Yuan, Joseph P. Lee, Kyupil Graham, Sarabeth Ahuja, Malini Ma, Rong Muallem, Shmuel TI Molecular Determinants of TRPC Channels Gating by STIM1 SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Yuan, Joseph P.; Graham, Sarabeth; Ma, Rong] Univ N Texas, Hlth Sci Ctr, Cardiovasc Res Inst, Ft Worth, TX USA. [Lee, Kyupil; Ahuja, Malini; Muallem, Shmuel] NIDCR, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 729.8 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860504410 ER PT J AU Zhang, SY Surapureddi, S Goldstein, JA AF Zhang, Shu-Yun Surapureddi, Sailesh Goldstein, Joyce A. TI PKC phosphorylation of Med25 is critical for Mediator assembly: Implications for HNF4 alpha signaling in drug metabolism SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Zhang, Shu-Yun; Surapureddi, Sailesh; Goldstein, Joyce A.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1180.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860501159 ER PT J AU Zhu, YY Hernandez, LM Dong, YQ Mueller, P Hirschfeld, S Forman, MR AF Zhu, Yeyi Hernandez, Ladia M. Dong, Yongquan Mueller, Peter Hirschfeld, Steven Forman, Michele R. TI Development and Validation of Infant Feeding Algorithms Used to Identify Factors Associated with Infant Feeding Practices SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Zhu, Yeyi; Hernandez, Ladia M.; Dong, Yongquan; Mueller, Peter; Forman, Michele R.] Univ Texas Austin, Austin, TX 78712 USA. [Hirschfeld, Steven] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 849.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 157GG UT WOS:000319883505229 ER PT J AU Zsengeller, ZK Mukhopadhyay, P Kalyanaraman, B Parikh, S Karumanchi, AS Stillman, IE Pacher, P AF Zsengeller, Zsuzsanna Kinga Mukhopadhyay, Partha Kalyanaraman, Balaraman Parikh, Samir Karumanchi, Ananth S. Stillman, Isaac E. Pacher, Pal TI Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Zsengeller, Zsuzsanna Kinga] Howard Hughes Med Inst Investigator, Boston, MA USA. [Mukhopadhyay, Partha; Parikh, Samir; Karumanchi, Ananth S.] Howard Hughes Med Inst Investigator, Div Nephrol, Boston, MA USA. [Stillman, Isaac E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Natl Inst Hlth Bethesda, Bethesda, MD USA. [Kalyanaraman, Balaraman] Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 1086.13 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500384 ER PT J AU Zuk, D AF Zuk, Dorit TI Careers beyond the bench - an overview SO FASEB JOURNAL LA English DT Meeting Abstract CT Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB) CY APR 20-24, 2013 CL Boston, MA SP ASPET, British Pharmacol Soc (BPS) C1 [Zuk, Dorit] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2013 VL 27 MA 89.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 156YK UT WOS:000319860500287 ER PT J AU Burg, ED Langan, ST Nash, HA AF Burg, E. D. Langan, S. T. Nash, H. A. TI Drosophila social clustering is disrupted by anesthetics and in narrow abdomen ion channel mutants SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Cholinergic; Drosophila; general volatile anesthetics; halothane; local enhancement; mushroom bodies; narrow abdomen; social behavior ID VOLATILE GENERAL-ANESTHETICS; MUSHROOM BODIES; FRUIT-FLIES; AGGREGATION PHEROMONE; SPATIAL-DISTRIBUTION; LOCOMOTOR-ACTIVITY; MELANOGASTER; BEHAVIOR; AGGRESSION; HALOTHANE AB Members of many species tend to congregate, a behavioral strategy known as local enhancement. Selective advantages of local enhancement range from efficient use of resources to defense from predators. While previous studies have examined many types of social behavior in fruit flies, few have specifically investigated local enhancement. Resource-independent local enhancement (RILE) has recently been described in the fruit fly using a measure called social space index (SSI), although the neural mechanisms remain unknown. Here, we analyze RILE of Drosophila under conditions that allow us to elucidate its neural mechanisms. We have investigated the effects of general volatile anesthetics, compounds that compromise higher order functioning of the type typically required for responding to social cues. We exposed Canton-S flies to non-immobilizing concentrations of halothane and found that flies had a significantly decreased SSI compared with flies tested in air. Narrow abdomen (na) mutants, which display altered responses to anesthetics in numerous behavioral assays, also have a significantly reduced SSI, an effect that was fully reversed by restoring expression of na by driving a UAS-NA rescue construct with NA-GAL4. We found that na expression in cholinergic neurons fully rescued the behavioral defect, whereas expression of na in glutamatergic neurons did so only partially. Our results also suggest a role for na expression in the mushroom bodies (MBs), as suppressing na expression in the MBs of NA-GAL4 rescue flies diminishes SSI. Our data indicate that RILE, a simple behavioral strategy, requires complex neural processing. C1 [Burg, E. D.; Langan, S. T.; Nash, H. A.] NIMH, Sect Neural Funct, NIH, Bethesda, MD 20892 USA. RP Burg, ED (reprint author), NIH, Bldg 35,Room 1B-1008,9000 Rockville Pike, Bethesda, MD 20892 USA. EM burged@mail.nih.gov FU DIRP of NIMH, NIH [MH 002228-27] FX The authors would like to thank Drs David Sandstrom, Anne F. Simon and Shuying Gao for helpful discussions. We would also like to thank Dr Bridget Lear for flies carrying the UAS-NA and NA-GAL4 inserts; Dr Jens Rister for the MB-GAL80 flies; Dr Aaron DiAntonio for the dVGlut-GAL4 flies and Dr Daniel Kalderon for the anti-DC0 antibody. The authors acknowledge Mr Tom Talbot of the Section on Instrumentation at NIMH for designing and fabricating the assay arenas and Dr Wayne Rasband for writing our data analysis macro. We also extend our appreciation to Mr Robert Scott for performing the whole-mount brain dissections and imaging, to Dr Dongyu Guo for assistance with behavior experiments and to Mrs Erin Kollins for help with data analysis. Special thanks to Dr Benajamin White for support and guidance in all aspects of this work after the death of our mentor and coauthor, Dr Howard Nash. Finally, we wish to dedicate this manuscript to the memory of Howard Nash, whose incisive mind, encyclopedic memory and critical acumen will be sorely missed, not only by those of us who worked with him but also by those who benefitted indirectly from these qualities through his seminal contributions to science, first in the area of DNA recombination and more recently in the fields of anesthetic action and Drosophila neuroscience. The work was supported entirely by the DIRP of NIMH, NIH (MH 002228-27). NR 61 TC 5 Z9 5 U1 2 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD APR PY 2013 VL 12 IS 3 BP 338 EP 347 DI 10.1111/gbb.12025 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 156PG UT WOS:000319834200007 PM 23398613 ER PT J AU Hansford, JR Pal, M Poplawski, N Haan, E Boog, B Ferrante, A Davis, J Niemela, JE Rao, VK Suppiah, R AF Hansford, Jordan R. Pal, Manika Poplawski, Nicola Haan, Eric Boog, Bernadette Ferrante, Antonio Davis, Joie Niemela, Julie E. Rao, V. Koneti Suppiah, Ram TI In utero and early postnatal presentation of autoimmune lymphoproliferative syndrome in a family with a novel FAS mutation SO HAEMATOLOGICA LA English DT Letter ID LYMPHOCYTE APOPTOSIS; SYNDROME ALPS; GENOTYPE C1 [Hansford, Jordan R.; Pal, Manika; Poplawski, Nicola; Suppiah, Ram] Womens & Childrens Hosp, Adelaide, SA, Australia. [Poplawski, Nicola; Haan, Eric] SA Pathol, SA Clin Genet Serv, Adelaide, SA, Australia. [Poplawski, Nicola; Haan, Eric; Boog, Bernadette; Ferrante, Antonio] Univ Adelaide, Discipline Pediat, Adelaide, SA, Australia. [Boog, Bernadette; Ferrante, Antonio] Womens & Childrens Hosp, SA Pathol, Dept Immunopathol, Adelaide, SA, Australia. [Davis, Joie; Rao, V. Koneti] NIAID, ALPS Unit, LCID, NIH, Bethesda, MD 20892 USA. [Niemela, Julie E.] NIH, Warren Grant Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. RP Suppiah, R (reprint author), Womens & Childrens Hosp, Adelaide, SA, Australia. EM ram.suppiah@health.sa.gov.au OI Niemela, Julie/0000-0003-4197-3792 NR 12 TC 2 Z9 2 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD APR PY 2013 VL 98 IS 4 BP E38 EP E39 DI 10.3324/haematol.2012.070524 PG 2 WC Hematology SC Hematology GA 157LN UT WOS:000319897700001 PM 22983578 ER PT J AU Wong, WT Dresner, S Forooghian, F Glaser, T Doss, L Zhou, M Cunningham, D Shimel, K Harrington, M Hammel, K Cukras, CA Ferris, FL Chew, EY AF Wong, Wai T. Dresner, Samuel Forooghian, Farzin Glaser, Tanya Doss, Lauren Zhou, Mei Cunningham, Denise Shimel, Katherine Harrington, Molly Hammel, Keri Cukras, Catherine A. Ferris, Frederick L. Chew, Emily Y. TI Treatment of Geographic Atrophy With Subconjunctival Sirolimus: Results of a Phase I/II Clinical Trial SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE age-related macular degeneration; geographic atrophy; sirolimus; rapamycin; clinical trial ID RETINAL-PIGMENT EPITHELIUM; DIABETIC MACULAR EDEMA; BREAST-CANCER CELLS; EYE DISEASE; FUNDUS AUTOFLUORESCENCE; MAMMALIAN PROTEIN; VISUAL-ACUITY; ELUTING STENT; DEGENERATION; RAPAMYCIN AB PURPOSE. To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). METHODS. The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 mu g) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. RESULTS. The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. CONCLUSIONS. Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.) C1 [Wong, Wai T.; Dresner, Samuel] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. [Cunningham, Denise; Shimel, Katherine] NEI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin; Glaser, Tanya; Doss, Lauren; Zhou, Mei; Cukras, Catherine A.; Ferris, Frederick L.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Harrington, Molly; Hammel, Keri] EMMES Corp, Rockville, MD USA. RP Wong, WT (reprint author), NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bldg 6,Room 215, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute, National Institutes of Health FX Supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 69 TC 19 Z9 19 U1 0 U2 7 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD APR PY 2013 VL 54 IS 4 BP 2941 EP 2950 DI 10.1167/iovs.13-11650 PG 10 WC Ophthalmology SC Ophthalmology GA 156KV UT WOS:000319821700065 PM 23548622 ER PT J AU Volkow, ND AF Volkow, Nora D. TI Impact of Fetal Drug Exposures on the Adolescent Brain SO JAMA PEDIATRICS LA English DT Editorial Material ID MATERNAL SMOKING; BEHAVIOR; SCIENCE; COCAINE C1 Natl Inst Drug Abuse, Rockville, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Rm 5274,MSC 9581, Rockville, MD 20892 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 19 TC 2 Z9 2 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6203 J9 JAMA PEDIATR JI JAMA Pediatr. PD APR PY 2013 VL 167 IS 4 BP 390 EP 391 PG 2 WC Pediatrics SC Pediatrics GA 156MH UT WOS:000319825800015 PM 23400257 ER PT J AU Sadowski, SM Kebebew, E AF Sadowski, Samira M. Kebebew, Electron TI Variations on a Theme Variant Venous Adrenal Anatomy at Work INVITED CRITIQUE SO JAMA SURGERY LA English DT Editorial Material C1 [Sadowski, Samira M.; Kebebew, Electron] NCI, Endocrine Oncol Branch, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), NCI, Endocrine Oncol Branch, Bldg 10 CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kebebewe@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6254 J9 JAMA SURG JI JAMA Surg. PD APR PY 2013 VL 148 IS 4 BP 384 EP 384 PG 1 WC Surgery SC Surgery GA 160QR UT WOS:000320134900018 PM 23715634 ER PT J AU Reynolds, EK Schreiber, WM Geisel, K MacPherson, L Ernst, M Lejuez, CW AF Reynolds, Elizabeth K. Schreiber, Whitney M. Geisel, Kathy MacPherson, Laura Ernst, Monique Lejuez, C. W. TI Influence of social stress on risk-taking behavior in adolescents SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Risk-taking behavior; Social anxiety; Adolescent; In vivo anxiety manipulation ID ANXIETY DISORDER; ALCOHOL-USE; TASK BART; DRUG-USE; MODEL; DRINKING; AVOIDANCE; FEELINGS; OUTCOMES; SPAI-23 AB Risk-taking behavior involves making choices with uncertain positive or negative outcomes. Evidence suggests that risk-taking behavior is influenced by emotional state. One such emotional experience is social anxiety, which has been related to both risk-avoidant and risk-seeking decision making. The present study examined a community sample of 34 adolescents grouped into low (Low SA Group) and high (High SA Group) social anxiety (SA). Both groups were compared on changes in performance on a risk taking task (Balloon Analogue Risk Task) between a social threat condition (modified Trier Social Stress Test, High Stress) and a control condition (Low Stress). These conditions were administered on different days, and the order was counterbalanced across subjects. A group x condition interaction revealed that the High SA Group showed greater risk-taking behavior when exposed to the High Stress Condition compared to the Low Stress Condition, while the Low SA Group evidenced no difference between the two conditions. Interpretations for the increased risk behavior under the condition of social stress for those high in social anxiety are discussed as well as implications for understanding the complex relationship between social anxiety and risk behavior. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Reynolds, Elizabeth K.] Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Schreiber, Whitney M.; Geisel, Kathy; MacPherson, Laura; Lejuez, C. W.] Univ Maryland, Dept Psychol, Ctr Addict Personal & Emot Res, College Pk, MD 20742 USA. [Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD USA. RP Reynolds, EK (reprint author), Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Dept Psychiat & Behav Sci, 1800 Orleans St 12th Floor, Baltimore, MD 21287 USA. EM ereyno19@jhmi.edu FU Intramural NIH HHS [ZIA MH002781-11]; NIAAA NIH HHS [R21 AA017685]; NIDA NIH HHS [T32 DA028855, R01 DA018647, R01 DA023384, R01 DA019405] NR 49 TC 12 Z9 13 U1 3 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD APR PY 2013 VL 27 IS 3 BP 272 EP 277 DI 10.1016/j.janxdis.2013.02.010 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 156AQ UT WOS:000319792800002 PM 23602940 ER PT J AU Rozzi, SJ Borelli, G Ryan, K Steiner, J Palchik, G Avdoshina, V Mocchetti, I AF Rozzi, S. J. Borelli, G. Ryan, K. Steiner, J. Palchik, G. Avdoshina, V Mocchetti, I TI PACAP27 IS A NEW NEUROPROTECTIVE COMPOUND AGAINST TAT-MEDIATED NEUROTOXICITY SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 Georgetown Univ, Dept Neurosci, Washington, DC 20007 USA. Georgetown Univ, Dept Physiol & Pharmacol, Washington, DC 20007 USA. NINDS, NIH, 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 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2013 VL 8 IS 2 BP 432 EP 432 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 163CA UT WOS:000320312000149 ER PT J AU Nath, A AF Nath, A. TI ERADICATION OF HIV RESERVOIRS FROM THE BRAIN. SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, 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 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2013 VL 8 IS 2 BP 442 EP 442 PG 1 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 163CA UT WOS:000320312000176 ER PT J AU Wojna, V Gerena, Y Bandaru, VVR Haughey, N Curry, T Raber, J Mayo, R Skolasky, RL Nath, A AF Wojna, V Gerena, Y. Bandaru, V. V. R. Haughey, N. Curry, T. Raber, J. Mayo, R. Skolasky, R. L. Nath, A. TI HAND AND HOST FACTORS IN WOMEN ON CART- EXPERIENCE OF OUR HIV-SEROPOSIVIE WOMEN COHORT. SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Meeting Abstract C1 [Wojna, V; Mayo, R.] Univ Puerto Rico, Div Neurol, NeuroAIDS SNRP, San Juan, PR 00936 USA. [Gerena, Y.] Univ Puerto Rico, Dept Pharmaceut Sci, San Juan, PR 00936 USA. [Bandaru, V. V. R.; Haughey, N.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Curry, T.] Univ Kentucky, Dept Obstet & Gynecol, Lexington, KY 40506 USA. [Raber, J.] Oregon Hlth & Sci Univ, Div Neurosci, Portland, OR 97239 USA. [Skolasky, R. L.] Johns Hopkins Univ, Dept Orthopead Surg, Baltimore, MD 21287 USA. [Nath, A.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD APR PY 2013 VL 8 IS 2 BP 443 EP 444 PG 2 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 163CA UT WOS:000320312000181 ER PT J AU Bekhuis, T Demner-Fushman, D Crowley, R AF Bekhuis, Tanja Demner-Fushman, Dina Crowley, Rebecca TI Comparative effectiveness research designs: an analysis of terms and coverage in Medical Subject Headings (MeSH) and Emtree SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article AB Objectives: We analyzed the extent to which comparative effectiveness research (CER) organizations share terms for designs, analyzed coverage of CER designs in Medical Subject Headings (MeSH) and Emtree, and explored whether scientists use CER design terms. Methods: We developed local terminologies (LTs) and a CER design terminology by extracting terms in documents from five organizations. We defined coverage as the distribution over match type in MeSH and Emtree. We created a crosswalk by recording terms to which design terms mapped in both controlled vocabularies. We analyzed the hits for queries restricted to titles and abstracts to explore scientists' language. Results: Pairwise LT overlap ranged from 22.64% (12/53) to 75.61% (31/41). The CER design terminology (n = terms) consisted of terms for primary study designs and a few terms useful for evaluating evidence, such as opinion paper and systematic review. Patterns of coverage were similar in MeSH and Emtree (gamma = 0.581, P=0.002). Conclusions: Stakeholder terminologies vary, and terms are inconsistently covered in MeSH and Emtree. The CER design terminology and crosswalk may be useful for expert searchers. For partially mapped terms, queries could consist of free text for modifiers such as nonrandomized or interrupted added to broad or related controlled terms. C1 [Bekhuis, Tanja; Crowley, Rebecca] Univ Pittsburgh, Dept Biomed Informat, Sch Med, Pittsburgh, PA 15206 USA. [Demner-Fushman, Dina] US Natl Lib Med, Commun Engn Branch, Lister Hill Natl Ctr Biomed Commun HNL32, Bethesda, MD 20814 USA. RP Bekhuis, T (reprint author), Univ Pittsburgh, Dept Biomed Informat, Sch Med, 5607 Baum Blvd,Room 514, Pittsburgh, PA 15206 USA. EM tcb24@pitt.edu; dina.demner@nih.gov; crowleyrs@upmc.edu RI Bekhuis, Tanja/D-4357-2015 OI Bekhuis, Tanja/0000-0002-8537-9077 FU NLM NIH HHS [4R00LM-010943-02, 1K99LM010943-01A1, R00 LM010943] NR 35 TC 6 Z9 6 U1 0 U2 8 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD APR PY 2013 VL 101 IS 2 BP 92 EP 100 DI 10.3163/1536-5050.101.2.004 PG 9 WC Information Science & Library Science SC Information Science & Library Science GA 156XX UT WOS:000319858300004 PM 23646024 ER PT J AU Whitney, W Dutcher, GA Keselman, A AF Whitney, Wanda Dutcher, Gale A. Keselman, Alla TI Evaluation of health information outreach: theory, practice, and future direction SO JOURNAL OF THE MEDICAL LIBRARY ASSOCIATION LA English DT Article ID COMMUNITY EMPOWERMENT; LITERACY AB Objective: Convincing evidence of the effectiveness of health information outreach projects is essential to ensure their continuity. This paper reviews the current state of health information outreach evaluation, characterizes strengths and weaknesses in projects' ability to measure their impact, and assesses enablers of and barriers to projects' success. It also relates the projects' characteristics to evaluation practices. The paper then makes recommendations for strengthening evaluation. Methods: Upon conducting a literature search, the authors identified thirty-three articles describing consumer health information outreach programs, published between 2000 and 2010. We then analyzed the outreach projects with respect to their goals and characteristics, evaluation methods and measures, and reported outcomes. Results: The results uncovered great variation in the quality of evaluation methods, outcome measures, and reporting. Outcome measures did not always match project objectives; few quantitative measures employed pretests or reported statistical significance; and institutional change was not measured in a structured way. While papers reported successful outcomes, greater rigor in measuring and documenting outcomes would be helpful. Conclusion: Planning outcome evaluation carefully and conducting research into mediators between health information and behavior will strengthen the ability to identify best practices and develop a theoretical framework and practical guidance for health information outreach. C1 [Whitney, Wanda] Natl Lib Med, Bethesda, MD 20894 USA. [Dutcher, Gale A.; Keselman, Alla] Natl Lib Med, Div Specialized Informat Serv, Bethesda, MD 20817 USA. RP Whitney, W (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM whitneyw@mail.nlm.nih.gov; dutcherg@mail.nlm.nih.gov; keselmana@mail.nih.gov FU Intramural NIH HHS NR 24 TC 3 Z9 3 U1 0 U2 7 PU MEDICAL LIBRARY ASSOC PI CHICAGO PA 65 EAST WACKER PLACE, STE 1900, CHICAGO, IL 60601-7298 USA SN 1536-5050 J9 J MED LIBR ASSOC JI J. Med. Libr. Assoc. PD APR PY 2013 VL 101 IS 2 BP 138 EP 146 DI 10.3163/1536-5050.101.2.009 PG 9 WC Information Science & Library Science SC Information Science & Library Science GA 156XX UT WOS:000319858300009 PM 23646029 ER PT J AU Calhoon, MB Scarborough, HS Miller, B AF Calhoon, Mary Beth Scarborough, Hollis S. Miller, Brett TI Interventions for struggling adolescent and adult readers: instructional, learner, and situational differences INTRODUCTION SO READING AND WRITING LA English DT Editorial Material ID MIDDLE SCHOOL STUDENTS; READING DISABILITIES; COMPONENTS C1 [Calhoon, Mary Beth] Lehigh Univ, Bethlehem, PA 18015 USA. [Scarborough, Hollis S.] Haskins Labs Inc, New Haven, CT USA. [Miller, Brett] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Calhoon, MB (reprint author), Lehigh Univ, Bethlehem, PA 18015 USA. EM mbc310@Lehigh.EDU NR 17 TC 3 Z9 3 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0922-4777 J9 READ WRIT JI Read. Writ. PD APR PY 2013 VL 26 IS 4 SI SI BP 489 EP 494 DI 10.1007/s11145-013-9442-7 PG 6 WC Education & Educational Research; Psychology, Educational SC Education & Educational Research; Psychology GA 155UG UT WOS:000319773100001 ER PT J AU Lee, KI Pastor, RW Andersen, OS Im, W AF Lee, Kyu Ii Pastor, Richard W. Andersen, Olaf S. Im, Wonpil TI Assessing smectic liquid-crystal continuum models for elastic bilayer deformations SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE Gramicidin A (gA); Voltage dependent anion channel (VDAC); Molecular dynamics simulations; Protein-lipid interactions ID MEMBRANE-PROTEIN FUNCTION; GRAMICIDIN CHANNELS; LIPID-BILAYERS; HYDROPHOBIC MISMATCH; FORCE-FIELD; FREE-ENERGY; CURVATURE; MODULATION; SIMULATIONS; CHOLESTEROL AB For four decades, since W. Helfrich's pioneering study of smectic A liquid crystals in 1973, continuum elastic models (CEMs) have been employed as tools to understand the energetics of protein-induced lipid bilayer deformations. Among the assumptions underlying this use is that all relevant protein-lipid interactions can be included in the continuum representation of the protein-bilayer interactions through the physical parameters determined for protein-free bilayers and the choice of boundary conditions at the protein/bilayer interface. To better understand this assumption, we review the general structure of CEMs, examine how different choices of boundary conditions and physical moduli profiles alter the predicted bilayer thickness profiles around gramicidin A (gA) and mitochondrial voltage-dependent anion channels (VDAC), respectively, and compare these profiles with those obtained from all-atom molecular dynamics simulations. We find that the profiles differ qualitatively in the first lipid shell around the channels, indicating that the CEMs do not capture accurately the consequences of the protein-induced local changes in lipid bilayer dynamics. Therefore, one needs to be careful when interpreting the results of CEM-based analyses of lipid bilayer-membrane protein interactions. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Lee, Kyu Ii; Im, Wonpil] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66047 USA. [Lee, Kyu Ii; Im, Wonpil] Univ Kansas, Ctr Bioinformat, Lawrence, KS 66047 USA. [Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Andersen, Olaf S.] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. RP Andersen, OS (reprint author), Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. EM sparre@med.cornell.edu; wonpil@ku.edu FU NSF [MCB-0918374, MCB-1157677]; TeraGrid/XSEDE resources [TG-MCB070009]; NIH [GM021342]; NIH, National Heart, Lung, and Blood Institute FX The authors are grateful to Huan Rui and Taehoon Kim for helpful discussion and analysis of the MD simulation results. This work was supported in part by NSF MCB-0918374, NSF MCB-1157677, TeraGrid/XSEDE resources (TG-MCB070009) (W.I.), NIH GM021342 (OSA), and the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute (R.W.P.). NR 49 TC 9 Z9 9 U1 1 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD APR PY 2013 VL 169 SI SI BP 19 EP 26 DI 10.1016/j.chemphyslip.2013.01.005 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 149HY UT WOS:000319310800004 PM 23348553 ER PT J AU Olsen, CM Nagle, CM Whiteman, DC Ness, R Pearce, CL Pike, MC Rossing, MA Terry, KL Wu, AH Risch, HA Yu, H Doherty, JA Chang-Claude, J Hein, R Nickels, S Wang-Gohrke, S Goodman, MT Carney, ME Matsuno, RK Lurie, G Moysich, K Kjaer, SK Jensen, A Hogdall, E Goode, EL Fridley, BL Vierkant, RA Larson, MC Schildkraut, J Hoyo, C Moorman, P Weber, RP Cramer, DW Vitonis, AF Bandera, EV Olson, SH Rodriguez-Rodriguez, L King, M Brinton, LA Yang, HN Garcia-Closas, M Lissowska, J Anton-Culver, H Ziogas, A Gayther, SA Ramus, SJ Menon, U Gentry-Maharaj, A Webb, PM AF Olsen, Catherine M. Nagle, Christina M. Whiteman, David C. Ness, Roberta Pearce, Celeste Leigh Pike, Malcolm C. Rossing, Mary Anne Terry, Kathryn L. Wu, Anna H. Risch, Harvey A. Yu, Herbert Doherty, Jennifer A. Chang-Claude, Jenny Hein, Rebecca Nickels, Stefan Wang-Gohrke, Shan Goodman, Marc T. Carney, Michael E. Matsuno, Rayna K. Lurie, Galina Moysich, Kirsten Kjaer, Susanne K. Jensen, Allan Hogdall, Estrid Goode, Ellen L. Fridley, Brooke L. Vierkant, Robert A. Larson, Melissa C. Schildkraut, Joellen Hoyo, Cathrine Moorman, Patricia Weber, Rachel P. Cramer, Daniel W. Vitonis, Allison F. Bandera, Elisa V. Olson, Sara H. Rodriguez-Rodriguez, Lorna King, Melony Brinton, Louise A. Yang, Hannah Garcia-Closas, Montserrat Lissowska, Jolanta Anton-Culver, Hoda Ziogas, Argyrios Gayther, Simon A. Ramus, Susan J. Menon, Usha Gentry-Maharaj, Aleksandra Webb, Penelope M. CA Australian Canc Study Ovarian Canc Australian Ovarian Canc Study Grp Ovarian Canc Assoc Consortium TI Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium SO ENDOCRINE-RELATED CANCER LA English DT Article DE ovarian cancer; obesity; BMI ID BODY-MASS INDEX; SELF-REPORTED WEIGHT; HORMONE-THERAPY; SEX-HORMONES; WOMEN; TUMORS; CLASSIFICATION; METAANALYSIS; HEIGHT; PREMENOPAUSAL AB Whilst previous studies have reported that higher BMI increases a woman's risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13 548 cases and 17 913 controls). We combined study-specific adjusted odds ratios (ORs) using a random-effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5 kg/m(2); 95% CI 1.18-1.30), invasive endometrioid (1.17; 1.11-1.23) and invasive mucinous (1.19; 1.06-1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94-1.02), but increased risks for low-grade serous invasive tumours (1.13, 1.03-1.25) and in pre-menopausal women (1.11; 1.04-1.18). Among post-menopausal women, the associations did not differ between hormone replacement therapy users and non-users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high-grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease. C1 [Olsen, Catherine M.; Nagle, Christina M.; Whiteman, David C.; Webb, Penelope M.; Australian Canc Study Ovarian Canc] Royal Brisbane Hosp, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Ness, Roberta] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Pearce, Celeste Leigh; Pike, Malcolm C.; Wu, Anna H.; Gayther, Simon A.; Ramus, Susan J.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Pike, Malcolm C.; Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Rossing, Mary Anne; Doherty, Jennifer A.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Terry, Kathryn L.; Cramer, Daniel W.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Australian Ovarian Canc Study Grp] Peter MacCallum Canc Ctr, East Melbourne, Vic, Australia. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, New Haven, CT 06510 USA. [Yu, Herbert; Matsuno, Rayna K.; Lurie, Galina] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynecol, D-89075 Ulm, Germany. [Goodman, Marc T.] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Carney, Michael E.] Univ Hawaii, John A Burns Sch Med, Dept Obstet & Gynecol, Honolulu, HI 96822 USA. [Moysich, Kirsten] Roswell Pk Canc Ctr, Buffalo, NY USA. [Kjaer, Susanne K.; Jensen, Allan; Hogdall, Estrid] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Kjaer, Susanne K.] Univ Copenhagen, Rigshosp, Juliane Marie Ctr, Gynecol Clin, DK-2100 Copenhagen, Denmark. [Goode, Ellen L.; Fridley, Brooke L.; Vierkant, Robert A.; Larson, Melissa C.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Schildkraut, Joellen; Hoyo, Cathrine; Moorman, Patricia; Weber, Rachel P.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Bandera, Elisa V.; Rodriguez-Rodriguez, Lorna] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [King, Melony] Univ Med & Dent New Jersey, Sch Publ Hlth, Piscataway, NJ 08854 USA. [Brinton, Louise A.; Yang, Hannah] NCI, Rockville, MD USA. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Lissowska, Jolanta] M Sklodowska Curie Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Menon, Usha; Gentry-Maharaj, Aleksandra] UCL, EGA Inst Womens Hlth, Dept Gynaecol Oncol, London WC1E 6BT, England. RP Olsen, CM (reprint author), Royal Brisbane Hosp, Queensland Inst Med Res, Locked Bag 2000, Brisbane, Qld 4029, Australia. EM catherine.olsen@qimr.edu.au RI friedlander, michael/G-3490-2013; Bandera, Elisa/M-4169-2014; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Nicklin, James/F-8035-2013; Olsen, Catherine/C-8785-2009; Bowtell, David/H-1007-2016; Whiteman, David/P-2728-2014; Wyld, David/B-8893-2015; OI Webb, Penelope/0000-0003-0733-5930; Lissowska, Jolanta/0000-0003-2695-5799; friedlander, michael/0000-0002-6488-0604; Bandera, Elisa/0000-0002-8789-2755; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Nicklin, James/0000-0001-5378-496X; Olsen, Catherine/0000-0003-4483-1888; Bowtell, David/0000-0001-9089-7525; Whiteman, David/0000-0003-2563-9559; Wyld, David/0000-0001-9523-4333; Ramus, Susan/0000-0003-0005-7798; Kjaer, Susanne/0000-0002-8347-1398 FU National Institutes of Health [R01 CA13689101A1, CA14089, CA17054, CA61132, CA63464]; California Cancer Research Program [0001389V20170, 2110200]; California Department of Health Services [050E8709]; Lon V Smith Foundation [LVS39420]; German Federal Ministry of Education and Research of Germany; Programme of Clinical Biomedical Research [01GB9401]; German Cancer Research Center; University of Ulm; Eve Appeal; Oak Foundation; University College Hospital; National Institute for Health Research Biomedical Research Centre; Royal Marsden Hospital; Biomedical Research Centre; National Health and Medical Research Council of Australia [199600]; US Army Medical Research and Materiel Command [DAMD 170110729, W81XWH0610220]; Cancer Council Tasmania; Cancer Foundation of Western Australia; US Department of Defence [W81XWH-10-1-0280]; Cancer Institute of New Jersey; Mermaid 1 and the Danish Cancer Society; Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA; Natl Inst of Hlth [N01 PC67010, R03 CA113148, R01 CA112523, R01 CA87538, R01 CA58598, N01 CN67001, N01 PC35137, 5R01 CA074850, 5R01 CA080742, R01 CA76016, R01-CA-122443, CA054419-10, P40 CA1005009, K07 CA095666, R01 CA83918, K22 CA138563 CA58860, CA58860, CA92044, RO1 CA61107] FX This work was supported by donations by the family and friends of Kathryn Sladek Smith to the Ovarian Cancer Research Fund. The studies that contributed to this analysis were funded by the National Institutes of Health (grant numbers R01 CA13689101A1, CA14089, CA17054, CA61132, CA63464, N01 PC67010 and R03 CA113148 (for USC), R01 CA112523 and R01 CA87538 (for DOV), R01 CA58598, N01 CN67001 and N01 PC35137 (for HAW), 5R01 CA074850 and 5R01 CA080742 (for CON), R01 CA76016 (for NCO), R01-CA-122443 (for MAY), CA054419-10, P40 CA1005009 (for NEC), K07 CA095666, R01 CA83918 and K22 CA138563 CA58860 (for NJO), CA58860, CA92044 (for UCI) and RO1 CA61107 (for MAL); the California Cancer Research Program (grant numbers 0001389V20170 and 2110200 (for USC)); the California Department of Health Services (subcontract 050E8709 (for USC)); the UCIBCS component of this research (UCI) was supported by the National Institutes of Health (grant numbers CA58860, CA92044) and the Lon V Smith Foundation (grant number LVS39420); the German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research (grant number 01GB9401), German Cancer Research Center and University of Ulm (for GER); the Eve Appeal, Oak Foundation, the University College Hospital, National Institute for Health Research Biomedical Research Centre and the Royal Marsden Hospital, Biomedical Research Centre (for UKO); the National Health and Medical Research Council of Australia (grant number 199600), US Army Medical Research and Materiel Command (grant numbers DAMD 170110729 and W81XWH0610220), Cancer Council Tasmania and Cancer Foundation of Western Australia (for AUS); the US Department of Defence (grant number W81XWH-10-1-0280 (for NEC)); the Cancer Institute of New Jersey (for NJO); Mermaid 1 and the Danish Cancer Society (for MAL); Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA (for POL). NR 45 TC 47 Z9 48 U1 0 U2 18 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD APR PY 2013 VL 20 IS 2 BP 251 EP 262 DI 10.1530/ERC-12-0395 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 152TS UT WOS:000319554600013 PM 23404857 ER PT J AU David, CN Rapoport, JL Gogtay, N AF David, Christopher N. Rapoport, Judith L. Gogtay, Nitin TI Treatments in context: transcranial direct current brain stimulation as a potential treatment in pediatric psychosis SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Review DE childhood-onset schizophrenia; pediatric psychosis treatment; transcranial direct current stimulation ID CHILDHOOD-ONSET SCHIZOPHRENIA; HUMAN MOTOR CORTEX; DORSOLATERAL PREFRONTAL CORTEX; CORTICAL SPREADING DEPRESSION; RANDOM NOISE STIMULATION; DOUBLE-BLIND; ELECTRICAL-STIMULATION; MAGNETIC STIMULATION; ANODAL POLARIZATION; PARKINSONS-DISEASE AB Childhood-onset schizophrenia is a chronic, severe form of schizophrenia, and is typically treatment resistant. Even after optimized pharmacotherapy, a majority (over 70%) of these pediatric patients present lasting psychotic symptoms and impaired cognition, necessitating the need for novel treatment modalities. Recent work in transcranial magnetic stimulation suggests moderate efficacy in symptom reduction in adult patients with schizophrenia; however, the transcranial magnetic stimulation treatment is cumbersome for this severely ill population. Transcranial direct current stimulation may provide a safe and effective adjuvant treatment for continued residual symptoms of schizophrenia. C1 [David, Christopher N.; Rapoport, Judith L.; Gogtay, Nitin] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20890 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 3N202,10 Ctr Dr, Bethesda, MD 20890 USA. EM gogtayn@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 FU Intramural NIH HHS [ZIA MH002581-22] NR 114 TC 4 Z9 4 U1 0 U2 5 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD APR PY 2013 VL 13 IS 4 BP 447 EP 458 DI 10.1586/ERN.13.29 PG 12 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 153ZZ UT WOS:000319642600015 PM 23545058 ER PT J AU Beller, EM Glasziou, PP Altman, DG Hopewell, S Bastian, H Chalmers, I Gotzsche, PC Lasserson, T Tovey, D AF Beller, Elaine M. Glasziou, Paul P. Altman, Douglas G. Hopewell, Sally Bastian, Hilda Chalmers, Iain Gotzsche, Peter C. Lasserson, Toby Tovey, David CA Prisma Abstracts Grp TI PRISMA for Abstracts: Reporting Systematic Reviews in Journal and Conference Abstracts SO PLOS MEDICINE LA English DT Review ID RANDOMIZED-TRIALS; INFORMATIVE ABSTRACTS; METAANALYSES; CONCLUSIONS; ARTICLES; QUALITY C1 [Beller, Elaine M.; Glasziou, Paul P.] Bond Univ, Ctr Res Evidence Based Practice, Gold Coast, Australia. [Altman, Douglas G.; Hopewell, Sally] Univ Oxford, Ctr Stat Med, Oxford, England. [Bastian, Hilda] Natl Lib Med, Natl Ctr Biotechnol Informat, Washington, DC USA. [Chalmers, Iain] James Lind Initiat, Oxford, England. [Gotzsche, Peter C.] Nordic Cochrane Ctr, Copenhagen, Denmark. [Lasserson, Toby; Tovey, David] Cochrane Editorial Unit, London, England. [Hopewell, Sally] INSERM, Paris, France. RP Beller, EM (reprint author), Bond Univ, Ctr Res Evidence Based Practice, Gold Coast, Australia. EM ebeller@bond.edu.au RI Glasziou, Paul/A-7832-2008; Beller, Elaine/E-1615-2013; OI Glasziou, Paul/0000-0001-7564-073X; Beller, Elaine/0000-0002-3241-2611; Bastian, Hilda/0000-0001-8544-7386 NR 33 TC 58 Z9 59 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD APR PY 2013 VL 10 IS 4 AR UNSP e1001419 DI 10.1371/journal.pmed.1001419 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 154JA UT WOS:000319669600006 PM 23585737 ER PT J AU Collins, PY Insel, TR Chockalingam, A Daar, A Maddox, YT AF Collins, Pamela Y. Insel, Thomas R. Chockalingam, Arun Daar, Abdallah Maddox, Yvonne T. TI Grand Challenges in Global Mental Health: Integration in Research, Policy, and Practice SO PLOS MEDICINE LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; LOW-INCOME; DEPRESSIVE SYMPTOMS; SYSTEMATIC ANALYSIS; PRIMARY-CARE; DISEASE; DISORDERS; WOMEN; COUNTRIES; INTERVENTION C1 [Collins, Pamela Y.; Insel, Thomas R.] NIMH, Off Director, NIH, Bethesda, MD 20892 USA. [Chockalingam, Arun] Simon Fraser Univ, World Hypertens League, Vancouver, BC, Canada. [Chockalingam, Arun] Simon Fraser Univ, Fac Hlth Sci, Vancouver, BC, Canada. [Daar, Abdallah] Univ Toronto, Grand Challenges Canada, Toronto, ON, Canada. [Daar, Abdallah] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Daar, Abdallah] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Daar, Abdallah] Univ Stellenbosch, Wallenberg Res Ctr, Stellenbosch Inst Adv Study STIAS, ZA-7600 Stellenbosch, South Africa. [Maddox, Yvonne T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Off Director, NIH, Bethesda, MD USA. RP Collins, PY (reprint author), NIMH, Off Director, NIH, Bethesda, MD 20892 USA. EM Pamela.Collins@nih.gov NR 54 TC 52 Z9 53 U1 8 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD APR PY 2013 VL 10 IS 4 AR UNSP e1001434 DI 10.1371/journal.pmed PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 154JA UT WOS:000319669600016 PM 23637578 ER PT J AU Laptook, AR McDonald, SA Shankaran, S Stephens, BE Vohr, BR Guillet, R Higgins, RD Das, A AF Laptook, Abbot R. McDonald, Scott A. Shankaran, Seetha Stephens, Bonnie E. Vohr, Betty R. Guillet, Ronnie Higgins, Rosemary D. Das, Abhik CA Natl Inst Child Hlth & Human Dev N TI Elevated temperature and 6- to 7-year outcome of neonatal encephalopathy SO ANNALS OF NEUROLOGY LA English DT Article ID HYPOXIC-ISCHEMIC ENCEPHALOPATHY; NORMAL BIRTH-WEIGHT; CEREBRAL-PALSY; BRAIN-DAMAGE; MODERATE HYPOTHERMIA; INTRAPARTUM FEVER; NEURONAL DAMAGE; TERM INFANTS; RISK-FACTOR; RAT-BRAIN AB Objective A study was undertaken to determine whether higher temperature after hypoxia-ischemia is associated with death or intelligence quotient (IQ)<70 at 6 to 7 years among infants treated with intensive care without hypothermia. Methods Control infants (noncooled, n=106) of the National Institute of Child Health and Human Development Neonatal Research Network hypothermia trial had serial esophageal and skin temperatures over 72 hours. Each infant's temperature was ranked to derive an average of the upper and lower quartile, and median of each site. Temperatures were used in logistic regressions to determine adjusted associations with death or IQ<70 at 6 to 7 years. Secondary outcomes were death, IQ<70, and moderate/severe cerebral palsy (CP). IQ and motor function were assessed with Wechsler Scales for Children and Gross Motor Function Classification System. Results are odds ratio (OR; per degree Celsius increment within the quartile or median) and 95% confidence interval (CI). Results Primary outcome was available for 89 infants. At 6 to 7 years, death or IQ<70 occurred in 54 infants (37 deaths, 17 survivors with IQ<70) and moderate/severe CP in 15 infants. Death or IQ<70 was associated with the upper quartile average of esophageal (OR=7.3, 95% CI=2.0-26.3) and skin temperature (OR=3.5, 95% CI=1.2-10.4). CP was associated with the upper quartile average of esophageal (OR=12.5, 95% CI=1.02-155) and skin temperature (OR=10.3, 95% CI=1.3-80.2). Interpretation Among noncooled infants of a randomized trial, elevated temperatures during the first postnatal days are associated with increased odds of a worse outcome at 6 to 7 years. Ann Neurol 2013;73:520-528 C1 [Laptook, Abbot R.; Stephens, Bonnie E.; Vohr, Betty R.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Laptook, Abbot R.; Stephens, Bonnie E.; Vohr, Betty R.] Women & Infants Hosp Rhode Isl, Providence, RI 02905 USA. [McDonald, Scott A.; Das, Abhik] RTI Int, Durham, NC USA. [Shankaran, Seetha] Wayne State Univ, Detroit, MI USA. [Guillet, Ronnie] Univ Rochester, Rochester, NY USA. [Higgins, Rosemary D.] NICHHD, NIH, Rockville, MD USA. RP Laptook, AR (reprint author), Women & Infants Hosp Rhode Isl, 101 Dudley St, Providence, RI 02905 USA. EM alaptook@wihri.org FU NIH Eunice Kennedy Shriver NICHD; NIH; Gerber Foundation; FDA; Environmental Protection Agency (Lanphear); Pfizer FX The NIH Eunice Kennedy Shriver NICHD provided grant support for the NRN's whole-body hypothermia trial and its 6-7-year school-age follow-up.; R.G.: grants/grants pending, NIH, Gerber Foundation, FDA. Among the other investigating participants, Dr C. Michael Cotten reports having served on the data and safety monitoring board for the Inhibitex phase 3 study of Vernonate for the prevention of infections in preterm infants; Dr Edward F. Donovan reports having received support from the Environmental Protection Agency (Lanphear) and Gerber Foundation; Dr Waldemar A. Carlo reports having served on the advisory board of Pediatrix Medical Group and ParadigmHealth and holding stock options at the Pediatrix Medical Group; and Dr David K. Stevenson reports having received research support from Pfizer. NR 33 TC 15 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2013 VL 73 IS 4 BP 520 EP 528 DI 10.1002/ana.23843 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 152HY UT WOS:000319523800013 PM 23595408 ER PT J AU Grimley, M Papanicolaou, G Prasad, V Dropulic, L Mommeja-Marin, H Brundage, T Chittick, G Margolskee, D AF Grimley, M. Papanicolaou, G. Prasad, V. Dropulic, L. Mommeja-Marin, H. Brundage, T. Chittick, G. Margolskee, D. TI CMX001 is a potential treatment for Adenovirus infection: preliminary antiviral activity results from an open-label, expanded access study of CMX001 for the treatment of serious or life-threatening diseases caused by double-stranded DNA viruses SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT) CY APR 07-10, 2013 CL London, ENGLAND SP European Grp Blood & Marrow Transplantat (EBMT) C1 [Grimley, M.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Papanicolaou, G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Prasad, V.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Dropulic, L.] NIH, Med Ctr, Bethesda, MD 20892 USA. [Mommeja-Marin, H.; Brundage, T.; Chittick, G.; Margolskee, D.] Chimerix Inc, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 SU 2 BP S56 EP S57 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 145OB UT WOS:000319025200124 ER PT J AU Kokkinou, D Traintafyllou, E Liga, M Barrett, A Spyridonidis, A AF Kokkinou, D. Traintafyllou, E. Liga, M. Barrett, A. Spyridonidis, A. TI Primed T-cells with low dose of human recombinant interleukin-2 (hrIL2) display reduced alloproliferative capacity in vitro SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT) CY APR 07-10, 2013 CL London, ENGLAND SP European Grp Blood & Marrow Transplantat (EBMT) C1 [Kokkinou, D.; Traintafyllou, E.; Liga, M.; Spyridonidis, A.] Univ Hosp Patras, Rion, Greece. [Barrett, A.] NIH, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 SU 2 BP S161 EP S162 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 145OB UT WOS:000319025200351 ER PT J AU Muraro, P Pasquini, M Atkins, H Bowen, J Farge, D Fassas, A Freedman, M Georges, G Hamerschlak, N Havdrova, E Kozak, T Mancardi, GL Morais, D Nash, R Pavletic, S Ouyang, J Saiz, A Badoglio, M Zhong, X Sormani, MP Saccardi, R AF Muraro, P. Pasquini, M. Atkins, H. Bowen, J. Farge, D. Fassas, A. Freedman, M. Georges, G. Hamerschlak, N. Havdrova, E. Kozak, T. Mancardi, G. Luigi Morais, D. Nash, R. Pavletic, S. Ouyang, J. Saiz, A. Badoglio, M. Zhong, X. Sormani, M. Pia Saccardi, R. TI Long-term outcomes after autologous haematopoietic cell transplantation for multiple sclerosis: a joint study from the Center for International Blood and Marrow Research (CIBMTR) and the European Group for Blood and Marrow Transplantat SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT) CY APR 07-10, 2013 CL London, ENGLAND SP European Grp Blood & Marrow Transplantat (EBMT) C1 [Muraro, P.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [Pasquini, M.; Zhong, X.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Atkins, H.; Freedman, M.] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Bowen, J.] Swedish Neurosci Inst, Seattle, WA USA. [Farge, D.] Hop St Louis, Paris, France. [Fassas, A.] George Papanicolaou Genberal Hosp, Thessaloniki, Greece. [Georges, G.; Nash, R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hamerschlak, N.] Albert Einstein Hosp, Sao Paulo, Brazil. [Havdrova, E.; Kozak, T.] Charles Univ Prague, Gen Univ Hosp, Prague, Czech Republic. [Mancardi, G. Luigi; Sormani, M. Pia] Univ Genoa, Genoa, Italy. [Morais, D.] Fac Med Ribeirao Preto, Ribeirao Preto, Brazil. [Pavletic, S.] NIH, Bethesda, MD 20892 USA. [Ouyang, J.] Hosp Nanjing, Nanjing, Jiangsu, Peoples R China. [Saiz, A.] Hosp Clin Barcelona, Barcelona, Spain. [Badoglio, M.] European Grp Blood & Marrow Transplantat, Paris, France. [Saccardi, R.] Univ Florence, Osped Careggi, Florence, Italy. RI Kozak, Tomas/K-3561-2012; Saiz, Albert/K-8236-2014; Hamerschlak, Nelson/M-8060-2015 OI Saiz, Albert/0000-0002-5793-8791; Hamerschlak, Nelson/0000-0002-5140-5310 NR 0 TC 2 Z9 2 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 SU 2 BP S1 EP S1 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 145OB UT WOS:000319025200002 ER PT J AU Spyridonidis, A Muranski, P Kerkar, S Tanimoto, K Hensel, N Melenhorst, I Barrett, A AF Spyridonidis, A. Muranski, P. Kerkar, S. Tanimoto, K. Hensel, N. Melenhorst, I. Barrett, A. TI Rapid generation of quadrivirus-specific CD8+and CD4+cytotoxic T-lymphocytes (CTLs) for adoptive transfer after stem cell transplantation (SCT) SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 39th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantation (EBMT) CY APR 07-10, 2013 CL London, ENGLAND SP European Grp Blood & Marrow Transplantat (EBMT) C1 [Spyridonidis, A.; Muranski, P.; Kerkar, S.; Tanimoto, K.; Hensel, N.; Melenhorst, I.; Barrett, A.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 SU 2 BP S181 EP S181 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 145OB UT WOS:000319025200396 ER PT J AU Olson, D Gulley, ML Tang, W Wokocha, C Mechanic, O Hosseinipour, M Gold, SH Nguluwe, N Mwansambo, C Shores, C AF Olson, Daniel Gulley, Margaret L. Tang, Weihua Wokocha, Clifford Mechanic, Oren Hosseinipour, Mina Gold, Stuart H. Nguluwe, Nelson Mwansambo, Charles Shores, Carol TI Phase I Clinical Trial of Valacyclovir and Standard of Care Cyclophosphamide in Children With Endemic Burkitt Lymphoma in Malawi SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article DE Burkitt lymphoma; Endemic; Epstein-Barr virus; Valacyclovir ID EPSTEIN-BARR-VIRUS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; ADVANCED NASOPHARYNGEAL CARCINOMA; SOLID-ORGAN TRANSPLANTATION; B-CELL LYMPHOMAS; EBV INFECTION; TUMOR BURDEN; CANCER; PLASMA; DNA AB Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken. Background: Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted. Patients and Methods: Children 3-15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome. Results: We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course. Conclusions: We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral loads that decreased over the course of their treatment, suggesting that phase II studies should investigate this correlation further. This study paves the way for a phase II efficacy trial of combined valacyclovir and CPM in the treatment of endemic Burkitt lymphoma. (C) 2013 Elsevier Inc. All rights reserved. C1 [Olson, Daniel; Hosseinipour, Mina; Nguluwe, Nelson] Univ North Carolina Project, Lilongwe, Malawi. [Olson, Daniel] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gulley, Margaret L.; Tang, Weihua] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Gulley, Margaret L.; Tang, Weihua; Gold, Stuart H.; Shores, Carol] UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Wokocha, Clifford; Mwansambo, Charles] Kamuzu Cent Hosp, Dept Pediat, Lilongwe, Malawi. [Mechanic, Oren] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Hosseinipour, Mina] Univ N Carolina, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Gold, Stuart H.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC USA. [Shores, Carol] Univ N Carolina, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. RP Olson, D (reprint author), Univ Colorado Denver, Dept Infect Dis, 13123 E 16th Ave,Box 055, Aurora, CO 80045 USA. EM daniel.olson@childrenscolorado.org FU National Institutes of Health Office of the director; Fogarty International Center; Office of AIDS Research; National Cancer Centre; National Eye Institute; National Heart, Blood and Lung Institute; National Institute of Dental; Craniofacial Research; National Institute on Drug Abuse; National Institute of Mental Health; National Institute of Allergy and Infectious Diseases; National Institutes of Health Office of Women's Health and Research through the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; American Relief and Recovery Act FX This work was supported by the National Institutes of Health Office of the director, Fogarty International Center, Office of AIDS Research, National Cancer Centre, National Eye Institute, National Heart, Blood and Lung Institute, National Institute of Dental and Craniofacial Research, National Institute on Drug Abuse, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, and National Institutes of Health Office of Women's Health and Research through the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988), and the American Relief and Recovery Act. NR 51 TC 1 Z9 1 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD APR PY 2013 VL 13 IS 2 BP 112 EP 118 DI 10.1016/j.clml.2012.11.003 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 148MJ UT WOS:000319248400003 PM 23260601 ER PT J AU Kristinsson, SY Bjorkholm, M Landgren, O AF Kristinsson, Sigurdur Y. Bjorkholm, Magnus Landgren, Ola TI Survival in Monoclonal Gammopathy of Undetermined Significance and Waldenstrom Macroglobulinemia SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article; Proceedings Paper CT 7th International Workshop on Waldenstrom's Macroglobulinemia (IWWM) CY AUG 23-26, 2012 CL Newport, RI DE Bortezomib; Fludarabine; Lymphoplasmacytic lymphoma survival; MGUS; Prognosis; Rituximab; Thalidomide; Treatment; Waldenstrom macroglobulinemia ID TERM-FOLLOW-UP; LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA; PROGNOSTIC-FACTORS; LONG-TERM; SCORING SYSTEM; PATTERNS; SWEDEN; PROGRESSION; FEATURES; UPDATE AB Monoclonal gammopathy of undetermined significance (MGUS) of IgM type is the strongest risk factor for the development of Waldenstrom macroglobulinemia (WM). The clinical management of WM has changed considerably over recent years, which is reflected in the use of new therapeutic agents (eg, purine analogues, monoclonal antibodies, and thalidomide- and bortezomib-based therapies), risk- and-response-adjusted stratification of treatments, and improvement in supportive care measures. However, because of the rarity of WM, there are few phase III randomized clinical studies to guide therapy and evaluate overall survival. In this review, we discuss the current knowledge on prognosis, survival patterns, and causes of death in individuals with MGUS. In addition, we discuss clinical studies as well as recent population-based studies on WM, with a focus on treatment, prognostic factors, and survival. Finally, new agents and future perspectives in these disorders are reviewed. C1 [Kristinsson, Sigurdur Y.; Bjorkholm, Magnus; Landgren, Ola] Karolinska Inst, Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden. [Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kristinsson, Sigurdur Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. [Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Kristinsson, SY (reprint author), Karolinska Univ Hosp, Dept Med, Div Haematol, SE-17176 Stockholm, Sweden. EM sigurdur.kristinsson@ki.se RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 NR 27 TC 3 Z9 3 U1 0 U2 3 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD APR PY 2013 VL 13 IS 2 BP 187 EP 190 DI 10.1016/j.clml.2013.02.010 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 148MJ UT WOS:000319248400017 PM 23490991 ER PT J AU Manasanch, EE Kristinsson, SY Landgren, O AF Manasanch, Elisabet E. Kristinsson, Sigurdur Y. Landgren, Ola TI Etiology of Waldenstrom Macroglobulinemia: Genetic Factors and Immune-related Conditions SO CLINICAL LYMPHOMA MYELOMA & LEUKEMIA LA English DT Article; Proceedings Paper CT 7th International Workshop on Waldenstrom's Macroglobulinemia (IWWM) CY AUG 23-26, 2012 CL Newport, RI DE Autoimmune disease; Familial aggregation; Immune-related; MYD88 L265P; Susceptibility ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKIN-LYMPHOMA; LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA; IGM MONOCLONAL GAMMOPATHY; FAMILIAL AGGREGATION; UNDETERMINED SIGNIFICANCE; SOMATIC MUTATION; RISK; PATTERNS; CELL AB Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, which indicates that repetitive immune stimulation and genetic factors play an important role. Here, the current understanding on the causes of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia are reviewed. Recent studies of the literature are discussed, and future population-based studies are proposed to further elucidate the molecular mechanisms that underlie these associations. Finally, the clinical implications of these data are outlined, and perspectives on clinical follow-up and counseling are provided. C1 [Manasanch, Elisabet E.; Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Kristinsson, Sigurdur Y.] Karolinska Inst, Div Hematol, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden. [Kristinsson, Sigurdur Y.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Kristinsson, Sigurdur Y.] Landspitali Natl Univ Hosp, Dept Hematol, Reykjavik, Iceland. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Intramural NIH HHS NR 33 TC 1 Z9 1 U1 0 U2 5 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 2152-2650 J9 CL LYMPH MYELOM LEUK JI Clin. Lymphoma Myeloma Leuk. PD APR PY 2013 VL 13 IS 2 BP 194 EP 197 DI 10.1016/j.clml.2013.02.002 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 148MJ UT WOS:000319248400019 PM 23473950 ER PT J AU Liu, JF Subramanian, KR Yoo, TS AF Liu, Jianfei Subramanian, Kalpathi R. Yoo, Terry S. TI An optical flow approach to tracking colonoscopy video SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article DE Colonoscopy; Tracking; Optical flow; Egomotion ID IMAGE REGISTRATION; CT COLONOGRAPHY; COLORECTAL-CANCER; MOTION; COMPUTATION; SCALE; REAL; DEFORMATIONS; BRONCHOSCOPY; SIMULATION AB We can supplement the clinical value of an optical colonoscopy procedure if we can continuously coalign corresponding virtual colonoscopy (from preoperative X-ray CT exam) and optical colonoscopy images. In this work, we demonstrate a computer vision algorithm based on optical flow to compute egomotion from live colonoscopy video, which is then used to navigate and visualize the corresponding patient anatomy from X-ray CT data. The key feature of the algorithm lies in the effective combination of sparse and dense optical flow fields to compute the focus of expansion (FOE); FOE permits independent computation of camera translational and rotational parameters, directly contributing to the algorithm's accuracy and robustness. We performed extensive evaluation via a colon phantom and clinical colonoscopy data. We constructed two colon like phantoms, a straight phantom and a curved phantom to measure actual colonoscopy motion; tracking accuracy was quantitatively evaluated by comparing estimated motion parameters (velocity and displacement) to ground truth. Thirty straight and curved phantom sequences were collected at 10, 15 and 20 mm/s (5 trials at each speed), to simulate typical velocities during colonoscopy procedures. The average error in velocity estimation was within 3 mm/s in both straight and curved phantoms. Displacement error was under 7 mm over a total distance of 287-288 mm in the straight and curved phantoms. Algorithm robustness was successfully demonstrated on 27 optical colonoscopy image sequences from 20 different patients, and spanning 5 different colon segments. Specific sequences among these were chosen to illustrate the algorithm's decreased sensitivity to (1) recording interruptions, (2) errors in colon segmentation, (3) illumination artifacts, (4) presence of fluid, and (5) changes in colon structure, such as deformation, polyp removal, and surgical tool movement during a procedure. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Liu, Jianfei] NIH, Imaging Biomarkers & Comp Aided Diag Lab, Ctr Clin, Bethesda, MD 20892 USA. [Subramanian, Kalpathi R.] Univ N Carolina, Dept Comp Sci, Charlotte, NC 28223 USA. [Yoo, Terry S.] NIH, Off High Performance Comp & Commun, Natl Lib Med, Bethesda, MD 20894 USA. RP Subramanian, KR (reprint author), Univ N Carolina, Dept Comp Sci, Charlotte, NC 28223 USA. EM jianfei.liu@nih.gov; krs@uncc.edu; yoo@nlm.nih.gov NR 64 TC 7 Z9 7 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 EI 1879-0771 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD APR PY 2013 VL 37 IS 3 BP 207 EP 223 DI 10.1016/j.compmedimag.2013.01.010 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 152RT UT WOS:000319549500003 PM 23490235 ER PT J AU Holmes, EC AF Holmes, Edward C. TI What can we predict about viral evolution and emergence? SO CURRENT OPINION IN VIROLOGY LA English DT Article ID METAGENOMIC ANALYSIS; INFECTIOUS-DISEASES; EMERGING PATHOGENS; RABIES VIRUS; RNA VIRUSES; INFLUENZA-A; BATS; HOST; TRANSMISSION; BIODIVERSITY AB Predicting the emergence of infectious diseases has been touted as one of the most important goals of biomedical science, with an array of funding schemes and research projects. However, evolutionary biology generally has a dim view of prediction, and there is a danger that erroneous predictions will mean a misuse of resources and undermine public confidence. Herein, I outline what can be realistically predicted about viral evolution and emergence, argue that any success in predicting what may emerge is likely to be limited, but that forecasting how viruses might evolve and spread following emergence is more tractable. I also emphasize that a properly grounded research program in disease prediction must involve a synthesis of ecological and genetic perspectives. C1 [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. EM edward.holmes@sydney.edu.au OI Holmes, Edward/0000-0001-9596-3552 FU NHMRC Australia; NIH/NIGMS [R01 GM080533-06] FX The author acknowledges financial support from an NHMRC Australia Fellowship and NIH/NIGMS grant R01 GM080533-06. NR 56 TC 15 Z9 15 U1 0 U2 37 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD APR PY 2013 VL 3 IS 2 BP 180 EP 184 DI 10.1016/j.coviro.2012.12.003 PG 5 WC Virology SC Virology GA 146ND UT WOS:000319096900012 PM 23273851 ER PT J AU Safronetz, D Geisbert, TW Feldmann, H AF Safronetz, David Geisbert, Thomas W. Feldmann, Heinz TI Animal models for highly pathogenic emerging viruses SO CURRENT OPINION IN VIROLOGY LA English DT Article ID SYRIAN-HAMSTER; FEVER AB Exotic and emerging viral pathogens associated with high morbidity and mortality in humans are being identified annually with recent examples including Lujo virus in southern Africa, Severe Fever with Thrombocytopenia Syndrome virus in China and a SARS-like coronavirus in the Middle East. The sporadic nature of these infections hampers our understanding of these diseases and limits the opportunities to design appropriate medical countermeasures against them. Because of this, animal models are utilized to gain insight into the pathogenesis of disease with the overall goal of identifying potential targets for intervention and evaluating specific therapeutics and vaccines. For these reasons it is imperative that animal models of disease recapitulate the human condition as closely as possible in order to provide the best predictive data with respect to the potential efficacy in humans. In this article we review the current status of disease models for highly pathogenic and emerging viral pathogens. C1 [Safronetz, David; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Galveston Natl Lab, Galveston, TX 77555 USA. [Geisbert, Thomas W.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Feldmann, H (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM feldmannh@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) FX Work on emerging viruses in the laboratories of the authors is supported by the Extramural and Intramural Programs of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). NR 12 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1879-6257 J9 CURR OPIN VIROL JI Curr. Opin. Virol. PD APR PY 2013 VL 3 IS 2 BP 205 EP 209 DI 10.1016/j.coviro.2013.01.001 PG 5 WC Virology SC Virology GA 146ND UT WOS:000319096900016 PM 23403208 ER PT J AU Voon, V Ekanayake, V Wiggs, E Kranick, S Ameli, R Harrison, NA Hallett, M AF Voon, Valerie Ekanayake, Vindhya Wiggs, Edythe Kranick, Sarah Ameli, Rezvan Harrison, Neil A. Hallett, Mark TI Response inhibition in motor conversion disorder SO MOVEMENT DISORDERS LA English DT Article DE conversion disorder; psychogenic movement disorder; response inhibition; IQ; cognition ID PSYCHOGENIC NONEPILEPTIC SEIZURES; INFERIOR FRONTAL GYRUS; MOVEMENT-DISORDERS; PARALYSIS; PSEUDOSEIZURES; PERFORMANCE; PSYCHOPATHOLOGY; ASSOCIATION; IMPAIRMENT; DEPRESSION AB Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P<.001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. (c) 2013 Movement Disorder Society C1 [Voon, Valerie] Univ Cambridge, Dept Psychiat, Cambridge, England. [Voon, Valerie] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England. [Voon, Valerie] Univ Cambridge, Cambridgeshire & Peterborough Fdn Trust, Cambridge, England. [Voon, Valerie; Wiggs, Edythe; Kranick, Sarah; Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. [Ekanayake, Vindhya] Purdue Univ, W Lafayette, IN 47907 USA. [Ameli, Rezvan] NIMH, NIH, Bethesda, MD 20892 USA. [Harrison, Neil A.] Univ Sussex, Brighton & Sussex Med Sch, Brighton, E Sussex, England. RP Voon, V (reprint author), Addenbrookes Hosp, Level E4,Box 189, Cambridge CB2 0QQ, England. EM voonval@gmail.com OI Harrison, Neil/0000-0002-9584-3769 FU Intramural National Institutes of Health FX This study was supported by the Intramural National Institutes of Health. NR 45 TC 7 Z9 7 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2013 VL 28 IS 5 BP 612 EP 618 DI 10.1002/mds.25435 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 144QG UT WOS:000318953900015 PM 23554084 ER PT J AU Kadhim, M Salomaa, S Wright, E Hildebrandt, G Belyakov, OV Prise, KM Little, MP AF Kadhim, Munira Salomaa, Sisko Wright, Eric Hildebrandt, Guido Belyakov, Oleg V. Prise, Kevin M. Little, Mark P. TI Non-targeted effects of ionising radiation-Implications for low dose risk SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Ionising radiation; Low dose; Non-targeted effects; Non-cancer disease; Health risk ID ATOMIC-BOMB SURVIVORS; INDUCED GENOMIC INSTABILITY; INDUCED CHROMOSOMAL INSTABILITY; INDUCED TRANSGENERATIONAL INSTABILITY; MINISATELLITE MUTATION-RATE; ALPHA-PARTICLE IRRADIATION; CHERNOBYL CLEANUP WORKERS; HEMATOPOIETIC STEM-CELLS; SOLID CANCER INCIDENCE; TUMOR-NECROSIS-FACTOR AB Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understandfng of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations. in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kadhim, Munira] Oxford Brookes Univ, Dept Biol & Med Sci, Oxford OX3 0BP, England. [Salomaa, Sisko] STUK Radiat & Nucl Safety Author, Helsinki 00881, Finland. [Wright, Eric] Univ Dundee, Sch Med, Coll Med Dent & Nursing, Dundee DD1 4HN, Scotland. [Hildebrandt, Guido] Univ Rostock, Dept Radiotherapy & Radiat Oncol, D-18051 Rostock, Germany. [Belyakov, Oleg V.] Tech Univ Denmark, Ctr Nucl Technol, Hevesy Lab, DK-4000 Roskilde, Denmark. [Prise, Kevin M.] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Little, Mark P.] NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. RP Kadhim, M (reprint author), Oxford Brookes Univ, Dept Biol & Med Sci, Oxford OX3 0BP, England. EM mkadhim@brookes.ac.uk RI Prise, Kevin/N-7872-2015; OI Prise, Kevin/0000-0001-6134-7946; Little, Mark/0000-0003-0980-7567 FU European Commission [FP6-036465]; National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was partially supported by the European Commission under the contract FP6-036465 (NOTE). This work was also supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, Division of Cancer Epidemiology and Genetics. The authors would like to thank Miss Kim Chapman, from Professor Kadhim's group, for formatting assistance. NR 227 TC 60 Z9 61 U1 1 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 EI 1388-2139 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD APR-JUN PY 2013 VL 752 IS 2 BP 84 EP 98 DI 10.1016/j.mrrev.2012.12.001 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 148LM UT WOS:000319246100003 PM 23262375 ER PT J AU Suhasini, AN Brosh, RM AF Suhasini, Avvaru N. Brosh, Robert M., Jr. TI Disease-causing missense mutations in human DNA helicase disorders SO MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH LA English DT Review DE Helicase; DNA repair; Replication; Human genetic disease; Genomic stability; Mutation ID BLOOMS-SYNDROME HELICASE; NUCLEOTIDE EXCISION-REPAIR; TOPOISOMERASE-III-ALPHA; ANEMIA GROUP J; SISTER-CHROMATID COHESION; ROTHMUND-THOMSON-SYNDROME; WERNER-SYNDROME HELICASE; WARSAW BREAKAGE SYNDROME; FANCONI-ANEMIA; XERODERMA-PIGMENTOSUM AB Helicases have important roles in nucleic acid metabolism, and their prominence is marked by the discovery of genetic disorders arising from disease-causing mutations. Missense mutations can yield unique insight to molecular functions and basis for disease pathology. XPB or XPD missense mutations lead to Xeroderma pigmentosum, Cockayne's syndrome, Trichothiodystrophy, or COFS syndrome, suggesting that DNA repair and transcription defects are responsible for clinical heterogeneity. Complex phenotypes are also observed for RECQL4 helicase mutations responsible for Rothmund-Thomson syndrome, Baller-Gerold syndrome, or RAPADILINO. Bloom's syndrome causing missense mutations are found in the conserved helicase and RecQ C-terminal domain of BLM that interfere with helicase function. Although rare, patient-derived missense mutations in the exonuclease or helicase domain of Werner syndrome protein exist. Characterization of WRN separation-of-function mutants may provide insight to catalytic requirements for suppression of phenotypes associated with the premature aging disorder. Characterized FANCJ missense mutations associated with breast cancer or Fanconi anemia interfere with FANCJ helicase activity required for DNA repair and the replication stress response. For example, a FA patient-derived mutation in the FANCJ Iron-Sulfur domain was shown to uncouple its ATPase and translocase activity from DNA unwinding. Mutations in DDX11 (ChlR1) are responsible for Warsaw Breakage syndrome, a recently discovered autosomal recessive cohesinopathy. Ongoing and future studies will address clinically relevant helicase mutations and polymorphisms, including those that interfere with key protein interactions or exert dominant negative phenotypes (e.g., certain mutant alleles of Twinkle mitochondrial DNA helicase). Chemical rescue may be an approach to restore helicase activity in loss-of-function helicase disorders. Genetic and biochemical analyses of disease-causing missense mutations in human helicase disorders have led to new insights to the molecular defects underlying aberrant cellular and clinical phenotypes. Published by Elsevier B.V. C1 [Suhasini, Avvaru N.; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, NIH Biomed Res Ctr, 251 Bayview Dr, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH, National Institute on Aging; Fanconi Anemia Research Fund FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the Fanconi Anemia Research Fund (RMB). We wish to thank Dr. Junko Oshima (University of Washington) for helpful discussion. NR 140 TC 19 Z9 19 U1 3 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5742 J9 MUTAT RES-REV MUTAT JI Mutat. Res.-Rev. Mutat. Res. PD APR-JUN PY 2013 VL 752 IS 2 BP 138 EP 152 DI 10.1016/j.mrrev.2012.12.004 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 148LM UT WOS:000319246100007 PM 23276657 ER PT J AU Balamurugan, K Sharan, S Klarmann, KD Zhang, Y Coppola, V Summers, GH Roger, T Morrison, DK Keller, JR Sterneck, E AF Balamurugan, Kuppusamy Sharan, Shikha Klarmann, Kimberly D. Zhang, Youhong Coppola, Vincenzo Summers, Glenn H. Roger, Thierry Morrison, Deborah K. Keller, Jonathan R. Sterneck, Esta TI FBXW7 alpha attenuates inflammatory signalling by downregulating C/EBP delta and its target gene Tlr4 SO NATURE COMMUNICATIONS LA English DT Article ID TOLL-LIKE RECEPTORS; CCAAT/ENHANCER-BINDING PROTEINS; HYPOXIA-INDUCIBLE FACTORS; UBIQUITIN LIGASE; TUMOR-CELLS; IMMUNE-SYSTEM; EXPRESSION; CANCER; MACROPHAGES; METASTASIS AB Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBP delta, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBP delta activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7 alpha (FBW7, Cdc4), whose gene expression is inhibited by C/EBP delta, targets C/EBP delta for degradation when C/EBP delta is phosphorylated by GSK-3 beta. Consequently, FBXW7 alpha suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7 alpha depletion alone is sufficient to augment pro-inflammatory signalling in vivo. Moreover, as inflammatory pathways are known to modulate tumour biology, Cebpd null mammary tumours, which have reduced metastatic potential, show altered expression of inflammation-associated genes. Together, these findings reveal a role for C/EBP delta upstream of Tlr4 signalling and uncover a function for FBXW7 alpha as an attenuator of inflammatory signalling. C1 [Balamurugan, Kuppusamy; Sharan, Shikha; Zhang, Youhong; Morrison, Deborah K.; Sterneck, Esta] Natl Canc Inst, Lab Cell & Dev Signalling, Frederick, MD 21702 USA. [Klarmann, Kimberly D.; Keller, Jonathan R.] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Lab Canc Prevent, Basic Sci Program, Frederick, MD 21702 USA. [Coppola, Vincenzo] Ohio State Univ, Ctr Comprehens Canc, Wexner Med Ctr, Dept MVIMG, Columbus, OH 43210 USA. [Summers, Glenn H.] NCI, FNLCR, Lab Anim Sci Program, SAIC Frederick, Frederick, MD 21702 USA. [Roger, Thierry] CHU Vaudois, Dept Med, Infect Dis Serv, CH-1011 Lausanne, Switzerland. [Roger, Thierry] Univ Lausanne, CH-1011 Lausanne, Switzerland. RP Sterneck, E (reprint author), Natl Canc Inst, Lab Cell & Dev Signalling, POB B, Frederick, MD 21702 USA. EM sternecg@mail.nih.gov RI Coppola, Vincenzo/E-2917-2011; Roger, Thierry/G-2007-2012 OI Coppola, Vincenzo/0000-0001-6163-1779; Roger, Thierry/0000-0002-9358-0109 FU NIH; Frederick National Lab; National Cancer Institute; Frederick National Laboratory (NIH) [HHSN261200800001E] FX This research was supported by the Intramural Research Program of the NIH, Frederick National Lab, National Cancer Institute and in part with Federal Funds from the Frederick National Laboratory (NIH) under contract no. HHSN261200800001E. We are thankful to the SAIC Laboratory Animal Sciences Program for excellent support and to the Department of Transfusion Medicine, Clinical Center, NIH, for providing elutriated monocytes. We thank Suzanne Specht and Linda Miller for excellent technical support, Kathleen Noer for technical assistance with flow cytometry, and Jennifer Mariano for her support with the metabolic labelling studies. For generously providing reagents, we thank Allan Weissman, Ira Daar, Alan Perantoni, William J. Muller (MMTV-Neu tumour cells), Keiichi I. Nakayama, Jian-Hua Mao and Johan Ericsson (Fbxw7 expression plasmids). We thank Giorgio Trinchieri, Howard Young, Peter Johnson and Andrew Hurwitz for helpful discussion and critical comments on the manuscript, Robert Leighty for help with the statistical analysis, Allan Weissman, Yien Che Tsai, Jennifer Mariano, Yoo-Seak Hwang, Arman Bashirova, Min Zhou and C. Andrew Stewart for valuable advice, and Jiro Wada and Allen Kane for preparation of the figures. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 53 TC 28 Z9 29 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2013 VL 4 AR 1662 DI 10.1038/ncomms2677 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143MR UT WOS:000318872100019 PM 23575666 ER PT J AU Li, HY Yang, L Fu, H Yan, JS Wang, Y Guo, H Hao, XS Xu, XH Jin, T Zhang, N AF Li, Hongyan Yang, Lei Fu, Hui Yan, Jianshe Wang, Ying Guo, Hua Hao, Xishan Xu, Xuehua Jin, Tian Zhang, Ning TI Association between G alpha i2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis SO NATURE COMMUNICATIONS LA English DT Article ID BREAST-CANCER METASTASIS; CHEMOTAXIS; PROTEIN; CELLS; COMPLEX; INVOLVEMENT; RECEPTORS; GROWTH; PHAGOCYTOSIS; MIGRATION AB The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between G alpha i2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a G alpha i2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of G alpha i2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis. C1 [Li, Hongyan; Yang, Lei; Fu, Hui; Guo, Hua; Hao, Xishan; Zhang, Ning] Tianjin Med Univ, Canc Inst & Hosp, Tianjin 300060, Peoples R China. [Li, Hongyan; Yang, Lei; Fu, Hui; Guo, Hua; Hao, Xishan; Zhang, Ning] Tianjin Med Univ, Res Ctr Basic Med Sci, Lab B, Tianjin 300060, Peoples R China. [Li, Hongyan; Yan, Jianshe; Xu, Xuehua; Jin, Tian] NIAID, Chemotaxis Signal Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Wang, Ying] Beichen Hosp, Tianjin 300400, Peoples R China. RP Zhang, N (reprint author), Tianjin Med Univ, Canc Inst & Hosp, Floor 6,Bldg C,Huan Hu Xi Rd, Tianjin 300060, Peoples R China. EM tjin@niaid.nih.gov; zhangning@tijmu.edu.cn FU NFSC [81125019, 81072160]; 973 Project [2012CBA01305, 2011CB933100, 2010CB933900]; Ministry of Education [20111202130001]; Changjiang Scholar Scholars and Innovative Research Team Grant [IRT1076]; NIAID/NIH FX We thank Dr Dale Hereld for helpful suggestions and Dr Lisha Qi for immunohistochemical evaluation. The research was supported by grants from NFSC (81125019 and 81072160), 973 Project (2012CBA01305, 2011CB933100 and 2010CB933900), grant from Ministry of Education (20111202130001), and Changjiang Scholar Scholars and Innovative Research Team Grant (IRT1076). The research was also supported by NIAID/NIH intramural funds. NR 32 TC 34 Z9 36 U1 0 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 APR PY 2013 VL 4 AR 1706 DI 10.1038/ncomms2680 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 143MR UT WOS:000318872100063 PM 23591873 ER PT J AU Freund, AM Keil, A AF Freund, Alexandra M. Keil, Andreas TI Out of mind, out of heart: Attention affects duration of emotional experience SO COGNITION & EMOTION LA English DT Article DE Emotion duration; Attention; Focus; Distraction ID TIME-COURSE; DISTRACTION; HAPPY; MOOD AB It has been suggested that the extent to which a person maintains attention to pleasant versus unpleasant aspects of a given stimulus has an effect on the self-reported affective state. This assumption was empirically tested in two experiments. In Study 1, participants received the instruction either to focus on a positive emotion-eliciting event (winning a tournament chess game) or to focus their attention on an affectively neutral distraction task (describing drawings). Study 2 used negative performance feedback in a cognitive task to induce unpleasant affect and included three experimental groups (waiting condition, continuing with the same cognitive task, distraction by a different cognitive task). Results converged to show that distracting attention away from the emotion-eliciting event leads to a shorter duration of the emotional experience. These findings support the attention-focus hypothesis. C1 [Freund, Alexandra M.] Univ Zurich, Dept Psychol, CH-8050 Zurich, Switzerland. [Keil, Andreas] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Keil, Andreas] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL USA. RP Freund, AM (reprint author), Univ Zurich, Dept Psychol, Binzmuehlestr 14-11, CH-8050 Zurich, Switzerland. EM freund@psychologie.uzh.ch RI Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 NR 23 TC 1 Z9 1 U1 1 U2 9 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0269-9931 J9 COGNITION EMOTION JI Cogn. Emot. PD APR 1 PY 2013 VL 27 IS 3 BP 549 EP 557 DI 10.1080/02699931.2012.725574 PG 9 WC Psychology, Experimental SC Psychology GA 146OV UT WOS:000319101300016 PM 22963519 ER PT J AU Battesti, A Gottesman, S AF Battesti, Aurelia Gottesman, Susan TI Roles of adaptor proteins in regulation of bacterial proteolysis SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID COMPETENCE TRANSCRIPTION FACTOR; ALTERNATIVE SIGMA-FACTOR; BACILLUS-SUBTILIS; ESCHERICHIA-COLI; CELL-CYCLE; SUBSTRATE RECOGNITION; RPOS PROTEOLYSIS; STRUCTURAL BASIS; TYROSINE KINASE; DNA-DAMAGE AB Elimination of non-functional or unwanted proteins is critical for cell growth and regulation. In bacteria, ATP-dependent proteases target cytoplasmic proteins for degradation, contributing to both protein quality control and regulation of specific proteins, thus playing roles parallel to that of the proteasome in eukaryotic cells. Adaptor proteins provide a way to modulate the substrate specificity of the proteases and allow regulated proteolysis. Advances over the past few years have provided new insight into how adaptor proteins interact with both substrates and proteases and how adaptor functions are regulated. An important advance has come with the recognition of the critical roles of anti-adaptor proteins in regulating adaptor availability. C1 [Battesti, Aurelia; Gottesman, Susan] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37,Rm 5132, Bethesda, MD 20892 USA. EM Gottesms@helix.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Michael Maurizi, Kumaran Ramamurthi, and members of our laboratory for their comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 56 TC 30 Z9 30 U1 3 U2 25 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD APR PY 2013 VL 16 IS 2 BP 140 EP 147 DI 10.1016/j.mib.2013.01.002 PG 8 WC Microbiology SC Microbiology GA 147PS UT WOS:000319180100006 PM 23375660 ER PT J AU Vitorovic-Todorovic, MD Eric-Nikolic, A Kolundzija, B Hamel, E Ristic, S Juranic, IO Drakulic, BJ AF Vitorovic-Todorovic, Maja D. Eric-Nikolic, Aleksandra Kolundzija, Branka Hamel, Ernest Ristic, Slavica Juranic, Ivan O. Drakulic, Branko J. TI (E)-4-Aryl-4-oxo-2-butenoic acid amides, chalcone-aroylacrylic acid chimeras: Design, antiproliferative activity and inhibition of tubulin polymerization SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Antitumor agents; Structure-activity relationships; 4-Aryl-4-oxo-2-butenoic acid amides; Inhibition of tubulin polymerization ID RAPID COLORIMETRIC ASSAY; BIOLOGICAL EVALUATION; IN-VITRO; DERIVATIVES; GROWTH; CELLS; CONFORMATIONS; PERSPECTIVE; METABOLISM; SURVIVAL AB Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 mu M. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 mu M. Compound 23 had an oral LD50 in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Vitorovic-Todorovic, Maja D.] Mil Tech Inst, Belgrade 11000, Serbia. [Eric-Nikolic, Aleksandra; Kolundzija, Branka] Inst Oncol & Radiol, Belgrade 11000, Serbia. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Ristic, Slavica] Galenika Ad Batajnicki Drum Bb, R&D Inst, Biomed Res, Belgrade 11000, Serbia. [Juranic, Ivan O.; Drakulic, Branko J.] Univ Belgrade, Dept Chem, IChTM, Belgrade 11000, Serbia. RP Vitorovic-Todorovic, MD (reprint author), Mil Tech Inst, Ratka Resanovica 1, Belgrade 11000, Serbia. EM majavitod@gmail.com RI Drakulic, Branko/A-8437-2011 OI Drakulic, Branko/0000-0002-3571-3153 FU Ministry of Education and Science of the Republic of Serbia [172035] FX This work was supported by the Ministry of Education and Science of the Republic of Serbia Grant 172035. Authors gratefully acknowledge Mr Milka Jadranin and Dr Nenad Milosavic for help with HPLC analysis. NR 47 TC 15 Z9 16 U1 1 U2 12 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR PY 2013 VL 62 BP 40 EP 50 DI 10.1016/j.ejmech.2013.01.006 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 139IX UT WOS:000318577500005 PM 23353745 ER PT J AU Zhang, YK Zhong, HY Lv, ZL Zhang, MF Zhang, T Li, QS Li, K AF Zhang, Yikai Zhong, Hanyu Lv, Zhiliang Zhang, Mingfeng Zhang, Tao Li, Qisheng Li, Ke TI Anti-hepatitis B virus and anti-cancer activities of novel isoflavone analogs SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Isoflavone analogs; Heck reaction; Synthesis; Anti-HBV activity; Anti-cancer activity ID COLORIMETRIC ASSAY; DERIVATIVES; FLAVONOIDS; APIGENIN; PROLIFERATION; INHIBITION; GROWTH AB We have synthesized a series of novel isoflavone analogs and evaluated their anti-HBV and anti-cancer activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on HBsAg and HBeAg levels, HBV DNA replication, as well as the growth of four human cancer cell lines to various extents, which supported the rationale of the design. In particular, compound 8f showed the highest activity against HBV infection and HBV-related liver cancer. Compound 71 (IC50 = 0.47 mu M) also exerted remarkable inhibitory effect on the growth lung cancer cell line A-549. (C) 2012 Elsevier Masson SAS. All rights reserved. C1 [Zhang, Yikai; Zhong, Hanyu; Lv, Zhiliang; Zhang, Mingfeng; Zhang, Tao; Li, Ke] Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China. [Li, Qisheng] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Li, K (reprint author), Second Mil Med Univ, Sch Pharm, Dept Med Chem, 325 Guohe Rd, Shanghai 200433, Peoples R China. EM proflike@sina.com RI Li, Qisheng/K-1909-2013 FU National Natural Science Foundation of China [21172259]; Shanghai Rising-Star Program [09QA1407000] FX This work was supported by the National Natural Science Foundation of China (Grant No. 21172259) and Shanghai Rising-Star Program (Grant No. 09QA1407000). We also thank staffs at the Key Laboratory of Drug Research for Special Environments of PLA. NR 20 TC 5 Z9 6 U1 2 U2 18 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR PY 2013 VL 62 BP 158 EP 167 DI 10.1016/j.ejmech.2012.09.017 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 139IX UT WOS:000318577500017 PM 23353737 ER PT J AU Lin, YJ Lai, CC Lai, CH Sue, SC Lin, CW Hung, CH Lin, TH Hsu, WY Huang, SM Hung, YL Tien, N Liu, X Chen, CL Tsai, FJ AF Lin, Ying-Ju Lai, Chien-Chen Lai, Chih-Ho Sue, Shih-Che Lin, Cheng-Wen Hung, Chien-Hui Lin, Ting-Hsu Hsu, Wei-Yi Huang, Shao-Mei Hung, Yi-Lin Tien, Ni Liu, Xiang Chen, Chao-Ling Tsai, Fuu-Jen TI Inhibition of enterovirus 71 infections and viral IRES activity by Fructus gardeniae and geniposide SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Enterovirus 71; Geniposide; Internal ribosome entry site; Fructus gardeniae ID RIBOSOME ENTRY SITE; MOLECULAR EPIDEMIOLOGY; INTERNAL INITIATION; CELLS; TRANSLATION; OUTBREAK; CROCETIN; MICE; RHABDOMYOSARCOMA; EXPRESSION AB Fructus gardeniae has long been used by traditional Chinese medical practitioners for its anti-inflammatory, anti-oxidant, anti-tumor and anti-hyperlipidemic characteristics. Here we describe our finding that E gardeniae greatly reduces anti-enterovirus 71 (EV71) activity, resulting in significant decreases in EV71 virus yields, EV71 infections, and internal ribosome entry site activity. We also found that geniposide, a primary F. gardeniae component, inhibited both EV71 replication and viral IRES activity. Our data suggest the presence of a mechanism that blocks viral protein translation. According to our findings, F. gardeniae and geniposide deserve a closer look as potential chemopreventive agents against EV71 infections. (C) 2013 Elsevier Masson SAS. All rights reserved. C1 [Lin, Ying-Ju; Lin, Ting-Hsu; Hsu, Wei-Yi; Huang, Shao-Mei; Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. [Lin, Ying-Ju; Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan. [Lin, Ying-Ju; Liu, Xiang] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Lai, Chien-Chen] Natl Chung Hsing Univ, Inst Mol Biol, Taichung 40227, Taiwan. [Lai, Chih-Ho] China Med Univ, Sch Med, Dept Microbiol, Taichung, Taiwan. [Sue, Shih-Che; Hung, Yi-Lin] Natl Tsing Hua Univ, Inst Bioinformat & Struct Biol, Dept Life Sci, Hsinchu, Taiwan. [Lin, Cheng-Wen; Tien, Ni] China Med Univ Hosp, Dept Lab Med, Taichung, Taiwan. [Lin, Cheng-Wen; Tien, Ni] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan. [Hung, Chien-Hui] Chang Gung Univ, Grad Inst Clin Med Sci, Chiayi, Taiwan. [Chen, Chao-Ling] China Med Univ, Sch Pharm, Taichung, Taiwan. RP Lin, YJ (reprint author), China Med Univ Hosp, Dept Med Res, Taichung, Taiwan. EM yjlin.kath@gmail.com; d0704@mail.cmuh.org.tw RI Liu, Xiang/F-5731-2014; Tsai, Fuu-Jen/J-4140-2015 FU China Medical University [CMU98-asia-03]; China Medical University Hospital [DMR-98-106]; Republic of China National Science Council [NSC 99-2628-B-039-001-MY3, NSC100-2320-B-039-012-MY3] FX This work was supported by grants from China Medical University (CMU98-asia-03), China Medical University Hospital (DMR-98-106), and the Republic of China National Science Council (NSC 99-2628-B-039-001-MY3 and NSC100-2320-B-039-012-MY3). We thank Dr. Willy W.L. Hong for technical assistance and suggestions, and Dr. Zachary Klase (NIAID, NIH) for his critical reading of our manuscript. NR 36 TC 15 Z9 17 U1 3 U2 30 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD APR PY 2013 VL 62 BP 206 EP 213 DI 10.1016/j.ejmech.2012.12.038 PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 139IX UT WOS:000318577500022 PM 23353754 ER PT J AU Abraham, AG D'Souza, G Jing, YZ Gange, SJ Sterling, TR Silverberg, MJ Saag, MS Rourke, SB Rachlis, A Napravnik, S Moore, RD Klein, MB Kitahata, MM Kirk, GD Hogg, RS Hessol, NA Goedert, JJ Gill, MJ Gebo, KA Eron, JJ Engels, EA Dubrow, R Crane, HM Brooks, JT Bosch, RJ Strickler, HD AF Abraham, Alison G. D'Souza, Gypsyamber Jing, Yuezhou Gange, Stephen J. Sterling, Timothy R. Silverberg, Michael J. Saag, Michael S. Rourke, Sean B. Rachlis, Anita Napravnik, Sonia Moore, Richard D. Klein, Marina B. Kitahata, Mari M. Kirk, Gregory D. Hogg, Robert S. Hessol, Nancy A. Goedert, James J. Gill, M. John Gebo, Kelly A. Eron, Joseph J. Engels, Eric A. Dubrow, Robert Crane, Heidi M. Brooks, John T. Bosch, Ronald J. Strickler, Howard D. CA North Amer AIDS Cohort Collaborati TI Invasive Cervical Cancer Risk Among HIV-Infected Women: A North American Multicohort Collaboration Prospective Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT Eurogin Conference CY JUL 08-11, 2012 CL Prague, CZECH REPUBLIC DE human papillomavirus; HIV-infection; invasive cervical cancer; immunosuppression ID HUMAN-IMMUNODEFICIENCY-VIRUS; SQUAMOUS INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS INFECTION; ABNORMAL PAPANICOLAOU SMEARS; FOLLOW-UP RECOMMENDATIONS; CYTOLOGIC ABNORMALITIES; ANTIRETROVIRAL THERAPY; POSITIVE WOMEN; UNITED-STATES; PAP TESTS AB Objective: HIV infection and low CD4(+) T-cell count are associated with an increased risk of persistent oncogenic human papillomavirus infection-the major risk factor for cervical cancer. Few reported prospective cohort studies have characterized the incidence of invasive cervical cancer (ICC) in HIV-infected women. Methods: Data were obtained from HIV-infected and -uninfected female participants in the North American AIDS Cohort Collaboration on Research and Design with no history of ICC at enrollment. Participants were followed from study entry or January 1996 through ICC, loss to follow-up, or December 2010. The relationship of HIV infection and CD4(+) T-cell count with risk of ICC was assessed using age-adjusted Poisson regression models and standardized incidence ratios. All cases were confirmed by cancer registry records and/or pathology reports. Cervical cytology screening history was assessed through medical record abstraction. Results: A total of 13,690 HIV-infected and 12,021 HIV-uninfected women contributed 66,249 and 70,815 person-years of observation, respectively. Incident ICC was diagnosed in 17 HIV-infected and 4 HIV-uninfected women (incidence rate of 26 and 6 per 100,000 person-years, respectively). HIV-infected women with baseline CD4(+) T-cells of >= 350, 200-349, and <200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in ICC incidence, respectively, compared with HIV-uninfected women (P-trend = 0.001). Of the 17 HIV-infected women, medical records for the 5 years before diagnosis showed that 6 had no documented screening, 5 had screening with low-grade or normal results, and 6 had high-grade results. Conclusions: This study found elevated incidence of ICC in HIV-infected compared with -uninfected women, and these rates increased with immunosuppression. C1 [Abraham, Alison G.; D'Souza, Gypsyamber; Jing, Yuezhou; Gange, Stephen J.; Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Strickler, Howard D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Sterling, Timothy R.] Vanderbilt Univ, Sch Med, Div Infect Dis, Nashville, TN 37212 USA. [Silverberg, Michael J.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Saag, Michael S.] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL USA. [Rourke, Sean B.; Rachlis, Anita] Univ Toronto, Ontario Treatment Network, Toronto, ON, Canada. [Napravnik, Sonia; Eron, Joseph J.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. [Moore, Richard D.; Gebo, Kelly A.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. [Klein, Marina B.] McGill Univ, Dept Med, Div Infect Dis, Chron Viral Illness Serv, Montreal, PQ, Canada. [Kitahata, Mari M.; Crane, Heidi M.] Univ Washington, Dept Med, Seattle, WA USA. [Hogg, Robert S.] Simon Fraser Univ, British Columbia Ctr Excellence & HIV AIDS, Dept Hlth Sci, Vancouver, BC, Canada. [Hessol, Nancy A.] Univ Calif San Francisco, Dept Clin Pharm & Med, San Francisco, CA 94143 USA. [Goedert, James J.; Engels, Eric A.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Gill, M. John] Univ Calgary, Dept Med, Calgary, AB, Canada. [Dubrow, Robert] Yale Univ, Sch Med, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Brooks, John T.] Ctr Dis Control & Prevent, Epidemiol Branch, Atlanta, GA USA. [Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP D'Souza, G (reprint author), Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 North Wolfe St,Suite E6132B, Baltimore, MD 21205 USA. EM aabraham@jhsph.edu; gdsouza@jhsph.edu RI Gill, John/G-7083-2016; OI Gill, John/0000-0002-8546-8790; Gange, Stephen/0000-0001-7842-512X; Hogg, Robert/0000-0003-3463-5488 FU Canadian Institutes of Health Research [169621, CBR-86906, CBR-94036, HCP-97105, KRS-86251, TGF-96118]; Intramural NIH HHS [Z01 CP010176-05, Z01 CP010176-07]; NCI NIH HHS [N02CP55504, P30 CA033572, R01 CA085178, R01-CA085178, R03 CA143956, Z01 CP010176]; NCRR NIH HHS [5-M01-RR-00052, M01 RR000052, RR025747, UL1 RR024131, UL1 RR025747, UL1-RR024131]; NIA NIH HHS [R01 AG026250]; NIAAA NIH HHS [U01 AA013566, U01-AA013566]; NIAID NIH HHS [AI-69432, AI-69434, K01 AI071725, K01 AI071754, K01-AI071725, K01-AI071754, K01AI071725, K23 AI001789, K23-AI-61-0320, P30 AI027757, P30 AI027763, P30 AI027767, P30 AI050410, P30 AI054999, P30-AI27757, P30-AI27767, P30-AI50410, P30-AI54999, R24 AI067039, R24-AI067039, U01 AI031834, U01 AI034989, U01 AI034993, U01 AI034994, U01 AI035004, U01 AI035039, U01 AI035040, U01 AI035041, U01 AI035042, U01 AI035043, U01 AI038855, U01 AI038858, U01 AI042590, U01 AI068634, U01 AI068636, U01 AI069432, U01 AI069434, U01 AI069918, U01-AI-31834, U01-AI-34989, U01-AI-34993, U01-AI-34994, U01-AI-35004, U01-AI-35039, U01-AI-35040, U01-AI-35041, U01-AI-35042, U01-AI-35043, U01-AI-42590, U01-AI069918, U01-AI38855, U01-AI38858, U01-AI68634, U01-AI68636, UM1 AI069432, UM1 AI069434]; NICHD NIH HHS [U01 HD032632, U01-HD-32632]; NIDA NIH HHS [R01 DA004334, R01 DA011602, R01 DA012568, R01-DA04334, R01-DA11602, R01-DA12568, U01 DA036297]; NIDCR NIH HHS [R01 DE021395, R01DE021395]; NIDDK NIH HHS [R01 DK080792]; NIMH NIH HHS [R01 MH054907, R01-MH54907]; NINDS NIH HHS [D43 NS078280]; PHS HHS [CDC200-2006-18797, AHQ290-01-0012, K24-00432] NR 35 TC 40 Z9 41 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2013 VL 62 IS 4 BP 405 EP 413 DI 10.1097/QAI.0b013e31828177d7 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 145SM UT WOS:000319037700011 PM 23254153 ER PT J AU Hosek, SG Siberry, G Bell, M Lally, M Kapogiannis, B Green, K Fernandez, MI Rutledge, B Martinez, J Garofalo, R Wilson, CM AF Hosek, Sybil G. Siberry, George Bell, Margo Lally, Michelle Kapogiannis, Bill Green, Keith Fernandez, M. Isabel Rutledge, Brandy Martinez, Jaime Garofalo, Robert Wilson, Craig M. CA Adolescent Trials Network HIV AIDS TI The Acceptability and Feasibility of an HIV Preexposure Prophylaxis (PrEP) Trial With Young Men Who Have Sex With Men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE pre-exposure prophylaxis; adolescents and young adults; combination HIV prevention ID ANTIRETROVIRAL THERAPY; PREVENTION; ADHERENCE; INFECTION; WOMEN AB Background: This study examined the feasibility of a combination prevention intervention for young men who have sex with men (YMSM), an anticipated target population for HIV preexposure prophylaxis (PrEP). Methods: Project PrEPare, a pilot study using a randomized 3-arm design, compared an efficacious behavioral HIV prevention intervention (Many Men, Many Voices-3 MV) alone, 3 MV combined with PrEP (tenofovir/emtricitabine), and 3 MV combined with placebo. Eligible participants were 18- to 22-year-old HIV-uninfected men who reported unprotected anal intercourse in the past year. Participants were screened for preliminary eligibility at youth venues and community organizations and were also referred through social networks. Laboratory screening determined final eligibility. Behavioral and biomedical data were collected at baseline and every 4 weeks thereafter for 24 weeks. Results: Sixty-eight youth (mean age = 19.97 years; 53% African American, 40% Latino) were enrolled; 58 were randomized. Self-reported medication adherence averaged 62% (range, 43%-83%), whereas rates of detectable tenofovir in plasma of participants in the emtricitabine/tenofovir disoproxil fumarate arm ranged from 63.2% (week 4) to 20% (week 24). There were 5 >= grade 2 adverse events possibly/probably related to the study medication. Sexual risk behavior declined from baseline to week 24 in all study arms. Conclusions: The feasibility of enrolling at-risk youth, particularly young men who have sex with men of color, into Project PrEPare has been demonstrated. The acceptability of the group intervention along with counseling and testing was high. Self-reported medication adherence and corresponding plasma drug concentrations were low indicating the need for enhanced adherence counseling. Exploration of PrEP use among youth in nonrandomized open label trials is warranted. C1 [Hosek, Sybil G.; Green, Keith; Martinez, Jaime] John H Stroger Jr Hosp Cook Cty, Dept Psychiat, Chicago, IL 60612 USA. [Siberry, George; Kapogiannis, Bill] NICHD, Maternal & Pediat Infect Dis Branch, PAMAB, Bethesda, MD USA. [Bell, Margo] John H Stroger Jr Hosp Cook Cty, Dept Pediat, Chicago, IL 60612 USA. [Lally, Michelle] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02912 USA. [Fernandez, M. Isabel] Nova SE Univ, Dept Osteopath Med, Ft Lauderdale, FL 33314 USA. [Rutledge, Brandy] Westat Corp, Rockville, MD USA. [Garofalo, Robert] Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. [Wilson, Craig M.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. RP Hosek, SG (reprint author), John H Stroger Jr Hosp Cook Cty, Dept Psychiat, 1900 W Polk St,Room 854, Chicago, IL 60612 USA. EM shosek@cookcountyhhs.org RI Lally, Michelle/I-4865-2016 OI Lally, Michelle/0000-0003-0716-4668 FU National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 HD040533-06]; National Institute on Drug Abuse; National Institute of Mental Health FX Supported by the grant U01 HD040533-06 from the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development with supplemental funding from the National Institute on Drug Abuse and National Institute of Mental Health. NR 19 TC 37 Z9 37 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2013 VL 62 IS 4 BP 447 EP 456 DI 10.1097/QAI.0b013e3182801081 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 145SM UT WOS:000319037700017 PM 24135734 ER PT J AU Godfrey, C Villa, C Dawson, L Swindells, S Schouten, JT AF Godfrey, Catherine Villa, Christie Dawson, Liza Swindells, Susan Schouten, Jeffrey T. TI Controlling Healthcare-Associated Infections in the International Research Setting SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter ID DRUG-RESISTANT TUBERCULOSIS; POSTEXPOSURE PROPHYLAXIS; MULTIDRUG-RESISTANT; SOUTH-AFRICA; IMPLEMENTATION; TRANSMISSION; KNOWLEDGE; PROGRAMS; INJURIES; EFFICACY C1 [Godfrey, Catherine] NIAID, HIV Res Branch, Therapeut Res Program, Div AIDS,NIH, Washington, DC USA. [Villa, Christie] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98104 USA. [Dawson, Liza] NIAID, Res Eth Team, Basic Sci Program, Div AIDS,NIH, Washington, DC USA. [Swindells, Susan] Univ Nebraska Med Ctr, Dept Med, Omaha, NE USA. [Schouten, Jeffrey T.] Univ Nebraska Med Ctr, Vaccine & Infect Dis Div, Omaha, NE USA. RP Godfrey, C (reprint author), NIAID, Div AIDS, NIH, 6700 B Rockledge Dr, Bethesda, MD 20892 USA. EM cgodfrey@niaid.nih.gov FU NIAID NIH HHS [U01 AI068636, U01AI068636, 5 U01 AI068614, U01 AI068614] NR 29 TC 3 Z9 3 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR 1 PY 2013 VL 62 IS 4 BP E115 EP E118 DI 10.1097/QAI.0b013e3182845b95 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 145SM UT WOS:000319037700002 PM 24135735 ER PT J AU Devkota, KP Covell, D Ransom, T McMahon, JB Beutler, JA AF Devkota, Krishna P. Covell, David Ransom, Tanya McMahon, James B. Beutler, John A. TI Growth Inhibition of Human Colon Carcinoma Cells by Sesquiterpenoids and Tetralones of Zygogynum calothyrsum SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID WINTERACEAE; CANCER AB Bioassay-guided phytochemical investigation of Zygogynum calothyrsum using the human colon carcinoma cell lines COLO205 and KM12 led to the isolation of three new drimane-type sesquiterpenoids, 1 beta-p-hydroxy-E-cinnamoyldrimeninol (1), 1 beta-p-hydroxy-E-cinnamoyl-5 alpha-hydroxydrimeninol (2), and methyl ether of 1 beta-p-hydroxy-E-cinnamoyl-12 alpha-methoxydrimeninol (3). Also isolated was the known 1 beta-p-coumaroyloxypolygodial (4) together with two new tetralones, 3'-deoxyisozygolone A (5) and calothyrlone A (9), three known tetralones, isozygolone A (6), zygolone A (7), and 4'-O-methylzygolone A (8), and a known cinnamolide (10). Compounds 1, 7, and 8 demonstrated higher cytotoxicity against COLO205 (GI(50) 18, 17, and 11 mu M, respectively) and KM12 (GI(50) 14, 14, and 17 mu M, respectively) than the other compounds. C1 [Devkota, Krishna P.; Ransom, Tanya; McMahon, James B.; Beutler, John A.] NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Covell, David] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. RP Beutler, JA (reprint author), NCI, Mol Targets Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM beutlerj@mail.nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. We thank W. Takeuchi for the plant collection, D. Soejarto and D. Newman for help in documenting the collection, as well as the Natural Products Support Group at NCI-Frederick for extraction, and S. Tarasov and M. Dyba (Biophysics Resource Core, Structural Biophysics Laboratory, CCR) and H. Bokesch (MTL) for assistance with mass spectrometry. NR 17 TC 9 Z9 9 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD APR PY 2013 VL 76 IS 4 BP 710 EP 714 DI 10.1021/np400042q PG 5 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 135CX UT WOS:000318264700031 PM 23517126 ER PT J AU Ramirez, AS Rutten, LJF Vanderpool, RC Moser, RP Hesse, BW AF Ramirez, A. Susana Rutten, Lila J. Finney Vanderpool, Robin C. Moser, Richard P. Hesse, Bradford W. TI Correlates and Geographic Patterns of Knowledge That Physical Activity Decreases Cancer Risk SO JOURNAL OF PRIMARY PREVENTION LA English DT Article DE Cancer risk perceptions; Cancer knowledge; Physical activity ID OF-SPORTS-MEDICINE; PUBLIC-HEALTH; PREVENTION; BEHAVIOR; BELIEFS; RECOMMENDATIONS; ASSOCIATION; PREDICTORS; NUTRITION; AWARENESS AB While many lifestyle-related cancer risk factors including tobacco use, poor diet, and sun exposure are well recognized by the general public, the role of physical activity in decreasing cancer risk is less recognized. Studies have demonstrated gender-, race/ethnicity-, and age-based disparities in cancer risk factor knowledge; however, beliefs and geographic factors that may be related to knowledge are under-examined. In this study, we analyzed data from the 2008 Health Information National Trends Survey to determine correlates of knowledge of the relationship between physical activity and reduced cancer risk in the adult US population. We generated geographic information system maps to examine the geographic distribution of this knowledge. Results revealed that there is confusion among US adults about the relationship between physical activity and cancer risk: Respondents who believed that cancer is not preventable had significantly lower odds of knowing that physical activity reduces cancer risk (p < .001) whereas respondents who believed that cancer is caused by one's behavior had almost two times the odds of knowing that physical activity reduces cancer risk (p < .001). Those who were aware of current physical activity guidelines were also significantly more likely to know that physical activity reduces cancer risk (p < .01). Observed geographic variability in knowledge was consistent with geographic trends in obesity and physical inactivity. Correlates of cancer risk factor knowledge point to opportunities for targeted interventions. C1 [Ramirez, A. Susana; Moser, Richard P.; Hesse, Bradford W.] NCI, Rockville, MD 20892 USA. [Rutten, Lila J. Finney] Mayo Clin, Rochester, MN USA. [Vanderpool, Robin C.] Univ Kentucky, Coll Publ Hlth, Lexington, KY USA. RP Ramirez, AS (reprint author), NCI, 6130 Execut Blvd,Suite 4051A,MSC 7150, Rockville, MD 20892 USA. EM ramirezas@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU CCR NIH HHS [HHSN261200800001C]; NCI NIH HHS [HHSN261200800001E]; PHS HHS [HHSN261200800001E] NR 30 TC 3 Z9 3 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0278-095X EI 1573-6547 J9 J PRIM PREV JI J. Prim. Prev. PD APR PY 2013 VL 34 IS 1-2 SI SI BP 31 EP 39 DI 10.1007/s10935-012-0289-5 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 143OY UT WOS:000318878200005 PM 23344632 ER PT J AU Briscione, MA Serafine, KM Merluzzi, AP Rice, KC Riley, AL AF Briscione, Maria A. Serafine, Katherine M. Merluzzi, Andrew P. Rice, Kenner C. Riley, Anthony L. TI The effects of the 5-HT3 receptor antagonist tropisetron on cocaine-induced conditioned taste aversions SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Tropisetron; Conditioned taste aversions; Antagonism; Serotonin ID TRANSPORTER KNOCKOUT MICE; STIMULUS PROPERTIES; DOPAMINE-TRANSPORTER; PLACE PREFERENCE; REWARD; RATS; STIMULATION; PREEXPOSURE; INVOLVEMENT; MECHANISMS AB Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. Recent work has shown that cocaine's actions on serotonin (5-HT) may be involved. To address this possibility, the present experiments examined a role of the specific 5-HT receptor, 5-HT3, in this effect given that it is implicated in a variety of behavioral effects of cocaine. This series of investigations first assessed the aversive effects of the 5-HT3 receptor antagonist tropisetron alone (Experiment 1). Specifically, in Experiment 1 male Sprague-Dawley rats were given repeated pairings of a novel saccharin solution and tropisetron (0, 0.056, 0.18 and 0.56 mg/kg). Following this, a non-aversion-inducing dose of tropisetron (0.18 mg/kg) was assessed for its ability to block aversions induced by a range of doses of cocaine (Experiment 2). Specifically, in Experiment 2 animals were given access to a novel saccharin solution and then injected with tropisetron (0 or 0.18 mg/kg) followed by an injection of various doses of cocaine (0, 10, 18 and 32 mg/kg). Cocaine induced dose-dependent taste aversions that were not blocked by tropisetron, suggesting that cocaine's aversive effects are not mediated by 5-HT, at least at this specific receptor subtype. At the intermediate dose of cocaine, aversions appeared to be potentiated, suggesting 5-HT3 may play a limiting role in cocaine's aversive effects. These data are discussed in the context of previous examinations of the roles of serotonin, dopamine, and norepinephrine in cocaine-induced aversions. (C) 2013 Elsevier Inc. All rights reserved. C1 [Briscione, Maria A.; Serafine, Katherine M.; Merluzzi, Andrew P.; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD 20892 USA. RP Briscione, MA (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, 4400 Mass Ave NW, Washington, DC 20016 USA. EM mariabriscione@gmail.com FU Mellon Foundation; Mathias Undergraduate Summer Research Award; American University's Scholars and Artists Fellowship; Intramural Research Program of the National Institute on Drug Abuse; Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism FX This work was supported in part by a grant from the Mellon Foundation to ALR and the Mathias Undergraduate Summer Research Award and the American University's Scholars and Artists Fellowship to MAB. A portion of this work was supported by the Intramural Research Programs of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism. Requests for reprints should be sent to Maria A. Briscione, Psychopharmacology Laboratory, Department of Psychology, American University, Washington, DC 20016 (or mariabriscione@gmail.com). NR 40 TC 1 Z9 1 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2013 VL 105 BP 112 EP 117 DI 10.1016/j.pbb.2013.02.003 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 136TX UT WOS:000318387400016 PM 23415734 ER PT J AU Newell, K Mannon, R Mehta, A Tomlanovich, S Morrison, Y Ikle, D Goodman, J Mehta, S Bridges, N Stock, P Larsen, C AF Newell, K. Mannon, R. Mehta, A. Tomlanovich, S. Morrison, Y. Ikle, D. Goodman, J. Mehta, S. Bridges, N. Stock, P. Larsen, C. TI Long-Term Calcineurin Inhibitor (CNI) and Corticosteroid (CS) Avoidance Using Belatacept: The CTOT-10 Experience SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Mannon, R.] Univ Alabama Birmingham, Birmingham, AL USA. [Tomlanovich, S.; Goodman, J.; Mehta, S.; Stock, P.] UC San Francisco, San Francisco, CA USA. [Morrison, Y.; Bridges, N.] NIAID, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 34 EP 35 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300016 ER PT J AU Harmon, W Guleria, I Ikle, D Armstrong, B Spaneas, L Morrison, Y Bridges, N Sayegh, M Chandraker, A AF Harmon, W. Guleria, I. Ikle, D. Armstrong, B. Spaneas, L. Morrison, Y. Bridges, N. Sayegh, M. Chandraker, A. TI Children Develop De Novo Anti-HLA Antibodies(Abs) Following Kidney Transplantation at a Higher Incidence Than Adults: An Analysis of the NIH CTOT/CCTPT-02 Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Harmon, W.; Guleria, I.; Spaneas, L.; Sayegh, M.; Chandraker, A.] Boston Childrens Hosp, Boston, MA USA. [Harmon, W.; Guleria, I.; Spaneas, L.; Sayegh, M.; Chandraker, A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Ikle, D.; Armstrong, B.] RHO, Chapel Hill, NC USA. [Morrison, Y.; Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 36 EP 37 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300022 ER PT J AU Hricik, D Nickerson, P Formica, R Poggio, E Rush, D Newell, K Goebel, J Gibson, I Fairchild, R Riggs, M Ikle, D Bridges, N Heeger, P AF Hricik, D. Nickerson, P. Formica, R. Poggio, E. Rush, D. Newell, K. Goebel, J. Gibson, I. Fairchild, R. Riggs, M. Ikle, D. Bridges, N. Heeger, P. TI Multicenter Valdiation of Urinary Biomarkers in Kidney Transplantation: Urinary CXCL9 Protein Correlates with Acute Rejection and Deterioration of Kidney Function. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Hricik, D.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Nickerson, P.; Rush, D.; Gibson, I.] Univ Manitoba, Winnipeg, MB, Canada. [Formica, R.] Yale Univ, Hew Haven, CT USA. [Poggio, E.; Fairchild, R.] Cleveland Clin, Cleveland, OH 44106 USA. [Newell, K.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Goebel, J.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Riggs, M.; Ikle, D.] Rho, Chapel Hill, NC USA. [Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. [Heeger, P.] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 98 EP 98 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300223 ER PT J AU Danziger-Isakov, L Frazier, T Worley, S Williams, N Bridges, N Sweet, S AF Danziger-Isakov, L. Frazier, T. Worley, S. Williams, N. Bridges, N. Sweet, S. CA CTOTC-05 Consortium TI Perceived Barriers to Adherence in Pediatric Transplantation from the Guardian's Perspective SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Danziger-Isakov, L.] Cincinnati Childrens, Cincinnati, OH USA. [Frazier, T.; Worley, S.] Cleveland Clin, Cleveland, OH USA. [Williams, N.; Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. [Sweet, S.] Washington Univ, St Louis, MO 63130 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 108 EP 109 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300255 ER PT J AU Chandraker, A Guleria, I Ikle, D Chin, H Vincenti, F Morrison, Y Bridges, N Harmon, W Sayegh, M AF Chandraker, A. Guleria, I. Ikle, D. Chin, H. Vincenti, F. Morrison, Y. Bridges, N. Harmon, W. Sayegh, M. TI Development of De Novo Anti-HLA Abs in Kidney Transplant Recipients: Final Analysis of the NIH CTOT02 Study SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Chandraker, A.; Guleria, I.; Harmon, W.; Sayegh, M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chandraker, A.; Guleria, I.; Harmon, W.; Sayegh, M.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Ikle, D.; Chin, H.] RHO, Chapel Hill, NC USA. [Vincenti, F.] UCSF, San Francisco, CA USA. [Morrison, Y.; Bridges, N.] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 113 EP 113 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300269 ER PT J AU Suessmuth, Y Stempora, L Johnson, B Cheeseman, J Morrison, Y Bridges, N Ikle, D Tomlanovich, S Stock, P Mannon, R Newell, K Larsen, C Mehta, A AF Suessmuth, Y. Stempora, L. Johnson, B. Cheeseman, J. Morrison, Y. Bridges, N. Ikle, D. Tomlanovich, S. Stock, P. Mannon, R. Newell, K. Larsen, C. Mehta, A. TI Comparison of Baseline and Day 28 Post Transplant Renal Allograft Samples from the CTOT-10 Belatacept Study. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Suessmuth, Y.; Stempora, L.; Johnson, B.; Cheeseman, J.; Newell, K.; Larsen, C.] Emory Transplant Ctr, Atlanta, GA USA. [Mannon, R.] Univ Alabama Birmingham, Birmingham, AL USA. [Tomlanovich, S.; Stock, P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Morrison, Y.; Bridges, N.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.] Rho, Chapel Hill, NC USA. RI Mehta, Aneesh/B-8054-2012 OI Mehta, Aneesh/0000-0002-6552-9162 NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 225 EP 225 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240300630 ER PT J AU Jindra, P Conway, S Ricklefs, S Porcella, S Alterovitz, G Wang, T Spellman, S McDermott, D Abdi, R AF Jindra, P. Conway, S. Ricklefs, S. Porcella, S. Alterovitz, G. Wang, T. Spellman, S. McDermott, D. Abdi, R. TI Genetic Polymorphism rs10912564 in TNFSF4 of the TNF Superfamily Is Associated with HCT Outcomes. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Jindra, P.; Conway, S.; Abdi, R.] Brigham & Womens Hosp, Div Renal, Transplant Res Ctr, Boston, MA 02115 USA. [Jindra, P.; Conway, S.; Abdi, R.] Childrens Hosp, Boston, MA 02115 USA. [Ricklefs, S.; Porcella, S.] NIAID, Genom Unit, Res Technol Branch, NIH, Hamilton, MO USA. [Alterovitz, G.] MIT, Children&s Hosp Informat, Dept Elect Engn & Comp Sci, Boston, MA USA. [Wang, T.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Spellman, S.] Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA. [McDermott, D.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 298 EP 298 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301103 ER PT J AU Mohiuddin, M Singh, A Corcoran, P Mayhew, C Hoyt, R Thomas, M Lewis, B Clark, T Eckhaus, M Reimann, K Ayares, D Horvath, K AF Mohiuddin, M. Singh, A. Corcoran, P. Mayhew, C. Hoyt, R. Thomas, M. Lewis, B. Clark, T. Eckhaus, M. Reimann, K. Ayares, D. Horvath, K. TI Transgenic Expression of Human Thrombomodulin in Donor Pigs Reduces the Incidence of Coagulopathies in a Pig to Baboon Cardiac Xenotransplantation Model. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Mohiuddin, M.; Singh, A.; Corcoran, P.; Mayhew, C.; Hoyt, R.; Horvath, K.] NHLBI, NIH, Bethesda, MD 20892 USA. [Thomas, M.; Lewis, B.; Clark, T.; Eckhaus, M.] NIH, ORS, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburgh, England. [Reimann, K.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 372 EP 372 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301364 ER PT J AU Singh, A Corcoran, P Lewis, B Hoyt, R Thomas, M Eckhaus, M Mayhew, C Clark, T Reimann, K Ayares, D Horvath, K Mohiuddin, M AF Singh, A. Corcoran, P. Lewis, B. Hoyt, R. Thomas, M. Eckhaus, M. Mayhew, C. Clark, T. Reimann, K. Ayares, D. Horvath, K. Mohiuddin, M. TI Complication Free Heterotopic Cardiac Xenograft Survival by Anti CD40 Antibody Mediated Co-Stimulation Blockade. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Singh, A.; Corcoran, P.; Hoyt, R.; Mayhew, C.; Horvath, K.; Mohiuddin, M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Lewis, B.; Thomas, M.; Eckhaus, M.; Clark, T.] NIH, ORS, Bethesda, MD 20892 USA. [Ayares, D.] Revivicor Inc, Blacksburgh, England. [Reimann, K.] Beth Israel Deaconess Med Ctr, Boston, MA USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 372 EP 372 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301365 ER PT J AU John, A Weiner, D Carpenter, M Hunsicker, L Kusek, J Pfeffer, M Solomon, S Weir, M Levey, A AF John, A. Weiner, D. Carpenter, M. Hunsicker, L. Kusek, J. Pfeffer, M. Solomon, S. Weir, M. Levey, A. TI Cardiovascular Disease and Kidney Disease Progression in Kidney Transplant Recipients. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [John, A.; Weiner, D.; Levey, A.] Tufts Med Ctr, Boston, MA USA. [Carpenter, M.] Univ N Carolina, Chapel Hill, NC USA. [Hunsicker, L.] Univ Iowa, Iowa City, IA USA. [Weir, M.] Univ Maryland, Baltimore, MD 21201 USA. [Pfeffer, M.; Solomon, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kusek, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 422 EP 422 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301534 ER PT J AU Engels, E AF Engels, E. TI Risk of Transmission of Cancer from Solid Organ Donors in the US SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Engels, E.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 536 EP 536 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301923 ER PT J AU Nee, R Abbott, K Little, D Ramsey-Goldman, R Agodoa, L Hurst, F Jindal, R AF Nee, R. Abbott, K. Little, D. Ramsey-Goldman, R. Agodoa, L. Hurst, F. Jindal, R. TI Racial Differences and Income Disparities Are Associated with Worse Allograft and Death Outcomes in Kidney Transplant Recipients with Lupus Nephritis. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 13th American Transplant Congress (ATC) CY MAY 18-22, 2013 CL Seattle, WA C1 [Nee, R.; Abbott, K.; Little, D.; Jindal, R.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Ramsey-Goldman, R.] Northwestern Univ, Chicago, IL 60611 USA. [Agodoa, L.] NIDDK, NIH, Bethesda, MD USA. [Hurst, F.] US FDA, Silver Spring, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD APR PY 2013 VL 13 SU 5 SI SI BP 541 EP 541 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 134UL UT WOS:000318240301942 ER PT J AU Leon-Sarmiento, FE Rizzo-Sierra, CV Bayona, EA Bayona-Prieto, J Doty, RL Bara-Jimenez, W AF Leon-Sarmiento, Fidias E. Rizzo-Sierra, Carlos V. Bayona, Edgardo A. Bayona-Prieto, Jaime Doty, Richard L. Bara-Jimenez, William TI Novel Mechanisms Underlying Inhibitory and Facilitatory Transcranial Magnetic Stimulation Abnormalities in Parkinson's Disease SO ARCHIVES OF MEDICAL RESEARCH LA English DT Article DE Brain motor cortex; Dopamine; Inhibition; Excitation; Transcranial magnetic stimulation; Basal ganglia; Surround inhibition ID MOTOR CORTEX EXCITABILITY; SUBTHALAMIC NUCLEUS STIMULATION; BASAL GANGLIA; CORTICAL EXCITABILITY; TYROSINE-HYDROXYLASE; MOVEMENT-DISORDERS; PREFRONTAL CORTEX; BRAIN-STIMULATION; EVOKED-POTENTIALS; DOPAMINE AB Background and Aims. The motor-evoked potential (MEP) induced by transcranial magnetic stimulation (TMS), its recruitment and the conditioning effects of weak stimuli in Parkinson's disease (PD) have shown contradictory results. The aim of this study is to definitively establish the influences of PD on the TMS-evoked MEP. Methods. We investigated resting and active motor thresholds, resting and active recruitment curves, and short interval intracortical inhibition (ICI) and facilitation (ICF) in 39 PD patients and 40 age-matched healthy controls. The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was used as a clinical measure. Results. MEPs to single pulses were slightly, but significantly, larger in the PD patients at rest, but increased much less than controls with voluntary muscle activation. PD patients also showed clearly and consistently less ICI and ICF by the conditioning pulse. Both ICI and ICF correlated with MEP threshold in healthy subjects, but not in PD patients. None of the TMS measures correlated with the UPDRS. Conclusions. This study strongly supports the view that PD-related MEPs reflect a disturbed signal-noise ratio of pyramidal neuron responses. Such disturbance may be due to a complex combination of altered presynaptic and surround inhibition that results in unbalanced excitatory/inhibitory input at the brain motor cortex level. (C) 2013 IMSS. Published by Elsevier Inc. C1 [Leon-Sarmiento, Fidias E.; Doty, Richard L.] Univ Penn, Ctr Smell & Taste, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Leon-Sarmiento, Fidias E.; Bara-Jimenez, William] NINDS, NIH, Human Motor Control Sect, Bethesda, MD USA. [Leon-Sarmiento, Fidias E.] Univ Nacl Unicolciencias, Mediciencias Res Grp, Unit Parkinson & Movement Disorders, Bogota, Colombia. [Rizzo-Sierra, Carlos V.] SVYASA Yoga Univ, ICMR Ctr Adv Res Yoga & Neurophysiol, Bangalore, Karnataka, India. [Rizzo-Sierra, Carlos V.; Bayona, Edgardo A.] Neuro Net, Lab Neurociencias Clin & Func, Bogota, Colombia. [Bayona-Prieto, Jaime] CIRINEO Neurorehabil, Bucaramanga, Colombia. [Bara-Jimenez, William] Bethesda Neurosci Clin, Bethesda, MD USA. RP Leon-Sarmiento, FE (reprint author), Ctr Smell & Taste, Dept Otorhinolaryngol Head & Neck Surg, 5 Ravdin,3400 Spruce St, Philadelphia, PA 19104 USA. EM feleones@gmail.com RI Doty, Richard/G-1602-2013 FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health; U.S. National Institutes of Health [RO1DA019055-04]; U.S. Department of Defense [W81XWH-09-1-0467] FX Dr. Fidias E. Leon-Sarmiento was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. Additional resources were provided by the U.S. National Institutes of Health (Grant No. RO1DA019055-04) and the U.S. Department of Defense (Grant No. W81XWH-09-1-0467). NR 77 TC 7 Z9 7 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0188-4409 J9 ARCH MED RES JI Arch. Med. Res. PD APR PY 2013 VL 44 IS 3 BP 221 EP 228 DI 10.1016/j.arcmed.2013.03.003 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 141RJ UT WOS:000318743900009 PM 23523962 ER PT J AU Glotzbach-Schoon, E Tadda, R Andreatta, M Troger, C Ewald, H Grillon, C Pauli, P Muhlberger, A AF Glotzbach-Schoon, Evelyn Tadda, Regina Andreatta, Marta Troeger, Christian Ewald, Heike Grillon, Christian Pauli, Paul Muehlberger, Andreas TI Enhanced discrimination between threatening and safe contexts in high-anxious individuals SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Trait anxiety; Contextual fear conditioning; Startle reflex; Virtual reality ID POSTTRAUMATIC-STRESS-DISORDER; VIRTUAL-REALITY ENVIRONMENT; TRAIT ANXIETY; FEAR RESPONSES; AVERSIVE EVENTS; NEGATIVE AFFECT; BED NUCLEUS; EXTINCTION; AMYGDALA; STARTLE AB Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT-). High-anxious participants tended to show faster acquisition of startle potentiation in the C.XT+ versus the CXT- than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety. (C) 2013 Elsevier B.V. All rights reserved. C1 [Glotzbach-Schoon, Evelyn; Tadda, Regina; Andreatta, Marta; Troeger, Christian; Ewald, Heike; Pauli, Paul; Muehlberger, Andreas] Univ Wurzburg, Dept Psychol Biol Psychol Clin Psychol & Psychoth, D-97070 Wurzburg, Germany. [Grillon, Christian] NIMH, Mood & Anxiety Disorder Program, Bethesda, MD 20892 USA. [Muehlberger, Andreas] Univ Regensburg, Dept Psychol, Chair Clin Psychol & Psychotherapy, D-93053 Regensburg, Germany. RP Muhlberger, A (reprint author), Univ Regensburg, Dept Psychol, Chair Clin Psychol & Psychotherapy, Univ Str 31, D-93053 Regensburg, Germany. EM andreas.muehlberger@psychologie.uni-regensburg.de OI Pauli, Paul/0000-0003-0692-6720 FU Deutsche Forschungsgemeinschaft (DFG): Collaborative Research Center "Fear, Anxiety, Anxiety Disorders" [SFB-TRR 58]; University of Wurzburg; National Institutes of Mental Health FX This work was supported by the Deutsche Forschungsgemeinschaft (DFG): Collaborative Research Center "Fear, Anxiety, Anxiety Disorders" SFB-TRR 58 project B1 to Paul Pauli and Andreas Muhlberger and a grant from the University of Wurzburg to Andreas Muhlberger for a research visit to the National Institute of Mental Health. Christian Grillon is supported by the Intramural Research Program of the National Institutes of Mental Health. NR 59 TC 23 Z9 24 U1 3 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD APR PY 2013 VL 93 IS 1 BP 159 EP 166 DI 10.1016/j.biopsycho.2013.01.011 PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 136RU UT WOS:000318381900022 PM 23384512 ER PT J AU Pike, NA Pemberton, V Allen, K Jacobs, JP Hsu, DT Lewis, AB Ghanayem, N Lambert, L Crawford, K Atz, T Korsin, R Xu, MF Ravishankar, C Cnota, J Pearson, GD AF Pike, Nancy A. Pemberton, Victoria Allen, Kerstin Jacobs, Jeffrey P. Hsu, Daphne T. Lewis, Alan B. Ghanayem, Nancy Lambert, Linda Crawford, Kari Atz, Teresa Korsin, Rosalind Xu, Mingfen Ravishankar, Chitra Cnota, James Pearson, Gail D. CA Pediat Heart Network Investigators TI Challenges and successes of recruitment in the "angiotensin-converting enzyme inhibition in infants with single ventricle trial" of the Pediatric Heart Network SO CARDIOLOGY IN THE YOUNG LA English DT Article DE Congenital heart disease; clinical trials; functionally univentricular heart ID RANDOMIZED CONTROLLED-TRIALS; CLINICAL-TRIALS; NORWOOD PROCEDURE; NEONATAL RESEARCH; CHILDREN; PARENTS; MULTICENTER; CONSENT; DISEASE; DESIGN AB Objectives: Identify trends of enrolment and key challenges when recruiting infants with complex cardiac diseases into a multi-centre, randomised, placebo-controlled drug trial and assess the impact of efforts to share successful strategies on enrolment of subjects. Methods: Rates of screening, eligibility, consent, and randomisation were determined for three consecutive periods of time. Sites collectively addressed barriers to recruitment and shared successful strategies resulting in the Inventory of Best Recruiting Practices. Study teams detailed institutional practices of recruitment in post-trial surveys that were compared with strategies of enrolment initially proposed in the Inventory. Results: The number of screened patients increased by 30% between the Initial Period and the Intermediate Period (p = 0.007), whereas eligibility decreased slightly by 7%. Of those eligible for entry into the study, the rate of consent increased by 42% (p = 0.025) and randomisation increased by 71% (p = 0.10). During the Final Period, after launch of a competing trial, fewer patients were screened (-14%, p = 0.06), consented (-19%, p = 0.12), and randomised (-34%, p = 0.012). Practices of recruitment in the post-trial survey closely mirrored those in the Inventory. Conclusions: Early identification and sharing of best strategies of recruitment among all recruiting sites can be effective in increasing recruitment of critically ill infants with congenital cardiac disease and possibly other populations. Strategies of recruitment should focus on those that build relationships with families and create partnerships with the medical providers who care for them. Competing studies pose challenges for enrolment in trials, but fostering trusting relationships with families can result in successful enrolment into multiple studies. C1 [Pike, Nancy A.] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90095 USA. [Pemberton, Victoria; Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. [Allen, Kerstin] New England Res Inst, Watertown, MA 02172 USA. [Jacobs, Jeffrey P.] Univ S Florida, All Childrens Hosp, Congenital Heart Inst Florida, St Petersburg, FL 33701 USA. [Hsu, Daphne T.] Childrens Hosp Montefiore, Div Cardiol, Bronx, NY USA. [Lewis, Alan B.] Childrens Hosp Los Angeles, Div Cardiol, Los Angeles, CA 90027 USA. [Ghanayem, Nancy] Childrens Hosp Wisconsin, Div Crit Care, Milwaukee, WI 53201 USA. [Lambert, Linda] Primary Childrens Med Ctr, Div Pediat Cardiothorac Surg, Salt Lake City, UT 84103 USA. [Crawford, Kari] Levine Childrens Hosp, Div Pediat Cardiol, Charlotte, NC USA. [Atz, Teresa] Med Univ S Carolina, Div Pediat Cardiol, Charleston, SC 29425 USA. [Korsin, Rosalind] Columbia Univ, Div Pediat Cardiol, New York, NY USA. [Xu, Mingfen] Duke Univ, Med Ctr, Div Pediat Cardiol, Durham, NC USA. [Ravishankar, Chitra] Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Cnota, James] Cincinnati Childrens Hosp Med Ctr, Div Cardiol, Cincinnati, OH USA. RP Pike, NA (reprint author), Univ Calif Los Angeles, Sch Nursing, 700 Tiverton Ave,Factor Bldg Room 3-938, Los Angeles, CA 90095 USA. EM npike@sonnet.ucla.edu OI Hsu, Daphne/0000-0002-2654-0430 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057]; Food and Drug Administration Office of Orphan Products Development FX Supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057) and the Food and Drug Administration Office of Orphan Products Development. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institute of Health. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00113087. NR 37 TC 4 Z9 4 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1047-9511 J9 CARDIOL YOUNG JI Cardiol. Young PD APR PY 2013 VL 23 IS 2 BP 248 EP 257 DI 10.1017/S1047951112000832 PG 10 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 139ZE UT WOS:000318623000012 PM 22931751 ER PT J AU Heitmann, RJ Hill, MJ Richter, KS DeCherney, AH Widra, EA AF Heitmann, Ryan J. Hill, Micah J. Richter, Kevin S. DeCherney, Alan H. Widra, Eric A. TI The simplified SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers SO JOURNAL OF ASSISTED REPRODUCTION AND GENETICS LA English DT Article DE In-vitro fertilization; Single blastocycst transfer; Embryo morphology; Implantation; Live birth ID ASSISTED REPRODUCTIVE TECHNOLOGY; PREGNANCY RATES; TRANSFER POLICY; IVF PROGRAM; OUTCOMES AB Prior studies have validated the ability of the SART embryo scoring system to correlate with outcomes in cleavage stage embryo transfers. However, this scoring system has not been evaluated in blastocyst transfers. The objective of this study was to estimate the correlation between the simplified SART embryo scoring system and ART cycle outcomes in single blastocyst transfers. All fresh, autologous single blastocyst transfers cycles from a large ART center from 2010 were analyzed. Blastocysts were given a single grade of good, fair, or poor based upon SART criteria which combines the grading of the inner cell mass and trophectoderm. Multiple logistic regression assessed the predictive value of the SART grade on embryo implantation and live birth. Seven hundred seventeen fresh, autologous single blastocyst transfers cycles were included in the analysis. The live birth rate was 52 % and included both elective and non-elective SBT. Chi square analysis showed higher live birth in good grade embryos as compared to fair (p = 0.03) and poor (p = 0.02). Univariate binary logistic regression analysis demonstrated SART embryo grading to be significantly correlated with both implantation and live birth (p < 0.01). This significance persisted when patient age, BMI, and the stage of the blastocyst were controlled for with multiple logistic regression. In five patients with a poor blastocyst score, there were no live births. These data demonstrate that the SART embryo scoring system is highly correlated to implantation and live birth in single blastocyst transfers. Patients with a good grade embryo are excellent candidates for a single blastocyst transfer. C1 [Heitmann, Ryan J.; Hill, Micah J.; DeCherney, Alan H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Richter, Kevin S.; Widra, Eric A.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Widra, EA (reprint author), Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. EM eric.widra@integramed.com FU intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH FX This research was supported, in part, by the intramural research program of the Program in Reproductive and Adult Endocrinology, NICHD, NIH. NR 18 TC 13 Z9 13 U1 0 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1058-0468 J9 J ASSIST REPROD GEN JI J. Assist. Reprod. Genet. PD APR PY 2013 VL 30 IS 4 BP 563 EP 567 DI 10.1007/s10815-013-9932-1 PG 5 WC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology SC Genetics & Heredity; Obstetrics & Gynecology; Reproductive Biology GA 136NM UT WOS:000318368600014 PM 23443889 ER PT J AU Bouladoux, N Hand, TW Naik, S Belkaid, Y AF Bouladoux, Nicolas Hand, Timothy W. Naik, Shruti Belkaid, Yasmine TI Microbiota and T lymphocytes: the best enemies SO M S-MEDECINE SCIENCES LA French DT News Item ID CELL RESPONSES C1 [Bouladoux, Nicolas; Hand, Timothy W.; Naik, Shruti; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bouladoux, N (reprint author), NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM bouladon@niaid.nih.gov FU Intramural NIH HHS [Z99 AI999999, ZIA AI001115-01] NR 11 TC 2 Z9 2 U1 0 U2 3 PU EDP SCIENCES S A PI LES ULIS CEDEX A PA 17, AVE DU HOGGAR, PA COURTABOEUF, BP 112, F-91944 LES ULIS CEDEX A, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD APR PY 2013 VL 29 IS 4 BP 349 EP 352 DI 10.1051/medsci/2013294005 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 140PV UT WOS:000318668300005 PM 23621927 ER PT J AU Chandramohan, V Keir, ST Bao, XH Pastan, IH Kuan, CT Bigner, DD AF Chandramohan, Vidyalakshmi Keir, Stephen T. Bao, Xuhui Pastan, Ira H. Kuan, Chien-Tsun Bigner, Darell D. TI DEVELOPMENT OF A NOVEL, SINGLE-CHAIN, TRISPECIFIC IMMUNOTOXIN, D2C7-Mel-14-PE38KDEL FOR TARGETED PEDIATRIC BRAIN TUMOR THERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference CY MAY 16-17, 2013 CL Fort Lauderdale, FL C1 [Chandramohan, Vidyalakshmi; Keir, Stephen T.; Bao, Xuhui; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Pediat Brain Tumor Fdn Inst Duke, Durham, NC USA. [Chandramohan, Vidyalakshmi; Keir, Stephen T.; Bao, Xuhui; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Pastan, Ira H.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2013 VL 15 SU 1 MA 0031 BP 7 EP 7 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 139GR UT WOS:000318570500028 ER PT J AU Guo, CC Chang, CC Wortham, M Chen, L Kernagis, D Qin, XX Cho, YW Chi, JT Grant, G McLendon, R Yan, H Ge, K Papadopoulos, N Bigner, D He, YP AF Guo, Changcun Chang, Chun-Chi Wortham, Matthew Chen, Lee Kernagis, Dawn Qin, Xiaoxia Cho, Young-wook Chi, Jen-Tsan Grant, Gerald McLendon, Roger Yan, Hai Ge, Kai Papadopoulos, Nickolas Bigner, Darell He, Yiping TI GLOBAL IDENTIFICATION OF MLL2-TARGETED LOCI REVEALS MLL2'S ROLE IN DIVERSE SIGNALING PATHWAYS SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference CY MAY 16-17, 2013 CL Fort Lauderdale, FL C1 [Guo, Changcun; Chang, Chun-Chi; Wortham, Matthew; Chen, Lee; Kernagis, Dawn; Qin, Xiaoxia; Chi, Jen-Tsan; Grant, Gerald; McLendon, Roger; Yan, Hai; Bigner, Darell; He, Yiping] Duke Univ, Med Ctr, Durham, NC USA. [Cho, Young-wook; Ge, Kai] NIDDK, NIH, Bethesda, MD USA. [Papadopoulos, Nickolas] Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2013 VL 15 SU 1 MA 0037 BP 9 EP 9 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 139GR UT WOS:000318570500034 ER PT J AU Kuan, CT Chandramohan, V Keir, S Pastan, I Bigner, D AF Kuan, Chien-Tsun Chandramohan, Vidyalakshmi Keir, Stephen Pastan, Ira Bigner, Darell TI GENERATION OF ANTI-PDGFR alpha IMMUNOTOXINS FOR BRAINSTEM GLIOMA TREATMENT SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference CY MAY 16-17, 2013 CL Fort Lauderdale, FL C1 [Kuan, Chien-Tsun; Chandramohan, Vidyalakshmi; Keir, Stephen; Bigner, Darell] Duke Univ, Med Ctr, Durham, NC USA. [Pastan, Ira] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2013 VL 15 SU 1 MA 0147 BP 39 EP 40 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 139GR UT WOS:000318570500142 ER PT J AU Hutt, M Nazarian, J Price, A Lim, KJ Warren, K Chang, H Eberhart, CG Raabe, EH AF Huett, Marianne Nazarian, Javad Price, Antoinette Lim, Kah Jing Warren, Katherine Chang, Howard Eberhart, Charles G. Raabe, Eric H. TI TARGETING THE NOTCH AND mTOR PATHWAYS IN DIFFUSE INTRINSIC PONTINE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference CY MAY 16-17, 2013 CL Fort Lauderdale, FL C1 [Huett, Marianne; Price, Antoinette; Lim, Kah Jing; Eberhart, Charles G.; Raabe, Eric H.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Nazarian, Javad] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Warren, Katherine] NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Chang, Howard] Michigan State Univ, Coll Med, E Lansing, MI 48824 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2013 VL 15 SU 1 MA 0165 BP 44 EP 44 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 139GR UT WOS:000318570500159 ER PT J AU Saratsis, A Yadavilli, S Snyder, K Kambhampati, M Hall, J Raabe, E Warren, K Packer, R Nazarian, J AF Saratsis, Amanda Yadavilli, Sridevi Snyder, Kendall Kambhampati, Madhuri Hall, Jordan Raabe, Eric Warren, Kathy Packer, Roger Nazarian, Javad TI COMPARATIVE MOLECULAR ANALYSIS OF PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA REVEALS TUMOR SUBTYPES WITH DIFFERENTIAL ACTIVITY OF SONIC HEDGEHOG PATHWAY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference CY MAY 16-17, 2013 CL Fort Lauderdale, FL C1 [Saratsis, Amanda] Georgetown Univ, Sch Med, Washington, DC USA. [Yadavilli, Sridevi; Kambhampati, Madhuri; Packer, Roger; Nazarian, Javad] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Snyder, Kendall] George Washington Univ, Washington, DC USA. [Hall, Jordan] Duke Univ, Sch Med, Durham, NC USA. [Raabe, Eric] Johns Hopkins Sch Med, Baltimore, MD USA. [Warren, Kathy] NCI, Bethesda, MD 20892 USA. OI Saratsis, Amanda/0000-0002-4913-2771 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD APR PY 2013 VL 15 SU 1 MA 0178 BP 47 EP 48 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 139GR UT WOS:000318570500172 ER PT J AU Berger, JR Aksamit, AJ Clifford, DB Davis, L Koralnik, IJ Sejvar, JJ Bartt, R Major, EO Nath, A AF Berger, Joseph R. Aksamit, Allen J. Clifford, David B. Davis, Larry Koralnik, Igor J. Sejvar, James J. Bartt, Russell Major, Eugene O. Nath, Avindra TI PML diagnostic criteria Consensus statement from the AAN Neuroinfectious Disease Section SO NEUROLOGY LA English DT Review ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HUMAN IMMUNODEFICIENCY VIRUS; POLYMERASE-CHAIN-REACTION; STEREOTAXIC BRAIN BIOPSY; JC-VIRUS; CEREBROSPINAL-FLUID; MULTIPLE-SCLEROSIS; ANTIRETROVIRAL THERAPY; IMMUNE RECONSTITUTION; NATALIZUMAB AB Objective: To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML). Methods: We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms "progressive multifocal leukoencephalopathy" with or without "JC virus" were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria. Results: A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML. Conclusion: Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended. C1 [Berger, Joseph R.] Univ Kentucky, Dept Neurol, Lexington, KY 40506 USA. [Aksamit, Allen J.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Clifford, David B.] Washington Univ, St Louis, MO USA. [Davis, Larry] Univ New Mexico, Dept Neurol, Albuquerque, NM 87131 USA. [Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Div Neurovirol, Dept Neurol, Boston, MA 02215 USA. [Koralnik, Igor J.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Dept Med, Boston, MA 02215 USA. [Sejvar, James J.] Ctr Dis Control, Atlanta, GA 30333 USA. [Bartt, Russell] Blue Sky Neurosci, Englewood, CO USA. [Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. [Nath, Avindra] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. RP Berger, JR (reprint author), Univ Kentucky, Dept Neurol, Lexington, KY 40506 USA. EM jrbneuro@uky.edu FU CMSC; AAN; Bayer; BiogenIdec; PML Consortium; NIH [U10 NS077384, MH22005, AI25903, R56-NS041198, R01-NS047029, R01-NS074995, K24-NS060950]; Alzheimer Association; Biogen Idec; NeurogesX; Tibotec; Pfizer; University of Kentucky and CMSC/ACTRIMS; ECTRIMS; National MS Society; Bristol-Myers Squibb; Ono Pharmaceuticals; Merck Serono; Hoffmann La Roche; GlaxoSmithKline; Perseid Therapeutics; Vertex Pharmaceutical; Johnson Johnson FX J. Berger serves on Data Safety Boards for Millennium and Amgen; has served on scientific advisory boards or as a consultant for Amgen, Bayer, BiogenIdec, Eisai, Genzyme, GlaxoSmithKline, Genentech, Novartis, and Pfizer; has received speaking fees from CMSC, AAN, Bayer, and BiogenIdec; and receives research support from the PML Consortium. A. Aksamit reports no disclosures. D. Clifford is funded by NIH grants U10 NS077384, MH22005, AI25903, and the Alzheimer Association. He serves on Data Safety Boards for Biogen, GSK, Millennium, Genzyme, Genentech, and Pfizer; has been a consultant to Amgen, Brinker, Biddle, Reath (PML Consortium), Genentech, Genzyme, Bristol-Myers Squibb, Millennium, Biogen Idec, and Pfizer; has received research support from Biogen Idec, NeurogesX, Tibotec, and Pfizer; and has received speaking fees from University of Kentucky and CMSC/ACTRIMS and ECTRIMS. L. Davis reports no disclosures. I. Koralnik is funded by NIH grants R56-NS041198, R01-NS047029, R01-NS074995, and K24-NS060950; has received a research grant from Biogen Idec and the National MS Society; served on scientific advisory boards for Hoffmann La-Roche, GlaxoSmithKline, and Merck Serono; received consulting fees from Bristol-Myers Squibb, Ono Pharmaceuticals, Merck Serono, Hoffmann La Roche, GlaxoSmithKline, Perseid Therapeutics, Vertex Pharmaceutical, and Johnson & Johnson; and receives royalties from Up-To-Date for topics on the management of HIV and CNS mass lesions and on PML. J. Sejvar, R. Bartt, E. Major, and A. Nath report no disclosures. Go to Neurology.org for full disclosures. NR 61 TC 122 Z9 125 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 15 BP 1430 EP 1438 DI 10.1212/WNL.0b013e31828c2fa1 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 139RM UT WOS:000318601600017 PM 23568998 ER PT J AU Martinez, A Finegersh, A Cannon, DM Dustin, I Nugent, A Herscovitch, P Theodore, WH AF Martinez, Ashley Finegersh, Andrey Cannon, Dara M. Dustin, Irene Nugent, Alison Herscovitch, Peter Theodore, William H. TI The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy SO NEUROLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SEROTONIN TRANSPORTER; MAJOR DEPRESSION; BIPOLAR DISORDER; HUMAN BRAIN; BINDING; PET; GENE; SEIZURES; EPISODES AB Objective: To study 5-HT transport and 5-HT1A receptors in temporal lobe epilepsy (TLE) and depression. Methods: Thirteen patients had PET with [C-11]DASB for 5-HTT and [F-18]FCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [C-11]DASB, 19 had [F-18]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [C-11]DASB binding. [F-18]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci. Results: Mean regional [C-11]DASB binding and asymmetry did not differ between patients and controls. [F-18]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [C-11]DASB asymmetry, with significantly higher [C-11]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [F-18]FCWAY asymmetry and [C-11]DASB asymmetry. Conclusions: Our study showed increased [C-11]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression. C1 [Martinez, Ashley; Finegersh, Andrey; Dustin, Irene; Theodore, William H.] NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Herscovitch, Peter] NIMH, PET Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Nugent, Alison] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Cannon, Dara M.] Natl Univ Ireland Galway, Clin Neuroimaging Lab, Dept Anat, Galway, Ireland. [Cannon, Dara M.] Natl Univ Ireland Galway, Dept Psychiat, Galway, Ireland. RP Theodore, WH (reprint author), NINDS, Clin Epilepsy Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov RI Cannon, Dara/C-1323-2009; OI Cannon, Dara/0000-0001-7378-3411; Nugent, Allison/0000-0003-2569-2480 FU Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH; GlaxoSmithKline FX Supported by Division of Intramural Research, National Institute of Neurological Disorders and Stroke, NIH.; A. Martinez and A. Finegersh report no disclosures. D. M. Cannon received research support from GlaxoSmithKline. I. Dustin, A. Nugent, and P. Herscovitch report no disclosures. W. H. Theodore receives an honorarium from Elsevier for editing Epilepsy Research. Go to Neurology.org for full disclosures. NR 40 TC 17 Z9 17 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 16 BP 1465 EP 1471 DI 10.1212/WNL.0b013e31828cf809 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 139TB UT WOS:000318606300008 PM 23516322 ER PT J AU Bhanushali, MJ Kranick, SM Freeman, AF Cuellar-Rodriguez, JM Battiwalla, M Gea-Banacloche, JC Hickstein, DD Pavletic, S Fahle, G Nath, A AF Bhanushali, Minal J. Kranick, Sarah M. Freeman, Alexandra F. Cuellar-Rodriguez, Jennifer M. Battiwalla, Minoo Gea-Banacloche, Juan C. Hickstein, Dennis D. Pavletic, Steven Fahle, Gary Nath, Avindra TI Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation SO NEUROLOGY LA English DT Article ID HUMAN HERPESVIRUS-6 ENCEPHALITIS; CLINICAL-FEATURES; HUMAN-HERPESVIRUS-6; RECIPIENTS AB Objective: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review. Methods: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT. Results: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT. Conclusion: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research. C1 [Bhanushali, Minal J.; Kranick, Sarah M.; Nath, Avindra] NINDS, NIH, Bethesda, MD 20892 USA. [Freeman, Alexandra F.; Cuellar-Rodriguez, Jennifer M.] NIAID, NIH, Bethesda, MD 20892 USA. [Battiwalla, Minoo] Natl Inst Heart Lung & Blood Inst NHLBI, Bethesda, MD USA. [Gea-Banacloche, Juan C.; Hickstein, Dennis D.; Pavletic, Steven] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Fahle, Gary] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Kranick, SM (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM sarah.kranick@nih.gov FU NIH; NINDS; NIAID; NHLBI; NCI FX This research was supported by the Intramural Research Program of the NIH, NINDS, NIAID, NHLBI, and NCI. NR 15 TC 23 Z9 24 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 16 BP 1494 EP 1500 DI 10.1212/WNL.0b013e31828cf8a2 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 139TB UT WOS:000318606300012 PM 23516318 ER PT J AU Bharucha-Goebel, DX Santi, M Medne, L Zukosky, K Dastgir, J Shieh, PB Winder, T Tennekoon, G Finkel, RS Dowling, JJ Monnier, N Bonnemann, CG AF Bharucha-Goebel, Diana Xerxes Santi, Mariarita Medne, Livija Zukosky, Kristin Dastgir, Jahannaz Shieh, Perry B. Winder, Thomas Tennekoon, Gihan Finkel, Richard S. Dowling, James J. Monnier, Nicole Boennemann, Carsten G. TI Severe congenital RYR1-associated myopathy The expanding clinicopathologic and genetic spectrum SO NEUROLOGY LA English DT Article ID CENTRAL CORE DISEASE; RYANODINE RECEPTOR RYR1; MALIGNANT HYPERTHERMIA; MUTATIONS; DOMINANT AB Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients. Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed. Results: Clinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores. Conclusions: This series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context. C1 [Bharucha-Goebel, Diana Xerxes; Medne, Livija; Tennekoon, Gihan] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA USA. [Santi, Mariarita] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA USA. [Zukosky, Kristin; Dastgir, Jahannaz; Boennemann, Carsten G.] NINDS, Neurogenet Branch, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Shieh, Perry B.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Winder, Thomas] Prevent Genet, Marshfield, WI USA. [Finkel, Richard S.] Nemours Childrens Hosp, Div Neurol, Orlando, FL USA. [Dowling, James J.] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA. [Monnier, Nicole] CHU Grenoble, Inst Biol & Pathol, Grenoble, France. RP Bonnemann, CG (reprint author), NINDS, Neurogenet Branch, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM carsten.bonnemann@nih.gov FU PTC Therapeutics; Genzyme Corp.; Santhera Pharmaceuticals [U54AR0526446-03, 1U54NS065712-01, 5R21NS058926-02, 5U54AR052646-03, R01NS043264, NHHSN265200423611C, RO1AR056973]; Spinal Muscular Atrophy Foundation; Families of Spinal Muscular Atrophy; Foundation for the Eradication of Duchenne; Muscular Dystrophy Association; Charcot-Marie-Tooth Association; Merck Pharmaceuticals [RC1AR058606, 09/30/2009-11, 1R21 AI078387, 07/01/2008-10, 1R21 AI078387-S1, 06/05/09-10/31/09, 1R41 A1071927, PI, 8/15/2006-10, R01 A1063623, 12/1/2004-09, 1U19AIO82726, 5/8/2009-14]; NIH [07/01/99-06/30/14, R01AI063623, 12/01/04-11/30/09, NIH1U19AI082726, 05/08/09-04/30/14, 04/01/09-03/31/13, 07/01/09-06/30/12]; Southern Biotechnology Associates; Upstate Pharmaceuticals; Santa Cruz Biotechnology FX D.X. Bharucha-Goebel, M. Santi, L. Medne, K. Zukosky, and J. Dastgir report no disclosures. P. B. Shieh is on the speaker's bureau for Grifols and has also served on the Neurology Advisory Board for Grifols. T. Winder is employed by the clinical laboratory-Prevention Genetics. G. Tennekoon reports no disclosures. R. S. Finkel serves on an advisory board for PTC Therapeutics, DuchenneConnect, Families of SMA, TREAT-NMD, and AVI (DSMB); consults with Isis Pharmaceuticals; receives commercial research support from PTC Therapeutics, Genzyme Corp., and Santhera Pharmaceuticals; receives government funding grants U54AR0526446-03, 1U54NS065712-01, 5R21NS058926-02, 5U54AR052646-03, R01NS043264, NHHSN265200423611C, and RO1AR056973; and receives research support from the Spinal Muscular Atrophy Foundation, Families of Spinal Muscular Atrophy, Foundation for the Eradication of Duchenne, Muscular Dystrophy Association, and Charcot-Marie-Tooth Association. His spouse (Dr. T. H. Finkel) receives commercial research support from Merck Pharmaceuticals; receives government funding grants (1) RC1AR058606, PI, 09/30/2009-11; (2) 1R21 AI078387, PI, 07/01/2008-10; (3) 1R21 AI078387-S1, PI, 06/05/09-10/31/09; (4) 1R41 A1071927, PI, 8/15/2006-10; (5) R01 A1063623, Co-I, 12/1/2004-09; (6) 1U19AIO82726, Co-I, 5/8/2009-14; (7) NIH, Program Project Core Director, 10% effort, 07/01/99-06/30/14 "Mechanism of Autoreactivity in SLE"; (8) R01AI063623 Co-I, 7.5% effort, 12/01/04-11/30/09 "High-throughput Selection for HIV-1 Resistant Viruses"; (9) NIH1U19AI082726 Program Project Co-I, 05/08/09-04/30/14 "Regulation of Type I IFNs in Tolerance and Autoimmunity"; (10) NIH R01 Co-I, 5% effort, 04/01/09-03/31/13 "Role of Small G Proteins in TCR-Cytoskeleton Interaction"; and (11) NIH T32 training grant Project Leader, 07/01/09-06/30/12; and receives licensing fee payments for technology or inventions from Southern Biotechnology Associates, Upstate Pharmaceuticals, and Santa Cruz Biotechnology. J. J. Dowling, N. Monnier, and C. G. Bonnemann report no disclosures. Go to Neurology.org for full disclosures. NR 24 TC 20 Z9 21 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 17 BP 1584 EP 1589 DI 10.1212/WNL.0b013e3182900380 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 140ZC UT WOS:000318694000012 PM 23553484 ER PT J AU Tsivgoulis, G Judd, S Letter, AJ Alexandrov, AV Howard, G Nahab, F Unverzagt, FW Moy, C Howard, VJ Kissela, B Wadley, VG AF Tsivgoulis, Georgios Judd, Suzanne Letter, Abraham J. Alexandrov, Andrei V. Howard, George Nahab, Fadi Unverzagt, Frederick W. Moy, Claudia Howard, Virginia J. Kissela, Brett Wadley, Virginia G. TI Adherence to a Mediterranean diet and risk of incident cognitive impairment SO NEUROLOGY LA English DT Article ID WHITE COMMUNITY RESIDENTS; ALZHEIMERS-DISEASE; RACIAL-DIFFERENCES; UNITED-STATES; STROKE REGARDS; FATTY-ACIDS; DEMENTIA; PREVALENCE; REASONS; BLACK AB Objective: We sought to determine the relationship of greater adherence to Mediterranean diet (MeD) and likelihood of incident cognitive impairment (ICI) and evaluate the interaction of race and vascular risk factors. Methods: A prospective, population-based, cohort of individuals enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 2003-2007, excluding participants with history of stroke, impaired cognitive status at baseline, and missing data on Food Frequency Questionnaires (FFQ), was evaluated. Adherence to a MeD (scored as 0-9) was computed from FFQ. Cognitive status was evaluated at baseline and annually during a mean follow-up period of 4.0 +/- 1.5 years using Six-item-Screener. Results: ICI was identified in 1,248 (7%) out of 17,478 individuals fulfilling the inclusion criteria. Higher adherence to MeD was associated with lower likelihood of ICI before (odds ratio [lsqb] OR [rsqb] 0.89; 95% confidence interval [lsqb] CI[rsqb] 0.79-1.00) and after adjustment for potential confounders (OR 0.87; 95% CI 0.76-1.00) including demographic characteristics, environmental factors, vascular risk factors, depressive symptoms, and self-reported health status. There was no interaction between race (p = 0.2928) and association of adherence to MeD with cognitive status. However, we identified a strong interaction of diabetes mellitus (p = 0.0134) on the relationship of adherence to MeD with ICI; high adherence to MeD was associated with a lower likelihood of ICI in nondiabetic participants (OR 0.81; 95% CI 0.70-0.94; p = 0.0066) but not in diabetic individuals (OR 1.27; 95% CI 0.95-1.71; p = 0.1063). Conclusions: Higher adherence to MeD was associated with a lower likelihood of ICI independent of potential confounders. This association was moderated by presence of diabetes mellitus. C1 Univ Athens, Dept Neurol 2, Sch Med, Attikon Hosp, GR-10679 Athens, Greece. [Tsivgoulis, Georgios; Alexandrov, Andrei V.] Univ Alabama Birmingham, Comprehens Stroke Ctr, Birmingham, AL USA. [Judd, Suzanne; Letter, Abraham J.; Howard, George] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL USA. [Howard, Virginia J.] Univ Alabama Birmingham, Dept Epidemiol, Sch Publ Hlth, Birmingham, AL USA. [Wadley, Virginia G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Tsivgoulis, Georgios] St Annes Univ Hosp Brno, Int Clin Res Ctr, Brno, Czech Republic. [Nahab, Fadi] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Unverzagt, Frederick W.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN USA. [Moy, Claudia] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Kissela, Brett] Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. RP Tsivgoulis, G (reprint author), Univ Alabama Birmingham, Comprehens Stroke Ctr, Birmingham, AL USA. EM tsivgoulisgiorg@yahoo.gr OI Alexandrov, Andrei V/0000-0001-8871-1023; Kissela, Brett/0000-0002-9773-4013 FU National Institute of Neurological Disorders and Stroke, NIH, Department of Health and Human Services [U01 NS041588]; European Regional Development Fund Project FNUSA-ICRC [CZ.1.05/1.1.00/02.0123] FX Supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, NIH, Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views and positions of the National Institute of Neurological Disorders and Stroke or the NIH. Representatives of the funding agency were involved in the review of the manuscript prior to submission for publication. G. Tsivgoulis has been supported by European Regional Development Fund Project FNUSA-ICRC (no. CZ.1.05/1.1.00/02.0123). NR 40 TC 23 Z9 27 U1 5 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 18 BP 1684 EP 1692 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 141AC UT WOS:000318696600017 PM 23628929 ER PT J AU Dietz, J Bradley, MM Jones, J Okun, MS Perlstein, WM Bowers, D AF Dietz, J. Bradley, M. M. Jones, J. Okun, M. S. Perlstein, W. M. Bowers, D. TI The late positive potential, emotion and apathy in Parkinson's disease SO NEUROPSYCHOLOGIA LA English DT Article DE Parkinson's disease; ERP; Late positive potential; Apathy; Emotion ID BASAL GANGLIA; BRAIN POTENTIALS; ATTENTION; SCHIZOPHRENIA; EXPRESSIVITY; NEGATIVITY; DEPRESSION; MOTIVATION; CIRCUITS; AROUSAL AB Parkinson's disease is associated with emotional changes including depression, apathy, and anxiety. The current study investigated emotional processing in non-demented individuals with Parkinson disease (PD) using an electrophysiological measure, the centro-parietal late positive potential (LPP). Non-demented patients with Parkinson's disease (n=17) and healthy control participants (n=16) viewed pleasant, neutral, and unpleasant pictures while EEG was recorded from a 64-channel geodesic net. The Parkinson patients did not differ from controls in terms of early electrophysiological components that index perceptual processing (occipital P100, N150, P250). Parkinson patients, however, showed reduced LPP amplitude specifically when viewing unpleasant, compared to pleasant, pictures as well as when compared to controls, consistent with previous studies suggesting a specific difference in aversive processing between PD patients and healthy controls. Importantly, LPP amplitude during unpleasant picture viewing was most attenuated for patients reporting high apathy. The data suggest that apathy in PD may be related to a deficit in defensive activation, and may be indexed cortically using event-related potentials. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Dietz, J.; Jones, J.; Perlstein, W. M.; Bowers, D.] Univ Florida, Dept Clin & Hlth Psychol, Gainesville, FL 32610 USA. [Dietz, J.; Bradley, M. M.] Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32611 USA. [Dietz, J.; Okun, M. S.; Bowers, D.] Ctr Movement Disorders & Neurorestorat, Gainesville, FL 32601 USA. [Jones, J.; Okun, M. S.; Bowers, D.] Univ Florida, Dept Neurol, Gainesville, FL 32611 USA. Univ Florida, Dept Neurosurg, Gainesville, FL 32611 USA. RP Dietz, J (reprint author), Univ Florida, POB 100165, Gainesville, FL 32610 USA. EM jdietz@phhp.ufl.edu OI jones, jacob/0000-0003-3544-7294; Okun, Michael/0000-0002-6247-9358 FU NINDS [F31NS073331-01, NS-079767]; National Parkinson Foundation Center of Excellence, Gaineville, FL FX This work was supported by NINDS (F31NS073331-01[JD]; NS-079767), the National Parkinson Foundation Center of Excellence, Gaineville, FL. NR 50 TC 11 Z9 12 U1 5 U2 32 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD APR PY 2013 VL 51 IS 5 BP 960 EP 966 DI 10.1016/j.neuropsychologia.2013.01.001 PG 7 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 140QK UT WOS:000318669800020 PM 23320979 ER PT J AU Makarova, KS Wolf, YI Koonin, EV AF Makarova, Kira S. Wolf, Yuri I. Koonin, Eugene V. TI Comparative genomics of defense systems in archaea and bacteria SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TOXIN-ANTITOXIN SYSTEMS; CRISPR-CAS SYSTEMS; RESTRICTION-MODIFICATION SYSTEMS; STREPTOMYCES-COELICOLOR A3(2); MESSENGER-RNA INTERFERASES; ABORTIVE INFECTION SYSTEM; HORIZONTAL GENE-TRANSFER; STRESS-RESPONSE SYSTEMS; ESCHERICHIA-COLI; IMMUNE-SYSTEM AB Our knowledge of prokaryotic defense systems has vastly expanded as the result of comparative genomic analysis, followed by experimental validation. This expansion is both quantitative, including the discovery of diverse new examples of known types of defense systems, such as restriction-modification or toxin-antitoxin systems, and qualitative, including the discovery of fundamentally new defense mechanisms, such as the CRISPR-Cas immunity system. Large-scale statistical analysis reveals that the distribution of different defense systems in bacterial and archaeal taxa is non-uniform, with four groups of organisms distinguishable with respect to the overall abundance and the balance between specific types of defense systems. The genes encoding defense system components in bacterial and archaea typically cluster in defense islands. In addition to genes encoding known defense systems, these islands contain numerous uncharacterized genes, which are candidates for new types of defense systems. The tight association of the genes encoding immunity systems and dormancy- or cell death-inducing defense systems in prokaryotic genomes suggests that these two major types of defense are functionally coupled, providing for effective protection at the population level. C1 [Makarova, Kira S.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU US Department of Health and Human Services; Intramural funds of the US Department of Health and Human Services FX Intramural funds of the US Department of Health and Human Services (to National Library of Medicine). Funding for open access charge: Intramural funds of the US Department of Health and Human Services (to National Library of Medicine). NR 139 TC 93 Z9 94 U1 9 U2 81 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 8 BP 4360 EP 4377 DI 10.1093/nar/gkt157 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139GJ UT WOS:000318569700010 PM 23470997 ER PT J AU Lander, GC Johnson, JE Rau, DC Potter, CS Carragher, B Evilevitch, A AF Lander, Gabriel C. Johnson, John E. Rau, Donald C. Potter, Clinton S. Carragher, Bridget Evilevitch, Alex TI DNA bending-induced phase transition of encapsidated genome in phage lambda SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LIQUID-CRYSTALLINE PHASE; DOUBLE-STRANDED DNA; DOUBLE HELICES; HYDRATION FORCES; CHOLESTERIC ORGANIZATION; CRYOELECTRON MICROSCOPY; INTERMOLECULAR FORCES; BACTERIOPHAGE; EJECTION; ATTRACTION AB The DNA structure in phage capsids is determined by DNA-DNA interactions and bending energy. The effects of repulsive interactions on DNA interaxial distance were previously investigated, but not the effect of DNA bending on its structure in viral capsids. By varying packaged DNA length and through addition of spermine ions, we transform the interaction energy from net repulsive to net attractive. This allowed us to isolate the effect of bending on the resulting DNA structure. We used single particle cryo-electron microscopy reconstruction analysis to determine the interstrand spacing of double-stranded DNA encapsidated in phage lambda capsids. The data reveal that stress and packing defects, both resulting from DNA bending in the capsid, are able to induce a long-range phase transition in the encapsidated DNA genome from a hexagonal to a cholesteric packing structure. This structural observation suggests significant changes in genome fluidity as a result of a phase transition affecting the rates of viral DNA ejection and packaging. C1 [Lander, Gabriel C.; Johnson, John E.; Potter, Clinton S.; Carragher, Bridget] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. [Rau, Donald C.] NIH, Lab Phys & Struct Biol, Program Phys Biol, Bethesda, MD 20892 USA. [Evilevitch, Alex] Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. [Evilevitch, Alex] Lund Univ, Dept Biochem & Struct Biol, Lund, Sweden. RP Evilevitch, A (reprint author), Carnegie Mellon Univ, Dept Phys, 5000 Forbes Ave, Pittsburgh, PA 15213 USA. EM alexe@cmu.edu RI Evilevitch, Alex/P-3103-2014 OI Evilevitch, Alex/0000-0002-0245-9574 FU National Institutes of Health (NIH) through the National Center for Research Resources' P41 program [RR017573]; Swedish Research Council, VR [622-2008-726]; NSF [CHE-1152770]; Damon Runyon Cancer Research Foundation; NIH [R01 GM 54076-16, R01 AI 5R01AI040101]; Intramural Research Program of the National Institutes of Health (in part), NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) FX The authors would like to thank Ting Liu and Dave Bauer for help with UV measurements, and William Gelbart, Luca Tubiana, Anton Petrov and Martin Castelnovo for important feedback and discussions. Electron microscopic imaging and reconstruction were conducted at the National Resource for Automated Molecular Microscopy, which is supported by the National Institutes of Health (NIH) through the National Center for Research Resources' P41 program [RR017573].; Swedish Research Council, VR [622-2008-726 to A.E.]; NSF [CHE-1152770 to A.E.]. G.C.L. acknowledges support from Damon Runyon Cancer Research Foundation. NIH [R01 GM 54076-16 to J.E.J.]; NIH [R01 AI 5R01AI040101 to J.E.J.]; Intramural Research Program of the National Institutes of Health (in part), NICHD (Eunice Kennedy Shriver National Institute of Child Health and Human Development) (to D. C. R.). Funding for open access charge: NSF [CHE-1152770 to A.E.]. NR 47 TC 11 Z9 11 U1 0 U2 24 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 8 BP 4518 EP + DI 10.1093/nar/gkt137 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139GJ UT WOS:000318569700001 PM 23449219 ER PT J AU Bowen, S Wangsa, D Ried, T Livak, F Hodes, RJ AF Bowen, Steven Wangsa, Darawalee Ried, Thomas Livak, Ferenc Hodes, Richard J. TI Concurrent V(D)J recombination and DNA end instability increase interchromosomal trans-rearrangements in ATM-deficient thymocytes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID T-CELL-RECEPTOR; RECURRENT CHROMOSOMAL TRANSLOCATIONS; DOUBLE-STRAND BREAKS; ATAXIA-TELANGIECTASIA; 12/23 RULE; IN-VIVO; B-CELLS; LYMPHOCYTES; RAG; IMMUNOGLOBULIN AB During the CD4(-)CD8(-) (DN) stage of T-cell development, RAG-dependent DNA breaks and V(D)J recombination occur at three T-cell receptor (TCR) loci: TCR beta, TCR gamma and TCR delta. During this stage, abnormal trans-rearrangements also take place between TCR loci, occurring at increased frequency in absence of the DNA damage response mediator ataxia telangiectasia mutated (ATM). Here, we use this model of physiologic trans-rearrangement to study factors that predispose to rearrangement and the role of ATM in preventing chromosomal translocations. The frequency of DN thymocytes with DNA damage foci at multiple TCR loci simultaneously is increased 2- to 3-fold in the absence of ATM. However, trans-rearrangement is increased 10 000- to 100 000-fold, indicating that ATM function extends beyond timely resolution of DNA breaks. RAG-mediated synaptic complex formation occurs between recombination signal sequences with unequal 12 and 23 base spacer sequences (12/23 rule). TCR trans-rearrangements violate this rule, as we observed similar frequencies of 12/23 and aberrant 12/12 or 23/23 recombination products. This suggests that trans-rearrangements are not the result of trans-synaptic complex formation, but they are instead because of unstable cis synaptic complexes that form simultaneously at distinct TCR loci. Thus, ATM suppresses trans-rearrangement primarily through stabilization of DNA breaks at TCR loci. C1 [Bowen, Steven] Univ Maryland, Dept Microbiol & Immunol, Grad Program Life Sci, Baltimore, MD 21201 USA. [Bowen, Steven; Hodes, Richard J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wangsa, Darawalee; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Livak, Ferenc] Univ Maryland, Marlene & Stuart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Bowen, S (reprint author), Univ Maryland, Dept Microbiol & Immunol, Grad Program Life Sci, Baltimore, MD 21201 USA. EM bowense@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institutes of Health intramural program FX Intramural Research Program of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Funding for open access charge: National Institutes of Health intramural program. NR 45 TC 13 Z9 13 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 8 BP 4535 EP 4548 DI 10.1093/nar/gkt154 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139GJ UT WOS:000318569700023 PM 23470994 ER PT J AU Seol, Y Hardin, AH Strub, MP Charvin, G Neuman, KC AF Seol, Yeonee Hardin, Ashley H. Strub, Marie-Paule Charvin, Gilles Neuman, Keir C. TI Comparison of DNA decatenation by Escherichia coli topoisomerase IV and topoisomerase III: implications for non-equilibrium topology simplification SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LOCAL JUXTAPOSITION GEOMETRY; SINGLE-MOLECULE MEASUREMENTS; DOUBLE-STRAND BREAKS; TYPE-2 TOPOISOMERASES; MAGNETIC TWEEZERS; ATP HYDROLYSIS; MECHANISM; DISCRIMINATION; REPLICATION; SPECIFICITY AB Type II topoisomerases are essential enzymes that regulate DNA topology through a strand-passage mechanism. Some type II topoisomerases relax supercoils, unknot and decatenate DNA to below thermodynamic equilibrium. Several models of this non-equilibrium topology simplification phenomenon have been proposed. The kinetic proofreading (KPR) model postulates that strand passage requires a DNA-bound topoisomerase to collide twice in rapid succession with a second DNA segment, implying a quadratic relationship between DNA collision frequency and relaxation rate. To test this model, we used a single-molecule assay to measure the unlinking rate as a function of DNA collision frequency for Escherichia coli topoisomerase IV (topo IV) that displays efficient non-equilibrium topology simplification activity, and for E. coli topoisomerase III (topo III), a type IA topoisomerase that unlinks and unknots DNA to equilibrium levels. Contrary to the predictions of the KPR model, topo IV and topo III unlinking rates were linearly related to the DNA collision frequency. Furthermore, topo III exhibited decatenation activity comparable with that of topo IV, supporting proposed roles for topo III in DNA segregation. This study enables us to rule out the KPR model for non-equilibrium topology simplification. More generally, we establish an experimental approach to systematically control DNA collision frequency. C1 [Seol, Yeonee; Hardin, Ashley H.; Strub, Marie-Paule; Neuman, Keir C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Charvin, Gilles] Inst Genet & Biol Mol & Cellulaire, F-67400 Illkirch Graffenstaden, France. RP Neuman, KC (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 10, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011; OI Neuman, Keir/0000-0002-0863-5671; charvin, gilles/0000-0002-6852-6952 FU National Heart, Lung, and Blood Institute, National Institutes of Health; Young Investigator Award from the Human Frontiers Science Program FX Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (in part); Young Investigator Award from the Human Frontiers Science Program (to K.C.N.) (in part). Funding for open access charge: The Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 49 TC 8 Z9 8 U1 2 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 8 BP 4640 EP 4649 DI 10.1093/nar/gkt136 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139GJ UT WOS:000318569700031 PM 23460205 ER PT J AU Li, FH Yin, Z Jin, GX Zhao, H Wong, STC AF Li, Fuhai Yin, Zheng Jin, Guangxu Zhao, Hong Wong, Stephen T. C. TI Chapter 17: Bioimage Informatics for Systems Pharmacology SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TIME-LAPSE MICROSCOPY; PARAMETRIC ACTIVE CONTOURS; CELL-POPULATION TRACKING; CONFOCAL IMAGE STACKS; EVERY PLANAR MAP; FLUORESCENCE MICROSCOPY; DENDRITIC SPINES; C. ELEGANS; LINEAGE CONSTRUCTION; VESSEL SEGMENTATION AB Recent advances in automated high-resolution fluorescence microscopy and robotic handling have made the systematic and cost effective study of diverse morphological changes within a large population of cells possible under a variety of perturbations, e.g., drugs, compounds, metal catalysts, RNA interference (RNAi). Cell population-based studies deviate from conventional microscopy studies on a few cells, and could provide stronger statistical power for drawing experimental observations and conclusions. However, it is challenging to manually extract and quantify phenotypic changes from the large amounts of complex image data generated. Thus, bioimage informatics approaches are needed to rapidly and objectively quantify and analyze the image data. This paper provides an overview of the bioimage informatics challenges and approaches in image-based studies for drug and target discovery. The concepts and capabilities of image-based screening are first illustrated by a few practical examples investigating different kinds of phenotypic changes caused by drugs, compounds, or RNAi. The bioimage analysis approaches, including object detection, segmentation, and tracking, are then described. Subsequently, the quantitative features, phenotype identification, and multidimensional profile analysis for profiling the effects of drugs and targets are summarized. Moreover, a number of publicly available software packages for bioimage informatics are listed for further reference. It is expected that this review will help readers, including those without bioimage informatics expertise, understand the capabilities, approaches, and tools of bioimage informatics and apply them to advance their own studies. C1 [Li, Fuhai; Yin, Zheng; Jin, Guangxu; Zhao, Hong; Wong, Stephen T. C.] Cornell Univ, Weil Med Coll, Methodist Hosp, Res Inst,NCI Ctr Modeling Canc Dev,Dept Syst Med, Houston, TX 14850 USA. RP Li, FH (reprint author), Cornell Univ, Weil Med Coll, Methodist Hosp, Res Inst,NCI Ctr Modeling Canc Dev,Dept Syst Med, Houston, TX 14850 USA. EM stwong@tmhs.org RI Yin, Zheng/J-9307-2015 OI Yin, Zheng/0000-0002-3547-0606 FU NIH [R01 LM008696, R01 CA121225, R01 LM009161, R01 AG028928, U54CA149169]; CPRIT [RP110532] FX The research is supported by NIH R01 LM008696, NIH R01 CA121225, NIH R01 LM009161, NIH R01 AG028928, NIH U54CA149169 and CPRIT RP110532. The funders had no role in the preparation of the manuscript. NR 139 TC 13 Z9 13 U1 1 U2 47 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2013 VL 9 IS 4 AR e1003043 DI 10.1371/journal.pcbi.1003043 PG 20 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 132LN UT WOS:000318069800038 PM 23633943 ER PT J AU Gomella, A Martin, EW Lynch, SK Morgan, NY Wen, H AF Gomella, Andrew Martin, Eric W. Lynch, Susanna K. Morgan, Nicole Y. Wen, Han TI Low dose hard x-ray contact microscopy assisted by a photoelectric conversion layer SO AIP ADVANCES LA English DT Article DE X-ray microscopy; X-ray tubes; zone plates ID RESOLUTION; BEAM; LITHOGRAPHY; RESIST; WATER AB Hard x-ray contact microscopy provides images of dense samples at resolutions of tens of nanometers. However, the required beam intensity can only be delivered by synchrotron sources. We report on the use of a gold photoelectric conversion layer to lower the exposure dose by a factor of 40 to 50, allowing hard x-ray contact microscopy to be performed with a compact x-ray tube. We demonstrate the method in imaging the transmission pattern of a type of hard x-ray grating that cannot be fitted into conventional x-ray microscopes due to its size and shape. Generally the method is easy to implement and can record images of samples in the hard x-ray region over a large area in a single exposure, without some of the geometric constraints associated with x-ray microscopes based on zone-plate or other magnifying optics. Copyright 2013 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 Unported License. [http://dx.doi.org/10.1063/1.4802886] C1 [Gomella, Andrew; Martin, Eric W.; Lynch, Susanna K.; Wen, Han] NHLBI, Imaging Phys Lab, Biophys & Biochem Ctr, NIH, Bethesda, MD 20892 USA. [Morgan, Nicole Y.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. RP Gomella, A (reprint author), NHLBI, Imaging Phys Lab, Biophys & Biochem Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wenh@nhlbi.nih.gov RI Wen, Han/G-3081-2010 OI Wen, Han/0000-0001-6844-2997 FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health [HL006143-01] FX We thank Keir Neuman of National Institutes for Health for his assistance with the AFM, Xianghui Xiao and Francesco deCarlo for their assistance at the APS 2-BM beamline. Part of the work was performed at the Nanofab facility of NIST. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no DE-AC02-06CH11357. The work was funded by the Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, under project # HL006143-01. NR 26 TC 0 Z9 0 U1 0 U2 4 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 2158-3226 J9 AIP ADV JI AIP Adv. PD APR PY 2013 VL 3 IS 4 AR 042121 DI 10.1063/1.4802886 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 135ER UT WOS:000318271100021 ER PT J AU Odet, F Gabel, S London, RE Goldberg, E Eddy, EM AF Odet, Fanny Gabel, Scott London, Robert E. Goldberg, Erwin Eddy, Edward M. TI Glycolysis and Mitochondrial Respiration in Mouse LDHC-Null Sperm SO BIOLOGY OF REPRODUCTION LA English DT Article DE capacitation; energy metabolism; hyperactivation; sperm motility ID PROTEIN-TYROSINE PHOSPHORYLATION; SOLUBLE ADENYLYL-CYCLASE; LACTATE-DEHYDROGENASE-C; ALPHA-CHLOROHYDRIN; ACROSOME REACTION; HUMAN SPERMATOZOA; BULL SPERMATOZOA; MALE-FERTILITY; MOTILITY; CAPACITATION AB We demonstrated previously that a knockout (KO) of the lactate dehydrogenase type C (Ldhc) gene disrupted male fertility and caused a considerable reduction in sperm glucose consumption, ATP production, and motility. While that study used mice with a mixed genetic background, the present study used C57BL/6 (B6) and 129S6 (129) Ldhc KO mice. We found that B6 KO males were subfertile and 129 KO males were infertile. Sperm from 129 wild-type (WT) mice have a lower glycolytic rate than sperm from B6 WT mice, resulting in a greater reduction in ATP production in 129 KO sperm than in B6 KO sperm. The lower glycolytic rate in 129 sperm offered a novel opportunity to examine the role of mitochondrial respiration in sperm ATP production and motility. We observed that in media containing a mitochondrial substrate (pyruvate or lactate) as the sole energy source, ATP levels and progressive motility in 129 KO sperm were similar to those in 129 WT sperm. However, when glucose was added, lactate was unable to maintain ATP levels or progressive motility in 129 KO sperm. The rate of respiration (ZO(2)) was high when 129 KO or WT sperm were incubated with lactate alone, but addition of glucose caused a reduction in ZO(2). These results indicate that in the absence of glucose, 129 sperm can produce ATP via oxidative phosphorylation, but in the presence of glucose, oxidative phosphorylation is suppressed and the sperm utilize aerobic glycolysis, a phenomenon known as the Crabtree effect. C1 [Odet, Fanny; Eddy, Edward M.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Gabel, Scott; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Goldberg, Erwin] Northwestern Univ, Dept Mol Biosci, Evanston, IL USA. RP Eddy, EM (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences [ES070076] FX Supported by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences (E.M.E., ES070076). NR 49 TC 16 Z9 18 U1 2 U2 13 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD APR PY 2013 VL 88 IS 4 AR 95 DI 10.1095/biolreprod.113.108530 PG 7 WC Reproductive Biology SC Reproductive Biology GA 138EF UT WOS:000318490800001 PM 23486916 ER PT J AU Herishanu, Y Katz, BZ Lipsky, A Wiestner, A AF Herishanu, Yair Katz, Ben-Zion Lipsky, Andrew Wiestner, Adrian TI Biology of Chronic Lymphocytic Leukemia in Different Microenvironments Clinical and Therapeutic Implications SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Chronic lymphocytic leukemia; Microenvironment; B-cell receptor signaling; Targeted therapy ID B-CELL-RECEPTOR; MARROW STROMAL CELLS; CHRONIC LYMPHOPROLIFERATIVE DISORDERS; FOLLICULAR DENDRITIC CELLS; TYROSINE KINASE INHIBITOR; MESENCHYMAL STEM-CELLS; GENE MUTATIONAL STATUS; HIGH-LEVEL EXPRESSION; HEAVY-CHAIN IIA; BONE-MARROW AB Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in peripheral blood, bone marrow, spleen, and lymph nodes. The trafficking, survival, and proliferation of CLL cells is tightly regulated by the surrounding tissue microenvironment and is mediated by antigenic stimulation, close interaction with various accessory cells and exposure to different cytokines, chemokines, and extracellular matrix components. In the last decade there have been major advances in the understanding of the reciprocal interactions between CLL cells and the various microenvironmental compartments. This article discusses the role of the microenvironment in the context of efforts to develop novel therapeutics that target the biology of CLL. C1 [Herishanu, Yair; Katz, Ben-Zion] Tel Aviv Sourasky Med Ctr, Inst Hematol, IL-64239 Tel Aviv, Israel. [Lipsky, Andrew; Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,CRC 3-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU Intramural Research Program of the National, Heart, Lung and Blood Institute, NIH FX Research Support: A.W. is supported by the Intramural Research Program of the National, Heart, Lung and Blood Institute, NIH. NR 237 TC 28 Z9 28 U1 1 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD APR PY 2013 VL 27 IS 2 BP 173 EP + DI 10.1016/j.hoc.2013.01.002 PG 35 WC Oncology; Hematology SC Oncology; Hematology GA 138SK UT WOS:000318530100003 PM 23561469 ER PT J AU Kuhrova, P Banas, P Best, RB Sponer, J Otyepka, M AF Kuehrova, Petra Banas, Pavel Best, Robert B. Sponer, Jiri Otyepka, Michal TI Computer Folding of RNA Tetraloops? Are We There Yet? SO JOURNAL OF CHEMICAL THEORY AND COMPUTATION LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; SARCIN RICIN LOOP; FORCE-FIELD; RIBOSOMAL-RNA; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; ENERGY LANDSCAPE; NUCLEIC-ACIDS; DNA HAIRPIN; TERTIARY INTERACTIONS AB RNA hairpin loops represent important RNA motifs with indispensable biological functions in RNA folding and tertiary interactions, with the 5'-UNCG-3' and 5'-GNRA-3' families being the most abundant. Molecular dynamics simulations represent a powerful method to investigate the structure, folding, and function of these tetraloops (TLs), but previous AMBER force fields were unable to maintain even the native structure of small TL RNAs. Here, we have used Replica Exchange Molecular Dynamics (REMD) with our recent reparameterization of AMBER RNA force field to study the folding of RNA hairpins containing representatives UNCG and GNRA TLs. We find that in each case, we are able to reach conformations within 2 A of the native structure, in contrast to results with earlier force fields. Although we find that the REMD simulation runs of a total of similar to 19 mu s (starting from both folded and unfolded state) in duration for each TL are still far from obtaining a representative equilibrium distribution at each temperature, we are nonetheless able to map the stable species on the folding energy landscape. The qualitative picture we obtain is consistent with experimental studies of RNA folding in that there are a number of stable on- and off-pathway intermediates en route to the native state. In particular, we have identified a misfolded-bulged state of GNRA TL, which shares many structural features with the X-ray structure of GNRA TL in the complex with restrictocin, namely the bulged out A(L4) base. Since this is the same conformation observed in the complex of the TL with restrictocin, we argue that GNRA TL is able to bind restrictocin via a "conformational selection" mechanism, with the R-L3 and A(L4) bases being exposed to the solvent prior to binding. In addition we have identified a misfolded-anti state of UUCG TL, which is structurally close to the native state except that the G(L4), nucleotide is in an anti-conformation instead of the native syn. Our data suggest that the UUCG misfolded-anti state may be a kinetic trap for the UUCG folding. C1 [Kuehrova, Petra; Banas, Pavel; Otyepka, Michal] Palacky Univ, Reg Ctr Adv Technol & Mat, Dept Phys Chem, Fac Sci, Olomouc 77146, Czech Republic. [Best, Robert B.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Banas, Pavel; Sponer, Jiri; Otyepka, Michal] Acad Sci Czech Republic, Inst Biophys, CS-61265 Brno, Czech Republic. [Sponer, Jiri] Masaryk Univ, CEITEC Cent European Inst Technol, Brno 62500, Czech Republic. RP Banas, P (reprint author), Palacky Univ, Reg Ctr Adv Technol & Mat, Dept Phys Chem, Fac Sci, 17 Listopadu 12, Olomouc 77146, Czech Republic. EM pavel.banas@upol.cz; michal.otyepka@upol.cz RI Otyepka, Michal/A-5922-2008; Sponer, Jiri/D-9467-2012; Best, Robert/H-7588-2016; Otyepka, Michal/D-1220-2017 OI Best, Robert/0000-0002-7893-3543; Otyepka, Michal/0000-0002-1066-5677 FU Ministry of Education, Youth and Sports of the Czech Republic [CZ.1.05/2.1/00/03.0058, CZ.1.07/2.3.00/20.0017, CZ.1.07/2.3.00/20.0058]; CEITEC - Central European Institute of Technology [CZ.1.0S/1.1.00/02.0068]; Grant Agency of the Czech Republic [P301/11/P558, P208/12/G016, P208/12/1878, P305/12/G034]; Royal Society University Research Fellowship; NIDDK, NIH FX This work was supported by The Operational Program Research and Development for Innovations-European Regional Development Fund (project CZ.1.05/2.1/00/03.0058 of the Ministry of Education, Youth and Sports of the Czech Republic), the Operational Program Education for Competitiveness - European Social Fund (projects CZ.1.07/2.3.00/20.0017 and CZ.1.07/2.3.00/20.0058 of the Ministry of Education, Youth and Sports of the Czech Republic), project "CEITEC - Central European Institute of Technology" (CZ.1.0S/1.1.00/02.0068) from European Regional Development Fund, and the Grant Agency of the Czech Republic (grants no. P301/11/P558, P208/12/G016, P208/12/1878, and P305/12/G034). RB. was supported by a Royal Society University Research Fellowship and the Intramural Research Program of the NIDDK, NIH. NR 97 TC 36 Z9 36 U1 1 U2 39 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9618 J9 J CHEM THEORY COMPUT JI J. Chem. Theory Comput. PD APR PY 2013 VL 9 IS 4 BP 2115 EP 2125 DI 10.1021/ct301086z PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 124BF UT WOS:000317438100025 PM 26583558 ER PT J AU Purohit, V Rapaka, R Frankenheim, J Avila, A Sorensen, R Rutter, J AF Purohit, Vishnudutt Rapaka, Rao Frankenheim, Jerry Avila, Albert Sorensen, Roger Rutter, Joni TI National Institute on Drug Abuse symposium report: drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia SO JOURNAL OF NEUROVIROLOGY LA English DT Review DE HIV; HAND; HAD; Dopamine; Drugs of abuse ID IMMUNODEFICIENCY-VIRUS TYPE-1; DIFFERENT REGIONS; DENDRITIC CELLS; BRAIN; TRANSPORTERS; EXPRESSION; INFECTION; DEATH AB The National Institute on Drug Abuse organized a symposium on drugs of abuse, dopamine, and HIV-associated neurocognitive disorders (HAND)/HIV-associated dementia (HAD) in Rockville, Maryland, October4, 2011. The purpose of this symposium was to evaluate the potential role of dopamine in the potentiation of HAND/HAD by drugs of abuse. A summary of the symposium has been presented in this report. C1 [Purohit, Vishnudutt; Rapaka, Rao; Frankenheim, Jerry; Avila, Albert; Sorensen, Roger; Rutter, Joni] NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, 6001 Execut Blvd Room 4282,MSC 9555, Bethesda, MD 20892 USA. EM vpurohit@nida.nih.gov OI Rutter, Joni/0000-0002-6502-2361 NR 15 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD APR PY 2013 VL 19 IS 2 BP 119 EP 122 DI 10.1007/s13365-013-0153-2 PG 4 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 138NJ UT WOS:000318515000002 PM 23456951 ER PT J AU Zumla, A Kim, P Maeurer, M Schito, M AF Zumla, Alimuddin Kim, Peter Maeurer, Markus Schito, Marco TI Zero deaths from tuberculosis: progress, reality, and hope SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material C1 [Zumla, Alimuddin] UCL, Ctr Clin Microbiol, Div Infect & Immun, London, England. [Zumla, Alimuddin] Univ Zambia Univ Coll London Med Sch UNZA UCLMS, Res andTraining Project, Univ Teaching Hosp, Lusaka, Zambia. [Kim, Peter] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Maeurer, Markus] Karolinska Inst, Div Therapeut Immunol LabMed & Microbiol, Stockholm, Sweden. [Schito, Marco] NIAID, Henry M Jackson Div AIDS, NIH, Bethesda, MD 20892 USA. RP Zumla, A (reprint author), UCL, Ctr Clin Microbiol, Div Infect & Immun, London, England. EM a.zumla@ucl.ac.uk OI Zumla, Alimuddin/0000-0002-5111-5735 FU PHS HHS [HHSN272200800014C] NR 6 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD APR PY 2013 VL 13 IS 4 BP 285 EP 287 DI 10.1016/S1473-3099(13)70039-2 PG 3 WC Infectious Diseases SC Infectious Diseases GA 136TL UT WOS:000318386200008 PM 23531385 ER PT J AU Klatser, P Anthony, R Barry, C Drobniewski, F Hoffner, S Niemann, S Gillespie, S AF Klatser, Paul Anthony, Richard Barry, Clifton Drobniewski, Francis Hoffner, Sven Niemann, Stefan Gillespie, Stephen TI Chasing Koch's chimera SO LANCET INFECTIOUS DISEASES LA English DT Editorial Material ID TUBERCULOSIS; VACCINATION; BCG C1 [Klatser, Paul; Anthony, Richard] Royal Trop Inst KIT, KIT Biomed Res, Amsterdam, Netherlands. [Barry, Clifton] NIAID, NIH, TB Res Sect, Bethesda, MD 20892 USA. [Drobniewski, Francis] Univ London, Queen Mary Coll, London, England. [Drobniewski, Francis] Univ London, Univ Coll, London, England. [Hoffner, Sven] Swedish Inst Communicable Dis Control, WHO Supranat TB Reference Lab, Solna, Sweden. [Niemann, Stefan] Natl Reference Ctr Mycobacteria, Borstel, Germany. [Gillespie, Stephen] Univ St Andrews, Sch Med, St Andrews, Fife, Scotland. RP Klatser, P (reprint author), Royal Trop Inst KIT, KIT Biomed Res, Amsterdam, Netherlands. EM p.klatser@kit.nl RI Barry, III, Clifton/H-3839-2012; Niemann, Stefan/C-9327-2011; Anthony, Richard/G-5654-2010 OI Klatser, Paul/0000-0003-2127-9138; Anthony, Richard/0000-0002-0550-5273 NR 15 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD APR PY 2013 VL 13 IS 4 BP 289 EP 291 DI 10.1016/S1473-3099(13)70041-0 PG 3 WC Infectious Diseases SC Infectious Diseases GA 136TL UT WOS:000318386200010 PM 23538218 ER PT J AU Lawn, SD Mwaba, P Bates, M Piatek, A Alexander, H Marais, BJ Cuevas, LE McHugh, TD Zijenah, L Kapata, N Abubakar, I McNerney, R Hoelscher, M Memish, ZA Migliori, GB Kim, P Maeurer, M Schito, M Zumla, A AF Lawn, Stephen D. Mwaba, Peter Bates, Matthew Piatek, Amy Alexander, Heather Marais, Ben J. Cuevas, Luis E. McHugh, Timothy D. Zijenah, Lynn Kapata, Nathan Abubakar, Ibrahim McNerney, Ruth Hoelscher, Michael Memish, Ziad A. Migliori, Giovanni Battista Kim, Peter Maeurer, Markus Schito, Marco Zumla, Alimuddin TI Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test SO LANCET INFECTIOUS DISEASES LA English DT Article ID POSITIVE RIFAMPICIN RESISTANCE; HIV-ASSOCIATED TUBERCULOSIS; RESOURCE-LIMITED SETTINGS; RAPID MOLECULAR-DETECTION; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; EXTRAPULMONARY TUBERCULOSIS; LOW-COST AB Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers. C1 [Lawn, Stephen D.; McNerney, Ruth] Univ London London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England. [Lawn, Stephen D.] Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Mwaba, Peter; Bates, Matthew; Kapata, Nathan; Zumla, Alimuddin] Univ Zambia Univ Coll London Med Sch UNZA UCLMS R, Univ Teaching Hosp, Lusaka, Zambia. [Mwaba, Peter; Kapata, Nathan] Minist Hlth, Lusaka, Zambia. [Bates, Matthew; McHugh, Timothy D.; Zumla, Alimuddin] UCL, Ctr Clin Microbiol, Div Infect & Immun, London NW3 2PF, England. [Abubakar, Ibrahim] UCL, Ctr Infect Dis Epidemiol, Dept Infect & Populat Hlth, London NW3 2PF, England. [Piatek, Amy] US Agcy Int Dev, Bur Global Hlth, Off Hlth Infect Dis & Nutr, Washington, DC 20523 USA. [Alexander, Heather] US Ctr Dis Control & Prevent, Div Global HIVAIDS, Ctr Global Hlth, Atlanta, GA USA. [Marais, Ben J.] Univ Sydney, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Marais, Ben J.] Univ Sydney, Childrens Hosp Westmead, Sydney Med Sch, Sydney, NSW 2006, Australia. [Cuevas, Luis E.] Univ Liverpool, Liverpool Sch Trop Med, Dept Clin Sci, Liverpool L3 5QA, Merseyside, England. [Zijenah, Lynn] Univ Zimbabwe, Coll Hlth Sci, Harare, Zimbabwe. [Abubakar, Ibrahim] Hlth Protect Agcy, London, England. [Hoelscher, Michael] Klinikum Univ Munich, Dept Infect Dis & Trop Med, Munich, Germany. [Memish, Ziad A.] Minist Hlth, Riyadh, Saudi Arabia. [Memish, Ziad A.] Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia. [Migliori, Giovanni Battista] WHO Collaborating Ctr TB & Lung Dis, Fdn S Maugeri, Care & Res Inst, Tradate, Italy. [Kim, Peter] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Maeurer, Markus] Karolinska Inst, Div Therapeut Immunol LabMed & Microbiol, S-10401 Stockholm, Sweden. [Maeurer, Markus] Karolinska Hosp, Ctr Allogene Stem Cell Transplantat, S-10401 Stockholm, Sweden. [Schito, Marco] NIAID, Henry M Jackson Fdn, Div AIDS, NIH, Bethesda, MD 20892 USA. RP Zumla, A (reprint author), UCL, Royal Free Hosp, Div Infect & Immun, Ctr Clin Microbiol, Royal Free Campus, London NW3 2PF, England. EM a.zumla@ucl.ac.uk RI Hoelscher, Michael/D-3436-2012; OI McHugh, Timothy D/0000-0003-4658-8594; MCNERNEY, Ruth/0000-0002-1957-443X; Abubakar, Ibrahim/0000-0002-0370-1430; Zumla, Alimuddin/0000-0002-5111-5735; Migliori, Giovanni Battista/0000-0002-2597-574X; Cuevas, Luis E./0000-0002-6581-0587 FU Wellcome Trust, UK; European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; UK Medical Research Council (MRC); UBS Optimus Foundation, Switzerland; University College London Hospitals Comprehensive Biomedical Research Centre (UCLH-CBRC); UCLH National Health Service Foundation Trust; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200800014C]; President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention FX SDL is supported by the Wellcome Trust, UK. PM, MB, MH, and AZ are supported by the European and Developing Countries Clinical Trials Partnership (EDCTP grants REMOX, PANACEA, and TB-NEAT), Netherlands. AZ receives support from the UK Medical Research Council (MRC); UBS Optimus Foundation, Switzerland; University College London Hospitals Comprehensive Biomedical Research Centre (UCLH-CBRC); and the UCLH National Health Service Foundation Trust. 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 number HHSN272200800014C, and by the President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention. The opinions expressed herein are those of the authors and do not reflect the official views or policies of the US Department of Health and Human Services or the authors' national governments, nor does mention of trade names, commercial practices, or organisations imply endorsement by the US Government or the authors' national governments. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 92 TC 164 Z9 174 U1 2 U2 55 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD APR PY 2013 VL 13 IS 4 BP 349 EP 361 DI 10.1016/S1473-3099(13)70008-2 PG 13 WC Infectious Diseases SC Infectious Diseases GA 136TL UT WOS:000318386200033 PM 23531388 ER PT J AU Wallis, RS Kim, P Cole, S Hanna, D Andrade, BB Maeurer, M Schito, M Zumla, A AF Wallis, Robert S. Kim, Peter Cole, Stewart Hanna, Debra Andrade, Bruno B. Maeurer, Markus Schito, Marco Zumla, Alimuddin TI Tuberculosis biomarkers discovery: developments, needs, and challenges SO LANCET INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EARLY BACTERICIDAL ACTIVITY; POTENTIAL SURROGATE MARKER; CLUSTER-RANDOMIZED-TRIAL; HIV-INFECTED PATIENTS; GAMMA RELEASE ASSAYS; C-REACTIVE PROTEIN; T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS AB Biomarkers are indispensable to the development of new tuberculosis therapeutics and vaccines. The most robust biomarkers measure factors that are essential to the underlying pathological process of the disease being treated, and thus can capture the full effects of many types of interventions on clinical outcomes in multiple prospective, randomised clinical trials. Many Mycobacterium tuberculosis and human biomarkers have been studied over the past decade. Present research focuses on three areas: biomarkers predicting treatment efficacy and cure of active tuberculosis, the reactivation of latent tuberculosis infection, and the induction of protective immune responses by vaccination. Many older, non-specific markers of inflammation, when considered in isolation, do not have sufficient predictive values for clinical use in tuberculosis. Although no new accurate, tuberculosis-specific biomarkers have yet been discovered, substantial progress has been made in some areas. However, the qualification of biomarkers as a surrogate for a clinical endpoint in tuberculosis is very challenging, and, for biomarkers that are non-culture-based, impossible to pursue without the availability of well characterised biobanks containing biospecimens from patients who have had adequate follow-up to establish long-term treatment outcome. We review progress in tuberculosis biomarker development and efforts being made to harness resources to meet future challenges. C1 [Wallis, Robert S.] Pfizer, Specialty Care, Groton, CT USA. [Wallis, Robert S.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Wallis, Robert S.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Kim, Peter] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Andrade, Bruno B.] NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Cole, Stewart] Ecole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland. [Hanna, Debra] Crit Path Inst, Salt Lake City, UT USA. [Maeurer, Markus] Karolinska Inst, Div Therapeut Immunol LabMed & MTC, Stockholm, Sweden. [Maeurer, Markus] Karolinska Hosp, CAST, S-10401 Stockholm, Sweden. [Schito, Marco] NIAID, Henry M Jackson Fdn, Div AIDS, NIH, Bethesda, MD 20892 USA. [Zumla, Alimuddin] UCL, Ctr Clin Microbiol, Div Infect & Immun, London, England. [Zumla, Alimuddin] Univ Teaching Hosp, Univ Zambia Univ Coll London Med Sch UNZA UCLMS R, Lusaka, Zambia. RP Zumla, A (reprint author), UCL, Royal Free Hosp, Dept Infect, Ctr Clin Microbiol, Rowland Hill St, London NW3 2PF, England. EM a.zumla@ucl.ac.uk RI Andrade, Bruno/J-9111-2012; OI Andrade, Bruno/0000-0001-6833-3811; Zumla, Alimuddin/0000-0002-5111-5735 FU European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands; EDCTP; TB-NEAT; UK Medical Research Council; UBS Optimus Foundation, Switzerland; University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre; NIH Intramural Research Program; UCLH National Health Service Foundation Trust FX We acknowledge support from the European and Developing Countries Clinical Trials Partnership (EDCTP), Netherlands, EDCTP grants REMOX PANACEA (AZ), and TB-NEAT (MM, AZ); UK Medical Research Council (AZ); UBS Optimus Foundation, Switzerland (AZ, MM); University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre (AZ); NIH Intramural Research Program (BBA); and the UCLH National Health Service Foundation Trust (AZ). NR 130 TC 89 Z9 91 U1 3 U2 46 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD APR PY 2013 VL 13 IS 4 BP 362 EP 372 DI 10.1016/S1473-3099(13)70034-3 PG 11 WC Infectious Diseases SC Infectious Diseases GA 136TL UT WOS:000318386200034 PM 23531389 ER PT J AU Hoffman, HJ Daly, KA Bainbridge, KE Casselbrant, ML Homoe, P Kvestad, E Kvaerner, KJ Vernacchio, L AF Hoffman, Howard J. Daly, Kathleen A. Bainbridge, Kathleen E. Casselbrant, Margaretha L. Homoe, Preben Kvestad, Ellen Kvaerner, Kari Jorunn Vernacchio, Louis TI Panel 1: Epidemiology, Natural History, and Risk Factors SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Review DE otitis media; epidemiology; natural history; risk factors; incidence; prevalence; disease burden; population-based study; cohort study; case-control study; hazard ratio; odds ratio; relative risk; logistic regression; randomized clinical trial; meta-analysis; quality of life ID ACUTE-OTITIS-MEDIA; FREQUENT EAR INFECTIONS; INDIVIDUAL PATIENT DATA; QUALITY-OF-LIFE; ENVIRONMENTAL TOBACCO-SMOKE; CYTOKINE GENE POLYMORPHISMS; RESPIRATORY-TRACT INFECTION; INFANT-DEATH-SYNDROME; 1ST 2 YEARS; UNITED-STATES AB Background. The First International Symposium on Recent Advances in Otitis Media (OM) with Effusion was held in Columbus, Ohio, in 1975. The symposium has been organized in the United States every 4 years since, followed by a research conference to (a) assess major research accomplishments, (b) identify important research questions and opportunities, (c) develop consensus on definitions and terminology, and (d) establish priorities with short-and long-term research goals. One of the principal areas reviewed quadrennially is Epidemiology, Natural History, and Risk Factors. Objective. To provide a review of recent literature on the epidemiology, natural history, and risk factors for OM. Data Sources and Review Methods. A search of OM articles in English published July 2007 to June 2011 was conducted using PubMed and related databases. Those with findings judged of importance for epidemiology, public health, and/or statistical methods were reviewed. Results. The literature has continued to expand, increasing understanding of the worldwide burden of OM in childhood, complications from treatment failures, and comorbidities. Novel risk factors, including genetic factors, have been examined for OM susceptibility. Population-based studies in Canada, the United States, and other countries confirmed reductions in OM prevalence. Although most studies concentrated on acute OM (AOM) or OM with effusion (OME), a few examined severe chronic suppurative OM (CSOM), a major public health problem in developing countries and for certain indigenous populations around the world. Conclusions and Implications for Practice. Recent publications have reinforced earlier epidemiological findings, while extending our knowledge in human population groups with high burden of OM. C1 [Hoffman, Howard J.; Bainbridge, Kathleen E.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, NIH, Bethesda, MD 20892 USA. [Daly, Kathleen A.] Univ Minnesota, Dept Otolaryngol, Minneapolis, MN USA. [Daly, Kathleen A.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. [Casselbrant, Margaretha L.] Univ Pittsburgh, Childrens Hosp, Sch Med, Div Pediat Otolaryngol, Pittsburgh, PA 15260 USA. [Homoe, Preben] Univ Copenhagen, Rigshosp, Dept Otorhinolaryngol Head & Neck Surg, DK-1168 Copenhagen, Denmark. [Kvestad, Ellen] Norwegian Inst Publ Hlth, Div Mental Hlth, Oslo, Norway. [Kvaerner, Kari Jorunn] Univ Oslo, Dept Hlth Management & Hlth Econ, Inst Hlth & Soc, Fac Med, Oslo, Norway. [Kvaerner, Kari Jorunn] Oslo Univ Hosp, Dept Res Innovat & Educ, Oslo, Norway. [Vernacchio, Louis] Childrens Hosp, Pediat Phys Org Childrens, Div Gen Pediat, Boston, MA 02115 USA. RP Hoffman, HJ (reprint author), Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Stat Program, NIH, Execut Plaza South Bldg,Suite 400A,6120 Execut Bl, Bethesda, MD 20892 USA. EM hoffmanh@nidcd.nih.gov OI Vernacchio, Louis/0000-0002-2012-5404 FU NIDCD [R13 NIDCD]; NIH [1R13DC011455-01]; National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH) FX NIDCD. This report was sponsored in part by NIH grant 1R13DC011455-01, which was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH). The views expressed are solely those of the authors and do not necessarily represent the agencies or institutions for which they work. NR 147 TC 13 Z9 13 U1 1 U2 12 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD APR PY 2013 VL 148 SU 4 BP E1 EP E25 DI 10.1177/0194599812460984 PG 25 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 136MF UT WOS:000318365300001 PM 23536527 ER PT J AU Wake, H Moorhouse, AJ Miyamoto, A Nabekura, J AF Wake, Hiroaki Moorhouse, Andrew J. Miyamoto, Akiko Nabekura, Junichi TI Microglia: actively surveying and shaping neuronal circuit structure and function SO TRENDS IN NEUROSCIENCES LA English DT Review DE microglia; synapse; psychiatric disease; glia; brain immune cells; synaptic plasticity ID CENTRAL-NERVOUS-SYSTEM; ADULT-MOUSE BRAIN; CLASS-I MHC; CELL-DEATH; SYNAPTIC PLASTICITY; SUBVENTRICULAR ZONE; ALZHEIMERS-DISEASE; MYELOID CELLS; RETT-SYNDROME; NEUROPSYCHIATRIC DISORDERS AB The traditional role of microglia has been in brain infection and disease, phagocytosing debris and secreting factors to modify disease progression. Recent evidence extends their role to healthy brain homeostasis, including the regulation of cell death, synapse elimination, neurogenesis, and neuronal surveillance. These actions contribute to the maturation and plasticity of neural circuits that ultimately shape behavior. Here we review microglial contributions to the development, plasticity, and maintenance of neural circuits with a focus on interactions with synapses. We introduce this topic by reviewing recent studies on the migration and proliferation of microglia within the brain, and conclude with the proposal that microglia dysfunction may adversely affect brain function, and thereby contribute to the development of psychiatric and neurological disorders. C1 [Wake, Hiroaki] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Nervous Syst Dev & Plast Sect, Bethesda, MD USA. [Moorhouse, Andrew J.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Miyamoto, Akiko; Nabekura, Junichi] Natl Inst Physiol Sci, Div Homeostat Dev, Okazaki, Aichi 444, Japan. [Miyamoto, Akiko; Nabekura, Junichi] Grad Sch Adv Study, Dept Physiol Sci, Hayama, Japan. [Nabekura, Junichi] Japan Sci & Technol Agcy, Saitama, Japan. RP Nabekura, J (reprint author), Natl Inst Physiol Sci, Div Homeostat Dev, Okazaki, Aichi 444, Japan. EM nabekura@nips.ac.jp RI Moorhouse, Andrew/B-8526-2011; OI Moorhouse, Andrew/0000-0001-7957-2498 FU Japan Society for the Promotion of Science; Japan Science and Technology Agency for Core Research for Evolutional Science and Technology FX We gratefully acknowledge Wai T. Wong, R. Douglas Fields, and Olena Bukalo for critical reading of the manuscript. This work was supported by a Japan Society for the Promotion of Science fellowship (to H.W.) and the Japan Science and Technology Agency for Core Research for Evolutional Science and Technology (to J.N.). NR 96 TC 100 Z9 103 U1 4 U2 39 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD APR PY 2013 VL 36 IS 4 BP 209 EP 217 DI 10.1016/j.tins.2012.11.007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 135WV UT WOS:000318322300002 PM 23260014 ER PT J AU Kedei, N Lewin, NE Geczy, T Selezneva, J Braun, DC Chen, JQ Herrmann, MA Heldman, MR Lim, L Mannan, P Garfield, SH Poudel, YB Cummins, TJ Rudra, A Blumberg, PM Keck, GE AF Kedei, Noemi Lewin, Nancy E. Geczy, Tamas Selezneva, Julia Braun, Derek C. Chen, Jinqiu Herrmann, Michelle A. Heldman, Madeleine R. Lim, Langston Mannan, Poonam Garfield, Susan H. Poudel, Yam B. Cummins, Thomas J. Rudra, Arnab Blumberg, Peter M. Keck, Gary E. TI Biological Profile of the Less Lipophilic and Synthetically More Accessible Bryostatin 7 Closely Resembles That of Bryostatin 1 SO ACS CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-KINASE-C; PROSTATE-CANCER CELLS; PHORBOL ESTER; LEUKEMIA-CELLS; AGENT BRYOSTATIN-1; PYRAN ANNULATION; DELTA; PATHWAYS; BINDING; MEMORY AB The bryostatins are a group of 20 macrolides isolated by Pettit and co-workers from the marine organism Bugula neritina. Bryostatin 1, the flagship member of the family, has been the subject of intense chemical and biological investigations due to its remarkably diverse biological activities including promising indications as therapy for cancer, Alzheimer's disease, and HIV. Other bryostatins, however, have attracted far less attention, most probably due to their relatively low natural abundance and associated scarcity of supply. Among all macrolides in this family, bryostatin 7 is biologically the most potent protein kinase C (PKC) ligand (in terms of binding affinity) and also the first bryostatin to be synthesized in the laboratory. Nonetheless, almost no biological studies have been carried out on this agent. We describe herein the total synthesis of bryostatin 7 based on our pyran annulation technology, which allows for the first detailed biological characterizations of bryostatin 7 with side-by-side comparisons to bryostatin 1. The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1. C1 [Kedei, Noemi; Lewin, Nancy E.; Geczy, Tamas; Selezneva, Julia; Braun, Derek C.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Jinqiu; Herrmann, Michelle A.; Heldman, Madeleine R.] NCI, Collaborat Prot Technol Resource, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Lim, Langston; Mannan, Poonam; Garfield, Susan H.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Poudel, Yam B.; Cummins, Thomas J.; Rudra, Arnab; Keck, Gary E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, 315 South 1400 East,RM 2020, Salt Lake City, UT 84112 USA. EM keck@chem.utah.edu RI Rudra, Arnab/E-6428-2013 OI Rudra, Arnab/0000-0002-1704-5534 FU National Institutes of Health [GM28961]; Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported by the National Institutes of Health through Grant GM28961 to G.K. and in part by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute (Z1A BC 005270). We thank C. Brodie for providing the human GFP-PKC alpha plasmid. NR 53 TC 14 Z9 14 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD APR PY 2013 VL 8 IS 4 BP 767 EP 777 DI 10.1021/cb300671s PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131NY UT WOS:000318001600015 PM 23369356 ER PT J AU Zhou, ZJ Wang, LR Chi, XQ Bao, JF Yang, LJ Zhao, WX Chen, Z Wang, XM Chen, XY Gao, JH AF Zhou, Zijian Wang, Lirong Chi, Xiaoqin Bao, Jianfeng Yang, Lijiao Zhao, Wenxiu Chen, Zhong Wang, Xiaomin Chen, Xiaoyuan Gao, Jinhao TI Engineered Iron-Oxide-Based Nanoparticles as Enhanced T-1 Contrast Agents for Efficient Tumor Imaging SO ACS NANO LA English DT Article DE T-1 contrast agent; ultrasmall nanoparticle; zwitterionic; renal clearance; tumor imaging ID MULTIFUNCTIONAL MAGNETIC NANOPARTICLES; NEPHROGENIC SYSTEMIC FIBROSIS; BIOLOGICAL APPLICATIONS; BIOMEDICAL APPLICATIONS; QUANTUM DOTS; RESONANCE; MRI; DESIGN; SIZE; BIODISTRIBUTION AB We report the design and synthesis of small-sized zwitterion-coated gadolinium-embedded iron oxide (Gd10) nanopartides, which exhibit a strong 71 contrast effect for tumor imaging through enhanced permeation and retention effect and the ability to clear out of the body in living subjects. The combination of spincanting effects and the collection of gadolinium species within small-sized Gd10 nanoparticles led to a significantly enhanced 71 contrast effect. For example, Gd10 nanoparticles with a diameter of similar to 4.8 nm exhibited a high r(1), relaxivity of 7.85 mM(-1) S-1 and a low r(2)/r(1) ratio of 5.24. After being coated with zwitterionic dopamine sulfonate molecules, the 4.8 nm Gd10 nanoparticles showed a steady hydrodynamic diameter (similar to 5.2 nm) in both PBS buffer and fetal bovine serum solution, indicating a low nonspecific protein absorption. This study provides a valuable strategy for the design of highly sensitive iron-oxide-based T-1 contrast agents with relatively long circulation half-lives (similar to 50 min), efficient tumor passive targeting (SKOV3, human ovarian cancer xenograft tumor as a model), and the possibility of rapid renal clearance after tumor imaging. C1 [Zhou, Zijian; Wang, Lirong; Yang, Lijiao; Gao, Jinhao] Xiamen Univ, State Key Lab Phys Chem Solid Surfaces, Key Lab Chem Biol Fujian Prov, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. [Zhou, Zijian; Wang, Lirong; Yang, Lijiao; Gao, Jinhao] Xiamen Univ, Dept Biol Chem, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. [Chi, Xiaoqin; Zhao, Wenxiu; Wang, Xiaomin] Xiamen Univ, Xiamen Key Lab Translat Med Digest Oncol, Res Inst Digest Dis, Zhongshan Hosp, Xiamen 361004, Peoples R China. [Bao, Jianfeng; Chen, Zhong] Xiamen Univ, Dept Elect Sci, Xiamen 361005, Peoples R China. [Bao, Jianfeng; Chen, Zhong] Xiamen Univ, Fujian Key Lab Plasma & Magnet Resonance, Xiamen 361005, Peoples R China. [Gao, Jinhao] Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Gao, JH (reprint author), Xiamen Univ, Ctr Mol Imaging & Translat Med, Sch Publ Hlth, Xiamen 361005, Peoples R China. EM jhgao@xmu.edu.cn RI Gao, Jinhao/F-5092-2010; Chen, Zhong/G-4601-2010 OI Gao, Jinhao/0000-0003-3215-7013; FU National Key Basic Research Program of China [2013CB933901, 2013CB8733802]; National Natural Science Foundation of China [21021061, 21222106, 81000662, 81201805]; Program for New Century Excellent Talents in University [NCET-10-0709] FX This work was partially supported by the National Key Basic Research Program of China (2013CB933901 and 2013CB8733802), National Natural Science Foundation of China (21021061, 21222106, 81000662, and 81201805), and Program for New Century Excellent Talents in University (NCET-10-0709). NR 55 TC 75 Z9 79 U1 17 U2 213 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD APR PY 2013 VL 7 IS 4 BP 3287 EP 3296 DI 10.1021/nn305991e PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 133MU UT WOS:000318143300043 PM 23473444 ER PT J AU Vizi, ES Buonanno, A AF Vizi, E. Sylvester Buonanno, Andres TI Special Issue Extrasynaptic ionotropic receptors SO BRAIN RESEARCH BULLETIN LA English DT Editorial Material ID CENTRAL-NERVOUS-SYSTEM; TRANSMITTER RELEASE; COMMUNICATION; TRANSPORTERS; ACTIVATION; CHANNELS C1 [Vizi, E. Sylvester] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1083 Budapest, Hungary. [Vizi, E. Sylvester] Semmelweis Univ, Inst Pharmacol & Pharmacotherapy, H-1085 Budapest, Hungary. [Buonanno, Andres] NICHD, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Vizi, ES (reprint author), Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, Szigony U 43, H-1083 Budapest, Hungary. EM esvizi@koki.mta.hu NR 26 TC 1 Z9 1 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD APR PY 2013 VL 93 SI SI BP 1 EP 3 DI 10.1016/j.brainresbull.2013.01.002 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 132HH UT WOS:000318058000001 PM 23313745 ER PT J AU Rippo, MR Babini, L Prattichizzo, F Graciotti, L Fulgenzi, G Ardori, FT Olivieri, F Borghetti, G Cinti, S Poloni, A Fazioli, F Procopio, AD AF Rippo, M. R. Babini, L. Prattichizzo, F. Graciotti, L. Fulgenzi, G. Ardori, F. Tomassoni Olivieri, F. Borghetti, G. Cinti, S. Poloni, A. Fazioli, F. Procopio, A. D. TI Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes SO CELL DEATH & DISEASE LA English DT Article DE bone marrow-derived mesenchymal stem cells; Fas ligand; proliferation; adipogenesis; peroxisome proliferator-activated receptor gamma ID HIV-INFECTED MEN; MULTILINEAGE DIFFERENTIATION; PPAR-GAMMA; LIGAND; SURVIVIN; FAT; EXPRESSION; DISEASE; METABOLISM; ACTIVATION AB Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate into several cell types. Bone marrow (BM)-MSCs mainly differentiate into osteoblasts or adipocytes. MSC interactions with their microenvironment directly affect their self-renewal/differentiation program. Here, we show for the first time that Fas ligand (FasL), a well-explored proapoptotic cytokine, can promote proliferation of BM-derived MSCs in vitro and inhibits their differentiation into adipocytes. BM-MSCs treated with a low FasL dose (0.5 ng/ml) proliferated more rapidly than untreated cells without undergoing spontaneous differentiation or apoptosis, whereas higher doses (25 ng/ml) induced significant though not massive BM-MSC death, with surviving cells maintaining a stem cell phenotype. At the molecular level, 0.5 ng/ml FasL induced ERK1/2 phosphorylation and survivin upregulation, whereas 25 ng/ml FasL induced caspase activation. Importantly, 25 ng/ml FasL reversibly prevented BM-MSC differentiation into adipocytes by modulating peroxisome proliferator-activated receptor gamma (PPAR gamma) and FABP4/aP2 expression induced by adipogenic medium. All such effects were inhibited by anti-Fas neutralizing antibody. The in vitro data regarding adipogenesis were confirmed using Fas(lpr) mutant mice, where higher PPAR gamma and FABP4/aP2 mRNA and protein levels were documented in whole tibia. These data show for the first time that the FasL/Fas system can have a role in BM-MSC biology via regulation of both proliferation and adipogenesis, and may have clinical relevance because circulating Fas/FasL levels decline with age and several age-related conditions, including osteoporosis, are characterized by adipocyte accumulation in BM. Cell Death and Disease (2013) 4, e594; doi:10.1038/cddis.2013.115; published online 18 April 2013 C1 [Rippo, M. R.; Babini, L.; Prattichizzo, F.; Graciotti, L.; Fulgenzi, G.; Olivieri, F.; Borghetti, G.; Fazioli, F.; Procopio, A. D.] Univ Politecn Marche, Dept Clin & Mol Sci, Lab Expt Pathol, I-60020 Ancona, Italy. [Fulgenzi, G.; Ardori, F. Tomassoni] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Olivieri, F.; Procopio, A. D.] Italian Natl Res Ctr Aging INRCA IRCCS, Ctr Clin Pathol & Innovat Therapies, Ancona, Italy. [Cinti, S.] Univ Politecn Marche, Univ Ancona, United Hosp, Dept Expt & Clin Med,Obes Ctr, I-60020 Ancona, Italy. [Poloni, A.] Univ Politecn Marche, Dept Clin & Mol Sci, Clin Hematol, I-60020 Ancona, Italy. RP Rippo, MR (reprint author), Univ Politecn Marche, Dept Clin & Mol Sci, Lab Expt Pathol, Via Tronto 10, I-60020 Ancona, Italy. EM m.r.rippo@univpm.it RI Olivieri, Fabiola/K-6465-2016; OI Olivieri, Fabiola/0000-0002-9606-1144; Fulgenzi, Gianluca/0000-0003-2646-7728 FU Italian Ministry of University and Research [prot. 2004058593_003]; Universita Politecnica delle Marche FX We are grateful to MC Albertini (University of Urbino, Urbino, Italy) for her critical reading of the manuscript; to L Tessarollo (Neural Development Section, Mouse Cancer Genetics Program, the National Cancer Institute, Frederick, Maryland) for generously making available lab resources for our mice experiments, and to S Modena for language editing (www.silviamodena.com). This work was supported by grants from the Italian Ministry of University and Research to MRR (prot. 2004058593_003) and from Universita Politecnica delle Marche to MRR and ADP. NR 47 TC 6 Z9 6 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD APR PY 2013 VL 4 AR e594 DI 10.1038/cddis.2013.115 PG 10 WC Cell Biology SC Cell Biology GA 132NL UT WOS:000318075500028 PM 23598406 ER PT J AU Brim, RL Pearson, SD AF Brim, Remy L. Pearson, Steven D. TI The use and reporting of patient-reported outcomes in phase III breast cancer trials SO CLINICAL TRIALS LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED CLINICAL-TRIALS; CLINICALTRIALS.GOV; REGISTRATION; ONCOLOGY; ISSUES; STOCK AB Background Public and government attention to patient-centered research outcomes has been increasing, evidenced by the recent formation of the Patient Centered Outcomes Research Institute. Drug development clinical trials can be made more patient-centered by collecting patient-reported outcome measures that can inform decision making by patients and their health-care providers. Patient-reported outcomes are important to collect in trials of breast cancer therapeutics, which encompass a wide range of treatment regimens and side effects. Purpose We sought to determine recent trends in the use of patient-reported outcomes in drug trials for the treatment of breast cancer and evaluate the reporting of these data in study publications. Methods We searched ClinicalTrials.gov for phase Ill breast cancer drug trials, recording information on start date, primary completion date, primary outcome measure, primary sponsor, stage of cancer, and patient-reported outcome use. To assess the reporting of patient-reported outcome data, Google.com and PubMed. gov were searched for all publications resulting from included trials. Results We found 236 eligible trials, starting between May 1989 and December 2011. Of these trials, 83 (35%) stipulated patient-reported outcome use. The rate of patient-reported outcome use in recent years has shown no increase over earlier time periods: 37% (1989-2000) versus 36% (2004-2007) versus 30% (2008-2011) (p = 0.8). Trials with sponsorship led by the pharmaceutical industry and trials including patients with locally advanced or metastatic disease had the highest rates of patient-reported outcome use (40/87 (46%) and 44/102 (43%), respectively). Among the 83 trials that collected patient-reported outcome measures, 36 were completed a minimum of 2 years before our analysis; of these 36 studies, 19 (53%) had published patient-reported outcome data. Limitations Data were limited to self-reported descriptions of trials listed on the ClinicalTrial.gov database, which is the best compendium of trial information available, but it is neither a complete nor a fully accurate record of all trials. Conclusions Patient-reported outcome use and reporting in breast cancer drug trials has remained relatively low despite calls for more patient-centered research. Increasing the collection and availability of patient-reported outcome data to guide clinical decisions will require aligned support from trial sponsors, researchers, journal editors, regulators and patient advocacy groups, who can all play important roles in implementing change. Clinical Trials 2013; 10: 243-249. http://ctj.sagepub.com C1 [Brim, Remy L.; Pearson, Steven D.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Technol Assessment, Inst Clin & Econ Review, Boston, MA 02114 USA. RP Brim, RL (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Rm 1C118, Bethesda, MD 20892 USA. EM remy.brim@nih.gov FU Intramural Research Program of the National Institutes of Health Clinical Center FX This research was supported by the Intramural Research Program of the National Institutes of Health Clinical Center. NR 32 TC 6 Z9 6 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2013 VL 10 IS 2 BP 243 EP 249 DI 10.1177/1740774513475529 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 135CJ UT WOS:000318263300006 PM 23539108 ER PT J AU McCaskill-Stevens, W Wilson, JW Cook, ED Edwards, CL Gibson, RV McElwain, DL Figueroa-Moseley, CD Paskett, ED Roberson, NL Wickerham, DL Wolmark, N AF McCaskill-Stevens, Worta Wilson, John W. Cook, Elise D. Edwards, Cora L. Gibson, Regina V. McElwain, Diane L. Figueroa-Moseley, Colmar D. Paskett, Electra D. Roberson, Noma L. Wickerham, D. Lawrence Wolmark, Norman TI National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial: Advancing the science of recruitment and breast cancer risk assessment in minority communities SO CLINICAL TRIALS LA English DT Article ID AFRICAN-AMERICAN WOMEN; STROKE INCIDENCE; VITAMIN-E; PREVENTION; BARRIERS; SELENIUM; SELECT AB Background One of the first chemoprevention trials conducted in the western hemisphere, the National Surgical Adjuvant Breast and Bowel Project's (NSABP) Breast Cancer Prevention Trial (BCPT), demonstrated the need to evaluate all aspects of recruitment in real time and to implement strategies to enroll racial and ethnic minority women. Purpose The purpose of this report is to review various patient recruitment efforts the NSABP developed to enhance the participation of racial and ethnic minority women in the Study of Tamoxifen and Raloxifene (STAR) trial and to describe the role that the recruitment process played in the implementation and understanding of breast cancer risk assessment in minority communities. Methods The NSABP STAR trial was a randomized, double-blinded study comparing the use of tamoxifen 20 mg/day to raloxifene 60 mg/day, for a 5-year period, to reduce the risk of developing invasive breast cancer. Eligible postmenopausal women were required to have a 5-year predicted breast cancer risk of 1.66% based on the modified Gail Model. For the current report, eligibility and enrollment data were tabulated by race/ethnicity for women who submitted STAR risk assessment forms (RAFs). Results A total of 184,460 RAFs were received, 145,550 (78.9%) from white women and 38,910 (21.1%) from minority women. Of the latter group, 21,444 (11.6%) were from African Americans/blacks, 791 3 (4.5%) from Hispanics/Latinas, and 9553 (5.2%) from other racial or ethnic groups. The percentages of risk-eligible women among African Americans, Hispanics/Latinas, others, and whites were 14.2%, 23.3%, 13.7%, and 57.4%, respectively. Programs targeting minority enrollment submitted large numbers of RAFs, but the eligibility rates of the women referred from those groups tended to be lower than the rates among women referred outside of those programs. The average number of completed risk assessments increased among minority women over the course of the recruitment period compared to those from whites. Limitations We have not addressed all identified barriers to the recruitment of minorities in clinical research. Our risk assessments and recruitment results do not reflect the modified Gail Model for African Americans. Conclusions Recruitment strategies used in STAR for racial and ethnic minorities contributed to doubling the minority enrollment compared to that in the BCPT and increased the awareness of breast cancer risk assessment in minority communities. Incorporation of new information into models to improve the risk estimation of diverse populations should prove beneficial. Clinical Trials 2013; 10: 280-291. http://ctj.sagepub.com C1 [McCaskill-Stevens, Worta] NCI, Bethesda, MD 20892 USA. [McCaskill-Stevens, Worta; Wilson, John W.; Wickerham, D. Lawrence; Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project NSABP, Operat Ctr, Pittsburgh, PA USA. [McCaskill-Stevens, Worta; Wilson, John W.; Wickerham, D. Lawrence; Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project NSABP, Ctr Biostat, Pittsburgh, PA USA. [Wilson, John W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Cook, Elise D.] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Edwards, Cora L.] Karmos Canc Inst, Canc Clin Trials Off, Detroit, MI USA. [Gibson, Regina V.] Univ Arkansas Med Sci, Dept Surg, Little Rock, AR 72205 USA. [McElwain, Diane L.] York Canc Ctr, York, PA USA. [Figueroa-Moseley, Colmar D.] Calif Dept Publ Hlth, Calif Tobacco Control Program, Sacramento, CA USA. [Paskett, Electra D.] Ohio State Univ, Dept Internal Med, Ctr Comprehens Canc, Div Canc Prevent & Control, Columbus, OH 43210 USA. [Roberson, Noma L.] Roberson Consulting Int, Amherst, NY USA. [Wickerham, D. Lawrence; Wolmark, Norman] Allegheny Gen Hosp, Allegheny Canc Ctr, Dept Hematol Oncol, Pittsburgh, PA 15212 USA. RP McCaskill-Stevens, W (reprint author), NCI, Community Oncol & Prevent Trials Res Grp, Canc Prevent Div, NIH,DDHS, 6130 Execut Blvd,MSC 7340, Bethesda, MD 20892 USA. EM wm57h@nih.gov FU Public Health Service from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services [U10-CA-37377, U10-CA-69974, U10-CA-12027, U10-CA-69651]; AstraZeneca; Eli Lilly FX This study was supported by Public Health Service grants U10-CA-37377, U10-CA-69974, U10-CA-12027, and U10-CA-69651 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, AstraZeneca, and Eli Lilly. NR 24 TC 10 Z9 10 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2013 VL 10 IS 2 BP 280 EP 291 DI 10.1177/1740774512470315 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 135CJ UT WOS:000318263300010 PM 23335675 ER PT J AU Dampier, CD Smith, WR Wager, CG Kim, HY Bell, MC Miller, ST Weiner, DL Minniti, CP Krishnamurti, L Ataga, KI Eckman, JR Hsu, LL McClish, D McKinlay, SM Molokie, R Osunkwo, I Smith-Whitley, K Telen, MJ AF Dampier, Carlton D. Smith, Wally R. Wager, Carrie G. Kim, Hae-Young Bell, Margaret C. Miller, Scott T. Weiner, Debra L. Minniti, Caterina P. Krishnamurti, Lakshmanan Ataga, Kenneth I. Eckman, James R. Hsu, Lewis L. McClish, Donna McKinlay, Sonja M. Molokie, Robert Osunkwo, Ifeyinwa Smith-Whitley, Kim Telen, Marilyn J. CA SCDCRN TI IMPROVE trial: A randomized controlled trial of patient-controlled analgesia for sickle cell painful episodes: rationale, design challenges, initial experience, and recommendations for future studies SO CLINICAL TRIALS LA English DT Article ID CLINICAL-TRIALS; IMMPACT RECOMMENDATIONS; VASOOCCLUSIVE EPISODES; DISEASE; CRISIS; CHILDREN; SCALE; ADOLESCENTS; MANAGEMENT; EMERGENCY AB Background The hallmark of sickle cell disease (SCD) is pain from a vaso-occlusive crisis. Although ambulatory pain accounts for most days in pain, pain is also the most common cause of hospitalization and is typically treated with parenteral opioids. The evidence base is lacking for most analgesic practice in SCD, particularly for the optimal opioid dosing for patient-controlled analgesia (PCA), in part because of the challenges of the trial design and conduct for this rare disease. Purpose The purpose of this report is to describe our Network's experiences with protocol development, implementation, and analysis, including overall study design, the value of pain assessments rather than 'crisis' resolution as trial endpoints, and alternative statistical analysis strategies. Methods The Improving Pain Management and Outcomes with Various Strategies (IMPROVE) PCA trial was a multisite inpatient randomized controlled trial comparing two PCA-dosing strategies in adults and children with SCD and acute pain conducted by the SCD Clinical Research Network. The specified primary endpoint was a 25-mm change in a daily average pain intensity using a Visual Analogue Scale, and a number of related pain intensity and pain interference measures were selected as secondary efficacy outcomes. A time-to-event analysis strategy was planned for the primary endpoint. Results 01 1116 individuals admitted for pain at 31 participating sites over a 6-month period, 38 were randomized and 4 withdrawn. The trial was closed early due to poor accrual, reflecting a substantial number of challenges encountered during trial implementation. Limitations While some of the design issues were unique to SCD or analgesic studies, many of the trial implementation challenges reflected the increasing complexity of conducting clinical trials in the inpatient setting with multiple care providers and evolving electronic medical record systems, particularly in the context of large urban academic medical centers. Lessons learned Complicated clinical organization of many sites likely slowed study initiation. More extensive involvement of research staff and site principal investigator in the clinical care operations improved site performance. During the subsequent data analysis, alternative statistical approaches were considered, the results of which should inform future efficacy assessments and increase future trial recruitment success by allowing substantial reductions in target sample size. Conclusions A complex randomized analgesic trial was initiated within a multisite disease network seeking to provide an evidence base for clinical care. A number of design considerations were shown to be feasible in this setting, and several pain intensity and pain interference measures were shown to be sensitive to time- and treatment-related improvements. While the premature closure and small sample size precluded definitive conclusions regarding treatment efficacy, this trial furnishes a template for design and implementation considerations that should improve future SCD analgesic trials. Clinical Trials 2013; 10: 319-331. http://ctj.sagepub.com C1 [Dampier, Carlton D.; Osunkwo, Ifeyinwa] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Dampier, Carlton D.; Osunkwo, Ifeyinwa] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA. [Smith, Wally R.; McClish, Donna] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. [Wager, Carrie G.; Kim, Hae-Young; Bell, Margaret C.; Miller, Scott T.; McKinlay, Sonja M.] New England Res Inst, Watertown, MA 02172 USA. [Weiner, Debra L.] Childrens Hosp, Boston, MA 02115 USA. [Minniti, Caterina P.] NIH, Hematol Branch, Bethesda, MD 20892 USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Ataga, Kenneth I.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Eckman, James R.] Emory Univ, Sch Med, Grady Mem Hosp, Atlanta, GA USA. [Hsu, Lewis L.; Molokie, Robert] Univ Illinois, Dept Pediat, Chicago, IL USA. [Smith-Whitley, Kim] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Telen, Marilyn J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Dampier, CD (reprint author), Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, 2015 Uppergate Dr,Rm 464, Atlanta, GA 30322 USA. EM cdampie@emory.edu RI sebastianovitsch, stepan/G-8507-2013 FU National Heart, Lung, and Blood Institute, National Institutes of Health [U10HL083721]; GlycoMimetics, Inc.; NHLBI-St Jude Children's Research Hospital Emmaus Medical, Inc.; ClinDatrix, Inc.-Querrey Harrow, Ltd.; HemaQuest; Eli Lilly; Glycomimetics; NIH; FDA; Ikaria FX This publication was made possible by grant number U10HL083721 from the National Heart, Lung, and Blood Institute, National Institutes of Health.; W.R.S. and C.D.D. were supported by GlycoMimetics, Inc.; S.T.M. was supported by the NHLBI-(SWiTCH Trial, BABY HUG Investigator) St Jude Children's Research Hospital (SWiTCH Trial) Emmaus Medical, Inc. and ClinDatrix, Inc.-(Glutamine Trial Investigator) Querrey & Harrow, Ltd.-(Expert Case Review); K.I.A. was supported by HemaQuest and Eli Lilly; L.L.H. received support from Glycomimetics and NIH; M.J.T. was the Consultant and Coordinating Principal Investigator for GlycoMimetics, Inc.; and D.L.W. received support from FDA and Ikaria and is on contract research for Dilafor, Inc. NR 45 TC 14 Z9 14 U1 0 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2013 VL 10 IS 2 BP 319 EP 331 DI 10.1177/1740774513475850 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 135CJ UT WOS:000318263300013 PM 23539110 ER PT J AU Kim, TH Lee, S Chen, XY AF Kim, Tae Hyung Lee, Seulki Chen, Xiaoyuan TI Nanotheranostics for personalized medicine SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE chemotherapy; drug delivery; molecular imaging; molecular profiling; nanotechnology; nanotheranostics; prodrugs ID ONCOLOGIC DRUG DEVELOPMENT; CANCER-THERAPY; MAGNETIC NANOPARTICLES; QUANTUM DOTS; MOLECULAR CLASSIFICATION; NANOSPHERE LITHOGRAPHY; MALIGNANT-MELANOMA; BREAST-CANCER; CATHEPSIN-B; IN-VIVO AB Nanotheranostics, the integration of diagnostic and therapeutic function in one system using the benefits of nanotechnology, is extremely attractive for personalized medicine. Because treating cancer is not a one-size-fits-all scenario, it requires therapy to be adapted to the patient's specific biomolecules. Personalized and precision medicine (PM) does just that. It identifies biomarkers to gain an understanding of the diagnosis and in turn treating the specific disorder based on the precise diagnosis. By predominantly utilizing the unique properties of nanoparticles to achieve biomarker identification and drug delivery, nanotheranostics can be applied to noninvasively discover and target image biomarkers and further deliver treatment based on the biomarker distribution. This is a large and hopeful role theranostics must fill. However, as described in this expert opinion, current nanotechnology-based theranostics systems engineered for PM applications are not yet sufficient. PM is an ever-growing field that will be a driving force for future discoveries in biomedicine, especially cancer theranostics. In this article, the authors dissect the requirements for successful nanotheranostics-based PM. C1 [Kim, Tae Hyung; Lee, Seulki] Johns Hopkins Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD USA. RP Lee, S (reprint author), Johns Hopkins Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. EM seulki@jhmi.edu; shawn.chen@nih.gov FU National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH; NIBIB [R00 EB013450] FX This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH and NIBIB award R00 EB013450. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 93 TC 46 Z9 48 U1 5 U2 63 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD APR PY 2013 VL 13 IS 3 BP 257 EP 269 DI 10.1586/ERM.13.15 PG 13 WC Pathology SC Pathology GA 133MQ UT WOS:000318142900012 PM 23570404 ER PT J AU Schairer, C Brinton, LA AF Schairer, Catherine Brinton, Louise A. TI The Effect of Estrogen Plus Progestin Hormone Therapy on Breast Cancer Mortality: Still Unresolved SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HEALTHY POSTMENOPAUSAL WOMEN; INITIATIVE RANDOMIZED-TRIAL; BENEFITS; RISKS C1 [Schairer, Catherine; Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Schairer, C (reprint author), NCI, 6210 Execut Blvd,Room 8026, Rockville, MD 20852 USA. EM schairec@exchange.nih.gov RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 10 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD APR PY 2013 VL 105 IS 8 BP 513 EP 514 DI 10.1093/jnci/djt058 PG 2 WC Oncology SC Oncology GA 132SN UT WOS:000318089100003 PM 23543780 ER PT J AU Long, JR Delahanty, RJ Li, GL Gao, YT Lu, W Cai, QY Xiang, YB Li, C Ji, BT Zheng, Y Ali, S Shu, XO Zheng, W AF Long, Jirong Delahanty, Ryan J. Li, Guoliang Gao, Yu-Tang Lu, Wei Cai, Qiuyin Xiang, Yong-Bing Li, Chun Ji, Bu-Tian Zheng, Ying Ali, Simak Shu, Xiao-Ou Zheng, Wei TI A Common Deletion in the APOBEC3 Genes and Breast Cancer Risk SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; COPY NUMBER VARIATION; SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; POLYMORPHISM; EXPRESSION; VARIANTS; STRATIFICATION; ALLELES; DISEASE AB Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk. We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai. Of the 268 common CNVs (minor allele frequency 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P 1.110(4)) and was replicated in stage 2 (odds ratio 1.35, 95% confidence interval [CI] 1.27 to 1.44; P 9.610(22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI 1.57 to 1.97) for a two-copy deletion (P 2.010(24)). We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer. C1 [Long, Jirong; Delahanty, Ryan J.; Li, Guoliang; Cai, Qiuyin; Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med,Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. [Lu, Wei; Zheng, Ying] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ali, Simak] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. RP Long, JR (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525W End Ave,8th Fl, Nashville, TN 37203 USA. EM jirong.long@vanderbilt.edu RI LI, GUOLIANG/E-7359-2015 OI LI, GUOLIANG/0000-0001-8493-4684 FU US National Institutes of Health [R01CA137013, R01CA148667, R01CA124558, R01CA064277, R37CA070867, R01CA118229, R01CA092585, R01CA122756]; Ingram Professorship and Research Reward funds; Department of Defense (DOD) Idea Awards [BC011118, BC050791]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX This work was supported in part by grants from the US National Institutes of Health grants (R01CA137013 to JL; R01CA148667, R01CA124558, R01CA064277, and R37CA070867 to WZ; R01CA118229 and R01CA092585 to X-OS; R01CA122756 to QC); Ingram Professorship and Research Reward funds (to WZ); and Department of Defense (DOD) Idea Awards (BC011118 to X-OS; BC050791 to QC). Sample preparation and genotyping assays were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 41 TC 45 Z9 46 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD APR PY 2013 VL 105 IS 8 BP 573 EP 579 DI 10.1093/jnci/djt018 PG 7 WC Oncology SC Oncology GA 132SN UT WOS:000318089100010 PM 23411593 ER PT J AU Zhang, F Ferrucci, L Culham, E Metter, EJ Guralnik, J Deshpande, N AF Zhang, Fang Ferrucci, Luigi Culham, Elsie Metter, E. Jeffrey Guralnik, Jack Deshpande, Nandini TI Performance on Five Times Sit-to-Stand Task as a Predictor of Subsequent Falls and Disability in Older Persons SO JOURNAL OF AGING AND HEALTH LA English DT Article DE falls; disability; activity of daily living (ADL); instrumental activity of daily living (IADL) ID LOWER-EXTREMITY FUNCTION; RISK-FACTORS; COMMUNITY; FRACTURES; ADULTS; WOMEN; EPIDEMIOLOGY; ASSOCIATION; IMPAIRMENT; BATTERY AB Objectives: To investigate whether the performance on 5 times sit-to-stand test (5tSTS) can predict subsequent falls, fall-related fracture, and activities of daily living (ADL) and instrumental activities of daily living (IADL) disability in older persons. Methods: A total of 948 older adults (age ayen 60) participated in this study. Ability and the time to finish 5tSTS were recorded at baseline. Number of falls, fall-related fractures, and the ability to complete ADL and IADL without assistance were recorded retrospectively at baseline and at the 3-year follow-up. Results: Inability to complete 5tSTS was a marginal predictor of falls (OR = 4.22) and a significant predictor of ADL- (OR = 24.70) and IADL-related disability (OR = 17.10) at 3-year follow-up. The need of longer time to complete 5tSTS was predictive of developing IADL-related disability at 3-year follow-up (OR = 4.22 [> 16.6 s]; OR = 2.49 [13.7 - 16.6 s]). Discussion: 5tSTS is an easily administered tool which can be used to predict subsequent ADL- and IADL-related disability. C1 [Zhang, Fang; Culham, Elsie; Deshpande, Nandini] Queens Univ, Sch Rehabil Therapy, Kingston, ON K7L 3N6, Canada. [Ferrucci, Luigi; Metter, E. Jeffrey] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Guralnik, Jack] Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Deshpande, N (reprint author), Queens Univ, Sch Rehabil Therapy, 31 George St, Kingston, ON K7L 3N6, Canada. EM nandinijd@yahoo.com FU NIA NIH HHS [N01-AG-821336, N01-AG-5-0002, N01-AG-916413] NR 34 TC 18 Z9 18 U1 4 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0898-2643 J9 J AGING HEALTH JI J. Aging Health PD APR PY 2013 VL 25 IS 3 BP 478 EP 492 DI 10.1177/0898264313475813 PG 15 WC Gerontology; Health Policy & Services SC Geriatrics & Gerontology; Health Care Sciences & Services GA 132DC UT WOS:000318047100006 PM 23407343 ER PT J AU Lorieau, JL Maltsev, AS Louis, JM Bax, A AF Lorieau, Justin L. Maltsev, Alexander S. Louis, John M. Bax, Ad TI Modulating alignment of membrane proteins in liquid-crystalline and oriented gel media by changing the size and charge of phospholipid bicelles SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Bicelle; Dipolar coupling; Fusion peptide; NMR; Orthogonal alignment; Saupe matrix ID RESIDUAL DIPOLAR COUPLINGS; DE-NOVO DETERMINATION; SOLID-STATE NMR; BIOLOGICAL MACROMOLECULES; TRANSLATIONAL DIFFUSION; POLYACRYLAMIDE GELS; BIOMOLECULAR NMR; WEAK ALIGNMENT; DYNAMICS; PEPTIDE AB We demonstrate that alignment of a structured peptide or small protein solubilized in mixed phospholipid:detergent micelles or bicelles, when embedded in a compressed gel or liquid crystalline medium, can be altered by either changing the phospholipid aggregate shape, charge, or both together. For the hemagglutinin fusion peptide solubilized in bicelles, we show that bicelle shape and charge do not change its helical hairpin structure but impact its alignment relative to the alignment medium, both in charged compressed acrylamide gel and in liquid crystalline d(GpG). The method can be used to generate sets of residual dipolar couplings that correspond to orthogonal alignment tensors, and holds promise for high-resolution structural refinement and dynamic mapping of membrane proteins. C1 [Lorieau, Justin L.; Maltsev, Alexander S.; Louis, John M.; Bax, Ad] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), Natl Inst Diabet & Digest & Kidney Dis NIDDK, Chem Phys Lab, NIH, Bldg 5,Room 126,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); Office of the Director, NIH FX We thank Annie Aniana for help with protein expression and purification, Nicolas A. Bax for measuring the cmc of DHPS, and Dennis A. Torchia for discussions and comments. This work was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH) and the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 64 TC 1 Z9 1 U1 2 U2 28 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD APR PY 2013 VL 55 IS 4 BP 369 EP 377 DI 10.1007/s10858-013-9720-3 PG 9 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 133YJ UT WOS:000318176500005 PM 23508769 ER PT J AU Pan, YM Wang, YL Bryant, SH AF Pan, Yongmei Wang, Yanli Bryant, Stephen H. TI Pharmacophore and 3D-QSAR Characterization of 6-Arylquinazolin-4-amines as Cdc2-like Kinase 4 (Clk4) and Dual Specificity Tyrosine-phosphorylation-regulated Kinase 1A (Dyrk1A) Inhibitors SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID PREGNANE-X-RECEPTOR; DOWN-SYNDROME; ACCURATE DOCKING; LEUCETTAMINE B; BINDING-SITES; FORCE-FIELD; 3D QSAR; PROTEIN; GLIDE; IDENTIFICATION AB Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure-activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R-2 and Q(2) (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure-activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors. C1 [Pan, Yongmei; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (NLM). We thank Helix Systems, High-Performance Computing at the NIH for making Maestro, Schrodinger available for this study. NR 48 TC 9 Z9 9 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD APR PY 2013 VL 53 IS 4 BP 938 EP 947 DI 10.1021/ci300625c PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 132ID UT WOS:000318060200019 PM 23496085 ER PT J AU Toepfner, N Wohlfarth, A Naue, J Auwarter, V Berner, R Hermanns-Clausen, M AF Toepfner, N. Wohlfarth, A. Naue, J. Auwaerter, V. Berner, R. Hermanns-Clausen, M. TI Accidental clozapine intoxication in a toddler: clinical and pharmacokinetic lessons learnt SO JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS LA English DT Article DE accidental; clozapine-N-oxide; CYP450; norclozapine; overdose ID ADOLESCENTS; CHILDREN AB What is known and Objective: Clozapine, a second generation antipsychotic which is relatively safe in overdose, has been used as an effective treatment alternative to traditional anti-psychotics. The therapeutic use in children remains controversial. However, in accordance with the increasing prescription in adults, the accidental ingestion in childhood becomes more frequent. We report the youngest case of accidental clozapine ingestion. Case summary: A 13-month-old girl presented with acute respiratory insufficiency and coma of unknown origin. The medical history, laboratory and radiological assessment did not link to aetiology until an almost spontaneous arousal after 22 h pointed towards intoxication. The initial standard drug screening using immunoassay had been negative. Hence, liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS) was performed, and clozapine was detected with a serum concentration of 736 ng/mL. What is new and Conclusion: This case illustrates the diagnostic and forensic pitfalls in a coma of unknown origin due to the limits of toxicological screening immunoassays. LC-MS/MS analysis by an established method showed clozapine metabolites (norclozapine and clozapine-N-oxide) are detectable for longer period, especially in urine, when compared with clozapine. The clinical course is presented in unique correlation with plasma and urine concentrations of clozapine and its metabolites. The elimination pattern of clozapine in toddlers is similar to adults, and the toxic dose was found to be lower when compared with school-age children and adults. C1 [Toepfner, N.; Berner, R.] Carl Gustav Carus Univ, Clin & Polyclin Pediat & Adolescent Med, D-01307 Dresden, Germany. [Wohlfarth, A.] Natl Inst Drug Abuse, NIH, Baltimore, MD USA. [Naue, J.; Auwaerter, V.] Univ Med Ctr, Inst Forens Med, Freiburg, Germany. [Hermanns-Clausen, M.] Univ Med Ctr, Poison Informat Ctr VIZ Freiburg, Freiburg, Germany. RP Toepfner, N (reprint author), Carl Gustav Carus Univ, Clin & Polyclin Pediat & Adolescent Med, Fetscherstr 74, D-01307 Dresden, Germany. EM nicole.toepfner@uniklinikum-dresden.de NR 13 TC 2 Z9 2 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-4727 J9 J CLIN PHARM THER JI J. Clin. Pharm. Ther. PD APR PY 2013 VL 38 IS 2 BP 165 EP 168 DI 10.1111/jcpt.12022 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 133TY UT WOS:000318164700017 PM 23167664 ER PT J AU Tao, Y Shi, M Conrardy, C Kuzmin, IV Recuenco, S Agwanda, B Alvarez, DA Ellison, JA Gilbert, AT Moran, D Niezgoda, M Lindblade, KA Holmes, EC Breiman, RF Rupprecht, CE Tong, SX AF Tao, Ying Shi, Mang Conrardy, Christina Kuzmin, Ivan V. Recuenco, Sergio Agwanda, Bernard Alvarez, Danilo A. Ellison, James A. Gilbert, Amy T. Moran, David Niezgoda, Michael Lindblade, Kim A. Holmes, Edward C. Breiman, Robert F. Rupprecht, Charles E. Tong, Suxiang TI Discovery of diverse polyomaviruses in bats and the evolutionary history of the Polyomaviridae SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID SEQUENCE; PHYLOGENY; VIRUSES; HOSTS; IDENTIFICATION; CORONAVIRUSES; COEVOLUTION; PROGRAM; GENOMES; PROTEIN AB Polyomaviruses (PyVs) have been identified in a wide range of avian and mammalian species. However, little is known about their occurrence, genetic diversity and evolutionary history in bats, even though bats are important reservoirs for many emerging viral pathogens. This study screened 380 specimens from 35 bat species from Kenya and Guatemala for the presence of PyVs by semi-nested pan-PyV FOR assays. PyV DNA was detected in 24 of the 380 bat specimens. Phylogenetic analysis revealed that the bat PyV sequences formed 12 distinct lineages. Full-genome sequences were obtained for seven representative lineages and possessed similar genomic features to known PyVs. Strikingly, this evolutionary analysis revealed that the bat PyVs were paraphyletic, suggestive of multiple species jumps between bats and other mammalian species, such that the theory of virus-host co-divergence for mammalian PyVs as a whole could be rejected. In addition, evidence was found for strong heterogeneity in evolutionary rate and potential recombination in a number of PyV complete genomes, which complicates both phylogenetic analysis and virus classification. In summary, this study revealed that bats are important reservoirs of PyVs and that these viruses have a complex evolutionary history. C1 [Tao, Ying; Conrardy, Christina; Tong, Suxiang] Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30333 USA. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Shi, Mang; Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Kuzmin, Ivan V.; Recuenco, Sergio; Ellison, James A.; Gilbert, Amy T.; Niezgoda, Michael; Rupprecht, Charles E.] Ctr Dis Control & Prevent, Div High Consequence Pathogens & Pathol, Atlanta, GA 30333 USA. [Agwanda, Bernard] Kenya Wildlife Serv, Natl Museum, Nairobi, Kenya. [Alvarez, Danilo A.; Moran, David] Univ Valle Guatemala, Ctr Hlth Studies, Guatemala City, Guatemala. [Lindblade, Kim A.] Ctr Dis Control & Prevent Cent Amer & Panama, Guatemala City, Guatemala. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Breiman, Robert F.] Ctr Dis Control & Prevent Kenya, Nairobi, Kenya. RP Tong, SX (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30333 USA. EM sot1@cdc.gov RI Shi, Mang/D-5118-2013; OI Ellison, James/0000-0003-4492-4857; Recuenco-Cabrera, Sergio/0000-0002-8446-7411; Holmes, Edward/0000-0001-9596-3552 FU Global Disease Detection Program TSC funds in the Centers for Disease Control and Prevention, Atlanta, Georgia FX The study was supported in part by the Global Disease Detection Program TSC funds in the Centers for Disease Control and Prevention, Atlanta, Georgia. We thank Shur-Wern Chem (Division of Viral Diseases, CDC, Atlanta, GA, USA) for her work in the validation of the pan-PyV PCR assay. We thank Ramon Medrano and Maria Luisa Muller from Universidad del Valle de Guatemala (Guatemala City, Guatemala) for support in the fieldwork and thank the Ministry of Agriculture and Ministry of Health from Guatemala. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. NR 38 TC 15 Z9 15 U1 2 U2 14 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2013 VL 94 BP 738 EP 748 DI 10.1099/vir.0.047928-0 PN 4 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 131LM UT WOS:000317995200005 PM 23239573 ER PT J AU Tumban, E Maes, NE Schirtzinger, EE Young, KI Hanson, CT Whitehead, SS Hanley, KA AF Tumban, Ebenezer Maes, Nyree E. Schirtzinger, Erin E. Young, Katherine I. Hanson, Christopher T. Whitehead, Stephen S. Hanley, Kathryn A. TI Replacement of conserved or variable sequences of the mosquito-borne dengue virus 3 ' UTR with homologous sequences from Modoc virus does not change infectivity for mosquitoes SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID WEST-NILE-VIRUS; STEM-LOOP STRUCTURE; COMPLETE GENOME SEQUENCE; NO KNOWN VECTOR; ENCEPHALITIS-VIRUS; PHYLOGENETIC-RELATIONSHIPS; 3'-UNTRANSLATED REGION; JAPANESE ENCEPHALITIS; VACCINE CANDIDATE; ENVELOPE PROTEINS AB The genus Flavivirus includes both vector-borne and no known vector (NKV) species, but the molecular determinants of transmission mode are not known. Conserved sequence differences between the two groups occur in 5' and 3' UTRs. To investigate the impact of these differences on transmission, chimeric genomes were generated, in which UTRs, UTRs+capsid, or the upper 3' UTR stem-loop of mosquito-borne dengue virus (DENV) were replaced with homologous regions from NKV Modoc virus (MODV); the conserved pentanucleotide sequence (CPS) was also deleted from the DENV genome. Virus was not recovered following transfection of these genomes in three different cell types. However, DENV genomes in which the CPS or variable region (VR) of the 3' UTR were replaced with MODV sequences were recovered and infected Aedes aegypti mosquitoes with similar efficiencies to DENV. These results demonstrate that neither vector-borne CPS nor VR is required for vector-borne transmission. C1 [Tumban, Ebenezer; Maes, Nyree E.; Hanley, Kathryn A.] New Mexico State Univ, Program Mol Biol, Las Cruces, NM 88003 USA. [Tumban, Ebenezer] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Schirtzinger, Erin E.; Young, Katherine I.; Hanley, Kathryn A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. [Hanson, Christopher T.; Whitehead, Stephen S.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Tumban, E (reprint author), New Mexico State Univ, Program Mol Biol, Las Cruces, NM 88003 USA. EM etumban@salud.unm.edu FU NIH, NIAID [NIH-K22-A164193, NIH-NM-INBRE P20 RR016480-05, NSF-NM-AMP HRD-0331446] FX We would like to thank Dr Robert Tesh for providing us with Modoc virus. We would also like to thank Dr Barbara Lyons, Dr Steve Hanson and Dr Jeffrey Arterburn for their suggestions. This study was supported in part by NIH-K22-A164193, NIH-NM-INBRE P20 RR016480-05, NSF-NM-AMP HRD-0331446 and the Intramural Research Program of the NIH, NIAID. NR 45 TC 3 Z9 3 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2013 VL 94 BP 783 EP 788 DI 10.1099/vir.0.046664-0 PN 4 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 131LM UT WOS:000317995200011 PM 23255623 ER PT J AU Kajihara, M Nakayama, E Marzi, A Igarashi, M Feldmann, H Takada, A AF Kajihara, Masahiro Nakayama, Eri Marzi, Andrea Igarashi, Manabu Feldmann, Heinz Takada, Ayato TI Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID VESICULAR STOMATITIS VIRUSES; SPIKE DELETION VARIANTS; EBOLA-VIRUS; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; NONHUMAN-PRIMATES; ENTRY; IDENTIFICATION; INFECTION; EPITOPES AB Marburg virus (MARV) and Ebola virus, members of the family Filoviridae, cause lethal haemorrhagic fever in humans and non-human primates. Although the outbreaks are concentrated mainly in Central Africa, these viruses are potential agents of imported infectious diseases and bioterrorism in non-African countries. Recent studies demonstrated that non-human primates passively immunized with virus-specific antibodies were successfully protected against fatal filovirus infection, highlighting the important role of antibodies in protective immunity for this disease. However, the mechanisms underlying potential evasion from antibody mediated immune pressure are not well understood. To analyse possible mutations involved in immune evasion in the MARV envelope glycoprotein (GP) which is the major target of protective antibodies, we selected escape mutants of recombinant vesicular stomatitis virus (rVSV) expressing MARV GP (rVSV Delta G/MARVGP) by using two GP-specific mAbs, AGP127-8 and MGP72-17, which have been previously shown to inhibit MARV budding. Interestingly, several rVSV Delta G/MARVGP variants escaping from the mAb pressure-acquired amino acid substitutions in the furin-cleavage site rather than in the mAb-specific epitopes, suggesting that these epitopes are recessed, not exposed on the uncleaved GP molecule, and therefore inaccessible to the mAbs. More surprisingly, some variants escaping mAb MGP72-17 lacked a large proportion of the mucin-like region of GP, indicating that these mutants efficiently escaped the selective pressure by deleting the mucin-like region including the mAb-specific epitope. Our data demonstrate that MARV GP possesses the potential to evade antibody mediated immune pressure due to extraordinary structural flexibility and variability. C1 [Kajihara, Masahiro; Nakayama, Eri; Takada, Ayato] Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido 0010020, Japan. [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Igarashi, Manabu] Hokkaido Univ, Res Ctr Zoonosis Control, Div Bioinformat, Sapporo, Hokkaido 0010020, Japan. [Takada, Ayato] Univ Zambia, Sch Vet Med, Lusaka, Zambia. RP Takada, A (reprint author), Hokkaido Univ, Res Ctr Zoonosis Control, Div Global Epidemiol, Sapporo, Hokkaido 0010020, Japan. EM atakada@czc.hokudai.ac.jp RI Igarashi, Manabu/F-6871-2012 FU Japan Initiative for Global Research Network on Infectious Diseases (J-GRID); Global COE Program; Ministry of Education, Culture, Sports, Science and Technology (MEXT); Ministry of Health, Labour and Welfare of Japan; Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) FX We thank Hiroko Miyamoto and Ayaka Yokoyama (Hokkaido University Research Center for Zoonosis Control), and Dr Hideki Ebihara (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories) for technical assistance and valuable advice, and Kim Barrymore for editing the manuscript. This work was supported by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID), the Global COE Program and a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Funding was also provided by a Grant-in-Aid from the Ministry of Health, Labour and Welfare of Japan and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). NR 38 TC 4 Z9 4 U1 2 U2 13 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD APR PY 2013 VL 94 BP 876 EP 883 DI 10.1099/vir.0.049114-0 PN 4 PG 8 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 131LM UT WOS:000317995200022 PM 23288419 ER PT J AU Beydoun, MA Beydoun, HA Kaufman, JS An, Y Resnick, SM O'Brien, R Ferrucci, L Zonderman, AB AF Beydoun, May A. Beydoun, Hind A. Kaufman, Jay S. An, Yang Resnick, Susan M. O'Brien, Richard Ferrucci, Luigi Zonderman, Alan B. TI Apolipoprotein E epsilon 4 Allele Interacts with Sex and Cognitive Status to Influence All-Cause and Cause-Specific Mortality in U.S. Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE apolipoprotein E genotype; dementia; mild cognitive impairment; mortality; cardiovascular disease ID CORONARY-HEART-DISEASE; ELDERLY FINNISH MEN; E GENOTYPE; AFRICAN-AMERICAN; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; E POLYMORPHISM; E PHENOTYPE; ASSOCIATION; DEMENTIA AB Objectives To confirm associations of apolipoprotein E (ApoE) epsilon 4 carrier status, sex, and time-dependent cognitive status with mortality risk and to investigate these joint effects of these associations in a cohort of community-dwelling U.S. adults. Design Prospective cohort study. Setting The Baltimore Longitudinal Study of Aging (BLSA). Participants Of 3,047 BLSA participants aged 17 to 98 at first visit (60.1% male), 1,704 with complete ApoE genotype data were included, of whom 1,461 aged 50 and older with one or more visits were eligible. Measurements Time to death from all, cardiovascular, and noncardiovascular causes. Results Probability of survival was lower for ApoE epsilon 4 carriers, particularly those who were older. A Cox proportional hazards model for all-cause mortality yielded a hazard ratio (HR) for ApoE epsilon 4 carrier versus noncarriers of 1.31 (95% confidence interval (CI)=1.021.68). This association was also found for cardiovascular mortality. Time-dependent all-cause dementia (HR=1.73, 95% CI= 1.332.26) and mild cognitive impairment (HR=1.95, 95% CI=1.422.67) increased all-cause mortality risk, associations that were also detected for noncardiovascular mortality. When individuals were free of cognitive impairment, a dose-response relationship with epsilon 4 alleles was found for all-cause mortality (HR=1.40, 95% CI=0.942.07 for 1 epsilon 4; HR=2.61, 95% CI=1.126.07 for 2 epsilon 4). After onset of Alzheimer's disease (AD), carrying only one epsilon 4 allele resulted in an approximately 77% greater all-cause mortality risk than in noncarriers. ApoE epsilon 4 carrier status increased all-cause mortality risk in men and interacted with time-dependent AD to increase the risk of this outcome (relative excess risk due to interaction=2.15, 95% CI=1.223.07). Conclusion ApoE epsilon 4 carrier status was found to increase all-cause and cardiovascular mortality risks and interacted with sex and time-dependent AD status to affect all-cause mortality. C1 [Beydoun, May A.; An, Yang; Resnick, Susan M.; Ferrucci, Luigi; Zonderman, Alan B.] NIA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Kaufman, Jay S.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [O'Brien, Richard] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Beydoun, MA (reprint author), NIA, Biomed Res Ctr, IRP, 251 Bayview Blvd,Suite 100,Room 04B118, Baltimore, MD 21224 USA. EM baydounm@mail.nih.gov FU NIA/NIH/IRP FX The authors declare no conflict of interest. This research was supported entirely by the NIA/NIH/IRP. NR 51 TC 12 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 IS 4 BP 525 EP 534 DI 10.1111/jgs.12156 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 130IN UT WOS:000317907600006 PM 23581910 ER PT J AU Wadiwala, MF Kamal, AK AF Wadiwala, Muhammad Faisal Kamal, Ayeesha Kamran TI My patient had a small vessel stroke, are two antiplatelet agents better than one? SO JOURNAL OF THE PAKISTAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Kamal, Ayeesha Kamran] Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Programme, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. Aga Khan Univ Hosp, Natl Inst Neurol Disorders & Stroke, Karachi, Pakistan. RP Kamal, AK (reprint author), Aga Khan Univ Hosp, Stroke Serv & Vasc Fellowship Programme, Int Cerebrovasc Translat Clin Res Training Progra, Fogarty Int Ctr, Karachi, Pakistan. EM ayeesha.kamal@aku.edu FU FIC NIH HHS [D43 TW008660] NR 1 TC 0 Z9 0 U1 0 U2 0 PU PAKISTAN MEDICAL ASSOC PI KARACHI PA PMA HOUSE, AGA KHAN III RD, KARACHI, 00000, PAKISTAN SN 0030-9982 J9 J PAK MED ASSOC JI J. Pak. Med. Assoc. PD APR PY 2013 VL 63 IS 4 BP 535 EP 536 PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 112HV UT WOS:000316584200029 PM 23905460 ER PT J AU Clayton, JA Joseph, S AF Clayton, Janine Austin Joseph, Stephanie TI Why research sex differences and similarities? SO MEDICAL PHYSICS LA English DT Editorial Material C1 [Clayton, Janine Austin] NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. [Joseph, Stephanie] US FDA, Off Special Hlth Issues, Silver Spring, MD 20993 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; Stephanie.Joseph@fda.hhs.gov NR 3 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD APR PY 2013 VL 40 IS 4 AR 040403 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 130UP UT WOS:000317945900004 PM 23556868 ER PT J AU Chou, JY Jun, HS Mansfield, BC AF Chou, Janice Y. Jun, Hyun Sik Mansfield, Brian C. TI The SLC37 family of phosphate-linked sugar phosphate antiporters SO MOLECULAR ASPECTS OF MEDICINE LA English DT Review DE SLC37; Sugar phosphate exchanger; Glucose-6-phosphate transporter; Endoplasmic reticulum; Glycogen storage disease type Ib; Glucose-6-phosphatase ID GLYCOGEN-STORAGE-DISEASE; PUTATIVE GLUCOSE-6-PHOSPHATE TRANSLOCASE; PHOSPHOHISTIDINE-ENZYME INTERMEDIATE; MAJOR FACILITATOR SUPERFAMILY; ACUTE MYELOGENOUS LEUKEMIA; COLONY-STIMULATING FACTOR; NEUTROPHIL DYSFUNCTION; LIVER-TRANSPLANTATION; CONGENITAL NEUTROPENIA; GENE-THERAPY AB The SLC37 family consists of four sugar-phosphate exchangers, A1, A2, A3, and A4, which are anchored in the endoplasmic reticulum (ER) membrane. The best characterized family member is SLC37A4, better known as the glucose-6-phosphate (G6P) transporter (G6PT). SLC37A1, SLC37A2, and G6PT function as phosphate (P-i)-linked G6P antiporters catalyzing G6P:P-i and P-i:P-i exchanges. The activity of SLC37A3 is unknown. G6PT translocates G6P from the cytoplasm into the lumen of the ER where it couples with either glucose-6-phosphatase-alpha (G6Pase-alpha) or G6Pase-beta to hydrolyze intraluminal G6P to glucose and P-i. The functional coupling of G6PT with G6Pase-alpha maintains interprandial glucose homeostasis and the functional coupling of G6PT with G6Pase-beta maintains neutrophil energy homeostasis and functionality. A deficiency in G6PT causes glycogen storage disease type Ib, an autosomal recessive disorder characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction. Neither SLC37A1 nor SLC37A2 can functionally couple with G6Pase-alpha or G6Pase-beta, and there are no known disease associations for them or SLC37A3. Since only G6PT matches the characteristics of the physiological ER G6P transporter involved in blood glucose homeostasis and neutrophil energy metabolism, the biological roles for the other SLC37 proteins remain to be determined. Published by Elsevier Ltd. C1 [Chou, Janice Y.; Jun, Hyun Sik; Mansfield, Brian C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular Differentiat, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Mansfield, Brian C.] Fdn Fighting Blindness, Columbia, MD 21046 USA. RP Chou, JY (reprint author), NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov OI Mansfield, Brian/0000-0002-8533-2789 FU Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.; This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 70 TC 4 Z9 4 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0098-2997 J9 MOL ASPECTS MED JI Mol. Asp. Med. PD APR-JUN PY 2013 VL 34 IS 2-3 SI SI BP 601 EP 611 DI 10.1016/j.mam.2012.05.010 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 135AK UT WOS:000318258200036 PM 23506893 ER PT J AU Manoli, I Kwan, JY Wang, Q Rushing, EJ Tsokos, M Arai, AE Burch, WM Dispenzieri, A McPherron, AC Gahl, WA AF Manoli, Irini Kwan, Justin Y. Wang, Qian Rushing, Elisabeth J. Tsokos, Maria Arai, Andrew E. Burch, Warner M. Dispenzieri, Angela McPherron, Alexandra C. Gahl, William A. TI Chronic myopathy due to immunoglobulin light chain amyloidosis SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Amyloidosis; Pax7; Satellite cells; Muscle hypertrophy ID PRIMARY SYSTEMIC AMYLOIDOSIS; SKELETAL-MUSCLE HYPERTROPHY; SATELLITE CELL ADDITION; UNDIAGNOSED DISEASES; PSEUDO-HYPERTROPHY; COUNTERPOINT; MUTATION; FEATURES; GENE AB Amyloid myopathy associated with a plasma cell dyscrasia is a rare cause of muscle hypertrophy. It can be a challenging diagnosis, since pathological findings are often elusive. In addition, the mechanism by which immunoglobulin light-chain deposition stimulates muscle overgrowth remains poorly understood. We present a 53-year old female with a 10-year history of progressive generalized muscle overgrowth. Congo-red staining and immunohistochemistry revealed perivascular lambda light chain amyloid deposits, apparent only in a second muscle biopsy. The numbers of central nuclei and satellite cells were increased, suggesting enhanced muscle progenitor cell formation. Despite the chronicity of the light chain disease, the patient showed complete resolution of hematologic findings and significant improvement of her muscle symptoms following autologous bone marrow transplantation. This case highlights the importance of early diagnosis and therapy for this treatable cause of a chronic myopathy with muscle hypertrophy. Published by Elsevier Inc. C1 [Manoli, Irini; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Manoli, Irini; Gahl, William A.] NIH, Intramural Program, Off Rare Dis Res, Bethesda, MD 20892 USA. [Manoli, Irini; Gahl, William A.] NIH, NIH Undiagnosed Dis Program, Bethesda, MD 20892 USA. [Kwan, Justin Y.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Wang, Qian; McPherron, Alexandra C.] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Rushing, Elisabeth J.] Univ Zurich, Dept Neuropathol, CH-8006 Zurich, Switzerland. [Tsokos, Maria] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Arai, Andrew E.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Burch, Warner M.] Duke Univ, Med Ctr, Dept Endocrinol, Durham, NC USA. [Dispenzieri, Angela] Mayo Clin, Transplant Ctr, Rochester, MN USA. RP Manoli, I (reprint author), NHGRI, NIH, 49 Convent Dr,Bldg 49,Room 3A30, Bethesda, MD 20892 USA. EM manolii@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941; Dispenzieri, Angela/0000-0001-8780-9512 FU National Human Genome Research Institute; National Institute of Neurological Diseases and Stroke; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA FX The authors would like to thank all the consultants involved in the evaluation of this case, including Drs. K. Fishbeck, B. Wilson, and T. Lehky of neurology, Drs. D. Rosing, K. Van Aalten and Ms. J. Audibert of cardiology, Drs. S. Vasu and P. Noel of hematology, and Dr. G. Joe of physiatry. Michelle Nehrebecky provided superb patient care, and Roxanne Fischer, Carla Ciccone and Richard Hess provided excellent technical assistance. This work was supported by the Intramural Research programs of the National Human Genome Research Institute, the National Institute of Neurological Diseases and Stroke, and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. NR 32 TC 5 Z9 5 U1 0 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 J9 MOL GENET METAB JI Mol. Genet. Metab. PD APR PY 2013 VL 108 IS 4 BP 249 EP 254 DI 10.1016/j.ymgme.2013.01.015 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 112HJ UT WOS:000316583000007 PM 23465863 ER PT J AU Maniwang, E Tayebi, N Sidransky, E AF Maniwang, Emerson Tayebi, Nahid Sidransky, Ellen TI Is Parkinson disease associated with lysosomal integral membrane protein type-2?: Challenges in interpreting association data SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Association; Single nucleotide polymorphism; Parkinson disease; SCARB2; Glucocerebrosidase; Lysosomal integral membrane protein type 2 (LIMP-2) ID GAUCHER-DISEASE; GLUCOCEREBROSIDASE; MUTATIONS; GENE; RECEPTOR; SCARB2 AB Several genetic risk factors have been identified for Parkinson disease (PD), including mutations in glucocerebrosidase (GBA1). Recently, two single nucleotide polymorphisms (SNPs) described as SCARB2 SNPs were reported to be associated with PD. SCARB2 is an attractive candidate gene for PD as it encodes for lysosomal integral membrane protein type 2 (LIMP-2), a protein involved in transporting glucocerebrosidase from the ER to the lysosome. The first SNP, rs6812193, located 64 kb upstream of SCARB2, was identified in a Parkinson disease Genome Wide Association study of Americans with European ancestry (p = 7.6 x 10(-10), OR = 0.84), but was not replicated in a study in the Han Chinese. The second SNP, rs6825004, located within intron 2 of SCARB2 was reported in an association study of Parkinson disease in Greece (p = 0.02, OR = 0.68). We explored whether the two SNPs impact SCARB2 expression or LIMP-2 protein levels, testing fifteen control samples. First, the genotypes for each subject were determined for both SNPs using a Taqman assay. Then, RNA and protein were extracted from the corresponding cell pellets. Neither the relative RNA expression by real-time PCR, nor LIMP-2 levels on Western blots correlated with SNP genotype. Thus, these two reported SNPs may not be related to SCARB2 and demonstrate the challenges in interpreting some association studies. While LIMP-2 could still play a role in PD pathogenesis, this study does not provide evidence that the SNPs identified are in fact related to LIMP-2. Published by Elsevier Inc. C1 [Maniwang, Emerson; Tayebi, Nahid; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Programs of the National Human Genome Research Institute and National Institutes of Health FX This research was supported by the Programs of the National Human Genome Research Institute and National Institutes of Health. NR 15 TC 8 Z9 9 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD APR PY 2013 VL 108 IS 4 BP 269 EP 271 DI 10.1016/j.ymgme.2013.01.012 PG 3 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 112HJ UT WOS:000316583000012 PM 23419877 ER PT J AU Eidahl, JO Crowe, BL North, JA McKee, CJ Shkriabai, N Feng, L Plumb, M Graham, RL Gorelick, RJ Hess, S Poirier, MG Foster, MP Kvaratskhelia, M AF Eidahl, Jocelyn O. Crowe, Brandon L. North, Justin A. McKee, Christopher J. Shkriabai, Nikoloz Feng, Lei Plumb, Matthew Graham, Robert L. Gorelick, Robert J. Hess, Sonja Poirier, Michael G. Foster, Mark P. Kvaratskhelia, Mamuka TI Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GROWTH-FACTOR; HIV-1 INTEGRASE; IN-VITRO; LENTIVIRAL INTEGRATION; RECOMBINANT HISTONES; CHROMATIN-BINDING; DNA INTEGRATION; DOMAIN; PROTEINS; IDENTIFICATION AB Lens epithelium-derived growth factor (LEDGF/p75) tethers lentiviral preintegration complexes (PICs) to chromatin and is essential for effective HIV-1 replication. LEDGF/p75 interactions with lentiviral integrases are well characterized, but the structural basis for how LEDGF/p75 engages chromatin is unknown. We demonstrate that cellular LEDGF/p75 is tightly bound to mononucleosomes (MNs). Our proteomic experiments indicate that this interaction is direct and not mediated by other cellular factors. We determined the solution structure of LEDGF PWWP and monitored binding to the histone H3 tail containing trimethylated Lys36 (H3K36me3) and DNA by NMR. Results reveal two distinct functional interfaces of LEDGF PWWP: a well-defined hydrophobic cavity, which selectively interacts with the H3K36me3 peptide and adjacent basic surface, which non-specifically binds DNA. LEDGF PWWP exhibits nanomolar binding affinity to purified native MNs, but displays markedly lower affinities for the isolated H3K36me3 peptide and DNA. Furthermore, we show that LEDGF PWWP preferentially and tightly binds to in vitro reconstituted MNs containing a tri-methyl-lysine analogue at position 36 of H3 and not to their unmodified counterparts. We conclude that cooperative binding of the hydrophobic cavity and basic surface to the cognate histone peptide and DNA wrapped in MNs is essential for high-affinity binding to chromatin. C1 [Eidahl, Jocelyn O.; McKee, Christopher J.; Shkriabai, Nikoloz; Feng, Lei; Plumb, Matthew; Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [Eidahl, Jocelyn O.; McKee, Christopher J.; Shkriabai, Nikoloz; Feng, Lei; Plumb, Matthew; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Crowe, Brandon L.; Foster, Mark P.] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA. [North, Justin A.; Poirier, Michael G.] Ohio State Univ, Dept Phys, Columbus, OH 43210 USA. [Graham, Robert L.; Hess, Sonja] CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA. [Gorelick, Robert J.] Frederick Natl Lab Canc Res, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Coll Pharm, 500 W 12Th Ave, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Foster, Mark/F-6332-2012; Hess, Sonja/K-4842-2013; Graham, Robert/A-7857-2010; Poirier, Michael/B-5378-2012 OI Foster, Mark/0000-0001-9645-7491; Hess, Sonja/0000-0002-5904-9816; FU National Institutes of Health [AI062520, GM103368, GM077234]; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; SAIC-Frederick, Inc. FX National Institutes of Health [AI062520 and GM103368 to M. K., GM077234 to M. P. F.]; National Cancer Institute, National Institutes of Health [under contract HHSN261200800001E with SAIC-Frederick, Inc. (to R. J. G.)]. 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. Funding for open access charge: National Institutes of Health [GM103368]. NR 52 TC 65 Z9 65 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 6 BP 3924 EP 3936 DI 10.1093/nar/gkt074 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JJ UT WOS:000318063400043 PM 23396443 ER PT J AU Fatoba, ST Tognetti, S Berto, M Leo, E Mulvey, CM Godovac-Zimmermann, J Pommier, Y Okorokov, AL AF Fatoba, Samuel T. Tognetti, Silvia Berto, Melissa Leo, Elisabetta Mulvey, Claire M. Godovac-Zimmermann, Jasminka Pommier, Yves Okorokov, Andrei L. TI Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-ALPHA; SACCHAROMYCES-CEREVISIAE; LYSINE ACETYLATION; HISTONE ACETYLATION; DORMANT ORIGINS; EXCESS MCM2-7; HUMAN-CELLS; S-PHASE; PROTEIN; STRESS AB The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis. C1 [Fatoba, Samuel T.; Tognetti, Silvia; Berto, Melissa; Leo, Elisabetta; Okorokov, Andrei L.] UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England. [Leo, Elisabetta; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mulvey, Claire M.; Godovac-Zimmermann, Jasminka] UCL, London NW3 2PF, England. RP Okorokov, AL (reprint author), UCL, Wolfson Inst Biomed Res, Gower St, London WC1E 6BT, England. EM a.okorokov@ucl.ac.uk RI Tognetti, Silvia/G-6059-2015; OI Tognetti, Silvia/0000-0002-7331-214X; Okorokov, Andrei/0000-0003-2477-3254 FU MRC [G0700001]; US National Cancer Institute, Center for Cancer Research [Z01 BC 006150-19LMP]; Wellcome Trust FX MRC New Investigator Research [G0700001 to A.O.]; Intramural Program of the US National Cancer Institute, Center for Cancer Research [Z01 BC 006150-19LMP to Y.P.]; Wellcome Trust Grant (to J.G.Z.). Funding for open access charge: MRC. NR 77 TC 7 Z9 7 U1 1 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 7 BP 4065 EP 4079 DI 10.1093/nar/gkt131 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133VD UT WOS:000318167900026 PM 23449222 ER PT J AU DuBose, AJ Lichtenstein, ST Narisu, N Bonnycastle, LL Swift, AJ Chines, PS Collins, FS AF DuBose, Amanda J. Lichtenstein, Stephen T. Narisu, Narisu Bonnycastle, Lori L. Swift, Amy J. Chines, Peter S. Collins, Francis S. TI Use of microarray hybrid capture and next-generation sequencing to identify the anatomy of a transgene SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA INTEGRATION; MOUSE MODEL; REARRANGEMENTS; MICE; TRANSLOCATION; EXPRESSION; GENE AB Transgenic animals are extensively used to model human disease. Typically, the transgene copy number is estimated, but the exact integration site and configuration of the foreign DNA remains uncharacterized. When transgenes have been closely examined, some unexpected configurations have been found. Here, we describe a method to recover transgene insertion sites and assess structural rearrangements of host and transgene DNA using microarray hybridization and targeted sequence capture. We used information about the transgene insertion site to develop a polymerase chain reaction genotyping assay to distinguish heterozygous from homozygous transgenic animals. Although we worked with a bacterial artificial chromosome transgenic mouse line, this method can be used to analyse the integration site and configuration of any foreign DNA in a sequenced genome. C1 [DuBose, Amanda J.; Lichtenstein, Stephen T.; Narisu, Narisu; Bonnycastle, Lori L.; Swift, Amy J.; Chines, Peter S.; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM collinsf@mail.nih.gov FU NIH Division of Intramural Research/NHGRI [Z01-HG200305] FX Funding for open access charge: NIH Division of Intramural Research/NHGRI Project Number Z01-HG200305. NR 15 TC 12 Z9 13 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 6 AR e70 DI 10.1093/nar/gks1463 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 132JJ UT WOS:000318063400005 PM 23314155 ER PT J AU Ramasamy, A Trabzuni, D Gibbs, JR Dillman, A Hernandez, DG Arepalli, S Walker, R Smith, C Ilori, GP Shabalin, AA Li, Y Singleton, AB Cookson, MR Hardy, J Ryten, M Weale, ME AF Ramasamy, Adaikalavan Trabzuni, Daniah Gibbs, J. Raphael Dillman, Allissa Hernandez, Dena G. Arepalli, Sampath Walker, Robert Smith, Colin Ilori, Gigaloluwa Peter Shabalin, Andrey A. Li, Yun Singleton, Andrew B. Cookson, Mark R. Hardy, John Ryten, Mina Weale, Michael E. CA NABEC UKBEC TI Resolving the polymorphism-in-probe problem is critical for correct interpretation of expression QTL studies SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ALLELE-SPECIFIC EXPRESSION; GENE-EXPRESSION; SEQUENCE; EQTL; MICROARRAYS; IMPUTATION; MISMATCHES; VARIANTS; DONATION; DATABASE AB Polymorphisms in the target mRNA sequence can greatly affect the binding affinity of microarray probe sequences, leading to false-positive and false-negative expression quantitative trait locus (QTL) signals with any other polymorphisms in linkage disequilibrium. We provide the most complete solution to this problem, by using the latest genome and exome sequence reference data to identify almost all common polymorphisms (frequency > 1% in Europeans) in probe sequences for two commonly used microarray panels (the gene-based Illumina Human HT12 array, which uses 50-mer probes, and exon-based Affymetrix Human Exon 1.0 ST array, which uses 25-mer probes). We demonstrate the impact of this problem using cerebellum and frontal cortex tissues from 438 neuropathologically normal individuals. We find that although only a small proportion of the probes contain polymorphisms, they account for a large proportion of apparent expression QTL signals, and therefore result in many false signals being declared as real. We find that the polymorphism-in-probe problem is insufficiently controlled by previous protocols, and illustrate this using some notable false-positive and false-negative examples in MAPT and PRICKLE1 that can be found in many eQTL databases. We recommend that both new and existing eQTL data sets should be carefully checked in order to adequately address this issue. C1 [Ramasamy, Adaikalavan; Ilori, Gigaloluwa Peter; Weale, Michael E.] Kings Coll London, Dept Med & Mol Genet, Guys Hosp, London SE1 9RT, England. [Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Hernandez, Dena G.; Hardy, John; Ryten, Mina] UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England. [Ramasamy, Adaikalavan; Trabzuni, Daniah; Gibbs, J. Raphael; Hernandez, Dena G.; Hardy, John; Ryten, Mina] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Trabzuni, Daniah] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia. [Gibbs, J. Raphael; Dillman, Allissa; Hernandez, Dena G.; Arepalli, Sampath; Singleton, Andrew B.; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Walker, Robert; Smith, Colin] Univ Edinburgh, MRC Sudden Death Brain Bank Project, Dept Neuropathol, Edinburgh EH8 9AG, Midlothian, Scotland. [Shabalin, Andrey A.; Li, Yun] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Li, Yun] Univ N Carolina, Dept Comp Sci, Dept Biostat, Dept Genet, Chapel Hill, NC 27599 USA. RP Weale, ME (reprint author), Kings Coll London, Dept Med & Mol Genet, Guys Hosp, 8th Floor,Tower Wing, London SE1 9RT, England. EM mina.ryten@ucl.ac.uk; michael.weale@kcl.ac.uk RI Hardy, John/C-2451-2009; sebastianovitsch, stepan/G-8507-2013; Traynor, Bryan/G-5690-2010; Singleton, Andrew/C-3010-2009; Weale, Michael/F-2587-2010; Ramasamy, Adaikalavan/G-2632-2010; Trabzuni, Daniah/C-4034-2012 OI Weale, Michael/0000-0003-4593-1186; Ramasamy, Adaikalavan/0000-0002-7598-2892; Shabalin, Andrey/0000-0003-0309-6821; Walker, Robert/0000-0001-7383-7846; Trabzuni, Daniah/0000-0003-4826-9570 FU Medical Research Council, UK, through MRC Sudden Death Brain Bank; King Faisal Specialist Hospital and Research Centre, Saudi Arabia; National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services [ZIA AG000932-04]; Medical Research Council, UK; [G0901254]; [G0802462] FX Medical Research Council, UK, through the MRC Sudden Death Brain Bank (to C. S.); Project Grant [G0901254 to J.H. and M.W.]; Training Fellowship [G0802462 to M. R.]; King Faisal Specialist Hospital and Research Centre, Saudi Arabia (to D. T.); Intramural Research Program of the National Institute on Aging, National Institutes of Health, part of the US Department of Health and Human Services [ZIA AG000932-04] (in part) (to work performed by the North American Brain Expression Consortium). Funding for open access charge: Medical Research Council, UK. NR 39 TC 23 Z9 23 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2013 VL 41 IS 7 AR e88 DI 10.1093/nar/gkt069 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 133VD UT WOS:000318167900015 PM 23435227 ER PT J AU Nicastro, HL Dunn, BK AF Nicastro, Holly L. Dunn, Barbara K. TI Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) SO NUTRIENTS LA English DT Review DE selenium; SELECT; prostate cancer; chemoprevention ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; BREAST-CANCER; DNA-DAMAGE; FOLLOW-UP; IN-VITRO; RISK; SUPPLEMENTATION; CHEMOPREVENTION; SURVIVAL AB The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 x 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention. C1 [Nicastro, Holly L.] NCI, Canc Prevent Fellowship Program, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD 20850 USA. [Dunn, Barbara K.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Rockville, MD 20850 USA. RP Dunn, BK (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, 9609 Med Ctr Dr, Rockville, MD 20850 USA. EM holly.nicastro@nih.gov; dunnb@mail.nih.gov NR 84 TC 18 Z9 18 U1 1 U2 31 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD APR PY 2013 VL 5 IS 4 BP 1122 EP 1148 DI 10.3390/nu5041122 PG 27 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 131TP UT WOS:000318019300007 PM 23552052 ER PT J AU Choyke, PL Turkbey, B AF Choyke, Peter L. Turkbey, Baris TI The State of Prostate MRI in 2013: Into the Breach SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID CANCER; FUSION; BIOPSY C1 [Choyke, Peter L.; Turkbey, Baris] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 9 TC 1 Z9 1 U1 0 U2 2 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD APR PY 2013 VL 27 IS 4 BP 274 EP + PG 2 WC Oncology SC Oncology GA 132IJ UT WOS:000318060800005 PM 23781690 ER PT J AU Yakel, JL AF Yakel, Jerrel L. TI Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Review ID LONG-TERM POTENTIATION; HIPPOCAMPAL SYNAPTIC PLASTICITY; CENTRAL-NERVOUS-SYSTEM; AMYLOID-BETA-PEPTIDE; ALPHA-7-NICOTINIC ACETYLCHOLINE-RECEPTORS; STRATUM-ORIENS INTERNEURONS; LIGAND-BINDING DOMAIN; RAT HIPPOCAMPAL; ALZHEIMERS-DISEASE; CA2+ PERMEABILITY AB The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability throughout the nervous system by acting on both the cys-loop ligand-gated nicotinic ACh receptor channels (nAChRs) and the G protein-coupled muscarinic ACh receptors (mAChRs). The hippocampus is an important area in the brain for learning and memory, where both nAChRs and mAChRs are expressed. The primary cholinergic input to the hippocampus arises from the medial septum and diagonal band of Broca, the activation of which can activate both nAChRs and mAChRs in the hippocampus and regulate synaptic communication and induce oscillations that are thought to be important for cognitive function. Dysfunction in the hippocampal cholinergic system has been linked with cognitive deficits and a variety of neurological disorders and diseases, including Alzheimer's disease and schizophrenia. My lab has focused on the role of the nAChRs in regulating hippocampal function, from understanding the expression and functional properties of the various subtypes of nAChRs, and what role these receptors may be playing in regulating synaptic plasticity. Here, I will briefly review this work, and where we are going in our attempts to further understand the role of these receptors in learning and memory, as well as in disease and neuroprotection. C1 Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233,Mail Drop F2-08, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 136 TC 33 Z9 36 U1 1 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD APR PY 2013 VL 465 IS 4 BP 441 EP 450 DI 10.1007/s00424-012-1200-1 PG 10 WC Physiology SC Physiology GA 131OU UT WOS:000318003800001 PM 23307081 ER PT J AU Becherel, OJ Yeo, AJ Stellati, A Heng, EYH Luff, J Suraweera, AM Woods, R Fleming, J Carrie, D McKinney, K Xu, XL Deng, CX Lavin, MF AF Becherel, Olivier J. Yeo, Abrey J. Stellati, Alissa Heng, Evelyn Y. H. Luff, John Suraweera, Amila M. Woods, Rick Fleming, Jean Carrie, Dianne McKinney, Kristine Xu, Xiaoling Deng, Chuxia Lavin, Martin F. TI Senataxin Plays an Essential Role with DNA Damage Response Proteins in Meiotic Recombination and Gene Silencing SO PLOS GENETICS LA English DT Article ID SEX-CHROMOSOME INACTIVATION; OCULOMOTOR APRAXIA TYPE-2; DOUBLE-STRAND BREAKS; CROSSING-OVER; GENOMIC INSTABILITY; GROWTH-RETARDATION; MAMMALIAN MEIOSIS; MISMATCH REPAIR; DEFICIENT MICE; PROPHASE-I AB Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx(-/-) revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome. C1 [Becherel, Olivier J.; Yeo, Abrey J.; Stellati, Alissa; Heng, Evelyn Y. H.; Luff, John; Suraweera, Amila M.; Woods, Rick; Lavin, Martin F.] Queensland Inst Med Res, Radiat Biol & Oncol Lab, Brisbane, Qld 4006, Australia. [Becherel, Olivier J.; Stellati, Alissa] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld, Australia. [Yeo, Abrey J.] Univ Queensland, Sch Med, Brisbane, Qld, Australia. [Fleming, Jean] Univ Otago, Dunedin, New Zealand. [Carrie, Dianne] Queensland Inst Med Res, QCF Transgen Lab, Brisbane, Qld 4006, Australia. [McKinney, Kristine] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Xu, Xiaoling; Deng, Chuxia] NIDDKD, Mammalian Genet Sect, NIH, Bethesda, MD 20892 USA. [Lavin, Martin F.] Univ Queensland, Clin Res Ctr, Brisbane, Qld, Australia. RP Becherel, OJ (reprint author), Queensland Inst Med Res, Radiat Biol & Oncol Lab, Brisbane, Qld 4006, Australia. EM Martin.Lavin@qimr.edu.au RI Lavin, Martin/F-5961-2014; Yeo, Abrey/D-9695-2015; deng, chuxia/N-6713-2016 OI Lavin, Martin/0000-0002-5940-4769; Yeo, Abrey/0000-0003-4470-4854; FU Australian National Health and Medical Research Council FX Funding was obtained from the Australian National Health and Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 32 Z9 33 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2013 VL 9 IS 4 AR e1003435 DI 10.1371/journal.pgen.1003435 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 132MS UT WOS:000318073300029 PM 23593030 ER PT J AU St Charles, J Petes, TD AF St Charles, Jordan Petes, Thomas D. TI High-Resolution Mapping of Spontaneous Mitotic Recombination Hotspots on the 1.1 Mb Arm of Yeast Chromosome IV SO PLOS GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; DAMAGE CHECKPOINT ACTIVATION; NONHOMOLOGOUS DNA ENDS; FORMATION IN-VIVO; SACCHAROMYCES-CEREVISIAE; GENE CONVERSION; HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; FORK PROGRESSION; REPLICATION FORK AB Although homologous recombination is an important pathway for the repair of double-stranded DNA breaks in mitotically dividing eukaryotic cells, these events can also have negative consequences, such as loss of heterozygosity (LOH) of deleterious mutations. We mapped about 140 spontaneous reciprocal crossovers on the right arm of the yeast chromosome IV using single-nucleotide-polymorphism (SNP) microarrays. Our mapping and subsequent experiments demonstrate that inverted repeats of Ty retrotransposable elements are mitotic recombination hotspots. We found that the mitotic recombination maps on the two homologs were substantially different and were unrelated to meiotic recombination maps. Additionally, about 70% of the DNA lesions that result in LOH are likely generated during G1 of the cell cycle and repaired during S or G2. We also show that different genetic elements are associated with reciprocal crossover conversion tracts depending on the cell cycle timing of the initiating DSB. C1 [St Charles, Jordan; Petes, Thomas D.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. [St Charles, Jordan] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC USA. RP St Charles, J (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM tom.petes@duke.edu FU NIH [GM24110, GM52319] FX The research was supported by NIH grants GM24110 and GM52319. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 16 Z9 16 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2013 VL 9 IS 4 AR e1003434 DI 10.1371/journal.pgen.1003434 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 132MS UT WOS:000318073300028 PM 23593029 ER PT J AU Wojciechowski, R Hysi, PG AF Wojciechowski, Robert Hysi, Pirro G. TI Focusing In on the Complex Genetics of Myopia SO PLOS GENETICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; REFRACTIVE ERROR; SUSCEPTIBILITY LOCUS; VISUAL IMPAIRMENT; PREVALENCE; SCHOOLCHILDREN; CHILDREN C1 [Wojciechowski, Robert] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Wojciechowski, Robert] NHGRI, Stat Genet Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Hysi, Pirro G.] Kings Coll London, Sch Med, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. RP Wojciechowski, R (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. EM rwojciec@jhsph.edu OI Wojciechowski, Robert/0000-0002-9593-4652 FU NEI NIH HHS [1K08EY022943-01, K08 EY022943] NR 23 TC 17 Z9 17 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2013 VL 9 IS 4 AR e1003442 DI 10.1371/journal.pgen.1003442 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 132MS UT WOS:000318073300036 PM 23593034 ER PT J AU Ayode, D McBride, CM de Heer, HD Watanabe, E Gebreyesus, T Tora, A Tadele, G Davey, G AF Ayode, Desta McBride, Colleen M. de Heer, Hendrik D. Watanabe, Emi Gebreyesus, Tsega Tora, Abebayehu Tadele, Getnet Davey, Gail TI A Qualitative Study Exploring Barriers Related to Use of Footwear in Rural Highland Ethiopia: Implications for Neglected Tropical Disease Control SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID CUTANEOUS LARVA MIGRANS; HOOKWORM INFECTION; SOUTHERN ETHIOPIA; RISK-FACTORS; PODOCONIOSIS; ELEPHANTIASIS; PREVALENCE; EPIDEMIOLOGY; STIGMA; HELMINTHIASIS AB Background: The role of footwear in protection against a range of Neglected Tropical Diseases (NTDs) is gaining increasing attention. Better understanding of the behaviors that influence use of footwear will lead to improved ability to measure shoe use and will be important for those implementing footwear programs. Methodology/Principal Findings: Using the PRECEDE-PROCEED model we assessed social, behavioral, environmental, educational and ecological needs influencing whether and when children wear shoes in a rural highland Ethiopian community endemic for podoconiosis. Information was gathered from 242 respondents using focus groups, semi-structured interviews and extended case studies. Shoe-wearing norms were said to be changing, with going barefoot increasingly seen as 'shameful'. Shoes were thought to confer dignity as well as protection against injury and cold. However, many practical and social barriers prevented the desire to wear shoes from being translated into practice. Limited financial resources meant that people were neither able to purchase more than one pair of shoes to ensure their longevity nor afford shoes of the preferred quality. As a result of this limited access, shoes were typically preserved for special occasions and might not be provided for children until they reached a certain age. While some barriers (for example fit of shoe and fear of labeling through use of a certain type of shoe) may be applicable only to certain diseases, underlying structural level barriers related to poverty (for example price, quality, unsuitability for daily activities and low risk perception) are likely to be relevant to a range of NTDs. Conclusions/Significance: Using well established conceptual models of health behavior adoption, we identified several barriers to shoe wearing that are amenable to intervention and which we anticipate will be of benefit to those considering NTD prevention through shoe distribution. C1 [Ayode, Desta; Tadele, Getnet] Univ Addis Ababa, Coll Social Sci, Addis Ababa, Ethiopia. [McBride, Colleen M.; Watanabe, Emi] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. [de Heer, Hendrik D.] No Arizona Univ, Dept Phys Therapy & Athlet Training, Flagstaff, AZ 86011 USA. [Gebreyesus, Tsega] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Tora, Abebayehu] Wolaita Sodo Univ, Dept Sociol, Sodo, Ethiopia. [Davey, Gail] Brighton & Sussex Med Sch, Brighton, E Sussex, England. RP Ayode, D (reprint author), Univ Addis Ababa, Coll Social Sci, Addis Ababa, Ethiopia. EM g.davey@bsms.ac.uk RI de Heer, Hendrik/D-3192-2013; OI de Heer, Hendrik/0000-0002-9241-5021; Davey, Gail/0000-0003-2796-7468 FU National Human Genome Research Institute, National Institutes of Health, Bethesda, USA FX The study was funded by an intramural grant from the National Human Genome Research Institute, National Institutes of Health, Bethesda, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 12 Z9 12 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2013 VL 7 IS 4 AR e2199 DI 10.1371/journal.pntd.0002199 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 133QC UT WOS:000318153100045 PM 23638211 ER PT J AU Carrington, LB Armijos, MV Lambrechts, L Scott, TW AF Carrington, Lauren B. Armijos, M. Veronica Lambrechts, Louis Scott, Thomas W. TI Fluctuations at a Low Mean Temperature Accelerate Dengue Virus Transmission by Aedes aegypti SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ALBOPICTUS DIPTERA; VECTOR COMPETENCE; EXTRINSIC INCUBATION; INDIAN-OCEAN; CULICIDAE; INFECTION; MOSQUITOS; SURVIVAL; CHIKUNGUNYA; SUSCEPTIBILITY AB Background: Environmental factors such as temperature can alter mosquito vector competence for arboviruses. Results from recent studies indicate that daily fluctuations around an intermediate mean temperature (26 degrees C) reduce vector competence of Aedes aeygpti for dengue viruses (DENV). Theoretical predictions suggest that the mean temperature in combination with the magnitude of the diurnal temperature range (DTR) mediate the direction of these effects. Methodology/Principal Findings: We tested the effect of temperature fluctuations on Ae. aegypti vector competence for DENV serotype-1 at high and low mean temperatures, and confirmed this theoretical prediction. A small DTR had no effect on vector competence around a high (30 degrees C) mean, but a large DTR at low temperature (20 degrees C) increased the proportion of infected mosquitoes with a disseminated infection by 60% at 21 and 28 days post-exposure compared to a constant 20 degrees C. This effect resulted from a marked shortening of DENV extrinsic incubation period (EIP) in its mosquito vector; i.e., a decrease from 29.6 to 18.9 days under the fluctuating vs. constant temperature treatment. Conclusions: Our results indicate that Ae. aegypti exposed to large fluctuations at low temperatures have a significantly shorter virus EIP than under constant temperature conditions at the same mean, leading to a considerably greater potential for DENV transmission. These results emphasize the value of accounting for daily temperature variation in an effort to more accurately understand and predict the risk of mosquito-borne pathogen transmission, provide a mechanism for sustained DENV transmission in endemic areas during cooler times of the year, and indicate that DENV transmission could be more efficient in temperate regions than previously anticipated. C1 [Carrington, Lauren B.; Armijos, M. Veronica; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Lambrechts, Louis] Inst Pasteur, CNRS URA 3012, Paris, France. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Carrington, LB (reprint author), Univ Melbourne, Nossal Inst Global Hlth, Parkville, Vic 3052, Australia. EM lbcarrington@gmail.com RI Lambrechts, Louis/A-2057-2010; OI Lambrechts, Louis/0000-0001-5958-2138; Carrington, Lauren Bree/0000-0001-9273-7912 FU Ecology of Infectious Disease program of the National Science Foundation [EF-0914384]; Bill and Melinda Gates Foundation Global Health [OPP52250]; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security FX The work was funded by grant EF-0914384 from the Ecology of Infectious Disease program of the National Science Foundation (www.nsf.gov), and grant OPP52250 from the Bill and Melinda Gates Foundation Global Health. TWS received funding from the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 33 Z9 34 U1 3 U2 39 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2013 VL 7 IS 4 AR e2190 DI 10.1371/journal.pntd.0002190 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 133QC UT WOS:000318153100042 PM 23638208 ER PT J AU Malhotra, S Yen, JY Honko, AN Garamszegi, S Caballero, IS Johnson, JC Mucker, EM Trefry, JC Hensley, LE Connor, JH AF Malhotra, Shikha Yen, Judy Y. Honko, Anna N. Garamszegi, Sara Caballero, Ignacio S. Johnson, Joshua C. Mucker, Eric M. Trefry, John C. Hensley, Lisa E. Connor, John H. TI Transcriptional Profiling of the Circulating Immune Response to Lassa Virus in an Aerosol Model of Exposure SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID EBOLA HEMORRHAGIC-FEVER; CD8 T-CELLS; MASTOMYS-NATALENSIS; CYNOMOLGUS MONKEYS; DENDRITIC CELLS; GUINEA-PIGS; NONHUMAN-PRIMATES; GENE-EXPRESSION; SIERRA-LEONE; INFECTION AB Lassa virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with LASV leads to the development of hemorrhagic fever in a significant number of cases, and it is estimated that thousands die each year from the disease. Little is known about the complex immune mechanisms governing the response to LASV or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response in the peripheral blood mononuclear cells (PBMCs) of non-human primates (NHP) following aerosol exposure to LASV. Sequential sampling over the entire disease course showed that there are strong transcriptional changes of the immune response to LASV exposure, including the early induction of interferon-responsive genes and Toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro-inflammatory cytokine response in LASV exposed NHPs. There was a distinct lack of cytokines such as IL1 beta and IL23 alpha, while immunosuppressive cytokines such as IL27 and IL6 were upregulated. Comparison of IRF/STAT1-stimulated gene expression with the viral load in LASV exposed NHPs suggests that mRNA expression significantly precedes viremia, and thus might be used for early diagnostics of the disease. Our results provide a transcriptomic survey of the circulating immune response to hemorrhagic LASV exposure and provide a foundation for biomarker identification to allow clinical diagnosis of LASV infection through analysis of the host response. C1 [Malhotra, Shikha; Yen, Judy Y.; Garamszegi, Sara; Caballero, Ignacio S.; Connor, John H.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Honko, Anna N.; Johnson, Joshua C.; Mucker, Eric M.; Trefry, John C.; Hensley, Lisa E.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Garamszegi, Sara; Caballero, Ignacio S.; Connor, John H.] Boston Univ, Grad Program Bioinformat, Boston, MA 02215 USA. [Hensley, Lisa E.] NIAID, Integrated Res Facil Ft Detrick, Div Clin Res, NIH, Frederick, MD USA. RP Malhotra, S (reprint author), Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. EM jhconnor@bu.edu OI Johnson, Joshua/0000-0002-5677-3841; Connor, John/0000-0002-8867-7256; Honko, Anna/0000-0001-9165-148X FU Joint Science and Technology Office for Chemical and Biological Defense; Defense Threat Reduction Agency [JSTO-CBD 4.0021.08.RD.B]; NSF Graduate Research Fellowships Program; Fulbright Commission Spain; Regional Government of Andalusia FX This research was supported by a grant through the Joint Science and Technology Office for Chemical and Biological Defense and the Defense Threat Reduction Agency (JSTO-CBD 4.0021.08.RD.B). SG was supported by the NSF Graduate Research Fellowships Program. ISC was supported by the Fulbright Commission Spain and the Regional Government of Andalusia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 12 Z9 12 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2013 VL 7 IS 4 AR e2171 DI 10.1371/journal.pntd.0002171 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 133QC UT WOS:000318153100025 PM 23638192 ER PT J AU Moore, M Sylla, M Goss, L Burugu, MW Sang, R Kamau, LW Kenya, EU Bosio, C Munoz, MD Sharakova, M Black, WC AF Moore, Michelle Sylla, Massamba Goss, Laura Burugu, Marion Warigia Sang, Rosemary Kamau, Luna W. Kenya, Eucharia Unoma Bosio, Chris de Lourdes Munoz, Maria Sharakova, Maria Black, William Cormack TI Dual African Origins of Global Aedes aegypti s.l. Populations Revealed by Mitochondrial DNA SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID YELLOW-FEVER MOSQUITO; GENETIC-STRUCTURE; ORAL INFECTION; NUCLEAR GENOME; DENGUE; VECTOR; CULICIDAE; DIPTERA; VIRUS; SUSCEPTIBILITY AB Background: Aedes aegypti is the primary global vector to humans of yellow fever and dengue flaviviruses. Over the past 50 years, many population genetic studies have documented large genetic differences among global populations of this species. These studies initially used morphological polymorphisms, followed later by allozymes, and most recently various molecular genetic markers including microsatellites and mitochondrial markers. In particular, since 2000, fourteen publications and four unpublished datasets have used sequence data from the NADH dehydrogenase subunit 4 mitochondrial gene to compare Ae. aegypti collections and collectively 95 unique mtDNA haplotypes have been found. Phylogenetic analyses in these many studies consistently resolved two clades but no comprehensive study of mtDNA haplotypes have been made in Africa, the continent in which the species originated. Methods and Findings: ND4 haplotypes were sequenced in 426 Ae. aegypti s.l. from Senegal, West Africa and Kenya, East Africa. In Senegal 15 and in Kenya 7 new haplotypes were discovered. When added to the 95 published haplotypes and including 6 African Aedes species as outgroups, phylogenetic analyses showed that all but one Senegal haplotype occurred in a basal clade while most East African haplotypes occurred in a second clade arising from the basal clade. Globally distributed haplotypes occurred in both clades demonstrating that populations outside Africa consist of mixtures of mosquitoes from both clades. Conclusions: Populations of Ae. aegypti outside Africa consist of mosquitoes arising from one of two ancestral clades. One clade is basal and primarily associated with West Africa while the second arises from the first and contains primarily mosquitoes from East Africa C1 [Moore, Michelle; Sylla, Massamba; Goss, Laura; Black, William Cormack] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Burugu, Marion Warigia; Sang, Rosemary] Kenya Govt Med Res Ctr, Ctr Virus Res, Nairobi, Kenya. [Kamau, Luna W.] Kenya Govt Med Res Ctr, Ctr Biotechnol Res & Dev, Nairobi, Kenya. [Kenya, Eucharia Unoma] Kenyatta Univ, Dept Biochem, Nairobi, Kenya. [Bosio, Chris] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. [de Lourdes Munoz, Maria] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Genet & Mol Biol, Mexico City, DF, Mexico. [Sharakova, Maria] Virginia Tech, Fralin Biotechnol Ctr, Blacksburg, VA USA. RP Moore, M (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. EM wcb4@lamar.colostate.edu FU NIH [R01AI083368]; NIH-NIAID [U01 AI088647] FX Senegal collections were supported by NIH R01AI083368 to MS and WCB. This work was also funded in part by NIH-NIAID U01 AI088647. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 4 Z9 4 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2013 VL 7 IS 4 AR e2175 DI 10.1371/journal.pntd.0002175 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 133QC UT WOS:000318153100029 PM 23638196 ER PT J AU Nash, TE Mahanty, S Garcia, HH AF Nash, Theodore E. Mahanty, Siddhartha Garcia, Hector H. TI Neurocysticercosis-More Than a Neglected Disease SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Editorial Material C1 [Nash, Theodore E.; Mahanty, Siddhartha] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Garcia, Hector H.] Univ Peruana Cayetano Heredia, Sch Sci, Dept Microbiol, Lima, Peru. [Mahanty, Siddhartha] Univ Peruana Cayetano Heredia, Ctr Global Hlth Tumbes, Lima, Peru. [Garcia, Hector H.] Inst Nacl Ciencias Neurol, Cysticercosis Unit, Lima, Peru. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 FU Wellcome Trust [091077] NR 12 TC 9 Z9 9 U1 0 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2013 VL 7 IS 4 AR e1964 DI 10.1371/journal.pntd.0001964 PG 3 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 133QC UT WOS:000318153100001 PM 23638190 ER PT J AU Pal, P Dowd, KA Brien, JD Edeling, MA Gorlatov, S Johnson, S Lee, I Akahata, W Nabel, GJ Richter, MKS Smit, JM Fremont, DH Pierson, TC Heise, MT Diamond, MS AF Pal, Pankaj Dowd, Kimberly A. Brien, James D. Edeling, Melissa A. Gorlatov, Sergey Johnson, Syd Lee, Iris Akahata, Wataru Nabel, Gary J. Richter, Mareike K. S. Smit, Jolanda M. Fremont, Daved H. Pierson, Theodore C. Heise, Mark T. Diamond, Michael S. TI Development of a Highly Protective Combination Monoclonal Antibody Therapy against Chikungunya Virus SO PLOS PATHOGENS LA English DT Article ID SEMLIKI-FOREST-VIRUS; WEST-NILE-VIRUS; SINDBIS VIRUS; E2 GLYCOPROTEIN; ESCAPE MUTANTS; ANTIGENIC SITE; MOUSE MODEL; INFECTION; FUSION; MICE AB Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-)) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans. C1 [Pal, Pankaj; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Dowd, Kimberly A.; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Brien, James D.; Lee, Iris; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Edeling, Melissa A.; Fremont, Daved H.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Gorlatov, Sergey; Johnson, Syd] MacroGenics, Rockville, MD USA. [Akahata, Wataru; Nabel, Gary J.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Richter, Mareike K. S.; Smit, Jolanda M.] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, Mol Virol Sect HPC EB88, NL-9713 AV Groningen, Netherlands. [Richter, Mareike K. S.; Smit, Jolanda M.] Univ Groningen, Groningen, Netherlands. [Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Heise, Mark T.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. RP Pal, P (reprint author), Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu FU Southeast Regional Center of Excellence for Emerging Infections and Biodefense [U54 AI 057157]; NIH [R01-AI104545]; Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID) FX U54 AI 057157: Southeast Regional Center of Excellence for Emerging Infections and Biodefense (to MTH), NIH grant R01-AI104545, and the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases (NIAID) supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 60 Z9 61 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2013 VL 9 IS 4 AR e1003312 DI 10.1371/journal.ppat.1003312 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 132MN UT WOS:000318072700050 PM 23637602 ER PT J AU Pollom, E Dang, KK Potter, EL Gorelick, RJ Burch, CL Weeks, KM Swanstrom, R AF Pollom, Elizabeth Dang, Kristen K. Potter, E. Lake Gorelick, Robert J. Burch, Christina L. Weeks, Kevin M. Swanstrom, Ronald TI Comparison of SIV and HIV-1 Genomic RNA Structures Reveals Impact of Sequence Evolution on Conserved and Non-Conserved Structural Motifs SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; REV-RESPONSE ELEMENT; SECONDARY STRUCTURE; TYPE-1 RNA; IN-VITRO; PHYLOGENETIC ANALYSIS; STRUCTURE PREDICTION; NUCLEOTIDE-SEQUENCE; MUTATIONAL ANALYSIS; FUNCTIONAL-ANALYSIS AB RNA secondary structure plays a central role in the replication and metabolism of all RNA viruses, including retroviruses like HIV-1. However, structures with known function represent only a fraction of the secondary structure reported for HIV-1(NL4-3). One tool to assess the importance of RNA structures is to examine their conservation over evolutionary time. To this end, we used SHAPE to model the secondary structure of a second primate lentiviral genome, SIVmac239, which shares only 50% sequence identity at the nucleotide level with HIV-1(NL4-3). Only about half of the paired nucleotides are paired in both genomic RNAs and, across the genome, just 71 base pairs form with the same pairing partner in both genomes. On average the RNA secondary structure is thus evolving at a much faster rate than the sequence. Structure at the Gag-Pro-Pol frameshift site is maintained but in a significantly altered form, while the impact of selection for maintaining a protein binding interaction can be seen in the conservation of pairing partners in the small RRE stems where Rev binds. Structures that are conserved between SIVmac239 and HIV-1(NL4-3) also occur at the 59 polyadenylation sequence, in the plus strand primer sites, PPT and cPPT, and in the stem-loop structure that includes the first splice acceptor site. The two genomes are adenosine-rich and cytidine-poor. The structured regions are enriched in guanosines, while unpaired regions are enriched in adenosines, and functionaly important structures have stronger base pairing than nonconserved structures. We conclude that much of the secondary structure is the result of fortuitous pairing in a metastable state that reforms during sequence evolution. However, secondary structure elements with important function are stabilized by higher guanosine content that allows regions of structure to persist as sequence evolution proceeds, and, within the confines of selective pressure, allows structures to evolve. C1 [Pollom, Elizabeth; Swanstrom, Ronald] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Dang, Kristen K.] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC USA. [Potter, E. Lake; Weeks, Kevin M.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Gorelick, Robert J.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Burch, Christina L.] Univ N Carolina, Dept Biol, Chapel Hill, NC USA. RP Weeks, KM (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM weeks@unc.edu; risunc@med.unc.edu OI Burch, Christina/0000-0001-7830-0124 FU National Institutes of Health (NIH) [R01-AI068462, R37-AI044667, T32-AI07001]; University of North Carolina (UNC) Center For AIDS Research NIH [P30 AI50410]; UNC Lineberger Comprehensive Cancer Center NIH [P30 CA16086]; National Cancer Institute, NIH [HHSN261200800001E]; SAIC-Frederick, Inc. FX This work was supported by funding from National Institutes of Health (NIH) (R01-AI068462 to KMW, and R37-AI044667 to RS). EP was supported by an NIH Training Grant (T32-AI07001). In addition, we received support from University of North Carolina (UNC) Center For AIDS Research NIH Award P30 AI50410 and UNC Lineberger Comprehensive Cancer Center NIH Award P30 CA16086. This project has also been funded in part with federal funds from the National Cancer Institute, NIH, under contract HHSN261200800001E with SAIC-Frederick, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 33 Z9 33 U1 2 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2013 VL 9 IS 4 AR e1003294 DI 10.1371/journal.ppat.1003294 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 132MN UT WOS:000318072700035 PM 23593004 ER PT J AU Podell, JL Kendall, PC Gosch, EA Compton, SN March, JS Albano, AM Rynn, MA Walkup, JT Sherrill, JT Ginsburg, GS Keeton, CP Birmaher, B Piacentini, JC AF Podell, Jennifer L. Kendall, Philip C. Gosch, Elizabeth A. Compton, Scott N. March, John S. Albano, Anne-Marie Rynn, Moira A. Walkup, John T. Sherrill, Joel T. Ginsburg, Golda S. Keeton, Courtney P. Birmaher, Boris Piacentini, John C. TI Therapist Factors and Outcomes in CBT for Anxiety in Youth SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE cognitive-behavioral therapy; child anxiety; therapist factors; collaboration; coach style ID COGNITIVE-BEHAVIORAL THERAPY; CHILDHOOD ANXIETY; FAMILY-THERAPY; MAJOR DEPRESSION; DISORDERED YOUTH; PANIC DISORDER; SYMPTOM CHANGE; CHILDREN; ADOLESCENTS; COMPETENCE AB This study examined the relationship between therapist factors and child outcomes in anxious youth who received cognitive-behavioral therapy (CBT) as part of the Child-Adolescent Anxiety Multimodal Study (CAMS). Of the 488 youth who participated in the CAMS project, 279 were randomly assigned to one of the CBT conditions (CBT only or CBT plus sertraline). Participants included youth (ages 7-17; M = 10.76) who met criteria for a principal anxiety disorder. Therapists included 38 cognitive-behavioral therapists. Therapist style, treatment integrity, and therapist experience were examined in relation to child outcome. Child outcome was measured via child, parent, and independent evaluator report. Therapists who were more collaborative and empathic, followed the treatment manual, and implemented it in a developmentally appropriate way had youth with better treatment outcomes. Therapist "coach" style was a significant predictor of child-reported outcome, with the collaborative "coach" style predicting fewer child-reported symptoms. Higher levels of therapist prior clinical experience and lower levels of prior anxiety-specific experience were significant predictors of better treatment outcome. Findings suggest that although all therapists used the same manual-guided treatment, therapist style, experience, and clinical skills were related to differences in child outcome. Clinical implications and recommendations for future research are discussed. C1 [Podell, Jennifer L.] Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Kendall, Philip C.] Temple Univ, Child & Adolescent Anxiety Disorders Clin, Philadelphia, PA 19122 USA. [Gosch, Elizabeth A.] Philadelphia Coll Osteopath Med, Dept Psychol, Philadelphia, PA USA. [Compton, Scott N.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [March, John S.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Albano, Anne-Marie] Columbia Univ, Div Child & Adolescent Psychiat, New York State Psychiat Inst, Clin Anxiety & Related Disorders, New York, NY 10027 USA. [Rynn, Moira A.] Columbia Univ, New York State Psychiat Inst, New York, NY 10027 USA. [Walkup, John T.] Weill Cornell Med Coll, Div Child & Adolescent Psychiat, New York, NY USA. [Sherrill, Joel T.] NIMH, Psychosocial Treatment Res Program, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Ginsburg, Golda S.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Keeton, Courtney P.] Johns Hopkins Univ, Sch Med, Div Child & Adolescent Psychiat, Baltimore, MD 21218 USA. [Birmaher, Boris] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Piacentini, John C.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. RP Kendall, PC (reprint author), Temple Univ, 478 Weiss Hall,1701 North 13th St, Philadelphia, PA 19122 USA. EM pkendall@temple.edu FU NIMH NIH HHS [U01 MH063747, U01 MH064003, U01 MH064088, U01 MH064089, U01 MH064092, U01 MH064107] NR 70 TC 8 Z9 8 U1 5 U2 34 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD APR PY 2013 VL 44 IS 2 BP 89 EP 98 DI 10.1037/a0031700 PG 10 WC Psychology, Multidisciplinary SC Psychology GA 133NZ UT WOS:000318146500004 PM 25419042 ER PT J AU Hamazaki, K Kim, HY AF Hamazaki, Kei Kim, Hee-Yong TI Differential modification of the phospholipid profile by transient ischemia in rat hippocampal CA1 and CA3 regions SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Polyunsaturated fatty acids; Ischemia; Hippocampus; Phospholipids ID DELAYED NEURONAL DEATH; FREE FATTY-ACID; DOCOSAHEXAENOIC ACID; GERBIL HIPPOCAMPUS; FOREBRAIN ISCHEMIA; CEREBRAL-ISCHEMIA; MASS-SPECTROMETRY; INDUCED APOPTOSIS; BRAIN ISCHEMIA; CELL-DEATH AB The hippocampal CA1 region is most susceptible to cerebral ischemia in both rodents and humans, whereas CA3 is remarkably resistant. Here, we investigated the possible role of membrane lipids in differential susceptibility in these regions. Transient ischemia was induced in rats via bilateral occlusion of common carotid arteries and membrane lipids were analyzed by mass spectrometry. While lipid profile differences between the intact CA1 and CA3 were rather minor, ischemia caused significant pyramidal cell death with concomittant reduction of phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, plasmalogen and sphingomyelin only in CA1 The phospholipid loss was evenly distributed in most molecular species. Ischemia also significantly increased cell death mediator ceramides only in CA1 Our data suggests that differential susceptibility to ischemia between CM and CA3 is not linked to their unique phospholipid profile. Also, selective activation of phospholipase A2, which primarily releases polyunsaturated fatty acids, might not be characteristic to cell death in CA1. Published by Elsevier Ltd. C1 [Hamazaki, Kei; Kim, Hee-Yong] NIAAA, Lab Mol Signaling, Div Intramural Clin & Biol Res, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Lab Mol Signaling, Div Intramural Clin & Biol Res, NIH, 5625 Fishers Lane,Room 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX The authors thank Dr. Sarah Spencer (University of Calgary, Department of Physiology and Biophysics), Dr. Sandor Batkai (NIAAA/ Laboratory of Physiological Studies), Dr. Lee Chedester (NIAAA/ Animal care unit) for technical advice of surgeries and Dr. Norio Horiguchi (NIAAA/ Laboratory of Physiological Studies) and Dr. Douglas Osei-hyiaman (NIAAA/ Laboratory of Physiological Studies) for technical advice of histology. This research was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 55 TC 3 Z9 4 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD APR PY 2013 VL 88 IS 4 BP 299 EP 306 DI 10.1016/j.plefa.2013.01.003 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 134EP UT WOS:000318193300006 PM 23395327 ER PT J AU Woods, AS Colsch, B Jackson, SN Post, J Baldwin, K Roux, A Hoffer, B Cox, BM Hoffer, M Rubovitch, V Pick, CG Schultz, JA Balaban, C AF Woods, Amina S. Colsch, Benoit Jackson, Shelley N. Post, Jeremy Baldwin, Kathrine Roux, Aurelie Hoffer, Barry Cox, Brian M. Hoffer, Michael Rubovitch, Vardit Pick, Chaim G. Schultz, J. Albert Balaban, Carey TI Gangliosides and Ceramides Change in a Mouse Model of Blast Induced Traumatic Brain Injury SO ACS CHEMICAL NEUROSCIENCE LA English DT Article ID TANDEM MASS-SPECTROMETRY; ELECTROSPRAY-IONIZATION; PRESSURE; SYSTEM AB Explosive detonations generate atmospheric pressure changes that produce nonpenetrating blast induced "mild" traumatic brain injury (bTBI). The structural basis for mild bTBI has been extremely controversial. The present study applies matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging to track the distribution of gangliosides in mouse brain tissue that were exposed to very low level of explosive detonations (2.5-5.5 psi peak overpressure). We observed major increases of the ganglioside GM2 in the hippocampus, thalamus, and hypothalamus after a single blast exposure. Moreover, these changes were accompanied by depletion of ceramides. No neurological or brain structural signs of injury could be inferred using standard light microscopic techniques. The first source of variability is generated by the Latency between blast and tissue sampling (peak intensity of the blast wave). These findings suggest that subtle molecular changes in intracellular membranes and plasmalemma compartments may be biomarkers for biological responses to mild bTBI. This is also the first report of a GM2 increase in the brains of mature mice from a nongenetic etiology. C1 [Woods, Amina S.; Colsch, Benoit; Jackson, Shelley N.; Post, Jeremy; Baldwin, Kathrine; Roux, Aurelie] NIDA, IRP, Struct Biol Unit, NIH, Baltimore, MD 21224 USA. [Hoffer, Barry] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Cox, Brian M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Hoffer, Michael] US Naval Hosp, San Diego, CA USA. [Rubovitch, Vardit; Pick, Chaim G.] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Balaban, Carey] Univ Pittsburgh, Pittsburgh, PA USA. [Woods, Amina S.; Post, Jeremy; Cox, Brian M.] Ctr Neurosci & Regenerat Med, Rockville, MD USA. [Schultz, J. Albert] Ionwerks Inc, Houston, TX USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 333 Cassell Dr,Room 1120, Baltimore, MD 21224 USA. EM awoods@mail.nih.gov OI Balaban, Carey/0000-0002-3570-3844 FU Intramural Research Program of the National Institute on Drug Abuse, NIH; Center for Neuroscience and Regenerative Medicine, Bethesda, MD (Department of Defense) through the Henry M. Jackson Foundation for the Advancement of Military Medicine; Office of National Drug Control Policy (ONDCP); SBIR Phase II NIH-NIDA [1RC3DA031431] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH, and by the Center for Neuroscience and Regenerative Medicine, Bethesda, MD (Department of Defense) through the Henry M. Jackson Foundation for the Advancement of Military Medicine. The authors thank the Office of National Drug Control Policy (ONDCP) for instrumentation funding, without which this and other projects could not have been accomplished. J.A.S. and C.B. acknowledge funding from SBIR Phase II NIH-NIDA grant 1RC3DA031431. NR 24 TC 24 Z9 24 U1 5 U2 41 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD APR PY 2013 VL 4 IS 4 BP 594 EP 600 DI 10.1021/cn300216h PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 129VV UT WOS:000317873000009 PM 23590251 ER PT J AU van Veghel, D Cleynhens, J Pearce, LV DeAndrea-Lazarus, IA Blumberg, PM Van Laere, K Verbruggen, A Bormans, G AF van Veghel, Daisy Cleynhens, Jan Pearce, Larry V. DeAndrea-Lazarus, Ian A. Blumberg, Peter M. Van Laere, Koen Verbruggen, Alfons Bormans, Guy TI New Transient Receptor Potential Vanilloid Subfamily Member 1 Positron Emission Tomography Radioligands: Synthesis, Radiolabeling, and Preclinical Evaluation SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE TRPV1; positron emission tomography; carbon-11; fluorine-18; I-123-RTX ID IODO-RESINIFERATOXIN; RAT-BRAIN; TRPV1; ANTAGONIST; DRUG; VR1; AMINOQUINAZOLINES; EXPRESSION; DISCOVERY; CAPSAICIN AB The transient receptor potential vanilloid subfamily member 1 (TRPV1) cation channel is known to be involved in pain nociception and neurogenic inflammation, and accumulating evidence suggests that it plays an important role in several central nervous system (CNS)-related disorders. TRPV1-specific positron emission tomography (PET) radioligands can serve as powerful tools in TRPV1-related (pre)clinical research and drug design. We have synthesized several potent TRPV1 antagonists and accompanying precursors for radiolabeling with carbon-11 or fluorine-18. The cinnamic acid derivative [C-11]DVV24 and the aminoquinazoline [F-18]DVV54 were successfully synthesized, and their biological behavior was studied. In addition, the in vivo behavior of a I-123-labeled analogue of iodo-resiniferatoxin (I-RTX), a well-known TRPV1 antagonist, was evaluated. The binding affinities of DVV24 and DVV54 for human TRPV1 were 163 +/- 28 and 171 +/- 48 nM, respectively. [C-11]DVV24, but not [F-18]DVV54 or I-123-RTX, showed retention in the trigeminal nerve, known to abundantly express TRPV1. Nevertheless, it appears that ligands with higher binding affinities will be required to allow in vivo imaging of TRPV1 via PET. C1 [van Veghel, Daisy; Cleynhens, Jan; Verbruggen, Alfons; Bormans, Guy] Katholieke Univ Leuven, Lab Radiopharm, Dept Pharmaceut & Pharmacol Sci, B-3000 Louvain, Belgium. [Pearce, Larry V.; DeAndrea-Lazarus, Ian A.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Van Laere, Koen] Univ Hosp, Louvain, Belgium. [Van Laere, Koen] Katholieke Univ Leuven, Louvain, Belgium. RP Bormans, G (reprint author), Lab Radiopharm, Campus Gasthuisberg O&N2,Herestr 49 Box 821, BE-3000 Louvain, Belgium. EM guy.bormans@pharm.kuleuven.be FU Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT); in vivo molecular imaging research (IMIR); Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research [Z1A BC 005270] FX This research was funded by a Ph.D. grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT), in part by in vivo molecular imaging research (IMIR), and in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research (Project Z1A BC 005270). NR 32 TC 5 Z9 5 U1 0 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD APR PY 2013 VL 4 IS 4 BP 624 EP 634 DI 10.1021/cn300233v PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 129VV UT WOS:000317873000012 PM 23421633 ER PT J AU Lam, TK Schully, SD Rogers, SD Benkeser, R Reid, B Khoury, MJ AF Lam, Tram Kim Schully, Sheri D. Rogers, Scott D. Benkeser, Rachel Reid, Britt Khoury, Muin J. TI Provocative Questions in Cancer Epidemiology in a Time of Scientific Innovation and Budgetary Constraints SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article AB In a time of scientific and technological developments and budgetary constraints, the National Cancer Institute's (NCI) Provocative Questions Project offers a novel funding mechanism for cancer epidemiologists. We reviewed the purposes underlying the Provocative Questions Project, present information on the contributions of epidemiologic research to the current Provocative Questions portfolio, and outline opportunities that the cancer epidemiology community might capitalize on to advance a research agenda that spans a translational continuum from scientific discoveries to population health impact. Cancer Epidemiol Biomarkers Prev; 22(4); 496-500. (c) 2013 AACR. C1 [Lam, Tram Kim; Schully, Sheri D.; Rogers, Scott D.; Reid, Britt; Khoury, Muin J.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Benkeser, Rachel] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. RP Lam, TK (reprint author), NCI, NIH, 6130 Execut Blvd,Suite 5143, Rockville, MD 20852 USA. EM lamt@mail.nih.gov FU Intramural CDC HHS [CC999999] NR 8 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 496 EP 500 DI 10.1158/1055-9965.EPI-13-0101 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900003 PM 23413299 ER PT J AU Ghazarian, AA Simonds, NI Bennett, K Pimentel, CB Ellison, GL Gillanders, EM Schully, SD Mechanic, LE AF Ghazarian, Armen A. Simonds, Naoko I. Bennett, Kelly Pimentel, Camilla B. Ellison, Gary L. Gillanders, Elizabeth M. Schully, Sheri D. Mechanic, Leah E. TI A Review of NCI's Extramural Grant Portfolio: Identifying Opportunities for Future Research in Genes and Environment in Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID GENOME-WIDE ASSOCIATION AB Background: Genetic and environmental factors jointly influence cancer risk. The NIH has made the study of gene-environment (GxE) interactions a research priority since the year 2000. Methods: To assess the current status of GxE research in cancer, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Years 2007 to 2009. Publications attributed to selected grants were also evaluated. Results: From the 1,106 research grants identified in our portfolio analysis, a random sample of 450 grants (40%) was selected for data abstraction; of these, 147 (33%) were considered relevant. The most common cancer type was breast (20%, n = 29), followed by lymphoproliferative (10%, n = 14), colorectal (9%, n = 13), melanoma/other skin (9%, n = 13), and lung/upper aerodigestive tract (8%, n = 12) cancers. The majority of grants were studies of candidate genes (68%, n = 100) compared with genome-wide association studies (GWAS) (8%, n = 12). Approximately one-third studied environmental exposures categorized as energy balance (37%, n = 54) or drugs/treatment (29%, n = 43). From the 147 relevant grants, 108 publications classified as GxE or pharmacogenomic were identified. These publications were linked to 37 of the 147 grant applications (25%). Conclusion: The findings from our portfolio analysis suggest that GxE studies are concentrated in specific areas. There is room for investments in other aspects of GxE research, including, but not limited to developing alternative approaches to exposure assessment, broadening the spectrum of cancer types investigated, and conducting GxE within GWAS. Impact: This portfolio analysis provides a cross-sectional review of NCI support for GxE research in cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 501-7. (c) 2013 AACR. C1 [Ghazarian, Armen A.; Simonds, Naoko I.; Bennett, Kelly; Pimentel, Camilla B.; Ellison, Gary L.; Gillanders, Elizabeth M.; Schully, Sheri D.; Mechanic, Leah E.] NCI, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Mechanic, LE (reprint author), NCI, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 5126, Bethesda, MD 20892 USA. EM mechanil@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 8 Z9 8 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 501 EP 507 DI 10.1158/1055-9965.EPI-13-0156 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900004 PM 23462918 ER PT J AU Khoury, MJ Lam, TK Ioannidis, JPA Hartge, P Spitz, MR Buring, JE Chanock, SJ Croyle, RT Goddard, KA Ginsburg, GS Herceg, Z Hiatt, RA Hoover, RN Hunter, DJ Kramer, BS Lauer, MS Meyerhardt, JA Olopade, OI Palmer, JR Sellers, TA Seminara, D Ransohoff, DF Rebbeck, TR Tourassi, G Winn, DM Zauber, A Schully, SD AF Khoury, Muin J. Lam, Tram Kim Ioannidis, John P. A. Hartge, Patricia Spitz, Margaret R. Buring, Julie E. Chanock, Stephen J. Croyle, Robert T. Goddard, Katrina A. Ginsburg, Geoffrey S. Herceg, Zdenko Hiatt, Robert A. Hoover, Robert N. Hunter, David J. Kramer, Barnet S. Lauer, Michael S. Meyerhardt, Jeffrey A. Olopade, Olufunmilayo I. Palmer, Julie R. Sellers, Thomas A. Seminara, Daniela Ransohoff, David F. Rebbeck, Timothy R. Tourassi, Georgia Winn, Deborah M. Zauber, Ann Schully, Sheri D. TI Transforming Epidemiology for 21st Century Medicine and Public Health SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CANCER-EPIDEMIOLOGY; TRANSLATIONAL RESEARCH; KNOWLEDGE INTEGRATION; GENOMICS RESEARCH; UNITED-STATES; BIG-DATA; OPPORTUNITIES; SCIENCE; THINKING; LESSONS AB In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits. Cancer Epidemiol Biomarkers Prev; 22(4); 508-16. (c) 2013 AACR. C1 [Khoury, Muin J.; Lam, Tram Kim; Croyle, Robert T.; Seminara, Daniela; Winn, Deborah M.; Schully, Sheri D.] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Hartge, Patricia; Chanock, Stephen J.; Hoover, Robert N.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kramer, Barnet S.] NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Dept Hlth Res & Policy,Sch Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Stat, Sch Humanities & Sci, Stanford, CA 94305 USA. [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Buring, Julie E.] Brigham & Womens Hosp, Div Med, Boston, MA 02115 USA. [Meyerhardt, Jeffrey A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Cambridge, MA 02138 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Cambridge, MA 02138 USA. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Goddard, Katrina A.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Ginsburg, Geoffrey S.] Duke Univ, Sch Med, Ctr Genom Med, Inst Genome Sci & Policy, Durham, NC USA. [Herceg, Zdenko] Int Agcy Res Canc, F-69372 Lyon, France. [Hiatt, Robert A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Olopade, Olufunmilayo I.] Univ Chicago Med, Dept Med, Ctr Clin Canc Genet & Global Hlth, Chicago, IL USA. [Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Off Director, Tampa, FL 33682 USA. [Ransohoff, David F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Ransohoff, David F.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Tourassi, Georgia] Oak Ridge Natl Lab, Computat Sci & Engn Div, Oak Ridge, TN USA. [Zauber, Ann] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM muk1@CDC.GOV RI Lauer, Michael/L-9656-2013; OI Tourassi, Georgia/0000-0002-9418-9638; Lauer, Michael/0000-0002-9217-8177; Palmer, Julie/0000-0002-6534-335X FU Novartis FX G.S. Ginsburg has a commercial research grant from Novartis. No potential conflicts of interest were disclosed by the other authors. NR 51 TC 50 Z9 52 U1 10 U2 80 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 508 EP 516 DI 10.1158/1055-9965.EPI-13-0146 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900005 PM 23462917 ER PT J AU Caporaso, NE AF Caporaso, Neil E. TI Why Precursors Matter SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CANCER-EPIDEMIOLOGY; MOLECULAR EPIDEMIOLOGY; PREVENTION; BIOMARKERS; PATHWAYS; FUTURE C1 [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Caporaso, NE (reprint author), NCI, NIH, EPS 7122,6120 Execut Blvd, Bethesda, MD 20892 USA. EM caporaso@nih.gov NR 16 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 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 518 EP 520 DI 10.1158/1055-9965.EPI-13-0135 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900006 PM 23549394 ER PT J AU Wacholder, S AF Wacholder, Sholom TI Precursors in Cancer Epidemiology: Aligning Definition and Function SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS INFECTION; LARGE-BOWEL CANCER; TRIALS TELL US; NATURAL-HISTORY; INTERPRETING PRECURSOR; CLINICAL-TRIALS; END-POINTS; WOMEN; GUANACASTE AB A precursor of a disease is a definable pathologic state that progresses directly to disease without a known intermediate step and whose presence substantially increases the likelihood of disease. Precancers, or precursors of cancer, can help provide detail about the dynamic pathogenesis process before clinical disease. Thereby, ascertainment of properly defined precancers can increase precision of estimates and power in epidemiologic and clinical studies. Besides providing targets for direct treatment and improving tools for risk assessment in screening programs, precancers can help establish temporal ordering of cause and effect; can identify relatively homogeneous subsets of cancer that have passed through a given precancer state; and provide a basis for choosing high-risk individuals for detailed longitudinal study. Although the most appropriate definition of the precancer will vary with its function in particular research or clinical applications, the proportion of cancers that progress from the precancer and risk of cancer progressing from the precancer can be important measures of the value of a precancer in translational efforts. Cancer Epidemiol Biomarkers Prev; 22(4); 521-7. (c) 2013 AACR. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Wacholder, S (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 5050, Bethesda, MD 20892 USA. EM WacholdS@mail.nih.gov FU Intramural NIH HHS [Z01 CP010181-05, ZIA CP010181-10] NR 38 TC 6 Z9 6 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 521 EP 527 DI 10.1158/1055-9965.EPI-13-0084 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900007 PM 23549395 ER PT J AU Goldstein, AM Tucker, MA AF Goldstein, Alisa M. Tucker, Margaret A. TI Dysplastic Nevi and Melanoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; TOTAL-BODY PHOTOGRAPHY; PRONE FAMILIES; CDKN2A MUTATIONS; MELANOCYTIC NEVI; NATURAL-HISTORY; ATYPICAL NEVI; MOLE SYNDROME; RISK-FACTORS; DIAGNOSIS AB Dysplastic nevi are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these 2 entities. Since initially being reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biologic importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still no single, universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi should be considered important because of their association with an increased risk for melanoma. Cancer Epidemiol Biomarkers Prev; 22(4); 528-32. (c) 2013 AACR. C1 [Goldstein, Alisa M.; Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, Execut Plaza South,Room 7004,6120 Execut Blvd,MSC, Bethesda, MD 20892 USA. EM goldstea@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU Intramural Research Program of the NIH, NCI, DCEG FX This research was supported by the Intramural Research Program of the NIH, NCI, DCEG. NR 44 TC 23 Z9 23 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 528 EP 532 DI 10.1158/1055-9965.EPI-12-1346 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900008 PM 23549396 ER PT J AU Goldin, LR McMaster, ML Caporaso, NE AF Goldin, Lynn R. McMaster, Mary L. Caporaso, Neil E. TI Precursors to Lymphoproliferative Malignancies SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID B-CELL LYMPHOCYTOSIS; UNDETERMINED SIGNIFICANCE MGUS; IGM MONOCLONAL GAMMOPATHY; MULTIPLE-MYELOMA; WALDENSTROMS MACROGLOBULINEMIA; 1ST-DEGREE RELATIVES; ADULT-POPULATION; NATURAL-HISTORY; LONG-TERM; HEMATOLOGICAL MALIGNANCIES AB We review monoclonal B-cell lymphocytosis (MBL) as a precursor to chronic lymphocytic leukemia and monoclonal gammopathy of undetermined significance (MGUS) as a precursor to plasma cell disorders. These conditions are present in the general population and increase with age. These precursors aggregate with lymphoproliferative malignancies in families suggesting shared inheritance. MBL and MGUS may share some of the same risk factors as their related malignancies but data are limited. Although these conditions are characterized by enhanced risk for the associated malignancy, the majority of individuals with these conditions do not progress to malignancy. A key focus for current work is to identify markers that predict progression to malignancy. Cancer Epidemiol Biomarkers Prev; 22(4); 533-9. (c) 2013 AACR. C1 [Goldin, Lynn R.; McMaster, Mary L.; Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, National Institute of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institute of Health, Bethesda, MD. NR 84 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 533 EP 539 DI 10.1158/1055-9965.EPI-12-1348 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900009 PM 23549397 ER PT J AU Taylor, PR Abnet, CC Dawsey, SM AF Taylor, Philip R. Abnet, Christian C. Dawsey, Sanford M. TI Squamous Dysplasia-The Precursor Lesion for Esophageal Squamous Cell Carcinoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HIGH-RISK POPULATION; VITAMIN MINERAL SUPPLEMENTATION; DOUBLE-BLIND INTERVENTION; GENOME-WIDE ASSOCIATION; DISEASE-SPECIFIC MORTALITY; HIGH-INCIDENCE AREA; HUMAN-PAPILLOMAVIRUS; GASTRIC CANCERS; PRECANCEROUS LESIONS; NUTRITION INTERVENTION AB Esophageal squamous cell carcinoma (ESCC) accounts for 80% of all esophageal cancers worldwide, and esophageal squamous dysplasia (ESD) is the only histopathology that predicts the development of ESCC. The prevalence of ESD parallels rates of invasive ESCC and is typically found in 25% or more of adults above the age of 35 years in populations in north central China, where risk for ESCC is among the highest in the world. Results of chemoprevention and early detection studies to prevent progression of ESD suggest that these approaches, coupled with emerging endoscopic therapies, offer promise for the prevention of esophageal cancer mortality in high-risk populations. Future research on ESD and ESCC should focus on finding additional modifiable risk factors and on identifying biomarkers to incorporate into early detection strategies. Cancer Epidemiol Biomarkers Prev; 22(4); 540-52. (c) 2013 AACR. C1 [Taylor, Philip R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Abnet, Christian C.; Dawsey, Sanford M.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Taylor, PR (reprint author), NCI, NIH, EPS, 6120 Execut Blvd,Rm 7006, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS [ZIA CP000112-08, ZIA CP000185-08] NR 97 TC 19 Z9 19 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 540 EP 552 DI 10.1158/1055-9965.EPI-12-1347 PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900010 PM 23549398 ER PT J AU Schiffman, M Wentzensen, N AF Schiffman, Mark Wentzensen, Nicolas TI Human Papillomavirus Infection and the Multistage Carcinogenesis of Cervical Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID OF-AMERICAN-PATHOLOGISTS; NEOPLASIA GRADE 3; EARLY END-POINTS; NATURAL-HISTORY; CLINICAL-PRACTICE; YOUNG-WOMEN; RISK; PREVENTION; POPULATION; CYTOLOGY AB This short review outlines our understanding of cervical cancer precursors, concentrating on the central etiologic role of persistent human papillomavirus infection. The stages of cervical carcinogenesis are better understood than for most other major cancers, providing a successful cancer etiology and prevention model. Cancer Epidemiol Biomarkers Prev; 22(4); 553-60. (C) 2013 AACR. C1 [Schiffman, Mark; Wentzensen, Nicolas] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7012, Rockville, MD 20852 USA. EM schiffmm@mail.nih.gov FU Qiagen; Roche FX M. Schiffman has commercial research support from Qiagen and Roche. No potential conflicts of interest were disclosed by the other author. NR 50 TC 43 Z9 47 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 553 EP 560 DI 10.1158/1055-9965.EPI-12-1406 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900011 PM 23549399 ER PT J AU de Moor, JS Mariotto, AB Parry, C Alfano, CM Padgett, L Kent, EE Forsythe, L Scoppa, S Hachey, M Rowland, JH AF de Moor, Janet S. Mariotto, Angela B. Parry, Carla Alfano, Catherine M. Padgett, Lynne Kent, Erin E. Forsythe, Laura Scoppa, Steve Hachey, Mark Rowland, Julia H. TI Cancer Survivors in the United States: Prevalence across the Survivorship Trajectory and Implications for Care SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID QUALITY-OF-LIFE; EARLY PALLIATIVE CARE; CELL LUNG-CANCER; BREAST-CANCER; HEALTH-STATUS; FOLLOW-UP; DISTRESS; IMPACT; MANAGEMENT; CHALLENGE AB Background: Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis. Methods: Incidence and survival data from 1975-2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. population. Results: As of January 1, 2012, approximately 13.7 million cancer survivors were living in the United States with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37% to 11.9 million. Conclusions: A coordinated agenda for research and practice is needed to address cancer survivors' long-term medical, psychosocial, and practical needs across the survivorship trajectory. Impact: Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population. Cancer Epidemiol Biomarkers Prev; 22(4); 561-70. (C) 2013 AACR. C1 [de Moor, Janet S.; Alfano, Catherine M.; Rowland, Julia H.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Mariotto, Angela B.] NCI, Surveillance Res Program, Bethesda, MD 20892 USA. [Parry, Carla; Padgett, Lynne] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Kent, Erin E.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Forsythe, Laura] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, Bethesda, MD 20892 USA. [Forsythe, Laura] Patient Ctr Outcomes Res Inst, Washington, DC USA. [Scoppa, Steve; Hachey, Mark] IMS, Falls Church, VA USA. RP de Moor, JS (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH, 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM janet.demoor@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 54 TC 154 Z9 156 U1 5 U2 30 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 561 EP 570 DI 10.1158/1055-9965.EPI-12-1356 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900012 PM 23535024 ER PT J AU Roland, KB Benard, VB Soman, A Breen, N Kepka, D Saraiya, M AF Roland, Katherine B. Benard, Vicki B. Soman, Ashwini Breen, Nancy Kepka, Deanna Saraiya, Mona TI Cervical Cancer Screening Among Young Adult Women in the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SERVICES TASK-FORCE; HUMAN-PAPILLOMAVIRUS; PAP-SMEAR; HORMONAL CONTRACEPTION; NATIONAL-HEALTH; US WOMEN; GUIDELINES; PREVENTION; BREAST; IMPACT AB Background: Cervical cancer screening guidelines have evolved significantly in the last decade for young adult women, with current recommendations promoting later initiation and longer intervals. Methods: Using self-reported cross-sectional National Health Interview Survey (NHIS) 2000-2010 data, trends in Papanicolaou (Pap) testing among women ages 18-29 years were examined. NHIS 2010 data were used to investigate age at first Pap test (N = 2,198), time since most recent Pap test (n = 1,622), and predictors of Pap testing within the last 12 months (n = 1,622). Results: The percentage of 18-year-olds who reported ever having a Pap test significantly decreased from 49.9% in 2000 to 37.9% in 2010. Mean age at first Pap test in 2010 was significantly younger for non-Hispanic black women (16.9 years), women < high school education (16.9 years), women who received the HPV vaccine (17.1 years), and women who have ever given birth (17.3 years). The majority reported their last Pap test within the previous 12 months (73.1%). Usual source of healthcare (OR, 2.31) and current birth control use (OR, 1.64) significantly increased chances of having a Pap test within the previous 12 months. Conclusions: From 2000 to 2010, there was a gradual decline in Pap test initiation among 18-year-olds; however, in 2010, many women reported <= 12 months since last screening. Evidence-based guidelines should be promoted, as screening young adult women for cervical cancer more frequently than recommended can cause considerable harms. Impact: A baseline of cervical cancer screening among young adult women in the United States to assess adherence to evidence-based screening guidelines. Cancer Epidemiol Biomarkers Prev; 22(4); 580-8. (C) 2013 AACR. C1 [Roland, Katherine B.; Benard, Vicki B.; Saraiya, Mona] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Canc Prevent & Control, Epidemiol & Appl Res Branch, Atlanta, GA 30341 USA. [Soman, Ashwini] Northrop Grumman, Atlanta, GA USA. [Breen, Nancy] NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Rockville, MD USA. [Kepka, Deanna] Univ Utah, Huntsman Canc Inst, Coll Nursing, Salt Lake City, UT USA. RP Roland, KB (reprint author), Ctr Dis Control & Prevent, 4770 Buford Hwy NE,MS K-55, Atlanta, GA 30341 USA. EM kroland@cdc.gov FU U.S. Government FX The study was supported by the U.S. Government. NR 50 TC 11 Z9 12 U1 2 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 580 EP 588 DI 10.1158/1055-9965.EPI-12-1266 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900014 PM 23355601 ER PT J AU Steinmaus, CM Ferreccio, C Romo, JA Yuan, Y Cortes, S Marshall, G Moore, LE Balmes, JR Liaw, J Golden, T Smith, AH AF Steinmaus, Craig M. Ferreccio, Catterina Acevedo Romo, Johanna Yuan, Yan Cortes, Sandra Marshall, Guillermo Moore, Lee E. Balmes, John R. Liaw, Jane Golden, Todd Smith, Allan H. TI Drinking Water Arsenic in Northern Chile: High Cancer Risks 40 Years after Exposure Cessation SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LUNG-CANCER; SKIN-LESIONS; YOUNG-ADULTS; IN-UTERO; MORTALITY; HEALTH; CONTAMINATION; BANGLADESH; CHILDHOOD; ASBESTOS AB Background: Millions of people worldwide are exposed to arsenic-contaminated water. In the largest city in northern Chile (Antofagasta), more than 250,000 people were exposed to high arsenic drinking water concentrations from 1958 until 1970 when a water treatment plant was installed. Because of its unique geology, limited water sources, and good historical records, lifetime exposure and long-term latency patterns can be assessed in this area with better accuracy than in other arsenic-exposed areas worldwide. Methods: We conducted a population-based case-control study in northern Chile from October 2007 to December 2010 involving 232 bladder and 306 lung cancer cases and 640 age-and gender-matched controls, with detailed information on past exposure and potential confounders, including smoking and occupation. Results: Bladder cancer ORs for quartiles of average arsenic concentrations in water before 1971 (<11, 11-90, 91-335, and >335 mg/L) were 1.00, 1.36 [95% confidence interval (CI), 0.78-2.37], 3.87 (2.25-6.64), and 6.50 (3.69-11.43), respectively. Corresponding lung cancer ORs were 1.00, 1.27 (0.81-1.98), 2.00 (1.24-3.24), and 4.32 (2.60-7.17). Bladder and lung cancer ORs in those highly exposed in Antofagasta during 1958 to 1970 but not thereafter were 6.88 (3.84-12.32) and 4.35 (2.57-7.36), respectively. Conclusions: The lung and bladder cancer risks that we found up to 40 years after high exposures have ended are very high. Impact: Our findings suggest that prevention, treatment, and other mortality reduction efforts in arsenic-exposed countries will be needed for decades after exposure cessation. Cancer Epidemiol Biomarkers Prev; 22(4); 623-30. (C) 2013 AACR. C1 [Steinmaus, Craig M.; Yuan, Yan; Balmes, John R.; Liaw, Jane; Smith, Allan H.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Steinmaus, Craig M.] Calif Environm Protect Agcy, Off Environm Hlth Hazard Assessment, Oakland, CA USA. [Ferreccio, Catterina; Acevedo Romo, Johanna; Cortes, Sandra; Marshall, Guillermo] Pontificia Univ Catolica Chile, Santiago, Chile. [Moore, Lee E.] NCI, Bethesda, MD 20892 USA. [Balmes, John R.; Golden, Todd] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Steinmaus, CM (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 50 Univ Hall,MC7360, Berkeley, CA 94720 USA. EM craigs@berkeley.edu RI sebastianovitsch, stepan/G-8507-2013 FU U.S. National Institute of Environmental Health Sciences [R01 ES014032-01, P42 ES04705] FX This work was supported by grants R01 ES014032-01 and P42 ES04705 from the U.S. National Institute of Environmental Health Sciences. NR 31 TC 47 Z9 50 U1 6 U2 56 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 623 EP 630 DI 10.1158/1055-9965.EPI-12-1190 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900019 PM 23355602 ER PT J AU Sampson, JN Boca, SM Shu, XO Stolzenberg-Solomon, RZ Matthews, CE Hsing, AW Tan, YT Ji, BT Chow, WH Cai, QY Liu, DK Yang, G Xiang, YB Zheng, W Sinha, R Cross, AJ Moore, SC AF Sampson, Joshua N. Boca, Simina M. Shu, Xiao Ou Stolzenberg-Solomon, Rachael Z. Matthews, Charles E. Hsing, Ann W. Tan, Yu Ting Ji, Bu-Tian Chow, Wong-Ho Cai, Qiuyin Liu, Da Ke Yang, Gong Xiang, Yong Bing Zheng, Wei Sinha, Rashmi Cross, Amanda J. Moore, Steven C. TI Metabolomics in Epidemiology: Sources of Variability in Metabolite Measurements and Implications SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POSTMENOPAUSAL WOMEN; BREAST-CANCER; CARDIOVASCULAR-DISEASE; PROFILES; PLASMA; RISK; BIOMARKERS; PROSTATE; HEALTH; REPRODUCIBILITY AB Background: Metabolite levels within an individual vary over time. This within-individual variability, coupled with technical variability, reduces the power for epidemiologic studies to detect associations with disease. Here, the authors assess the variability of a large subset of metabolites and evaluate the implications for epidemiologic studies. Methods: Using liquid chromatography/mass spectrometry (LC/MS) and gas chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolites were measured in 60 women at baseline and year-one of the Shanghai Physical Activity Study, and observed patterns were confirmed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening study. Results: Although the authors found high technical reliability (median intraclass correlation = 0.8), reliability over time within an individual was low. Taken together, variability in the assay and variability within the individual accounted for the majority of variability for 64% of metabolites. Given this, a metabolite would need, on average, a relative risk of 3 (comparing upper and lower quartiles of "usual" levels) or 2 (comparing quartiles of observed levels) to be detected in 38%, 74%, and 97% of studies including 500, 1,000, and 5,000 individuals. Age, gender, and fasting status factors, which are often of less interest in epidemiologic studies, were associated with 30%, 67%, and 34% of metabolites, respectively, but the associations were weak and explained only a small proportion of the total metabolite variability. Conclusion: Metabolomics will require large, but feasible, sample sizes to detect the moderate effect sizes typical for epidemiologic studies. Impact: We offer guidelines for determining the sample sizes needed to conduct metabolomic studies in epidemiology. Cancer Epidemiol Biomarkers Prev; 22(4); 631-40. (C) 2013 AACR. C1 [Sampson, Joshua N.; Boca, Simina M.; Stolzenberg-Solomon, Rachael Z.; Matthews, Charles E.; Ji, Bu-Tian; Sinha, Rashmi; Cross, Amanda J.; Moore, Steven C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shu, Xiao Ou; Cai, Qiuyin; Yang, Gong; Zheng, Wei] Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Dept Med, Div Epidemiol, Nashville, TN USA. [Shu, Xiao Ou; Cai, Qiuyin; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Canc Inst, Palo Alto, CA USA. [Tan, Yu Ting; Liu, Da Ke; Xiang, Yong Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Chow, Wong-Ho] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Sampson, JN (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM joshua.sampson@nih.gov RI matthews, Charles/E-8073-2015; Sinha, Rashmi/G-7446-2015; Moore, Steven/D-8760-2016 OI matthews, Charles/0000-0001-8037-3103; Sinha, Rashmi/0000-0002-2466-7462; Moore, Steven/0000-0002-8169-1661 FU NIH; Breast Cancer Research Stamp Fund; [R37CA070867] FX This study is, in part, supported by the Intramural Research Program of the NIH and the Breast Cancer Research Stamp Fund, awarded through competitive peer review. SWHS was supported by R37CA070867. NR 41 TC 41 Z9 41 U1 4 U2 34 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 631 EP 640 DI 10.1158/1055-9965.EPI-12-1109 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900020 PM 23396963 ER PT J AU Mondul, AM Shui, IM Yu, K Travis, RC Stevens, VL Campa, D Schumacher, FR Ziegler, RG Bueno-de-Mesquita, HB Berndt, S Crawford, ED Gapstur, SM Gaziano, JM Giovannucci, E Haiman, CA Henderson, BE Hunter, DJ Johansson, M Key, TJ Le Marchand, L Lindstrom, S McCullough, ML Navarro, C Overvad, K Palli, D Purdue, M Stampfer, MJ Weinstein, SJ Willett, WC Yeager, M Chanock, SJ Trichopoulos, D Kolonel, LN Kraft, P Albanes, D AF Mondul, Alison M. Shui, Irene M. Yu, Kai Travis, Ruth C. Stevens, Victoria L. Campa, Daniele Schumacher, Frederick R. Ziegler, Regina G. Bueno-de-Mesquita, H. Bas Berndt, Sonja Crawford, E. D. Gapstur, Susan M. Gaziano, J. Michael Giovannucci, Edward Haiman, Christopher A. Henderson, Brian E. Hunter, David J. Johansson, Mattias Key, Timothy J. Le Marchand, Loic Lindstroem, Sara McCullough, Marjorie L. Navarro, Carmen Overvad, Kim Palli, Domenico Purdue, Mark Stampfer, Meir J. Weinstein, Stephanie J. Willett, Walter C. Yeager, Meredith Chanock, Stephen J. Trichopoulos, Dimitrios Kolonel, Laurence N. Kraft, Peter Albanes, Demetrius TI Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer-Results from the Breast and Prostate Cancer Cohort Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENOME-WIDE ASSOCIATION; D-BINDING PROTEIN; SUSCEPTIBILITY LOCI; POLYMORPHISMS; PREVENTION; VARIANTS AB Background: Studies suggest that vitamin D status may be associated with prostate cancer risk although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D [25(OH)D] status. We examined prostate cancer risk in relation to single-nucleotide polymorphisms (SNP) in four genes shown to predict circulating levels of 25(OH)D. Methods: SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the National Cancer Institute (NCI) Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer. Results: We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D [per A allele, OR, 0.86; 95% confidence interval (CI), 0.80-0.93; P-trend = 0.0002) but an increased risk for nonaggressive disease (per A allele: OR, 1.10; 95% CI, 1.04-1.17; P-trend = 0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6-8 vs. 0-1 alleles, 0.66; 95% CI, 0.44-0.98; P-trend = 0.003). Conclusions: In this large, pooled analysis, genetic variants related to lower 25(OH)D levels were associated with a decreased risk of aggressive prostate cancer. Impact: Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 22(4); 688-96. (C) 2013 AACR. C1 [Mondul, Alison M.; Yu, Kai; Ziegler, Regina G.; Berndt, Sonja; Purdue, Mark; Weinstein, Stephanie J.; Yeager, Meredith; Chanock, Stephen J.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Shui, Irene M.; Giovannucci, Edward; Hunter, David J.; Lindstroem, Sara; Stampfer, Meir J.; Willett, Walter C.; Trichopoulos, Dimitrios; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.; Stampfer, Meir J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Cardiovasc Dis, Boston, MA 02115 USA. [Giovannucci, Edward; Hunter, David J.; Stampfer, Meir J.; Willett, Walter C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Boston, MA USA. [Travis, Ruth C.; Key, Timothy J.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Stevens, Victoria L.; Gapstur, Susan M.; McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Campa, Daniele] Univ Pisa, Dept Biol, Pisa, Italy. [Palli, Domenico] Canc Res & Prevent Inst ISPO, Florence, Italy. [Schumacher, Frederick R.; Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Crawford, E. D.] Univ Colorado Hosp, Sect Urol Oncol, Aurora, CO USA. [Johansson, Mattias] IARC, Lyon, France. [Le Marchand, Loic; Kolonel, Laurence N.] Univ Hawaii, Epidemiol Program, Ctr Canc, Honolulu, HI 96822 USA. [Navarro, Carmen] CIBERESP, Barcelona, Spain. [Navarro, Carmen] Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain. [Overvad, Kim] Aarhus Univ, Dept Epidemiol, Sch Publ Hlth, Aarhus, Denmark. [Overvad, Kim] Aarhus Univ Hosp, Dept Cardiol, Cardiovasc Res Ctr, Aalborg Hosp, DK-8000 Aarhus, Denmark. RP Mondul, AM (reprint author), NCI, NIH, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM mondulam@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Campa, Daniele/K-1617-2016; OI Campa, Daniele/0000-0003-3220-9944; Mondul, Alison/0000-0002-8843-1416; PALLI, Domenico/0000-0002-5558-2437 FU U.S. NIH, NCI [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; NIH/NCI, Division of Cancer Epidemiology and Genetics; National Research Service Award from the NCI, NIH [T32 CA09001]; U.S. Army Department of Defense; NCI at the NIH; U.S. Public Health Service contracts from the NCI, NIH [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, HHSN261200800001E] FX This work was supported by the U.S. NIH, NCI cooperative agreements U01-CA98233-07 (to D.J. Hunter), U01-CA98710-06 (to M.J. Thun), U01-CA98216-06 to (E. Riboli and R. Kaaks), and U01-CA98758-07 (to B.E. Henderson) and Intramural Research Program of NIH/NCI, Division of Cancer Epidemiology and Genetics. I.M. Shui was supported by a National Research Service Award (T32 CA09001) from the NCI, NIH and a U.S. Army Department of Defense Prostate Cancer Post-doctoral Fellowship. The ATBC Study was supported by the Intramural Research Program of the NCI at the NIH. In addition, this research was supported by U.S. Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C, and HHSN261200800001E) from the NCI, NIH. NR 28 TC 15 Z9 15 U1 2 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 688 EP 696 DI 10.1158/1055-9965.EPI-13-0007-T PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900027 PM 23377224 ER PT J AU Pelser, C Mondul, AM Hollenbeck, AR Park, Y AF Pelser, Colleen Mondul, Alison M. Hollenbeck, Albert R. Park, Yikyung TI Dietary Fat, Fatty Acids, and Risk of Prostate Cancer in the NIH-AARP Diet and Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ALPHA-LINOLENIC ACID; FOOD-FREQUENCY QUESTIONNAIRE; RETIRED-PERSONS DIET; UNITED-STATES; NATIONAL-INSTITUTES; AMERICAN-ASSOCIATION; MULTIETHNIC COHORT; BREAST; ENERGY; PHOSPHOLIPIDS AB Background: Observational studies report inconsistent associations of fat and fatty acids with prostate cancer. Methods: We investigated associations between dietary fats and fatty acids and risk of prostate cancer in the NIH-American Association of Retired Persons (AARP) Diet and Health Study. Diet was assessed at baseline with self-administered food-frequency questionnaires. Cases were determined by linkage with state cancer registries. HR and 95% confidence intervals (CI) were estimated with Cox proportional hazards models. Results: Among 288,268 men with average follow-up of nine years, 23,281 prostate cancer cases (18,934 nonadvanced and 2,930 advanced including 725 fatal cases) were identified. Total fat and mono-and polyunsaturated fat intakes were not associated with incidence of prostate cancer. Saturated fat intake was related to increased risk of advanced prostate cancer (HRQuintile (5 vs. Qunitile 1 (Q1 vs. Q5)), 1.21; 95% CI, 1.00-1.46; P-trend = 0.03) and fatal prostate cancer (HRQ5 vs. Q1, 1.47; 95% CI, 1.01-2.15; P-trend = 0.04). alpha-Linolenic acid (ALA) intake was related to increased risk of advanced prostate cancer (HRQ5 vs. Q1, 1.17; 95% CI, 1.04-1.31; P-trend = 0.01). Eicosapentanoic acid (EPA) intake was related to decreased risk of fatal prostate cancer (HRQ5 vs. Q1, 0.82; 95% CI, 0.64-1.04; P-trend = 0.02). Conclusion: Our study suggests that the associations of fat and fatty acids differ by prostate cancer severity. Saturated fat, ALA, and EPA intakes were related to the risk of advanced or fatal prostate cancer but not to nonadvanced prostate cancer. Impact: Identifying factors associated with advanced prostate cancer could reduce morbidity and mortality. Cancer Epidemiol Biomarkers Prev; 22(4); 697-707. (C) 2013 AACR. C1 [Pelser, Colleen] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Mondul, Alison M.; Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Pelser, C (reprint author), NCI, Canc Prevent Fellowship Program, 6120 Execut Blvd,EPS 3025, Rockville, MD 20852 USA. EM colleen.pelser@nih.gov OI Mondul, Alison/0000-0002-8843-1416; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute FX This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute. Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the FCDC under contract with the FDOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. Cancer incidence data from Arizona were collected by the Arizona Cancer Registry, Division of Public Health Services, Arizona Department of Health Services. Cancer incidence data from Texas were collected by the Texas Cancer Registry, Cancer Epidemiology and Surveillance Branch, Texas Department of State Health Services. Cancer incidence data from Nevada were collected by the Nevada Central Cancer Registry, Center for Health Data and Research, Bureau of Health Planning and Statistics, State Health Division, State of Nevada Department of Health and Human Services. NR 47 TC 29 Z9 29 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2013 VL 22 IS 4 BP 697 EP 707 DI 10.1158/1055-9965.EPI-12-1196-T PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 130ZW UT WOS:000317960900028 PM 23549401 ER PT J AU Okupa, AY Sorkness, CA Mauger, DT Jackson, DJ Lemanske, RF AF Okupa, Adesua Y. Sorkness, Christine A. Mauger, David T. Jackson, Daniel J. Lemanske, Robert F., Jr. TI Daily Diaries vs Retrospective Questionnaires to Assess Asthma Control and Therapeutic Responses in Asthma Clinical Trials Is Participant Burden Worth the Effort? SO CHEST LA English DT Article ID CHILDHOOD ASTHMA; ELECTRONIC DIARIES; PATIENT COMPLIANCE; SYMPTOM DIARY; VALIDATION AB Background: Presently, there is insufficient information to compare the value of daily diaries vs retrospective questionnaires for assessing symptoms in relationship to asthma control in clinical trials. Daily symptom diaries are often burdensome to gather, incomplete, susceptible to fabrication, and of questionable reliability. There is also concern that retrospective symptom questionnaires may be subject to poor recall and may be insensitive. Methods: To compare these two methods of assessing symptoms reporting, we analyzed data collected during the Best Add-on Therapy Giving Effective Responses (BADGER) trial. During the trial, asthma control in 182 children aged 6 to 17 years was assessed in two ways: (1) by asthma control days (ACDs) determined by manually recorded daily diary symptom and rescue medication use scores and (2) by monthly retrospective report of symptoms embedded within the age-appropriate version of the Asthma Control Test (ACT). Correlations between ACDs and ACT mires were analyzed, and the sensitivity of each method for measuring asthma control and determining the differential response among the three BADGER treatments was evaluated. Results: Although validated using a 4-week recall period, ACT correlated better with daily diary information from the last 2 weeks of the 4-week recall (r = 0.46) than from the first 2 weeks (r = 0.34). In addition, clinically significant differential treatment responses were detected using ACDs but not ACT scores. Conclusions: The results of this study indicate that daily diaries used to determine ACDs can be a more sensitive tool than ACT for assessing differential treatment responses with respect to asthma control. CHEST 2013; 143(4):993-999 C1 [Okupa, Adesua Y.; Sorkness, Christine A.; Jackson, Daniel J.; Lemanske, Robert F., Jr.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Mauger, David T.] Penn State Univ, Dept Publ Hlth Sci, Hershey, PA USA. [Mauger, David T.] NHLBI, Childhood Asthma Res & Educ CARE Network, Bethesda, MD 20892 USA. RP Okupa, AY (reprint author), Univ Wisconsin Madison, Ctr Clin Sci, 600 Highland Ave,K4-916, Madison, WI 53792 USA. EM aokupa@medicine.wisc.edu FU National Heart, Lung, and Blood Institute [HL064307, HL064288, HL064295, HL064287, HL064305, HL064313]; National Institute of Allergy and Infectious Diseases [T32AI007635]; Clinical Translational Science Award program of the National Center for Research Resources [UL1-RR025011, UL1-RR025780, UL1-RR024992]; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; GlaxoSmithKline plc; Merck Co, Inc.; Gilead; National Institutes of Health; Pharmaxis Ltd; Merck Co, Inc; Sunovion Pharmaceuticals Inc; SABoney & Associates, LLC; American Institute of Research; Genentech, Inc; Double Helix Bio-Technology Development Ltd.; University of Wisconsin School of Medicine and Public Health; University of Wisconsin Medical Foundation FX This, work was supported by grants from the National Heart, Lung, and Blood Institute [HL064307, HL064288, HL064295, HL064287, HL064305, and HL064313], the National Institute of Allergy and Infectious Diseases [T32AI007635], and the Clinical Translational Science Award program of the National Center for Research Resources [UL1-RR025011 (Wisconsin), UL1-RR025780 (Colorado), and UL1-RR024992(St. Louis, Missouri)]. This study was performed in part by the General Clinical Research Center, Washington University School of Medicine in St Louis [M01-RR00036]; National Jewish. Health [M01-RR00051]; and the University of Wisconsin [M01-RR03186].; The authors have reported to CHEST the following conflicts of interest: Dr Sorkness has received funding from the National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases. Dr Mauger received consultant fees from GlaxoSmithKline plc and Merck & Co, Inc. Dr Jackson received consultant fees from Gilead. Dr Lemanske received grant support from the National Institutes of Health to plan and participate in the development and conduct of the BASALT (Best Adjustment Strategy for Asthma in Long Term) trial; grant support from Pharmaxis Ltd to conduct another. research trial; and consultant fees from GlaxoSmithKline plc; Merck & Co, Inc; Sepracor (now Sunovion Pharmaceuticals Inc); SABoney & Associates, LLC; American Institute of Research; Genentech, Inc; and Double Helix Bio-Technology Development Ltd. He also received honoraria for participation in educational programs from the Michigan Public Health Institute; Allegheny General Hospital; American Academy of Pediatrics; West Penn Allegheny Health System; Colorado Allergy and Asthma Society; Pennsylvania Allergy and Asthma Association; Harvard Pilgrim Health Care, Inc; California Society of Allergy, Asthma and Immunology; New York Allergy Society; World Allergy Organization; and American College of Chest Physicians. Additionally, Dr Lemanske has received royalty payments from UpToDate, Inc, and Elsevier BY and salary from the University of Wisconsin School of Medicine and Public Health and the University of Wisconsin Medical Foundation. Dr Okupa has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. NR 23 TC 12 Z9 12 U1 1 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD APR PY 2013 VL 143 IS 4 BP 993 EP 999 DI 10.1378/chest.12-1055 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 129VG UT WOS:000317871500020 PM 23287844 ER PT J AU Blelloch, R Gutkind, JS AF Blelloch, Robert Gutkind, J. Silvio TI Epigenetics, noncoding RNAs, and cell signaling - crossroads in the regulation of cell fate decisions SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 [Blelloch, Robert] Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. [Blelloch, Robert] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. [Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Blelloch, R (reprint author), Univ Calif San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA. EM BlellochR@stemcell.ucsf.edu NR 0 TC 3 Z9 3 U1 0 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD APR PY 2013 VL 25 IS 2 BP 149 EP 151 DI 10.1016/j.ceb.2013.02.019 PG 3 WC Cell Biology SC Cell Biology GA 130AW UT WOS:000317886100001 PM 23498659 ER PT J AU Iglesias-Bartolome, R Callejas-Valera, JL Gutkind, JS AF Iglesias-Bartolome, Ramiro Callejas-Valera, Juan Luis Gutkind, J. Silvio TI Control of the epithelial stem cell epigenome: the shaping of epithelial stem cell identity SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID HISTONE DEMETHYLASE JMJD3; SKIN HOMEOSTASIS; DNA METHYLATION; DIFFERENTIATION; TISSUE; MECHANISMS; SENESCENCE; EPIDERMIS; CANCER; AGE AB The squamous epithelium covering the skin and oral mucosa relies on epithelial stem cells for tissue renewal. Dynamic changes in DNA methylation, histone methylation and acetylation, and higher order chromatin structure are required to preserve their self-renewal capacity while orchestrating the timely execution of cell differentiation programs. This complex network of epigenetic modifications shapes the epithelial stem cell identity and fate. Pathological alterations can be perceived by aberrant chromatin sensors, such as the INK4/ARF locus, which initiate tumor suppressive cell senescence programs, and can often result in epithelial stem cell exhaustion. Unveiling the mechanisms controlling the epigenome in epithelial stem cells may help protect against the loss of their tissue regenerative capacity, thereby preventing premature aging without increasing cancer risk. C1 [Iglesias-Bartolome, Ramiro; Callejas-Valera, Juan Luis; Gutkind, J. Silvio] NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NIDR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Iglesias-Bartolome, Ramiro/H-4460-2014 OI Iglesias-Bartolome, Ramiro/0000-0002-0792-1254 FU Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research FX We thank Dr. Morgan O'Hayre for insightful suggestions. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Dental and Craniofacial Research. We apologize to all of our colleagues for not citing some of their original studies due to strict space limitations. NR 47 TC 12 Z9 12 U1 1 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 EI 1879-0410 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD APR PY 2013 VL 25 IS 2 BP 162 EP 169 DI 10.1016/j.ceb.2013.01.009 PG 8 WC Cell Biology SC Cell Biology GA 130AW UT WOS:000317886100003 PM 23434069 ER PT J AU Chongwatpol, J Sharda, R AF Chongwatpol, Jongsawas Sharda, Ramesh TI Achieving Lean Objectives through RFID: A Simulation-Based Assessment SO DECISION SCIENCES LA English DT Article ID SUPPLY-CHAIN; TECHNOLOGY; IMPACT; PERFORMANCE; INFORMATION; IDENTIFICATION; INTEGRATION; MANAGEMENT; ERRORS AB Lean concepts in manufacturing have focused on elimination of wastes within the business processes. This study investigates whether addition of radio frequency identification (RFID) technologies in the manufacturing process can complement Lean manufacturing. Specifically, will more accurate information from RFID-based solutions help achieve the goals of Lean initiatives in manufacturing plant performance and, if yes, in what specific ways? The analysis is based on a comparison of the following three automatic identification technologies: existing (one-dimensional) 1D barcode, 2D barcode, and the use of RFID in a real job-shop environment where items are manufactured for meeting actual demand and also future forecast demand. We analyze the effect of information visibility in these settings by examining the various types of wastes that are typically addressed in Lean initiatives. The results of a discrete-event simulation suggest that employing RFID in Lean manufacturing initiatives can reduce some wastes but not necessarily all types of waste. We observe an increase in overproduction waste in our setting, although other wastes are reduced with improved information visibility. Overall, our results indicate that manufacturing organizations should explore information visibility through RFID to enhance their Lean initiatives. [Submitted: November 8, 2010. Revised: June 13, 2011; October 17, 2011; February 21, 2012; May 18, 2012. Accepted: June 15, 2012.] C1 [Chongwatpol, Jongsawas] NIDA, Sch Business, Bangkok 10240, Thailand. [Sharda, Ramesh] Oklahoma State Univ, Spears Sch Business, Inst Res Informat Syst, Stillwater, OK 74078 USA. RP Chongwatpol, J (reprint author), NIDA, Sch Business, 118 Seri Thai Rd, Bangkok 10240, Thailand. EM jongsawas.c@nida.ac.th; sharda@okstate.edu NR 42 TC 3 Z9 3 U1 8 U2 40 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0011-7315 J9 DECISION SCI JI Decis. Sci. PD APR PY 2013 VL 44 IS 2 BP 239 EP 266 DI 10.1111/deci.12007 PG 28 WC Management SC Business & Economics GA 127BV UT WOS:000317670700001 ER PT J AU Nansel, TR Lipsky, LM Iannotti, RJ AF Nansel, T. R. Lipsky, L. M. Iannotti, R. J. TI Cross-sectional and longitudinal relationships of body mass index with glycemic control in children and adolescents with type 1 diabetes mellitus SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE BMI; Children; Adolescents; Longitudinal ID CARDIOVASCULAR-DISEASE RISK; WEIGHT-GAIN; US CHILDREN; COMPLICATIONS TRIAL; INTENSIVE THERAPY; METABOLIC-CONTROL; BLOOD-PRESSURE; PREVALENCE; OVERWEIGHT; YOUTH AB Aims: Weight gain is an oft-cited outcome of improved glycemic control in adults with type 1 diabetes, though few studies have investigated this in youth. The purpose of this paper was to examine cross-sectional and longitudinal associations of body mass index (BMI, kg/m(2)) with glycemic control in youth with type 1 diabetes (n = 340, 12.5 +/- 1.7 year, 49% female, duration >= 1 year) participating in a 2-year multi-center intervention study targeting family diabetes management. Methods: BMI was calculated from height and weight measured at clinic visits. Glycohemoglobin (HbA1c) at each visit was assayed centrally. Cross-sectional associations of baseline BMI with glycemic control, and of change in BMI and HbA1c with baseline values, were examined. Longitudinal associations of time-varying BMI and HbA1c were examined using a multilevel linear mixed effects model controlling for time-varying time (months), insulin dose (units/kg/day), regimen, Tanner stage, and time invariant baseline diabetes duration, BMI, treatment group and sociodemographic characteristics. Results: Baseline HbA1c was unrelated to baseline BMI, but was related positively to subsequent BMI change (p = 0.04) and inversely to HbA1c change (p = 0.002). Baseline BMI was inversely related to BMI change (p = 0.01) and unrelated to HbA1c change. In multilevel regression, BMI was related inversely to HbA1c (%) (beta +/- SE = -0.11 +/- 0.02, p < 0.001) and positively to insulin dose (0.23 +/- 0.07, p = 0.001). In the treatment group only, BMI was positively related to pump regimen (0.18 +/- 0.08, p = 0.02). Conclusions: Increased insulin administered to improve glycemic control may contribute to increased BMI in youth with type 1 diabetes, indicating the importance of determining ways to minimize weight gain while optimizing glycemic control. Published by Elsevier Ireland Ltd. C1 [Nansel, T. R.; Lipsky, L. M.; Iannotti, R. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Eunice, LA USA. RP Nansel, TR (reprint author), 6100 Execut Blvd,Room 7B13 MSC 7510, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Lipsky, Leah/0000-0003-2645-4388 FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development [s N01-HD-3-3360]; Children's Memorial Hospital, Chicago, Illinois [N01-HD-4-3363]; Texas Children's Hospital, Houston, Texas [N01-HD-4-3362]; Nemours Children's Clinic, Jacksonville, Florida [N01-HD-4-3361]; Joslin Diabetes Center, Boston, Massachusetts [N01-HD-4-3364] FX The authors wish to acknowledge the contributions of the research staff at the participating clinical sites and the families who participated in the study. This research was funded by the intramural research program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development, contract #s N01-HD-3-3360, James Bell Associated; N01-HD-4-3363, Children's Memorial Hospital, Chicago, Illinois; N01-HD-4-3362, Texas Children's Hospital, Houston, Texas; N01-HD-4-3361, Nemours Children's Clinic, Jacksonville, Florida; and N01-HD-4-3364, Joslin Diabetes Center, Boston, Massachusetts. NR 32 TC 7 Z9 8 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 EI 1872-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD APR PY 2013 VL 100 IS 1 BP 126 EP 132 DI 10.1016/j.diabres.2012.12.025 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 128BY UT WOS:000317744300025 PM 23339757 ER PT J AU Parkman, HP Yates, K Hasler, WL Nguyen, L Pasricha, PJ Snape, WJ Farrugia, G Koch, KL Calles, J Abell, TL Sarosiek, I McCallum, RW Lee, L Unalp-Arida, A Tonascia, J Hamilton, F AF Parkman, Henry P. Yates, Katherine Hasler, William L. Linda Nguyen Pasricha, Pankaj J. Snape, William J. Farrugia, Gianrico Koch, Kenneth L. Calles, Jorge Abell, Thomas L. Sarosiek, Irene McCallum, Richard W. Lee, Linda Unalp-Arida, Aynur Tonascia, James Hamilton, Frank TI Cholecystectomy and Clinical Presentations of Gastroparesis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Gastroparesis; Cholecystectomy; Gallbladder; Gastric emptying; Diabetes ID UPPER GASTROINTESTINAL DISORDERS; BECK DEPRESSION INVENTORY; IRRITABLE-BOWEL-SYNDROME; QUALITY-OF-LIFE; SYMPTOM SEVERITY; VALIDATION; DISEASE; SURGERY; INDEX AB Many patients with gastroparesis have had their gallbladders removed. To determine if clinical presentations of patients with gastroparesis differ in those with prior cholecystectomy compared to patients who have not had their gallbladder removed. Gastroparetic patients were prospectively enrolled in the NIDDK Gastroparesis Registry. Detailed history and physical examinations were performed; patients filled out questionnaires including patient assessment of GI symptoms. Of 391 subjects with diabetic or idiopathic gastroparesis (IG), 142 (36 %) had a prior cholecystectomy at the time of enrollment. Patients with prior cholecystectomy were more often female, older, married, and overweight or obese. Cholecystectomy had been performed in 27/59 (46 %) of T2DM compared to 19/78 (24 %) T1DM and 96/254 IG (38 %) (p = 0.03). Patients with cholecystectomy had more comorbidities, particularly chronic fatigue syndrome, fibromyalgia, depression, and anxiety. Postcholecystectomy gastroparesis patients had increased health care utilization, and had a worse quality of life. Independent characteristics associated with prior cholecystectomy included insidious onset (OR = 2.06; p = 0.01), more comorbidities (OR = 1.26; p < 0.001), less severe gastric retention (OR(severe) = 0.68; overall p = 0.03) and more severe symptoms of retching (OR = 1.19; p = 0.02) and upper abdominal pain (OR = 1.21; p = 0.02), less severe constipation symptoms (OR = 0.84; p = 0.02), and not classified as having irritable bowel syndrome (OR = 0.51; p = 0.02). Etiology was not independently associated with a prior cholecystectomy. Symptom profiles in patients with and without cholecystectomy differ: postcholecystectomy gastroparesis patients had more severe upper abdominal pain and retching and less severe constipation. These data suggest that prior cholecystectomy is associated with selected manifestations of gastroparesis. C1 [Parkman, Henry P.] Temple Univ, Sch Med, Gastroenterol Sect, Philadelphia, PA 19140 USA. [Yates, Katherine; Lee, Linda; Unalp-Arida, Aynur; Tonascia, James] Johns Hopkins Univ, Baltimore, MD USA. [Hasler, William L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Linda Nguyen; Pasricha, Pankaj J.] Stanford Univ, Palo Alto, CA 94304 USA. [Snape, William J.] Calif Pacific Med Ctr, San Francisco, CA USA. [Farrugia, Gianrico] Mayo Clin, Rochester, MN USA. [Koch, Kenneth L.; Calles, Jorge] Wake Forest Univ, Winston Salem, NC 27109 USA. [Abell, Thomas L.] Univ Mississippi, Jackson, MS 39216 USA. [Sarosiek, Irene; McCallum, Richard W.] Texas Tech Univ, Lubbock, TX 79409 USA. [Hamilton, Frank] NIDDKD, Bethesda, MD 20892 USA. RP Parkman, HP (reprint author), Temple Univ, Sch Med, Gastroenterol Sect, 8th Floor 3401 North Broad St, Philadelphia, PA 19140 USA. EM henry.parkman@temple.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008] FX The Gastroparesis Clinical Research Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK073983, U01DK073975, U01DK073985, U01DK074007, U01DK073974, U01DK074008). NR 35 TC 12 Z9 12 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD APR PY 2013 VL 58 IS 4 BP 1062 EP 1073 DI 10.1007/s10620-013-2596-y PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 126HX UT WOS:000317605800023 PM 23456496 ER PT J AU Mayne, EW Craig, MT McBain, CJ Paulsen, O AF Mayne, Elizabeth W. Craig, Michael T. McBain, Chris J. Paulsen, Ole TI Dopamine suppresses persistent network activity via D1-like dopamine receptors in rat medial entorhinal cortex SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cortex; slow oscillation; UP states ID PREFRONTAL CORTEX; CORTICAL ACTIVITY; LESS-THAN-1 HZ; IN-VIVO; MECHANISMS; MODULATION; INHIBITION; NEURONS; EXCITATION; STATE AB Cortical networks display persistent activity in the form of periods of sustained synchronous depolarizations (UP states') punctuated by periods of relative hyperpolarization (DOWN states'), which together form the slow oscillation. UP states are known to be synaptically generated and are sustained by a dynamic balance of excitation and inhibition, with fast ionotropic glutamatergic excitatory and GABAergic inhibitory conductances increasing during the UP state. Previously, work from our group demonstrated that slow metabotropic GABA receptors also play an important role in terminating the UP state, but the effects of other neuromodulators on this network phenomenon have received little attention. Given that persistent activity is a neural correlate of working memory and that signalling through dopamine receptors has been shown to be critical for working memory tasks, we examined whether dopaminergic neurotransmission affected the slow oscillation. Here, using an in vitro model of the slow oscillation in rat medial entorhinal cortex, we showed that dopamine strongly and reversibly suppressed cortical UP states. We showed that this effect was mediated through D1-like and not D2-like dopamine receptors, and we found no evidence that tonic dopaminergic transmission affected UP states in our model. C1 [Mayne, Elizabeth W.; Craig, Michael T.; Paulsen, Ole] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Mayne, Elizabeth W.; McBain, Chris J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Craig, Michael T.; Paulsen, Ole] Univ Cambridge, Physiol Lab, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. RP Paulsen, O (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. EM op210@cam.ac.uk RI Craig, Michael/E-7070-2011 OI Craig, Michael/0000-0001-8481-6709 FU Wellcome Trust OXION initiative; National Institute of Child Health and Human Development (NICHD); Wellcome Trust; NIH; Rhodes Trust FX This work was supported by the Wellcome Trust OXION initiative (M.T.C. and O.P.) and a National Institute of Child Health and Human Development (NICHD) intramural award (C.J.M.). M.T.C. held a Wellcome Trust Prize Studentship. E.W.M. is supported by the NIH MD/PhD Partnership Training programme and by the Rhodes Trust. NR 27 TC 8 Z9 8 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2013 VL 37 IS 8 BP 1242 EP 1247 DI 10.1111/ejn.12125 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 129ON UT WOS:000317850800004 PM 23336973 ER PT J AU O'Reilly, M Kohn, DB Bartlett, J Benson, J Brooks, PJ Byrne, BJ Camozzi, C Cornetta, K Crystal, RG Fong, YM Gargiulo, L Gopal-Srivastava, R High, KA Jacobson, SG Jambou, RC Montgomery, M Rosenthal, E Samulski, RJ Skarlatos, SI Sorrentino, B Wilson, JM Xie, Y Corrigan-Curay, J AF O'Reilly, Marina Kohn, Donald B. Bartlett, Jeffrey Benson, Janet Brooks, Philip J. Byrne, Barry J. Camozzi, Carlos Cornetta, Kenneth Crystal, Ronald G. Fong, Yuman Gargiulo, Linda Gopal-Srivastava, Rashmi High, Katherine A. Jacobson, Samuel G. Jambou, Robert C. Montgomery, Maureen Rosenthal, Eugene Samulski, R. Jude Skarlatos, Sonia I. Sorrentino, Brian Wilson, James M. Xie, Yun Corrigan-Curay, Jacqueline TI Gene Therapy for Rare Diseases: Summary of a National Institutes of Health Workshop, September 13, 2012 SO HUMAN GENE THERAPY LA English DT Editorial Material ID IMMUNODEFICIENCY; HEMOPHILIA; ACTIVATION; VECTOR AB Gene therapy has shown clinical efficacy for several rare diseases, using different approaches and vectors. The Gene Therapy for Rare Diseases workshop, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities and Office of Rare Diseases Research, brought together investigators from different disciplines to discuss the challenges and opportunities for advancing the field including means for enhancing data sharing for preclinical and clinical studies, development and utilization of available NIH resources, and interactions with the U.S. Food and Drug Administration. C1 [O'Reilly, Marina; Gargiulo, Linda; Jambou, Robert C.; Montgomery, Maureen; Rosenthal, Eugene; Xie, Yun; Corrigan-Curay, Jacqueline] NIH, Off Biotechnol Act, Off Sci Policy, Off Director, Bethesda, MD 20892 USA. [Kohn, Donald B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bartlett, Jeffrey] Calimmune Inc, Los Angeles, CA 90024 USA. [Benson, Janet] Lovelace Resp Res Inst, Appl Toxicol & Gene Therapy Pharmacol Toxicol Pro, Albuquerque, NM 87108 USA. [Brooks, Philip J.; Gopal-Srivastava, Rashmi] NIH, Off Rare Dis Res, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Powell Gene Therapy Ctr, Gainesville, FL 32610 USA. [Byrne, Barry J.] Univ Florida, Coll Med, Dept Pediat, Gainesville, FL 32610 USA. [Camozzi, Carlos] Orphazyme, Copenhagen, Denmark. [Cornetta, Kenneth] Indiana Univ, Sch Med, Dept Med & Mol Genet, Vector Prod Facil, Indianapolis, IN 46202 USA. [Crystal, Ronald G.] Weill Cornell Med Coll, Dept Med Genet, Arthur & Rochelle Belfer Gene Therapy Core Facil, New York, NY 10021 USA. [Fong, Yuman] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [High, Katherine A.] Univ Penn, Ctr Cellular & Mol Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA. [High, Katherine A.] Childrens Hosp Philadelphia, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Jacobson, Samuel G.] Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Samulski, R. Jude] Univ N Carolina, Sch Med, Gene Therapy Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Skarlatos, Sonia I.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Sorrentino, Brian] St Jude Childrens Res Hosp, Expt Hematol Div, Memphis, TN 38105 USA. [Wilson, James M.] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Wilson, James M.] Univ Penn, Dept Lab Med, Philadelphia, PA 19104 USA. RP Corrigan-Curay, J (reprint author), NIH, Off Biotechnol Act, 6705 Rockledge Dr,Suite 750, Bethesda, MD 20892 USA. EM corrigaja@od.nih.gov RI Wilson, James/F-9220-2011; Kohn, Donald/N-5085-2016 OI Wilson, James/0000-0002-9630-3131; Kohn, Donald/0000-0003-1840-6087 FU NHLBI NIH HHS [P40 HL116242] NR 16 TC 12 Z9 12 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2013 VL 24 IS 4 BP 355 EP 362 DI 10.1089/hum.2013.064 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 129GE UT WOS:000317826200001 PM 23517518 ER PT J AU Rocha, EM Cotrim, AP Zheng, CY Riveros, PP Baum, BJ Chiorini, JA AF Rocha, Eduardo M. Cotrim, Ana P. Zheng, Changyu Riveros, Paola Perez Baum, Bruce J. Chiorini, John A. TI Recovery of Radiation-Induced Dry Eye and Corneal Damage by Pretreatment with Adenoviral Vector-Mediated Transfer of Erythropoietin to the Salivary Glands in Mice SO HUMAN GENE THERAPY LA English DT Article ID GENE-TRANSFER; NONHUMAN-PRIMATES; SJOGRENS-SYNDROME; OXYGEN RADICALS; PAROTID-GLANDS; IRRADIATION; EXPRESSION; CONJUNCTIVAL; PREVENTION; THERAPY AB Therapeutic doses of radiation (RTx) causes dry eye syndrome (DES), dry mouth, and as in other sicca syndromes, they are incurable. The aims of this work are as follows: (a) to evaluate a mouse model of DES induced by clinically relevant doses of radiation, and (b) to evaluate the protective effect of erythropoietin (Epo) in preventing DES. C3H female mice were subjected to five sessions of RTx, with or without pre-RTx retroductal administration of the AdLTR2EF1a-hEPO (AdEpo) vector in the salivary glands (SG), and compared with naive controls at Day 10 (10d) (8Gy fractions) and 56 days (56d) (6Gy fractions) after RTx treatment. Mice were tested for changes in lacrimal glands (LG), tear secretion (phenol red thread), weight, hematocrit (Hct), and markers of inflammation, as well as microvessels and oxidative damage. Tear secretion was reduced in both RTx groups, compared to controls, by 10d. This was also seen at 56d in RTx but not AdEpo + RTx group. Hct was significantly higher in all AdEpo + RTx mice at 10d and 56d. Corneal epithelium was significantly thinner at 10d in the RTx group compared with AdEpo + RTx or the control mice. There was a significant reduction at 10d in vascular endothelial growth factor (VEGF)-R2 in LG in the RTx group that was prevented in the AdEpo + RTx group. In conclusion, RTx is able to induce DES in mice. AdEpo administration protected corneal epithelia and resulted in some recovery of LG function, supporting the value of further studies using gene therapy for extraglandular diseases. C1 [Rocha, Eduardo M.] Univ Sao Paulo, Dept Ophthalmol Otorhinolaryngol & Head & Neck Su, Fac Med Ribeirao Preto, BR-14049900 Ribeirao Preto, SP, Brazil. [Cotrim, Ana P.; Zheng, Changyu; Riveros, Paola Perez; Baum, Bruce J.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Rocha, EM (reprint author), Univ Sao Paulo, Dept Ophthalmol Otorhinolaryngol & Head & Neck Su, Fac Med Ribeirao Preto, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM emrocha@fmrp.usp.br RI Rocha, Eduardo/D-6002-2011 OI Rocha, Eduardo/0000-0001-9888-7313 FU Division of Intramural Research, NIDCR; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA) FX The authors would like to thank William Swaim, Beverly Handelman, and Ilias Alevizos from NIDCR/NIH for assistance with this work. The authors also acknowledge the NIH Fellows Editorial Board for editorial assistance with this manuscript. This study received financial support from the Division of Intramural Research, NIDCR. In addition, E.M.R. was supported by grants from the following Brazilian governmental institutions: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); and Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA). NR 37 TC 5 Z9 5 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD APR PY 2013 VL 24 IS 4 BP 417 EP 423 DI 10.1089/hum.2012.111 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 129GE UT WOS:000317826200006 PM 23402345 ER PT J AU Avins, AL Lee, JY Meyers, CM Barry, MJ AF Avins, Andrew L. Lee, Jeannette Y. Meyers, Catherine M. Barry, Michael J. CA CAMUS Study Grp TI Safety and Toxicity of Saw Palmetto in the CAMUS Trial SO JOURNAL OF UROLOGY LA English DT Article DE prostate; Serenoa; prostatic hyperplasia; lower urinary tract symptoms; phytotherapy ID BENIGN PROSTATIC HYPERPLASIA; SERENOA-REPENS; INDUCED PANCREATITIS; EXTRACT; PHYTOTHERAPY; HERB AB Purpose: Extracts of the saw palmetto berry are used by many men in the United States as self-treatment for lower urinary tract symptoms due to benign prostatic hyperplasia. While the most recent data from double-blind clinical trials do not support efficacy superior to that of placebo, there are sparse data on saw palmetto toxicity. Materials and Methods: A total of 369 patients were randomized in the CAMUS (Complementary and Alternative Medicine for Urological Symptoms) trial, of whom 357 were included in this modified intent to treat analysis. Participants were randomized to 320, 640 and 960 mg daily of an ethanolic saw palmetto extract or to an identical-appearing placebo in an escalating manner at 6-month intervals for a total of 18 months of followup. Adverse event assessments, vital signs, and blood and urine laboratory tests were obtained at regular intervals. Results: There were no statistically significant differences between the groups in the rates of serious or nonserious adverse events, changes in vital signs, digital prostate examination findings or study withdrawal rates. Overall, there were no significant intergroup differences in laboratory test abnormalities, while differences in individual laboratory tests were rare and small in magnitude. No evidence of significant dose-response phenomena was identified. Conclusions: The saw palmetto extract used in the CAMUS trial showed no evidence of toxicity at doses up to 3 times the usual clinical dose during an 18-month period. C1 [Avins, Andrew L.] No Calif Kaiser Permanente Div Res, Oakland, CA 94612 USA. [Avins, Andrew L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Avins, Andrew L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lee, Jeannette Y.] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [Meyers, Catherine M.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Barry, Michael J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Avins, AL (reprint author), No Calif Kaiser Permanente Div Res, 2000 Broadway,3rd Floor, Oakland, CA 94612 USA. EM andrew.avins@ucsf.edu FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778, U01 DK63788]; National Center for Complementary and Alternative Medicine; Office of Dietary Supplements, National Institutes of Health FX Supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Cooperative Agreements U01 DK63795, U01 DK63797, U01 DK63825, U01 DK63835, U01 DK63866, U01 DK63833, U01 DK63862, U01 DK63840, U01 DK63883, U01 DK63831, U01 DK63778 and U01 DK63788, the National Center for Complementary and Alternative Medicine, and the Office of Dietary Supplements, National Institutes of Health. NR 27 TC 3 Z9 3 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD APR PY 2013 VL 189 IS 4 BP 1415 EP 1420 DI 10.1016/j.juro.2012.10.002 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 127TN UT WOS:000317721800064 PM 23063633 ER PT J AU Gail, MH Pfeiffer, RM Cai, TX AF Gail, Mitchell H. Pfeiffer, Ruth M. Cai, Tianxi TI Special Issue: Risk Assessment and Evaluation of Predictions SO LIFETIME DATA ANALYSIS LA English DT Editorial Material C1 [Gail, Mitchell H.; Pfeiffer, Ruth M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM gailm@nih.gov NR 6 TC 0 Z9 0 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD APR PY 2013 VL 19 IS 2 SI SI BP 139 EP 141 DI 10.1007/s10985-013-9253-9 PG 3 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 131FR UT WOS:000317978600001 PM 23563996 ER PT J AU Yang, S AF Yang, Song TI Semiparametric inference on the absolute risk reduction and the restricted mean survival difference SO LIFETIME DATA ANALYSIS LA English DT Article DE Absolute risk reduction; Clinical trial; Non-proportional hazards; Restricted mean survival; Semiparametric analysis; Simultaneous inference ID ESTROGEN PLUS PROGESTIN; CONFIDENCE BANDS; COX MODEL; HAZARDS; INTERVALS; DISEASE; RATIOS; TRIAL; TIME; LIFE AB For time-to-event data, when the hazards are non-proportional, in addition to the hazard ratio, the absolute risk reduction and the restricted mean survival difference can be used to describe the time-dependent treatment effect. The absolute risk reduction measures the direct impact of the treatment on event rate or survival, and the restricted mean survival difference provides a way to evaluate the cumulative treatment effect. However, in the literature, available methods are limited for flexibly estimating these measures and making inference on them. In this article, point estimates, pointwise confidence intervals and simultaneous confidence bands of the absolute risk reduction and the restricted mean survival difference are established under a semiparametric model that can be used in a sufficiently wide range of applications. These methods are motivated by and illustrated for data from the Women's Health Initiative estrogen plus progestin clinical trial. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Yang, S (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr MSC 7913, Bethesda, MD 20892 USA. EM yangso@nhlbi.nih.gov NR 24 TC 4 Z9 4 U1 1 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD APR PY 2013 VL 19 IS 2 SI SI BP 219 EP 241 DI 10.1007/s10985-013-9243-y PG 23 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 131FR UT WOS:000317978600005 PM 23392737 ER PT J AU Oh, J Zackowski, K Chen, M Newsome, S Saidha, S Smith, SA Diener-West, M Prince, J Jones, CK Van Zijl, PCM Calabresi, PA Reich, DS AF Oh, Jiwon Zackowski, Kathleen Chen, Min Newsome, Scott Saidha, Shiv Smith, Seth A. Diener-West, Marie Prince, Jerry Jones, Craig K. Van Zijl, Peter C. M. Calabresi, Peter A. Reich, Daniel S. TI Multiparametric MRI correlates of sensorimotor function in the spinal cord in multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE MRI; multiple sclerosis; spinal cord; cross-sectional area; diffusion-tensor imaging; magnetization-transfer ratio; fractional anisotropy; diffusivity; clinical dysfunction ID MAGNETIZATION-TRANSFER RATIO; CERVICAL CORD; RADIAL DIFFUSIVITY; MS PATIENTS; DISABILITY; ABNORMALITIES; HISTOPATHOLOGY; ATROPHY; MYELIN; DAMAGE AB Background: Spinal cord (SC) pathology is a major contributor to clinical disability in multiple sclerosis (MS). Conventional magnetic resonance imaging (MRI), specifically SC-MRI lesion load measures that include lesion count and volume, demonstrate only a modest relationship with the clinical status of MS patients. Although SC cross-sectional area (CSA) correlates better with clinical dysfunction than MRI lesion count, SC atrophy likely signifies irreversible tissue loss. Using quantitative MRI indices sensitive to early and late microstructural changes in the spinal cord, we searched for the presence of better correlations between MRI measures and clinical status in MS. Objectives: We investigated whether diffusion-tensor imaging indices and the magnetization-transfer ratio (MTR) were better associated with the clinical status of MS patients than conventional SC-MRI measures. Methods: A total of 129 MS patients underwent 3-tesla cervical SC-MRI and quantitative sensorimotor function testing, using the Vibratron-II and dynamometer. Regions-of-interest circumscribed the SC on axial slices between C3-C4. We calculated SC-CSA, fractional anisotropy (FA), mean diffusivity (MD), perpendicular diffusivity (lambda(perpendicular to)), parallel diffusivity (lambda(parallel to)) and MTR. We used multivariable linear regression to determine if there were any associations between MRI indices and clinical measures of dysfunction. Results: All MRI indices were significantly different in subjects with MS versus healthy controls, and between the progressive versus relapsing MS subtypes, with the exception of lambda(parallel to). In multivariable regression models that were adjusted for age, sex, brain parenchymal fraction, and SC-CSA, the MRI indices independently explained variability in hip flexion strength (p-values: MD, lambda(perpendicular to), lambda(parallel to) < 0.001; FA = 0.07), vibration sensation threshold (p-values: FA = 0.04; MTR = 0.05; lambda(perpendicular to) = 0.06), and Expanded Disability Status Scale scores (p-values: FA = 0.003; MD = 0.03; lambda(perpendicular to) = 0.005; MTR = 0.02). Conclusions: In a large, heterogeneous MS sample, quantitative SC-MRI indices demonstrated independent associations with system-specific and global clinical dysfunction. Our findings suggest that the indices studied may provide important information about microstructural SC changes and the substrates of limb disability in MS. The identified structure-function relationships underpin the potential utility of these measures in assessments of therapeutic efficacy. C1 [Oh, Jiwon; Zackowski, Kathleen; Chen, Min; Newsome, Scott; Saidha, Shiv; Diener-West, Marie; Prince, Jerry; Jones, Craig K.; Van Zijl, Peter C. M.; Calabresi, Peter A.; Reich, Daniel S.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Zackowski, Kathleen; Jones, Craig K.; Van Zijl, Peter C. M.] Kennedy Krieger Inst, Baltimore, MD USA. [Smith, Seth A.] Vanderbilt Univ, Inst Imaging Sci, Nashville, TN USA. [Reich, Daniel S.] NINDS, NIH, Bethesda, MD 20892 USA. RP Oh, J (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM joh20@jhmi.edu RI sebastianovitsch, stepan/G-8507-2013; Prince, Jerry/A-3281-2010; Reich, Daniel/E-5701-2010 OI Prince, Jerry/0000-0002-6553-0876; Reich, Daniel/0000-0002-2628-4334 FU Multiple Sclerosis Society of Canada Postdoctoral Fellowship; National Institutes of Health/National Institute of Child Health and Development [HD049476]; Dana Foundation grant; National Multiple Sclerosis Society [TR 3760-A-3]; Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund; EMD-Serono Grant; National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering [EB009120]; National Institutes of Health/National Center for Research Resources/National Institute of Biomedical Imaging and Bioengineering [P41EB015909]; Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX This work was supported by the Multiple Sclerosis Society of Canada Postdoctoral Fellowship (to JO); National Institutes of Health/National Institute of Child Health and Development (K01 grant number HD049476, to KZ); a Dana Foundation grant (to KZ); National Multiple Sclerosis Society (grant number TR 3760-A-3, to PAC); Braxton Debbie Angela Dillon and Skip (DADS) Donor Advisor Fund (to PAC); EMD-Serono Grant (to PAC); National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (grant number EB009120, to SAS); National Institutes of Health/National Center for Research Resources/National Institute of Biomedical Imaging and Bioengineering (grant number P41EB015909, to PCMV); and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (to DSR). NR 37 TC 23 Z9 23 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD APR PY 2013 VL 19 IS 4 BP 427 EP 435 DI 10.1177/1352458512456614 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 128DY UT WOS:000317750500006 PM 22891033 ER PT J AU Goldstein, A Wolfe, LA AF Goldstein, Amy Wolfe, Lynne A. TI The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders SO NEUROTHERAPEUTICS LA English DT Review DE Mitochondria; ATP; mtDNA; nDNA; Respiratory chain; OXPHOS ID HEREDITARY OPTIC NEUROPATHY; FATTY-ACID OXIDATION; ENERGY-METABOLISM; LACTIC-ACIDOSIS; LIPOIC ACID; DISEASE; EXERCISE; DNA; DICHLOROACETATE; MYOPATHY AB The incidence of mitochondrial diseases has been estimated at 11.5/100,000 (1:8500) worldwide. In the USA up to 4000 newborns annually are expected to develop a mitochondrial disease. More than 50 million adults in the USA also suffer from diseases in which primary or secondary mitochondrial dysfunction is involved. Mitochondrial dysfunction has been identified in cancer, infertility, diabetes, heart diseases, blindness, deafness, kidney disease, liver disease, stroke, migraine, dwarfism, and resulting from numerous medication toxicities. Mitochondrial dysfunction is also involved in normal aging and age-related neurodegenerative diseases, such as Parkinson and Alzheimer diseases. Yet most treatments available are based on empiric data and clinician experience because of the lack of randomized controlled clinical trials to provide evidence-based treatments for these disorders. Here we explore the current state of research for the treatment of mitochondrial disorders. C1 [Goldstein, Amy] UPMC, Childrens Hosp Pittsburgh, Div Child Neurol, Pittsburgh, PA USA. [Wolfe, Lynne A.] NIH, Undiagnosed Dis Program, Bethesda, MD 20892 USA. RP Wolfe, LA (reprint author), NIH, Undiagnosed Dis Program, 10 Ctr DR,MSC 1205,RM 3-2551, Bethesda, MD 20892 USA. EM lynne.wolfe@nih.gov NR 44 TC 7 Z9 7 U1 0 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1933-7213 EI 1878-7479 J9 NEUROTHERAPEUTICS JI Neurotherapeutics PD APR PY 2013 VL 10 IS 2 BP 320 EP 328 DI 10.1007/s13311-012-0175-0 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 127EC UT WOS:000317677900012 PM 23355364 ER PT J AU Smith, WM Larson, TA Meleth, AD Krishnadev, N Nussenblatt, RB Sen, HN AF Smith, Wendy M. Larson, Theresa A. Meleth, A. Dhanu Krishnadev, Nupura Nussenblatt, Robert B. Sen, H. Nida TI Corticosteroid-associated Osteonecrosis: A Rare, but Serious, Complication in Uveitis SO OCULAR IMMUNOLOGY AND INFLAMMATION LA English DT Article DE avascular necrosis; corticosteroid; osteonecrosis; prednisone; uveitis ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; FEMORAL-HEAD; IDIOPATHIC OSTEONECROSIS; THERAPY; MRI; DISEASE AB Purpose: To examine the incidence and prevalence of osteonecrosis in uveitis patients. Methods: An electronic medical record database search was conducted to identify uveitis patients with osteonecrosis and the number at risk for corticosteroid-related osteonecrosis from 2003 to 2012. The clinical and ophthalmologic features of the uveitis patients with osteonecrosis were assessed with retrospective chart reviews. Results: Six uveitis patients with osteonecrosis were identified, comprising a prevalence of 1.5%. The incidence density was 0.19 per 100 person-years of follow-up. The uveitides included sarcoidosis, sympathetic ophthalmia, idiopathic retinal vasculitis, idiopathic chronic anterior and intermediate uveitis, Vogt-Koyanagi Harada disease, and Cogan syndrome. The duration of systemic corticosteroid treatment ranged from 6 weeks to 6 years. The potential systemic risk factors were Raynaud phenomenon, antiphospholipid and autoantibodies, sickle cell trait, and thalassemia. Conclusions: Although osteonecrosis appears to be a rare complication among uveitis patients, physicians should strive to minimize systemic corticosteroid use when appropriate. A higher level of suspicion for osteonecrosis may be warranted in patients with additional systemic risk factors. C1 [Smith, Wendy M.; Larson, Theresa A.; Meleth, A. Dhanu; Krishnadev, Nupura; Nussenblatt, Robert B.; Sen, H. Nida] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,10-10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov RI sebastianovitsch, stepan/G-8507-2013 FU National Eye Institute Intramural Research Program FX This study was funded by the National Eye Institute Intramural Research Program. NR 12 TC 1 Z9 1 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0927-3948 J9 OCUL IMMUNOL INFLAMM JI Ocul. Immunol. Inflamm. PD APR PY 2013 VL 21 IS 2 BP 102 EP 107 DI 10.3109/09273948.2012.740129 PG 6 WC Ophthalmology SC Ophthalmology GA 124WH UT WOS:000317498500002 PM 23252656 ER PT J AU Church, G AF Church, George TI Personal Profile: Interview with George Church SO REJUVENATION RESEARCH LA English DT Editorial Material ID LIFE EXPECTANCY; PH.D C1 [Church, George] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Church, George] NIH, Ctr Excellence Genom Sci, Bethesda, MD 20892 USA. RP Church, G (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 32 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 1549-1684 J9 REJUV RES JI Rejuv. Res. PD APR PY 2013 VL 16 IS 2 BP 171 EP 172 DI 10.1089/rej.2013.1427 PG 2 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 129IM UT WOS:000317832600012 ER PT J AU Kadir, Z Ma, XL Li, JY Zhang, FC AF Kadir, Zibirnisa Ma, Xiaolin Li, Jinyao Zhang, Fuchun TI Granulocyte-Macrophage Colony-Stimulating Factor Enhances the Humoral Immune Responses of Mouse Zona Pellucida 3 Vaccine Strategy Based on DNA and Protein Coadministration in BALB/c Mice SO REPRODUCTIVE SCIENCES LA English DT Article DE mZP3; GM-CSF; humoral responses; DCs ID IN-VITRO; SYNTHETIC PEPTIDES; REVERSIBLE CONTRACEPTION; TRANSGENIC MICE; HUMAN ZP3; IMMUNOCONTRACEPTION; ZONA-PELLUCIDA-3; ANTIBODIES; ADJUVANT; OOCYTES AB We recently demonstrated that co-administration of mouse zona pellucida 3 (mZP3) DNA and protein vaccine enhanced the contraception of mice by increasing humoral immune responses. In this study, we try to use granulocyte-macrophage colony-stimulating factor (GM-CSF) to further improve the humoral immune responses induced by mZP3 DNA and protein co-administration. BALB/c mice were intranasally pre-injected with GM-CSF 4 days before co-administration. Compared to DNA and protein coadministration without GM-CSF, the combination of GM-CSF and coadministration significantly enhances humoral immune responses, especially the level of secretory immunoglobulin A (sIgA) in vaginal washes. The enhanced antibody responses are correlated with the upregulated level of interleukin 4 (IL-4) and enhanced maturation of dendritic cells (DCs). Thus, GM-CSF is a potential candidate adjuvant to be used for the development of a safe and effective contraceptive vaccine. C1 [Kadir, Zibirnisa; Ma, Xiaolin; Zhang, Fuchun] Xinjiang Univ, Xinjiang Key Lab Biol Resources & Genet Engn, Coll Life Sci & Technol, Urumqi 830046, Peoples R China. [Li, Jinyao] Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. RP Li, JY (reprint author), Frederick Natl Lab Canc Res, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, 1050 Boyles St,Bldg 535,Room 226, Frederick, MD 21702 USA. EM lijinyao@gmail.com; zfcxju@xju.edu.cn FU Natural Science Foundation of China [30760136]; animal science Foundation of key discipline of Autonomous Region [20101102] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Natural Science Foundation of China (No 30760136) and animal science Foundation of key discipline of Autonomous Region (No 20101102) NR 31 TC 3 Z9 3 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD APR PY 2013 VL 20 IS 4 BP 400 EP 407 DI 10.1177/1933719112459236 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 131KE UT WOS:000317991100007 PM 23111125 ER PT J AU Li, QQ Wang, GD Liang, HS Li, JLM Huang, FR Agarwal, PK Zhong, YH Reed, E AF Li, Q. Quentin Wang, Gangduo Liang, Huasheng Li, Jueli M. Huang, Furong Agarwal, Piyush K. Zhong, Yuhua Reed, Eddie TI beta-Elemene Promotes Cisplatin-induced Cell Death in Human Bladder Cancer and Other Carcinomas SO ANTICANCER RESEARCH LA English DT Article DE Apoptosis; bladder cancer; cisplatin resistance; Chinese medicine; beta-elemene; caspases ID TUMOR-CELLS; SYNTHETIC ANALOGS; UROTHELIAL CANCER; OVARIAN-CANCER; APOPTOSIS; CHEMOTHERAPY; GROWTH; TRIAL; CYCLE; METHOTREXATE AB Cisplatin-based combination treatment is the most effective systemic chemotherapy for bladder cancer; however, resistance to cisplatin remains a significant problem in the treatment of this disease. beta-Elemene is a new natural compound that blocks cell-cycle progression and has a broad spectrum of antitumor activity. This study was conducted to explore the potential of beta-elemene as a chemosensitizer for enhancing the therapeutic efficacy and potency of cisplatin in bladder cancer and other solid carcinomas. beta-Elemene not only markedly inhibited cell growth and proliferation but also substantially increased cisplatin cytotoxicity towards human bladder cancer 5637 and T-24 cells. Similarly, beta-elemene also enhanced cisplatin sensitivity and augmented cisplatin cytotoxicity in small-cell lung cancer and carcinomas of the brain, breast, cervix, ovary, and colorectal tract in vitro, with dose-modifying factors ranging from 5 to 124. beta-Elemene-enhanced cisplatin cytotoxicity was associated with increased apoptotic cell death, as determined by DNA fragmentation, and increased activities of caspase-3, -7, -8, -9, and -10 in bladder cancer cell lines. Collectively, these results suggest that beta-elemene augments the antitumor activity of cisplatin in human bladder cancer by enhancing the induction of cellular apoptosis via a caspase-dependent mechanism. Cisplatin combined with beta-elemene as a chemosensitizer warrants further pre-clinical therapeutic studies and may be useful for the treatment of cisplatin-resistant bladder cancer and other types of carcinomas. C1 [Liang, Huasheng; Zhong, Yuhua] Beihai Inst Endocrine & Metab Dis, Beihai 536000, Guangxi, Peoples R China. [Li, Q. Quentin; Agarwal, Piyush K.; Reed, Eddie] NIH, Bethesda, MD 20892 USA. [Li, Q. Quentin; Wang, Gangduo; Huang, Furong; Reed, Eddie] West Virginia Univ, Sch Med, Morgantown, WV USA. [Li, Jueli M.] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. RP Li, QQ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov; zhongyh111@163.com OI Agarwal, Piyush/0000-0002-6042-6834 FU Natural Science Foundation of Science & Technology Department of Guangxi Province [0991294]; Guangxi Scientific Research and Technological Development Program [200901059]; National Institutes of Health [P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003]; West Virginia University School of Medicine Research Grant FX This publication was made possible by grants from the Natural Science Foundation of Science & Technology Department of Guangxi Province (No. 0991294) and the Guangxi Scientific Research and Technological Development Program (No. 200901059), and by grants from the National Institutes of Health (Nos. P20RR16440-010003, P20RR16440-020003, P20RR16440-030003, P20RR16440-040003) and a West Virginia University School of Medicine Research Grant (to Q. Q. Li). NR 37 TC 15 Z9 17 U1 0 U2 7 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD APR PY 2013 VL 33 IS 4 BP 1421 EP 1428 PG 8 WC Oncology SC Oncology GA 126PD UT WOS:000317632200021 PM 23564782 ER PT J AU Nakamura, N Dai, QS Williams, J Goulding, EH Willis, WD Brown, PR Eddy, EM AF Nakamura, Noriko Dai, Qunsheng Williams, Jason Goulding, Eugenia H. Willis, William D. Brown, Paula R. Eddy, Edward M. TI Disruption of a Spermatogenic Cell-Specific Mouse Enolase 4 (Eno4) Gene Causes Sperm Structural Defects and Male Infertility SO BIOLOGY OF REPRODUCTION LA English DT Article DE fibrous sheath; gene expression; glycolysis; spermatid; testis ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE-S; FIBROUS SHEATH; GLYCOLYTIC-ENZYMES; PROCESSED PSEUDOGENES; MAMMALIAN SPERMATOZOA; ENERGY-METABOLISM; TYPE-1 HEXOKINASE; MALE-FERTILITY; HUMAN GENOME; TESTIS AB Sperm utilize glycolysis to generate ATP required for motility, and several spermatogenic cell-specific glycolytic isozymes are associated with the fibrous sheath (FS) in the principal piece of the sperm flagellum. We used proteomics and molecular biology approaches to confirm earlier reports that a novel enolase is present in mouse sperm. We then found that a pan-enolase antibody, but not antibodies to ENO2 and ENO3, recognized a protein in the principal piece of the mouse sperm flagellum. Database analyses identified two previously uncharacterized enolase family-like candidate genes, 64306537H0Rik and Gm5506. Northern analysis indicated that 64306537H0Rik (renamed Eno4) was transcribed in testes of mice by Postnatal Day 12. To determine the role of ENO4, we generated mice using embryonic stem cells in which an Eno4 allele was disrupted by a gene trap containing a beta galactosidase (beta-gal) reporter (Eno4(+/Gt)). Expression of beta-gal occurred in the testis, and male mice homozygous for the gene trap allele (Eno4(Gt/Gt)) were infertile. Epididymal sperm numbers were 2-fold lower and sperm motility was reduced substantially inEno4(Gt/Gt) mice compared to wild-type mice. Sperm from Eno4(Gt/Gt) mice had a coiled flagellum and a disorganized FS. The Gm5506 gene encodes a protein identical to ENO1 and also is transcribed at a low level in testis. We conclude that ENO4 is required for normal assembly of the FS and provides most of the enolase activity in sperm and that Eno1 and/or Gm5506 may encode a minor portion of the enolase activity in sperm. C1 [Nakamura, Noriko; Dai, Qunsheng; Goulding, Eugenia H.; Willis, William D.; Brown, Paula R.; Eddy, Edward M.] NIEHS, Gamete Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Williams, Jason] NIEHS, Prot Microcharacterizat Core Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eddy, EM (reprint author), NIEHS, LRDT, NIH, C4-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [ES070076] FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (E. M. E., ES070076). NR 49 TC 21 Z9 25 U1 0 U2 6 PU SOC STUDY REPRODUCTION PI MADISON PA 1691 MONROE ST,SUITE # 3, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD APR PY 2013 VL 88 IS 4 AR 90 DI 10.1095/biolreprod.112.107128 PG 12 WC Reproductive Biology SC Reproductive Biology GA 124NP UT WOS:000317471700013 PM 23446454 ER PT J AU Yang, SC Ji, Y Gattinoni, L Zhang, L Yu, ZY Restifo, NP Rosenberg, SA Morgan, RA AF Yang, Shicheng Ji, Yun Gattinoni, Luca Zhang, Ling Yu, Zhiya Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. TI Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE CD62L; TCR gene therapy; T cell receptor; Central memory cells; Effector memory cells; Tumor immunity ID TUMOR-INFILTRATING LYMPHOCYTES; PLURIPOTENT STEM-CELLS; HUMAN PERIPHERAL-BLOOD; CENTRAL-MEMORY; METASTATIC MELANOMA; IN-VIVO; CANCER REGRESSION; TRANSFER THERAPY; GENE-EXPRESSION; CD8+T CELLS AB The genetic modification of CD8+ T cells using anti-tumor T-cell receptors (TCR) or chimeric antigen receptors is a promising approach for the adoptive cell therapy of patients with cancer. We previously developed a simplified method for the clinical-scale generation of central memory-like (Tcm) CD8+ T cells following transduction with lentivirus encoding anti-tumor TCR and culture in the presence of IL-2. In this study, we compared different cytokines or combinations of IL-2, IL-7, IL-12, IL-15, and IL-21 to expand genetically engineered CD8+ T cells. We demonstrated that specific cytokine combinations IL-12 plus IL-7 or IL-21 for 3 days followed by withdrawal of IL-12 yielded the phenotype of CD62L(high)CD28(high) CD127(high)CD27(high)CCR7(high), which is associated with less-differentiated T cells. Genes associated with stem cells (SOX2, NANOG, OCT4, and LIN28A), were also up-regulated by this cytokine cocktail. Moreover, the use of IL-12 plus IL-7 or IL-21 yielded CD8 T cells showing enhanced persistence in the NOD/SCID/gamma c-/- mouse model. This defined cytokine combination could also alter highly differentiated TIL from melanoma patients into cells with a less-differentiated phenotype. The methodology that we developed for generating a less-differentiated anti-tumor CD8+ T cells ex vivo may be ideal for the adoptive immunotherapy of cancer. C1 [Yang, Shicheng; Ji, Yun; Gattinoni, Luca; Zhang, Ling; Yu, Zhiya; Restifo, Nicholas P.; Rosenberg, Steven A.; Morgan, Richard A.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,CRC 3 W-3864, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research FX We thank Arnold Mixon and Shawn Farid in the FACS laboratory and all members in the TIL laboratory at the Surgery Branch for providing technical support and maintenance of PBL and tumor cells from patients. This work is supported by the Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. NR 43 TC 27 Z9 31 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD APR PY 2013 VL 62 IS 4 BP 727 EP 736 DI 10.1007/s00262-012-1378-2 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 126OJ UT WOS:000317626900010 PM 23207483 ER PT J AU Zhang, LP Bassig, BA Mora, JL Vermeulen, R Ge, YC Curry, JD Hu, W Shen, M Qiu, CY Ji, ZY Reiss, B McHale, CM Liu, SW Guo, WH Purdue, MP Yue, F Li, LY Smith, MT Huang, HL Tang, XJ Rothman, N Lan, Q AF Zhang, Luoping Bassig, Bryan A. Mora, Joseph L. Vermeulen, Roel Ge, Yichen Curry, John D. Hu, Wei Shen, Min Qiu, Chuangyi Ji, Zhiying Reiss, Boris McHale, Cliona M. Liu, Songwang Guo, Weihong Purdue, Mark P. Yue, Fei Li, Laiyu Smith, Martyn T. Huang, Hanlin Tang, Xiaojiang Rothman, Nathaniel Lan, Qing TI Alterations in serum immunoglobulin levels in workers occupationally exposed to trichloroethylene SO CARCINOGENESIS LA English DT Article ID NON-HODGKIN-LYMPHOMA; ALCOHOL-CONSUMPTION; HOST DEFENSES; T-CELLS; ACTIVATION; RISK; MICE; IGM; INHALATION; INFECTION AB Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n 80) and unexposed controls (n 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL. C1 [Zhang, Luoping; Mora, Joseph L.; Curry, John D.; Ji, Zhiying; McHale, Cliona M.; Guo, Weihong; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. [Bassig, Bryan A.; Hu, Wei; Shen, Min; Purdue, Mark P.; Rothman, Nathaniel; Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Vermeulen, Roel; Reiss, Boris] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 Utrecht, Netherlands. [Ge, Yichen; Qiu, Chuangyi; Yue, Fei; Li, Laiyu; Huang, Hanlin; Tang, Xiaojiang] Guangdong Poison Control Ctr, Guangzhou 510300, Guangdong, Peoples R China. [Liu, Songwang] Qiaotou Hosp, Dongguan 523523, Guangdong, Peoples R China. RP Zhang, LP (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. EM luoping@berkeley.edu; qingl@mail.nih.gov RI sebastianovitsch, stepan/G-8507-2013; Hu, Wei/M-3524-2013; Vermeulen, Roel/F-8037-2011; Purdue, Mark/C-9228-2016 OI Vermeulen, Roel/0000-0003-4082-8163; Purdue, Mark/0000-0003-1177-3108 FU National Institutes of Health and National Cancer Institute; National Institute of Environmental Health Sciences [P42ES04705, P30ES01896]; Northern California Center for Occupational and Environmental Health; Department of Science and Technology of Guangdong Province, China [2007A050100004] FX Intramural funds from National Institutes of Health and National Cancer Institute; National Institute of Environmental Health Sciences (P42ES04705 and P30ES01896 to M.T.S.); Northern California Center for Occupational and Environmental Health and Department of Science and Technology of Guangdong Province, China (2007A050100004 to X.T.). NR 25 TC 7 Z9 9 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2013 VL 34 IS 4 BP 799 EP 802 DI 10.1093/carcin/bgs403 PG 4 WC Oncology SC Oncology GA 123PB UT WOS:000317401200008 PM 23276795 ER PT J AU Hasebe, T Fu, LZ Miller, TC Zhang, Y Shi, YB Ishizuya-Oka, A AF Hasebe, Takashi Fu, Liezhen Miller, Thomas C. Zhang, Yu Shi, Yun-Bo Ishizuya-Oka, Atsuko TI Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells SO CELL AND BIOSCIENCE LA English DT Article DE Adult organ-specific stem cell; Thyroid hormone receptor; Dedifferentiation; Apoptosis; Metamorphosis; Xenopus laevis and tropicalis; Cell-cell interaction; Matrix metalloproteinase; Extracellular matrix (ECM) ID MATRIX-METALLOPROTEINASE STROMELYSIN-3; XENOPUS-LAEVIS METAMORPHOSIS; TARGETED GENE DISRUPTION; AMPHIBIAN METAMORPHOSIS; NUCLEAR RECEPTOR; EPITHELIAL DEVELOPMENT; EXTRACELLULAR-MATRIX; CONNECTIVE-TISSUE; SONIC HEDGEHOG; POSTEMBRYONIC DEVELOPMENT AB The mammalian intestine has long been used as a model to study organ-specific adult stem cells, which are essential for organ repair and tissue regeneration throughout adult life. The establishment of the intestinal epithelial cell self-renewing system takes place during perinatal development when the villus-crypt axis is established with the adult stem cells localized in the crypt. This developmental period is characterized by high levels of plasma thyroid hormone (T3) and T3 deficiency is known to impair intestinal development. Determining how T3 regulates adult stem cell development in the mammalian intestine can be difficult due to maternal influences. Intestinal remodeling during amphibian metamorphosis resembles perinatal intestinal maturation in mammals and its dependence on T3 is well established. A major advantage of the amphibian model is that it can easily be controlled by altering the availability of T3. The ability to manipulate and examine this relatively rapid and localized formation of adult stem cells has greatly assisted in the elucidation of molecular mechanisms regulating their formation and further revealed evidence that supports conservation in the underlying mechanisms of adult stem cell development in vertebrates. Furthermore, genetic studies in Xenopus laevis indicate that T3 actions in both the epithelium and the rest of the intestine, most likely the underlying connective tissue, are required for the formation of adult stem cells. Molecular analyses suggest that cell-cell interactions involving hedgehog and BMP pathways are critical for the establishment of the stem cell niche that is essential for the formation of the adult intestinal stem cells. C1 [Hasebe, Takashi; Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Kawasaki, Kanagawa 2110063, Japan. [Fu, Liezhen; Miller, Thomas C.; Zhang, Yu; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PCRM, Sect Mol Morphogenesis, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, PCRM, Sect Mol Morphogenesis, NIH, Bethesda, MD 20892 USA. EM shi@helix.nih.gov; a-oka@nms.ac.jp FU Intramural Research Program of NICHD, NIH FX This research was supported in part by the Intramural Research Program of NICHD, NIH. NR 140 TC 14 Z9 14 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD APR 1 PY 2013 VL 3 AR 18 DI 10.1186/2045-3701-3-18 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127VY UT WOS:000317728200001 PM 23547658 ER PT J AU Scher, AI Eiriksdottir, G Garcia, M Feit, P Smith, AV Harris, TB Roecklein, KA Gudmundsson, LS Gudnason, V Launer, LJ AF Scher, Ann I. Eiriksdottir, Gudny Garcia, Melissa Feit, Preethy Smith, Albert V. Harris, Tamara B. Roecklein, Kathryn A. Gudmundsson, Larus S. Gudnason, Vilmundur Launer, Lenore J. TI Lack of association between the MTHFR C677T variant and migraine with aura in an older population: Could selective survival play a role? SO CEPHALALGIA LA English DT Article DE Migraine; folate; MTHFR; association studies in genetics; selective survival; selection bias ID METHYLENETETRAHYDROFOLATE REDUCTASE GENE; CORONARY-HEART-DISEASE; WOMEN PROSPECTIVE COHORT; CARDIOVASCULAR-DISEASE; HUMAN LONGEVITY; STROKE RISK; ALL-CAUSE; HOMOCYSTEINE; MORTALITY; GENOTYPE AB Background: Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort). Methods: Participants are a sub-sample (n = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association. Results: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.3-1.0), p = 0.07), significantly for women (ORTT 0.45 (0.2-0.9), p = 0.03). Assuming the 'true' (e. g. mid-life) effect of the TT genotype is ORTT 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e. g. ORTT 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers. Conclusion: The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations. C1 [Scher, Ann I.; Feit, Preethy; Gudmundsson, Larus S.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Scher, Ann I.; Garcia, Melissa; Harris, Tamara B.; Gudmundsson, Larus S.; Launer, Lenore J.] NIA, Lab Populat Sci, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Roecklein, Kathryn A.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. RP Scher, AI (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ann.scher@usuhs.edu RI sebastianovitsch, stepan/G-8507-2013; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845 FU National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament) FX This study was supported by a grant from the National Institutes of Health (N01-AG-1-2100), National Institute on Aging Intramural Research Program, the Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). NR 49 TC 3 Z9 4 U1 0 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD APR PY 2013 VL 33 IS 5 BP 308 EP 315 DI 10.1177/0333102412469739 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 123XR UT WOS:000317425800004 PM 23230240 ER PT J AU Wu, JHY Lemaitre, RN Manichaikul, A Guan, WH Tanaka, T Foy, M Kabagambe, EK Djousse, L Siscovick, D Fretts, AM Johnson, C King, IB Psaty, BM McKnight, B Rich, SS Chen, YDI Nettleton, JA Tang, WH Bandinelli, S Jacobs, DR Browning, BL Laurie, CC Gu, XJ Tsai, MY Steffen, LM Ferrucci, L Fornage, M Mozaffarian, D AF Wu, Jason H. Y. Lemaitre, Rozenn N. Manichaikul, Ani Guan, Weihua Tanaka, Toshiko Foy, Millennia Kabagambe, Edmond K. Djousse, Luc Siscovick, David Fretts, Amanda M. Johnson, Catherine King, Irena B. Psaty, Bruce M. McKnight, Barbara Rich, Stephen S. Chen, Yii-Der I. Nettleton, Jennifer A. Tang, Weihong Bandinelli, Stefania Jacobs, David R., Jr. Browning, Brian L. Laurie, Cathy C. Gu, Xiangjun Tsai, Michael Y. Steffen, Lyn M. Ferrucci, Luigi Fornage, Myriam Mozaffarian, Dariush TI Genome-Wide Association Study Identifies Novel Loci Associated With Concentrations of Four Plasma Phospholipid Fatty Acids in the De Novo Lipogenesis Pathway Results From the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE epidemiology; fatty acids; genome-wide association study; lipogenesis ID MIDDLE-AGED ADULTS; ENDOPLASMIC-RETICULUM; ATHEROSCLEROSIS RISK; INTERMITTENT HYPOXIA; SYNTHASE INHIBITORS; ALCOHOL-CONSUMPTION; HEPATIC STEATOSIS; ADIPOSE-TISSUE; PPAR-ALPHA; ER STRESS AB Background-Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. Methods and Results-Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of >= 1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7x10(-11)) and lower 18:0 (P=2.2x10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6x10(-13)) and 18:1n-9 (P=2.2x10(-32)) and lower 18:0 (P=1.3x10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8x10(-9)). GCKR (glucokinase regulator; P=9.8x10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7x10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7x10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1x10(-8)). Conclusions-Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose-and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology. (Circ Cardiovasc Genet. 2013;6:171-183.) C1 [Wu, Jason H. Y.; Mozaffarian, Dariush] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA 02115 USA. [Wu, Jason H. Y.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Lemaitre, Rozenn N.; Siscovick, David; Fretts, Amanda M.; Johnson, Catherine; Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [McKnight, Barbara; Laurie, Cathy C.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Browning, Brian L.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Genom, Div Biostat & Epidemiol, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Guan, Weihua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Tang, Weihong; Jacobs, David R., Jr.; Steffen, Lyn M.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Tsai, Michael Y.] Univ Minnesota, Sch Publ Hlth, Lab Med & Pathol, Minneapolis, MN USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Foy, Millennia; Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Kabagambe, Edmond K.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Djousse, Luc] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging,Dept Med, Boston, MA 02115 USA. [Mozaffarian, Dariush] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. [Djousse, Luc] Boston VA Healthcare Syst, Boston, MA USA. [King, Irena B.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Chen, Yii-Der I.] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. RP Wu, JHY (reprint author), Harvard Univ, Sch Publ Hlth, Kresge Bldg 913,677 Huntington Ave, Boston, MA 02115 USA. EM jasonwu@hsph.harvard.edu RI Browning, Brian/A-1178-2010; Djousse, Luc/F-5033-2017 OI Browning, Brian/0000-0001-6454-6633; Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN2682011 00007C, HHSN268201100008C, HHSN268201100009C, HHSN 268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402, U01-HG-004729, U01-HG-004446, U01-HG-004424]; National Institutes of Health [HSN268200625226C]; NIH [UL1RR025005]; NIH Roadmap for Medical Research; NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL105756]; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; National Center for Research Resources CTSI [UL 1RR033176]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Italian Ministry of Health [ICS110.1/RF97.71]; US National Institute on Aging [263 MD 9164, 263 MD 821336]; Intramural research program of the National Institute on Aging, National Institutes of Health; MESA; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [5K01DK082729-02]; National Heart, Lung, and Blood Institute [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, R01-HL-084099, N01-HC-95159, N01-HC-95169, RR-024156, N02-HL-6-4278]; [R01HL071051]; [R01HL071205]; [R01HL071250]; [R01HL071251]; [R01HL071252]; [R01HL071258]; [R01HL071259] FX The ARIC Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN2682011 00007C, HHSN268201100008C, HHSN268201100009C, HHSN 268201100010C, HHSN268201100011C, HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HSN268200625226C. The authors 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 NIH and NIH Roadmap for Medical Research. The CHS research reported in this article was supported by the NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, and N01-HC-45133, and grants HL080295, HL075366, HL087652, and HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping were supported, in part, by National Center for Research Resources CTSI grant UL 1RR033176 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Coronary Artery Risk Development in Young Adults CARDIA study is funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from the NHLBI to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the National Human Genome Research Institute and R01-HL-084099 from the NHLBI to Dr Fornage. Statistical analyses and fatty acid measures were funded by R01-HL-084099 from the NHLBI to Dr Foy. The InCHIANTI Study baseline (1998-2000) was supported as a targeted project (ICS110.1/RF97.71) by the Italian Ministry of Health, in part by the US National Institute on Aging (contracts 263 MD 9164 and 263 MD 821336), and in part by the Intramural research program of the National Institute on Aging, National Institutes of Health. The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SHARe were supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the NHLBI. Funding for MESA SHARe genotyping was provided by NHLBI contract N02-HL-6-4278. MESA Family is conducted and supported in collaboration with MESA investigators, and support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, and R01HL071259. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Dr Nettleton is supported by a K01 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK082729-02).; The authors thank the other investigators, the staff, and the participants of the ARIC study, the CARDIA study, the CHS study, the MESA study, and the InCHIANTI study for their important contributions. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. A full list of principal CARDIA investigators and institutions can be found at http://www.cardia.dopm.uab.edu/study-information/participating-instituti ons. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The authors acknowledge the essential role of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium in the development and support of this manuscript. CHARGE members include National Heart, Lung, and Blood Institute's (NHLBI's) Atherosclerosis Risk in Communities (ARIC) Study, National Institute of Health (NIH) and Icelandic Heart Association's Age, Gene/Environment Susceptibility (AGES) Study, NHLBI's Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS), and the Netherland's Rotterdam Study (RS). NR 74 TC 21 Z9 21 U1 0 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD APR PY 2013 VL 6 IS 2 BP 171 EP + DI 10.1161/CIRCGENETICS.112.964619 PG 37 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 128AW UT WOS:000317741400006 PM 23362303 ER PT J AU Saydah, SH Pavkov, ME Zhang, C Lacher, DA Eberhardt, MS Burrows, NR Narva, AS Eggers, PW Williams, DE AF Saydah, Sharon H. Pavkov, Meda E. Zhang, Cindy Lacher, David A. Eberhardt, Mark S. Burrows, Nilka Rios Narva, Andrew S. Eggers, Paul W. Williams, Desmond E. TI Albuminuria Prevalence in First Morning Void Compared with Previous Random Urine from Adults in the National Health and Nutrition Examination Survey, 2009-2010 SO CLINICAL CHEMISTRY LA English DT Article ID GLOMERULAR-FILTRATION-RATE; CREATININE RATIO; KIDNEY-FUNCTION; US POPULATION; SPOT URINE; MICROALBUMINURIA; EXCRETION; EQUATION; SAMPLES; ISSUES AB BACKGROUND: Albuminuria, defined as urine albumin/creatinine ratio (ACR) >= 30 mg/g, is a diagnostic component of chronic kidney disease (CKD). National estimates of ACR and CKD prevalence have been based on single random urine samples. Although 2 urine samples or a first morning void are known to produce different estimates of ACR, the impact of differing urine sampling schemes on nationally estimated rates of CKD is unknown. METHODS: In 2009-2010, the National Health and Nutrition Examination Survey (NHANES) participants provided 2 untimed urine samples for sequential ACR measurement: an initial random urine collected in the NHANES mobile examination center and a subsequent first morning void collected at home. Rates of albuminuria were calculated in the overall population and broken down by demographics, diagnosed diabetes and hypertension status, and estimated glomerular filtration rate (eGFR). RESULTS: Overall, 43.5% of adults with increased ACR (>= 30 mg/g) in a random urine also had increased ACR in a first morning urine. This percentage was higher among individuals >= 50 years old (48.9%), males (53.3%), participants with diagnosed diabetes (56.3%) and hypertension (51.5%), and eGFR <60 mL/min/1.72m(2) (56.9%). The use of confirmed increased ACR (defined as the presence of ACR >= 30 mg/g in both samples taken within 10 days) to define CKD resulted in a lower overall prevalence (11.6%) than first morning urine (12.7%) or random spot urine only (15.2%). CONCLUSIONS: ACR measured on random urine samples appears to overestimate the prevalence of albuminuria compared to first morning urine collections. (C) 2013 American Association for Clinical Chemistry C1 [Saydah, Sharon H.; Pavkov, Meda E.; Burrows, Nilka Rios; Williams, Desmond E.] CDC, Div Diabet Translat, Atlanta, GA 30333 USA. [Zhang, Cindy; Lacher, David A.; Eberhardt, Mark S.] CDC, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Atlanta, GA 30333 USA. [Narva, Andrew S.; Eggers, Paul W.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Saydah, SH (reprint author), Ctr Dis Control & Prevent, Div Diabet Translat, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM ssaydah@cdc.gov FU Intramural CDC HHS [CC999999] NR 34 TC 12 Z9 14 U1 0 U2 4 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD APR PY 2013 VL 59 IS 4 BP 675 EP 683 DI 10.1373/clinchem.2012.195644 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 122SK UT WOS:000317338200016 PM 23315482 ER PT J AU Ionescu, DF Niciu, MJ Mathews, DC Richards, EM Zarate, CA AF Ionescu, Dawn F. Niciu, Mark J. Mathews, Daniel C. Richards, Erica M. Zarate, Carlos A., Jr. TI NEUROBIOLOGY OF ANXIOUS DEPRESSION: A REVIEW SO DEPRESSION AND ANXIETY LA English DT Review DE anxiety; anxious depression; biomarkers; depression; neurobiology ID ANTIDEPRESSANT TREATMENT RESPONSE; STAR-ASTERISK-D; MAJOR DEPRESSION; NONANXIOUS DEPRESSION; LIFE EVENTS; ANXIETY DISORDERS; PERCEPTUAL ASYMMETRY; UNIPOLAR DEPRESSION; GENERALIZED ANXIETY; COMORBID ANXIETY AB Anxious depression is a common, distinct clinical subtype of major depressive disorder (MDD). This review summarizes current neurobiological knowledge regarding anxious depression. Peer-reviewed articles, published January 1970 through September 2012, were identified via PUBMED, EMBASE, and Cochrane Library, using the following key words: anxious depression electroencephalography (EEG), anxious depression functional magnetic resonance imaging (fMRI), anxious depression genetics, anxious depression neurobiology, and anxious melancholia neurobiology. Despite a general dearth of neurobiological research, the results suggest that anxious depressionwhen defined either syndromally or dimensionallyhas distinct neurobiological findings that separate it from nonanxious depression. Structural neuroimaging, EEG, genetics, and neuropsychiatric studies revealed differences in subjects with anxious depression compared to other groups. Endocrine differences between individuals with anxious depression and those with nonanxious depression have also been noted, as evidenced by abnormal responses elicited by exogenous stimulation of the system. Despite these findings, heterogeneity in the definition of anxious depression complicates the results. Because exploring the neurobiology of this depressive subtype is important for improving diagnosis, prognosis, and treatment, enrichment strategies to decrease heterogeneity within the field should be employed for future research. C1 [Ionescu, Dawn F.; Niciu, Mark J.; Mathews, Daniel C.; Richards, Erica M.; Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ionescu, DF (reprint author), NIMH, Expt Therapeut & Pathophysiol Branch, Intramural Res Program, NIH, Bldg 10,CRC Room 7-5545,10 Ctr Dr,MSC 1282, Bethesda, MD 20892 USA. EM dawn.ionescu@nih.gov RI Niciu, Mark/J-1766-2014; Ionescu, Dawn/K-5675-2015 OI Niciu, Mark/0000-0002-5612-3021; FU Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH); NARSAD Independent Investigator; Brain & Behavior Mood Disorders Research Award FX Contract grant sponsor: Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH).; Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH), by a NARSAD Independent Investigator to CAZ, and by the Brain & Behavior Mood Disorders Research Award to CAZ. Dr. Zarate is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the U.S. government but will share a percentage of any royalties that may be received by the government. The remaining authors have no conflict of interest to disclose, financial or otherwise. Ioline Henter provided invaluable editorial assistance. NR 64 TC 22 Z9 26 U1 9 U2 51 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD APR PY 2013 VL 30 IS 4 BP 374 EP 385 DI 10.1002/da.22095 PG 12 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 126GJ UT WOS:000317600800011 PM 23495126 ER PT J AU Doty, TJ Japee, S Ingvar, M Ungerleider, LG AF Doty, Tracy J. Japee, Shruti Ingvar, Martin Ungerleider, Leslie G. TI Fearful Face Detection Sensitivity in Healthy Adults Correlates With Anxiety-Related Traits SO EMOTION LA English DT Article DE intersubject variability; masked fearful faces; state anxiety; neuroticism; harm avoidance ID FACIAL EXPRESSIONS; VISUAL AWARENESS; SOCIAL ANXIETY; ANGRY FACES; EMOTION; ATTENTION; BIAS; PERSONALITY; DISORDERS; AMYGDALA AB Threatening faces have a privileged status in the brain, which can be reflected in a processing advantage. However, this effect varies among individuals, even healthy adults. For example, one recent study showed that fearful face detection sensitivity correlated with trait anxiety in healthy adults (S. Japee, L. Crocker, F. Carver, L. Pessoa, & L. G. Ungerleider, 2009. Individual differences in valence modulation of face-selective M170 response. Emotion, 9, 59-69). Here, we expanded on those findings by investigating whether intersubject variability in fearful face detection is also associated with state anxiety, as well as more broadly with other traits related to anxiety. To measure fearful face detection sensitivity, we used a masked face paradigm where the target face was presented for only 33 ms and was immediately followed by a neutral face mask. Subjects then rated their confidence in detecting either fear or no fear in the target face. Fearful face detection sensitivity was calculated for each subject using signal detection theory. Replicating previous results, we found a significant positive correlation between trait anxiety and fearful face detection sensitivity. However, this behavioral advantage did not correlate with state anxiety. We also found that fearful face detection sensitivity correlated with other personality measures, including neuroticism and harm avoidance. Our data suggest that fearful face detection sensitivity varies parametrically across the healthy population, is associated broadly with personality traits related to anxiety, but remains largely unaffected by situational fluctuations in anxiety. These results underscore the important contribution of anxiety-related personality traits to threat processing in healthy adults. C1 [Doty, Tracy J.; Japee, Shruti; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Doty, Tracy J.; Ingvar, Martin] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Doty, TJ (reprint author), USA, Res Lab, Translat Neurosci Branch, 459 Mulberry Point Rd, Aberdeen, MD 21005 USA. EM tracy.doty@alumni.duke.edu RI Doty, Tracy Jill/J-3962-2012; OI Doty, Tracy/0000-0001-9921-2457; Ingvar, Martin/0000-0002-9041-5714 FU Intramural NIH HHS [Z99 MH999999] NR 34 TC 10 Z9 10 U1 4 U2 23 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 J9 EMOTION JI Emotion PD APR PY 2013 VL 13 IS 2 BP 183 EP 188 DI 10.1037/a0031373 PG 6 WC Psychology, Experimental SC Psychology GA 125FI UT WOS:000317524600002 PM 23398584 ER PT J AU Brantsaeter, AL Whitworth, KW Ydersbond, TA Haug, LS Haugen, M Knutsen, HK Thomsen, C Meltzer, HM Becher, G Sabaredzovic, A Hoppin, JA Eggesbo, M Longnecker, MP AF Brantsaeter, A. L. Whitworth, K. W. Ydersbond, T. A. Haug, L. S. Haugen, M. Knutsen, H. K. Thomsen, C. Meltzer, H. M. Becher, G. Sabaredzovic, A. Hoppin, J. A. Eggesbo, M. Longnecker, M. P. TI Determinants of plasma concentrations of perfluoroalkyl substances in pregnant Norwegian women SO ENVIRONMENT INTERNATIONAL LA English DT Article DE Perfluoroalkyl substances; Reproductive history; Pregnancy; Dietary exposure ID GLOMERULAR-FILTRATION RATE; NATIONAL BIRTH COHORT; PERFLUORINATED COMPOUNDS; CHILD COHORT; PERFLUOROOCTANOATE PFOA; POLYFLUOROALKYL COMPOUNDS; MATERNAL CONCENTRATIONS; SERUM CONCENTRATIONS; PRENATAL EXPOSURE; DIETARY EXPOSURE AB Background: Perfluoroalkyl substances (PFASs) are widespread pollutants that have been associated with adverse health effects although not on a consistent basis. Diet has been considered the main source of exposure. The aim of the present study was to identify determinants of four plasma PFASs in pregnant Norwegian women. Methods: This study is based in the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Our sample included 487 women who enrolled in MoBa from 2003 to 2004. A questionnaire regarding sociodemographic, medical, and reproductive history was completed at 17 weeks of gestation and a dietary questionnaire was completed at 22 weeks of gestation. Maternal plasma samples were obtained around 17 weeks of gestation. Plasma concentrations of four PFASs (perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA)) were examined in relation to demographic, lifestyle, dietary, and pregnancy-related covariates. Predictors were identified by optimizing multiple linear regression models using Akaike's information criterion (AIC). Results: Parity was the determinant with the largest influence on plasma PFAS concentrations, with r(2) between 0.09 and 0.32 in simple regression models. In optimal multivariate models, when compared to nulliparous women, parous women had 46%, 70%, 19%, and 62% lower concentrations of PFOS, PFOA, PFHxS, and PFNA respectively (p<0.001 except for PFHxS, p<0.01). In all these models, duration of breastfeeding was associated with reduced PFAS levels. PFOA showed the largest reduction from breastfeeding, with a 2-3% reduction per month of breastfeeding in typical cases. Levels of PFOS, PFOA, and PFNA increased with time since most recent pregnancy. While pregnancy-related factors were the most important predictors, diet was a significant factor explaining up to 4% of the variance. One quartile increase in estimated dietary PFAS intake was associated with plasma PFOS, PFOA, PFHxS, and PFNA concentration increases of 72%, 33%, 5.8% and 9.8%, respectively, resulting in small, although non-trivial absolute changes in PFAS concentrations. Conclusion: Previous pregnancies and breastfeeding duration were the most important determinants of PFASs in this sample of pregnant women. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Brantsaeter, A. L.; Haug, L. S.; Haugen, M.; Knutsen, H. K.; Thomsen, C.; Meltzer, H. M.; Becher, G.; Sabaredzovic, A.] Norwegian Inst Publ Hlth, Div Environm Med, NO-0403 Oslo, Norway. [Whitworth, K. W.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, San Antonio, TX 78229 USA. [Ydersbond, T. A.] Stat Norway, N-0033 Oslo, Norway. [Hoppin, J. A.; Longnecker, M. P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Eggesbo, M.] Norwegian Inst Publ Hlth, Div Epidemiol, NO-0403 Oslo, Norway. RP Brantsaeter, AL (reprint author), Norwegian Inst Publ Hlth, Div Environm Med, POB 4404, NO-0403 Oslo, Norway. EM Anne.Lise.Brantsaeter@fhi.no; Kristina.W.Whitworth@uth.tmc.edu; trond.arild.ydersbond@ssb.no; Line.Smastuen.Haug@fhi.no; Margaretha.Haugen@fhi.no; Helle.Knutsen@fhi.no; Cathrine.Thomsen@fhi.no; Helle.Margrete.Meltzer@fhi.no; Georg.Becher@fhi.no; Azemira.Sabaredzovic@fhi.no; hoppin1@niehs.nih.gov; Merete.Eggesbo@fhi.no; longnec1@niehs.nih.gov RI Brantsaeter, Anne Lise/H-7014-2016; OI Brantsaeter, Anne Lise/0000-0001-6315-7134; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336; Meltzer, Helle Margrete/0000-0002-3591-7017 FU Norwegian Ministry of Health; Ministry of Education and Research, NIH/NIEHS [NO1-ES-75558]; NIH/NINDS [U01 NS 047537-01, 2 U01 NS047537-06A1]; Norwegian Research Council/FUGE [151918/S10]; Intramural Research Program, The National Institutes of Environmental Health Sciences (NIEHS), the National Institutes of Health (NIH) FX 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 NO1-ES-75558), NIH/NINDS (grant no.1 U01 NS 047537-01 and grant no. 2 U01 NS047537-06A1), and the Norwegian Research Council/FUGE (grant no. 151918/S10). This study was supported in part by the Intramural Research Program, The National Institutes of Environmental Health Sciences (NIEHS), the National Institutes of Health (NIH). NR 60 TC 42 Z9 43 U1 4 U2 38 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 EI 1873-6750 J9 ENVIRON INT JI Environ. Int. PD APR PY 2013 VL 54 BP 74 EP 84 DI 10.1016/j.envint.2012.12.014 PG 11 WC Environmental Sciences SC Environmental Sciences & Ecology GA 124HI UT WOS:000317454000010 PM 23419425 ER PT J AU Drechsler, M Kemmerich, K Weber, C Murphy, PM Soehnlein, O AF Drechsler, M. Kemmerich, K. Weber, C. Murphy, P. M. Soehnlein, O. TI Lack of formyl-peptide receptor 1 reduces atherosclerotic lesion formation SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Meeting Abstract C1 [Drechsler, M.; Kemmerich, K.; Weber, C.; Soehnlein, O.] Univ Munich, IPEK, Munich, Germany. [Murphy, P. M.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD APR PY 2013 VL 43 SU 1 SI SI BP 21 EP 21 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 120AE UT WOS:000317141000063 ER PT J AU Xiong, YM Castro, E Yagi, R Zhu, JF Lesourne, R Love, PE Feigenbaum, L Bosselut, R AF Xiong, Yumei Castro, Ehydel Yagi, Ryoji Zhu, Jinfang Lesourne, Renaud Love, Paul E. Feigenbaum, Lionel Bosselut, Remy TI Thpok-independent repression of Runx3 by Gata3 during CD4(+) T-cell differentiation in the thymus SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD4-CD8 differentiation; Gata3; Runx3; T-cell development; Transcription ID TRANSCRIPTION FACTOR GATA-3; LINEAGE CHOICE; THYMOCYTE DIFFERENTIATION; LYMPHOCYTE DEVELOPMENT; CONDITIONAL DELETION; POSITIVE SELECTION; EXPRESSION; RECEPTOR; COMMITMENT; FATE AB CD4(+) helper T cells are essential for immune responses and differentiate in the thymus from CD4(+)CD(8)+ double-positive (DP) thymocytes. The transcription factor Runx3 inhibits CD4(+) T-cell differentiation by repressing Cd4 gene expression; accordingly, Runx3 is not expressed in DP thymocytes or developing CD4(+) T cells. The transcription factor Thpok is upregulated in CD4-differentiating thymocytes and required to repress Runx3. However, how Runx3 is controlled at early stages of CD4(+) T-cell differentiation, before the onset of Thpok expression, remains unknown. Here we show that Gata3, a transcription factor preferentially and transiently upregulated by CD4(+) T-cell precursors, represses Runx3 and binds the Runx3 locus in vivo. Accordingly, we show that high-level Gata3 expression and expression of Runx3 are mutually exclusive. Furthermore, whereas Runx3 represses Cd4, we show that Gata3 promotes Cd4 expression in Thpok-deficient thymocytes. Thus, in addition to its previously documented role in promoting CD4-lineage gene-expression, Gata3 represses CD8-lineage gene expression. These findings identify Gata3 as a critical pivot of CD4-CD8 lineage differentiation. C1 [Xiong, Yumei; Castro, Ehydel; Bosselut, Remy] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Castro, Ehydel; Feigenbaum, Lionel] NCI, SAIC, Frederick, MD USA. [Yagi, Ryoji; Zhu, Jinfang] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Lesourne, Renaud; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cellular & Dev Biol, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Bosselut, R (reprint author), NCI, Lab Immune Cell Biol, NIH, Bldg 37,Room 3032,37 Convent Dr, Bethesda, MD 20892 USA. EM remy@helix.nih.gov RI Lesourne, Renaud/M-1855-2014; Zhu, Jinfang/B-7574-2012 FU Intramural Research Programs of the National Cancer Institute, Center for Cancer Researc; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank D. Littman for Runx3fl/fl mice, E. Rothenberg for insightful discussions and for sharing unpublished results, B. Taylor and S. Banerjee for cell sorting, T.-A. Lewis for mouse technical support, and Andrea C. Carpenter, B.J. Fowlkes, and Melanie Vacchio for reading the manuscript. Supported by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 46 TC 7 Z9 7 U1 0 U2 6 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 APR PY 2013 VL 43 IS 4 BP 918 EP 928 DI 10.1002/eji.201242944 PG 11 WC Immunology SC Immunology GA 129RI UT WOS:000317859200010 PM 23310955 ER PT J AU Brinton, LA Trabert, B Shalev, V Lunenfeld, E Sella, T Chodick, G AF Brinton, Louise A. Trabert, Britton Shalev, Varda Lunenfeld, Eitan Sella, Tal Chodick, Gabriel TI In vitro fertilization and risk of breast and gynecologic cancers: a retrospective cohort study within the Israeli Maccabi Healthcare Services SO FERTILITY AND STERILITY LA English DT Article DE In vitro fertilization (IVF); cancer; risk ID OVULATION-STIMULATING DRUGS; EPITHELIAL OVARIAN-CANCER; POPULATION-BASED COHORT; STATES CASE-CONTROL; FERTILITY DRUGS; COLLABORATIVE ANALYSIS; CLOMIPHENE CITRATE; INFERTILE WOMEN; UTERINE-CANCER; WHITE WOMEN AB Objective: To assess long-term cancer risks associated with in vitro fertilization (IVF). Design: Record-linkage study. Setting: Health maintenance organization in Israel. Patient(s): A total of 87,403 women evaluated and/or treated for infertility on or after September 25, 1994, who were followed for cancer development through June 22, 2011: 522 breast, 41 endometrial, 45 ovarian, 311 in situ cervical, and 32 invasive cervical cancers were identified. Intervention(s): None. Main Outcome Measure(s): Hazard ratios (HRs) for specific cancers. Result(s): We found no significant relationships of IVF exposures to the risks of breast, endometrial, or ovarian cancers. However, compared with women with no fertility treatment, the HR for ovarian cancer associated with IVF was 1.58 (95% confidence interval [CI] 0.75-3.29), with higher risk among those receiving four or more cycles (HR 1.78, 95% CI 0.76-4.13). There was also a nonsignificantly elevated risk for endometrial cancer among women who received 1-3 IVF cycles (HR 1.94, 95% CI 0.73-5.12), but additional cycles were associated with less risk. In contrast, the risk of in situ cervical cancer was significantly reduced and invasive cervical cancer nonsignificantly reduced among women receiving IVF as well as other fertility treatments. Conclusion(s): Our results regarding long-term effects were largely reassuring, but women receiving IVF should continue to be monitored given that the procedures involve potent ovulation stimulators and repeated ovarian punctures. (Fertil Steril (R) 2013;99:1189-96. (c) 2013 by American Society for Reproductive Medicine.) C1 [Brinton, Louise A.; Trabert, Britton] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Shalev, Varda; Sella, Tal; Chodick, Gabriel] Maccabi Healthcare Serv, Epidemiol & Database Res Unit, Tel Aviv, Israel. [Shalev, Varda] Tel Aviv Univ, Sackler Fac Med, Sch Publ Hlth, IL-69978 Tel Aviv, Israel. [Lunenfeld, Eitan; Sella, Tal; Chodick, Gabriel] Ben Gurion Univ Negev, IVF, Beer Sheva, Israel. [Lunenfeld, Eitan; Sella, Tal; Chodick, Gabriel] Ben Gurion Univ Negev, Fertil Unit, Dept Obstet, Soroka Med Ctr, Beer Sheva, Israel. [Lunenfeld, Eitan; Sella, Tal; Chodick, Gabriel] Ben Gurion Univ Negev, Fac Hlth Sci, Beer Sheva, Israel. RP Brinton, LA (reprint author), NCI, 6120 Execut Blvd, Rockville, MD 20852 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Trabert, Britton/F-8051-2015 OI Brinton, Louise/0000-0003-3853-8562; FU Intramural Research Program of the National Institutes of Health FX Supported in part by the Intramural Research Program of the National Institutes of Health. NR 53 TC 29 Z9 30 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2013 VL 99 IS 5 BP 1189 EP 1196 DI 10.1016/j.fertnstert.2012.12.029 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 123MI UT WOS:000317393700011 PM 23375197 ER PT J AU Gomez-Lopez, N Estrada-Gutierrez, G Colin, A Flores-Pliego, A Flores-Escobar, X Oehninger, S Barroso, G AF Gomez-Lopez, Nardhy Estrada-Gutierrez, Guadalupe Colin, Alinne Flores-Pliego, Arturo Flores-Escobar, Xochitl Oehninger, Sergio Barroso, Gerardo TI The apoptotic pathway in fertile and subfertile men: a case-control and prospective study to examine the impact of merocyanine 540 bodies on ejaculated spermatozoa SO FERTILITY AND STERILITY LA English DT Article DE Apoptosis; male infertility; M540 bodies; human spermatozoa ID PLASMA-MEMBRANE TRANSLOCATION; DNA FRAGMENTATION; OXIDATIVE STRESS; HUMAN SPERM; M540 BODIES; HUMAN SEMEN; ANNEXIN-V; IN-SITU; DAMAGE; QUALITY AB Objective: To evaluate the presence of merocyanine 540 (M540) bodies and their impact on the measurement of apoptotic biomarkers in human spermatozoa. Design: Case-control, prospective study. Setting: Academic centers. Patient(s): Fertile and subfertile subjects. Intervention(s): Semen samples from subfertile and fertile men, 11 per group, were analyzed for basic semen parameters and early (annexin-V binding) and late (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) sperm apoptotic biomarkers by flow cytometry. Samples were also stained with M540 to assess the presence of M540 apoptotic bodies. Main Outcome Measure(s): Presence of M540 apoptotic bodies. Result(s): Groups differed significantly in the expression of early and late apoptosis biomarkers. The percentage of M540 bodies between groups was not different. The exclusion of M540 bodies from TUNEL results did not have a significant impact on measurement in either fertile or subfertile groups. Conclusion(s): This study confirmed the occurrence of M540 bodies in semen and that male factor infertility is associated with an increased expression of apoptosis biomarkers. Moreover, we demonstrated that the presence of M540 bodies did not affect the quantification of apoptotic biomarkers in either group. (Fertil Steril (R) 2013; 99:1242-8. (C) 2013 by American Society for Reproductive Medicine.) C1 [Gomez-Lopez, Nardhy; Estrada-Gutierrez, Guadalupe; Flores-Pliego, Arturo; Flores-Escobar, Xochitl; Barroso, Gerardo] Inst Nacl Perinatol Isidro Espinosa Reyes, Mexico City, DF, Mexico. [Colin, Alinne; Barroso, Gerardo] Amer British Cowdray Med Ctr, Div Reprod Hlth, Mexico City 05300, DF, Mexico. [Gomez-Lopez, Nardhy] Wayne State Univ, Sch Med, NICHD, Perinatol Res Branch,NIH, Detroit, MI USA. [Oehninger, Sergio] Eastern Virginia Med Sch, Jones Inst Reprod Med, Norfolk, VA 23501 USA. RP Barroso, G (reprint author), Amer British Cowdray Med Ctr, Div Obstet & Gynecol, Ave Carlos Graef Fernandez 154, Mexico City 05300, DF, Mexico. EM barrosog@me.com RI Gomez-Lopez, Nardhy/R-7664-2016; OI Gomez-Lopez, Nardhy/0000-0002-3406-5262; Flores Pliego, Arturo/0000-0001-7876-6098 NR 43 TC 5 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2013 VL 99 IS 5 BP 1242 EP 1248 DI 10.1016/j.fertnstert.2012.11.052 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 123MI UT WOS:000317393700023 PM 23290743 ER PT J AU Hill, MJ Richter, KS Heitmann, RJ Graham, JR Tucker, MJ DeCherney, AH Browne, PE Levens, ED AF Hill, Micah J. Richter, Kevin S. Heitmann, Ryan J. Graham, James R. Tucker, Michael J. DeCherney, Alan H. Browne, Paulette E. Levens, Eric D. TI Trophectoderm grade predicts outcomes of single-blastocyst transfers SO FERTILITY AND STERILITY LA English DT Article DE Trophectoderm; inner cell mass; embryo stage; live birth; ART ID IN-VITRO FERTILIZATION; EMBRYO ASSESSMENT; PREGNANCY RATES; TRANSFER POLICY; IMPLANTATION; MORPHOLOGY; DAY-5 AB Objective: To estimate the effect of the embryo stage, trophectoderm (TE) morphology grade, and inner cell mass (ICM) morphology grade on live birth in single-blastocyst transfers. Design: Retrospective cohort study. Setting: Large private assisted reproductive technologies (ART) practice. Patient(s): Fresh autologous ART cycles. Intervention(s): None. Main Outcome Measure(s): Live birth. Result(s): A total of 694 single-blastocyst transfers met the inclusion criteria. Univariate regression analysis showed embryo stage and TE score to be correlated with implantation and live birth. Live birth rates were 57%, 40%, and 25% for TE grades A, B, and C, respectively. There was no significant association between ICM grade and implantation or live birth. Live birth rates were 53%, 52%, and 0% for ICM grades A, B, and C respectively. Multiple logistic regression analysis showed that only patient age and TE grade were significantly associated with implantation and live birth, whereas ICM grade was not significantly associated with outcome. The TE score had the strongest correlation with live birth. Conclusion(s): TE grading, but not ICM grading, significantly correlated with implantation and live birth for single-blastocyst transfers. (Fertil Steril (R) 2013; 99:1283-9. (C) 2013 by American Society for Reproductive Medicine.) C1 [Hill, Micah J.; Richter, Kevin S.; Heitmann, Ryan J.; Graham, James R.; Tucker, Michael J.; DeCherney, Alan H.; Browne, Paulette E.; Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD 20850 USA. [Hill, Micah J.; Heitmann, Ryan J.; DeCherney, Alan H.; Levens, Eric D.] Eunice Kennedy Shriver NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. RP Levens, ED (reprint author), Shady Grove Fertil Reprod Sci Ctr, 15001 Shady Grove Rd, Rockville, MD 20850 USA. EM edlevens@gmail.com FU intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health FX Supported in part by the intramural research program of the Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government. NR 30 TC 31 Z9 32 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2013 VL 99 IS 5 BP 1283 EP + DI 10.1016/j.fertnstert.2012.12.003 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 123MI UT WOS:000317393700029 PM 23312233 ER PT J AU Thoma, ME McLain, AC Louis, JF King, RB Trumble, AC Sundaram, R Louis, GMB AF Thoma, Marie E. McLain, Alexander C. Louis, Jean Fredo King, Rosalind B. Trumble, Ann C. Sundaram, Rajeshwari Louis, Germaine M. Buck TI Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach SO FERTILITY AND STERILITY LA English DT Article DE Current duration; fecundity; infertility; epidemiology; reproduction ID ESTIMATING TIME; PREGNANCY; FECUNDITY; FERTILITY; DESIGN; LIFE AB Objective: To estimate the prevalence of infertility using a current duration approach for comparison with a traditional constructed measure. Design: Cross-sectional survey. Setting: Not applicable. Patient(s): A nationally representative sample of females aged 15-44 years. Intervention(s): None. Main Outcome Measure(s): Infertility prevalence estimated by two approaches: [1] a constructed measure derived from questions on sexual activity, contraception, relationship status, and pregnancy, and [2] a measure based on estimated time to pregnancy derived from the respondents' current duration of pregnancy attempt (i.e., current duration approach). Associations with self-reported descriptive characteristics using weighted logistic regression or parametric survival models for each respective approach. Result(s): Infertility prevalence was approximately twofold higher using the current duration approach (15.5%; 95% confidence interval 8.6%-27.5%) vs. the constructed measure (7.0%; 95% confidence interval 6.2%-7.8%). Both methods identified similar patterns of increasing age, lower education, nulliparity, and history of gynecologic disorders as being associated with measures of impaired fecundity, whereas opposing patterns were seen for racial/ethnic identification and poverty status. Conclusion(s): Infertility prevalence based on a current duration approach was consistent with other US prospective cohort studies with preconception enrollment. These findings underscore the importance of definition and methodologic approach for estimating the prevalence of infertility. (Fertil Steril (R) 2013; 99: 1324-31. (C) 2013 by American Society for Reproductive Medicine.) Key Words: Current duration, fecundity, infertility, epidemiology, reproduction C1 [Thoma, Marie E.; McLain, Alexander C.; Louis, Jean Fredo; Trumble, Ann C.; Sundaram, Rajeshwari; Louis, Germaine M. Buck] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [King, Rosalind B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Populat Res Ctr, NIH, Rockville, MD 20852 USA. RP Thoma, ME (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM methoma2000@yahoo.com OI McLain, Alexander/0000-0002-5475-0670; Louis, Jean F/0000-0003-0339-647X; Sundaram, Rajeshwari/0000-0002-6918-5002; Buck Louis, Germaine/0000-0002-1774-4490 FU US Department of Health and Human Services: Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), National Institutes of Health (NIH); US Department of Health and Human Services: Office of Population Affairs; US Department of Health and Human Services: CDC's National Center for Health Statistics; US Department of Health and Human Services: CDC's Division of HIV/AIDS Prevention; US Department of Health and Human Services: CDC's Division of Sexually Transmitted Disease Prevention; US Department of Health and Human Services: CDC's Division of Reproductive Health; US Department of Health and Human Services: Office of the Assistant Secretary for Planning and Evaluation; US Department of Health and Human Services: Children's Bureau of the Administration for Children and Families; Intramural Research Program, NICHD, NIH FX The 2002 National Survey of Family Growth was conducted by the Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics with the support and assistance of a number of other organizations and individuals, and with the participation and funding support of the following programs of the US Department of Health and Human Services: Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), National Institutes of Health (NIH); Office of Population Affairs; CDC's National Center for Health Statistics; CDC's Division of HIV/AIDS Prevention; CDC's Division of Sexually Transmitted Disease Prevention; CDC's Division of Reproductive Health; Office of the Assistant Secretary for Planning and Evaluation; and Children's Bureau of the Administration for Children and Families. Analyses and preparation of the manuscript was funded by the Intramural Research Program, NICHD, NIH. NR 42 TC 80 Z9 84 U1 0 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2013 VL 99 IS 5 BP 1324 EP + DI 10.1016/j.fertnstert.2012.11.037 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 123MI UT WOS:000317393700036 PM 23290741 ER PT J AU Wolff, EF He, YX Black, DM Brinton, EA Budoff, MJ Cedars, MI Hodis, HN Lobo, RA Manson, JE Merriam, GR Miller, VM Naftolin, F Pal, L Santoro, N Zhang, HP Harman, SM Taylor, HS AF Wolff, Erin Foran He, Yunxiao Black, Dennis M. Brinton, Eliot A. Budoff, Mathew J. Cedars, Marcelle I. Hodis, Howard N. Lobo, Rogerio A. Manson, JoAnn E. Merriam, George R. Miller, Virginia M. Naftolin, Fredrick Pal, Lubna Santoro, Nanette Zhang, Heping Harman, S. Mitchell Taylor, Hugh S. TI Self-reported menopausal symptoms, coronary artery calcification, and carotid intima-media thickness in recently menopausal women screened for the Kronos early estrogen prevention study (KEEPS) SO FERTILITY AND STERILITY LA English DT Article DE KEEPS; estrogen; cardiovascular; menopause; CAC; CIMT; palpitations; depression ID POSTMENOPAUSAL HORMONE-THERAPY; RANDOMIZED CONTROLLED-TRIAL; CONTROLLED CLINICAL-TRIAL; SUBCLINICAL ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; HEART-DISEASE; FOLLOW-UP; AORTIC CALCIFICATION; VASOMOTOR SYMPTOMS; MAJOR DEPRESSION AB Objective: To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis. Design: Cross-sectional analysis. Setting: Multicenter, randomized controlled trial. Patient(s): Recently menopausal women (n = 868) screened for the Kronos Early Estrogen Prevention Study (KEEPS). Intervention(s): None. Main Outcome Measure(s): Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum E-2 levels, and measures of atherosclerosis were assessed. Atherosclerosis was quantified using coronary artery calcium (CAC) Agatston scores (n = 771) and carotid intima-media thickness (CIMT). Logistic regression model of menopausal symptoms and E-2 was used to predict CAC. Linear regression model of menopausal symptoms and E-2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, E-2, CAC, and CIMT were assessed. Result(s): In early menopausal women screened for KEEPS, neither E-2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations and depression approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E-2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness, and E-2. Conclusion(s): Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine whether baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease. C1 [Wolff, Erin Foran] NICHHD, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [He, Yunxiao; Pal, Lubna; Zhang, Heping; Taylor, Hugh S.] Yale Univ, Sch Med, New Haven, CT USA. [Black, Dennis M.; Cedars, Marcelle I.] Univ San Francisco, Sch Med, San Francisco, CA 94117 USA. [Brinton, Eliot A.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Budoff, Mathew J.] Harbor Univ Calif, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Hodis, Howard N.] Univ So Calif, Core Imaging & Reading Ctr, Atherosclerosis Res Inst, Los Angeles, CA USA. [Lobo, Rogerio A.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Manson, JoAnn E.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Merriam, George R.] Vet Adm Puget Sound Hlth Care Syst, Spokane, WA USA. [Merriam, George R.] Univ Washington, Sch Med, Spokane, WA USA. [Miller, Virginia M.] Mayo Clin, Coll Med, Rochester, MN USA. [Naftolin, Fredrick] NYU, Sch Med, New York, NY USA. [Santoro, Nanette] Univ Colorado, Sch Med, Denver, CO USA. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ USA. RP Wolff, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bldg 10,CRC Room 1E-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM wolffe@mail.nih.gov FU Novartis; Amgen; Merck; Roche; Eli Lilly Research; Phoenix-based Kronos Longevity Research Institute; Aurora Foundation; National Institutes of Health (NIH) [HL90639, 1 UL1 RR024150]; Mayo Foundation; Brigham and Women's Hospital/Harvard Medical School CTSA [CTSA UL1 RR024139]; University of California San Francisco CTSA from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH [UL1 RR024131]; NIH Roadmap for Medical Research; NIH [R01DA016750, U10HD55925] FX E.F.W. has nothing to disclose. Y.H. has nothing to disclose. D. M. B. reports grants from Novartis, Amgen, Merck, and Roche (all unrelated to this study). E. A. B. has nothing to disclose. M.J.B. has nothing to disclose. M. I. C. has nothing to disclose. H.N.H. has nothing to disclose. R. A. L. has nothing to disclose. J.E.M. has nothing to disclose. G. R. M. reports a consultancy with Novo Nordisk and a grant from Eli Lilly Research (both unrelated to this study). V. M. M. has nothing to disclose. F.N. has nothing to disclose. L. P. has nothing to disclose. N.S. has nothing to disclose. H.Z. has nothing to disclose. S. M. H. has nothing to disclose. H. S. T. reports a consultancy with and grants from Pfizer (unrelated to this work).; The core KEEPS was funded by the Phoenix-based Kronos Longevity Research Institute, which is supported by the not-for-profit Aurora Foundation and carried out at nine US academic medical centers. Other support included the National Institutes of Health (NIH) HL90639 to V.M.M., 1 UL1 RR024150, Mayo (Clinical and Translational Science Award [CTSA]) 1 UL1 RR024150, the Mayo Foundation, Brigham and Women's Hospital/Harvard Medical School CTSA, CTSA UL1 RR024139, and University of California San Francisco CTSA UL1 RR024131 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH and NIH Roadmap for Medical Research. Partially supported by NIH grants R01DA016750 and U10HD55925 (H.Z., Y.H.). NR 55 TC 22 Z9 23 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD APR PY 2013 VL 99 IS 5 BP 1385 EP 1391 DI 10.1016/j.fertnstert.2012.11.053 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 123MI UT WOS:000317393700044 PM 23312232 ER PT J AU Khan, TA Shah, T Prieto, D Zhang, WL Price, J Fowkes, GR Cooper, J Talmud, PJ Humphries, SE Sundstrom, J Hubacek, JA Ebrahim, S Lawlor, DA Ben-Shlomo, Y Abdollahi, MR Slooter, AJC Szolnoki, Z Sandhu, M Wareham, N Frikke-Schmidt, R Tybjaerg-Hansen, A Fillenbaum, G Heijmans, BT Katsuya, T Gromadzka, G Singleton, A Ferrucci, L Hardy, J Worrall, B Rich, SS Matarin, M Whittaker, J Gaunt, TR Whincup, P Morris, R Deanfield, J Donald, A Smith, GD Kivimaki, M Kumari, M Smeeth, L Khaw, KT Nalls, M Meschia, J Sun, K Hui, RT Day, I Hingorani, AD Casas, JP AF Khan, Tauseef A. Shah, Tina Prieto, David Zhang, Weili Price, Jackie Fowkes, Gerald R. Cooper, Jackie Talmud, Philippa J. Humphries, Steve E. Sundstrom, Johan Hubacek, Jaroslav A. Ebrahim, Shah Lawlor, Debbie A. Ben-Shlomo, Yoav Abdollahi, Mohammad R. Slooter, Arjen J. C. Szolnoki, Zoltan Sandhu, Manjinder Wareham, Nicholas Frikke-Schmidt, Ruth Tybjaerg-Hansen, Anne Fillenbaum, Gerda Heijmans, Bastiaan T. Katsuya, Tomohiro Gromadzka, Grazyna Singleton, Andrew Ferrucci, Luigi Hardy, John Worrall, Bradford Rich, Stephen S. Matarin, Mar Whittaker, John Gaunt, Tom R. Whincup, Peter Morris, Richard Deanfield, John Donald, Ann Smith, George Davey Kivimaki, Mika Kumari, Meena Smeeth, Liam Khaw, Kay-Tee Nalls, Michael Meschia, James Sun, Kai Hui, Rutai Day, Ian Hingorani, Aroon D. Casas, Juan P. TI Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Stroke; lipids; apolipoprotein E; cardiovascular disease; systematic review; meta-analysis; biomarkers ID INTIMA-MEDIA THICKNESS; GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; ONSET ALZHEIMERS-DISEASE; BRITISH WOMENS HEART; GENE POLYMORPHISMS; TRANSPORT PROTEIN; LDL-CHOLESTEROL; COMMON VARIANTS AB Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke. C1 [Khan, Tauseef A.; Prieto, David; Ebrahim, Shah; Whittaker, John; Smeeth, Liam; Casas, Juan P.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Shah, Tina; Hingorani, Aroon D.] UCL, Div Med, Ctr Clin Pharmacol, London, England. [Zhang, Weili; Sun, Kai; Hui, Rutai] Chinese Acad Med Sci, Fu Wai Hosp, Key Lab Clin Cardiovasc Genet, Beijing 100730, Peoples R China. [Price, Jackie; Fowkes, Gerald R.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Cooper, Jackie; Talmud, Philippa J.; Humphries, Steve E.] UCL, Div Med, Ctr Cardiovasc Genet, London, England. [Sundstrom, Johan] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden. [Sundstrom, Johan] Univ Uppsala Hosp, Uppsala Clin Res Ctr, Uppsala, Sweden. [Hubacek, Jaroslav A.] Cardiovasc Res Ctr, Prague, Czech Republic. [Hubacek, Jaroslav A.] Inst Clin & Expt Med, Prague, Czech Republic. [Lawlor, Debbie A.; Ben-Shlomo, Yoav; Gaunt, Tom R.; Smith, George Davey; Day, Ian] Univ Bristol, Sch Social & Community Med, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Abdollahi, Mohammad R.; Gaunt, Tom R.; Day, Ian] Univ Bristol, Sch Social & Community Med, Bristol Genet Epidemiol Labs, Bristol, Avon, England. [Slooter, Arjen J. C.] Univ Med Ctr, Dept Intens Care, Utrecht, Netherlands. [Szolnoki, Zoltan] Pandy Cty Hosp, Dept Neurol & Cerebrovasc Dis, Gyula, Hungary. [Sandhu, Manjinder] Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 4RN, England. [Wareham, Nicholas] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England. [Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Fillenbaum, Gerda] Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA. [Heijmans, Bastiaan T.] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Katsuya, Tomohiro] Osaka Univ, Grad Sch Med, Dept Clin Gene Therapy, Suita, Osaka, Japan. [Gromadzka, Grazyna] Inst Psychiat & Neurol, Dept Neurol 2, Warsaw, Poland. [Singleton, Andrew; Nalls, Michael] NIA, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Hardy, John] UCL, Inst Neurol, London, England. [Worrall, Bradford] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Matarin, Mar] UCL, UCL Inst Neurol, Dept Clin & Expt Epilepsy, London, England. [Whincup, Peter] Univ London, Community Hlth Serv, London, England. [Morris, Richard] Royal Free Hosp, UCL Dept Primary Care & Populat Hlth, London NW3 2QG, England. [Deanfield, John; Donald, Ann] UCL, Inst Child Hlth, Vasc Physiol Unit, London, England. [Smith, George Davey] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Kivimaki, Mika; Kumari, Meena; Hingorani, Aroon D.; Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England. [Khaw, Kay-Tee] Addenbrookes Hosp, Clin Gerontol Unit, Cambridge, England. [Meschia, James] Mayo Clin, Jacksonville, FL 32224 USA. RP Hingorani, AD (reprint author), UCL, Div Med, Ctr Clin Pharmacol, London, England. EM a.hingorani@ucl.ac.uk; juan.pablo-casas@lshtm.ac.uk RI Hardy, John/C-2451-2009; sebastianovitsch, stepan/G-8507-2013; Singleton, Andrew/C-3010-2009; Gaunt, Tom/O-3918-2014; Sundstrom, Johan/A-6286-2009; Matarin, Mar/F-1771-2016; Davey Smith, George/A-7407-2013; OI Kumari, Meena/0000-0001-9716-1035; Lawlor, Debbie A/0000-0002-6793-2262; Prieto-Merino, David/0000-0001-5001-0061; Morris, Richard/0000-0001-7240-4563; Whincup, Peter/0000-0002-5589-4107; Talmud, Philippa/0000-0002-5560-1933; Humphries, Stephen E/0000-0002-8221-6547; Gaunt, Tom/0000-0003-0924-3247; Sundstrom, Johan/0000-0003-2247-8454; Matarin, Mar/0000-0002-4717-5735; Davey Smith, George/0000-0002-1407-8314; Khan, Tauseef/0000-0002-3713-2248; Shah, Tina/0000-0001-7724-7210; Kivimaki, Mika/0000-0002-4699-5627 FU London School of Hygiene & Tropical Medicine; British Heart Foundation Senior Fellowship [FS/05/125]; British Heart Foundation [PG2008/015, RG/02/005, RG/04/003]; Wellcome Trust Senior Fellowship in Clinical Science; British Heart Foundation Intermediate Fellowship [FS/05/065/19497]; British Heart Foundation project [PG/07/131/24254]; UK Medical Research Council; University of Bristol; RCUK; Swedish Research Council [2007-5942, 2006-6555]; Swedish Heart Lung Foundation [20041151]; Centre for Cardiovascular Research and Institute for Clinical and Experimental Medicine project [00023001]; NESTOR stimulation programme for geriatric research in The Netherlands (Ministry of Health and Ministry of Education); Netherlands Organization for Scientific Research (NWO); Netherlands Prevention fund; municipality of Rotterdam; International Alzheimer Research Foundation (IARF); Fund for Scientific Research (FWO-F), Flanders, Belgium; Ministry of Education, Science, Sports and Culture of Japan [18590265, 18590811, 19650188, 21390223]; Ministry of Science and Technology of China [2011CB503900, 2009DFB30050, 2006CB503805]; National Institute of Neurological Disorders and Stroke (US) [R01 NS39987, R01 NS42733]; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services [Z01 AG000954-06, Z01 AG000015-50, 2003-078]; National Institute for Neurological Disorders and Stroke (US) [R01 NS39987, R01 NS42733]; National Institute on Aging (NIA) [AG1764406S1]; British Medical Research Council; US National Institutes of Health [NHLBI 33014, NHLBl R01HL036310-20A2, NIA R01AG013196, R01AG034454]; Du Pont Pharma, Wilmington, USA; Medical Research Council, UK; Department of Health Policy Research Programme; British Heart Foundation (BHF Project) [PG/06/002]; British Heart Foundation (DoH Project) [0090041]; Chief Scientist Office in Scotland; Chest Heart and Stroke Scotland; Wellcome Trust; European Community Concerted Action MRH4 COMAC Epidemiology; European Commission [BMH1-CT92-0206]; Swedish Heart-Lung Foundation; Erik, Karin och Gosta Selanders Foundation; Thureus Foundation; Lisa och Johan Gronbergs Foundation; Loo och Hans Ostermans Foundation; Uppsala University; [1M0510] FX T.A.K. is funded by a Graduate Teaching Assistantship of London School of Hygiene & Tropical Medicine. A.D.H. was funded by a British Heart Foundation Senior Fellowship (FS/05/125). S.E.H, J.C. and P.J.T. are supported by the British Heart Foundation (PG2008/015). L.S. is funded by a Wellcome Trust Senior Fellowship in Clinical Science. T.R.G. was the recipient of a British Heart Foundation Intermediate Fellowship FS/05/065/19497 and T.R.G., I.D., S.E., D.A.L. and Y.B.S. are the recipients of a British Heart Foundation project grant PG/07/131/24254. D.A.L., G.D.S., T.R.G. and I.D. work in a UK Medical Research Council-supported centre. M.R.A. as funded by postdoctoral support from the University of Bristol which funded some set-up costs of Bristol Genetic Epidemiology Laboratory (M.R.A., T.R.G., I.D.). RCUK funding to I.D. and G.D.S. supported a Collaboration Development Workshop in Cardiovascular Genetics held in Beijing in March 2010. Tamuno Alfred is thanked for statistical support. J.S. is funded by the Swedish Research Council (2007-5942) and the Swedish Heart Lung Foundation (20041151). J.A.H. is funded by Centre for Cardiovascular Research and Institute for Clinical and Experimental Medicine project 00023001 (IKEM CR). A.J.S. is supported by the NESTOR stimulation programme for geriatric research in The Netherlands (Ministry of Health and Ministry of Education), the Netherlands Organization for Scientific Research (NWO), the Netherlands Prevention fund, the municipality of Rotterdam, the International Alzheimer Research Foundation (IARF), and the Fund for Scientific Research (FWO-F), Flanders, Belgium. T.K. (Tomohiro Katsuya) was supported by Grants-in-Aid for Scientific Research (18590265, 18590811, 19650188, 21390223) from the Ministry of Education, Science, Sports and Culture of Japan. R.H. is supported by the grants from the Ministry of Science and Technology of China (2011CB503900, 2009DFB30050 and 2006CB503805). M.A.N., A.B.S., J.H., B.B.W., S.R., T.G.B., R.D.B., J.F.M.: ISGS and SWISS received funding from grants from the National Institute of Neurological Disorders and Stroke (US), R01 NS39987 and R01 NS42733. 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 number Z01 AG000954-06. This work used samples and clinical data from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (http://ccr.coriell.org/ninds), human subjects protocol numbers 2003-081 and 2004-147. The inclusion of BLSA samples 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 number Z01 AG000015-50, human subjects protocol number 2003-078. The ISGS study was funded by a grant from the National Institute for Neurological Disorders and Stroke (US; R01 NS42733) (J Meschia, P.I.). The SWISS study was funded by a grant from the National Institute for Neurological Disorders and Stroke (US; R01 NS39987 (J Meschia, P.I.). 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).; Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Aging (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies, UK. The data were collected by the National Centre for Social Research. Northwick Park Heart Study II (NPHS-II) was supported by the British Medical Research Council, the US National Institutes of Health (NHLBI 33014) and Du Pont Pharma, Wilmington, USA. The Whitehall II study (is supported by the US National Institutes of Health (NHLBl R01HL036310-20A2, NIA R01AG013196 and R01AG034454), the British Heart Foundation (RG/02/005) and the Medical Research Council, UK. Edinburgh Artery Study (EAS) was funded by the British Heart Foundation. The British Regional Heart Study (BRHS) is a British Heart Foundation Research Group and is supported by British Heart Foundation (RG/04/003). The views expressed in this publication are those of the authors and not necessarily those of the funding bodies. The British Women's Heart and Health Study (BWHHS) was funded by the Department of Health Policy Research Programme and the British Heart Foundation (BHF Project Grant No: PG/06/002 and DoH Project Grant No: 0090041). The Caerphilly Prospective Study (CaPS) was established by the former MRC Epidemiology Unit in Cardiff. Diabetes UK supported the creation of UDACS. The AAA Trial (AAAT) was funded by the British Heart Foundation, Chief Scientist Office in Scotland, Chest Heart and Stroke Scotland and Wellcome Trust. The EARSI study was supported by the European Community Concerted Action MRH4 COMAC Epidemiology, and the EARSII study was supported by the European Commission Contract BMH1-CT92-0206. Analyses in the Czech-MONICA study were supported by project grants No. 00023001 (I.K.E.M., C.R.) and 1M0510 (M.S.M.T., C.R.). The Uppsala Longitudinal Study of Adult Men (ULSAM) study was supported by the Swedish Research Council (2006-6555), Swedish Heart-Lung Foundation, Erik, Karin och Gosta Selanders Foundation, Thureus Foundation, Lisa och Johan Gronbergs Foundation, Loo och Hans Ostermans Foundation and Uppsala University. NR 80 TC 40 Z9 40 U1 2 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2013 VL 42 IS 2 BP 475 EP 492 DI 10.1093/ije/dyt034 PG 18 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 126OS UT WOS:000317627800022 PM 23569189 ER PT J AU Boffetta, P Islami, F Vedanthan, R Pourshams, A Kamangar, F Khademi, H Etemadi, A Salahi, R Semnani, S Emadi, A Abnet, CC Brennan, P Pharoah, PD Dawsey, SM Malekzadeh, R AF Boffetta, Paolo Islami, Farhad Vedanthan, Rajesh Pourshams, Akram Kamangar, Farin Khademi, Hooman Etemadi, Arash Salahi, Rasool Semnani, Shahryar Emadi, Ashkan Abnet, Christian C. Brennan, Paul Pharoah, Paul D. Dawsey, Sanford M. Malekzadeh, Reza TI A U-shaped relationship between haematocrit and mortality in a large prospective cohort study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Anaemia; cancer; cardiovascular disease; erythrocytosis; haematocrit; mortality ID CORONARY-HEART-DISEASE; OF-THE-LITERATURE; PERIPHERAL ARTERIAL-DISEASE; RANDOMIZED CONTROLLED-TRIAL; HIGH-RISK AREA; ESOPHAGEAL CANCER; IRON-DEFICIENCY; CARDIOVASCULAR-DISEASE; RHEUMATOID-ARTHRITIS; INCOME COUNTRIES AB Background Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values. Methods Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate similar to 99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals. Results There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study. Conclusions Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low-and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT. C1 [Boffetta, Paolo; Islami, Farhad] Mt Sinai Sch Med, Inst Transit Epidemiol, New York, NY 10029 USA. [Boffetta, Paolo; Islami, Farhad] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY 10029 USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Islami, Farhad; Pourshams, Akram; Khademi, Hooman; Etemadi, Arash; Salahi, Rasool; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Vedanthan, Rajesh] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Khademi, Hooman; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Semnani, Shahryar] Golestan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. [Emadi, Ashkan] Univ Maryland Greenebaum Canc Ctr, Sch Med, Dept Med, Div Hematol & Oncol, Baltimore, MD USA. [Pharoah, Paul D.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. RP Boffetta, P (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA. EM paolo.boffetta@mssm.edu RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; Semnani, Shahryar/N-2270-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; Semnani, Shahryar/0000-0002-8768-6142; Malekzadeh, Reza/0000-0003-1043-3814 FU Tehran University of Medical Sciences [81/15]; Cancer Research UK [C20/A5860]; US National Cancer Institute; International Agency for Research on Cancer; Fogarty International Center, NIH [K01TW009218] FX The Golestan Cohort Study was supported by Tehran University of Medical Sciences (grant number: 81/15), Cancer Research UK (grant number: C20/A5860), the Intramural Research Program of the US National Cancer Institute, and various collaborative research agreements with the International Agency for Research on Cancer. R. Vedanthan is supported by Grant Number K01TW009218 from the Fogarty International Center, NIH. NR 70 TC 3 Z9 3 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD APR PY 2013 VL 42 IS 2 BP 601 EP 615 DI 10.1093/ije/dyt013 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 126OS UT WOS:000317627800034 PM 23569195 ER PT J AU Savage, SA Gadalla, SM Chanock, SJ AF Savage, Sharon A. Gadalla, Shahinaz M. Chanock, Stephen J. TI The Long and Short of Telomeres and Cancer Association Studies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PREDISPOSITION FACTOR; LENGTH; METAANALYSIS; DYSFUNCTION; MORTALITY C1 [Savage, Sharon A.; Gadalla, Shahinaz M.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7018, Rockville, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 17 TC 12 Z9 12 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD APR PY 2013 VL 105 IS 7 BP 448 EP 449 DI 10.1093/jnci/djt041 PG 2 WC Oncology SC Oncology GA 126MG UT WOS:000317620500003 PM 23468461 ER PT J AU Gillet, JP Varma, S Gottesman, MM AF Gillet, Jean-Pierre Varma, Sudhir Gottesman, Michael M. TI The Clinical Relevance of Cancer Cell Lines SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID DRUG-DISCOVERY; STEM-CELLS; MULTIDRUG-RESISTANCE; KINASE INHIBITOR; CONNECTIVITY MAP; GENE-EXPRESSION; MOUSE MODELS; SENSITIVITY; MISIDENTIFICATION; CONTAMINATION AB Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models has been continuously questioned. Based upon recent studies that have fueled the debate, we review the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models. All cancer cell lines do not have equal value as tumor models. Some have been successful, whereas others have failed. However, the success stories should not obscure the growing body of data that motivates us to develop new in vitro preclinical models that would substantially increase the success rate of new in vitroassessed cancer treatments. C1 [Gillet, Jean-Pierre; Gottesman, Michael M.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] HiThru Analyt LLC, Laurel, MD USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, 37 Convent Dr,Rm 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU Intramural NIH HHS NR 54 TC 65 Z9 67 U1 0 U2 16 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD APR PY 2013 VL 105 IS 7 BP 452 EP 458 DI 10.1093/jnci/djt007 PG 7 WC Oncology SC Oncology GA 126MG UT WOS:000317620500005 PM 23434901 ER PT J AU Cameron, D Bodenreider, O Yalamanchili, H Danh, T Vallabhaneni, S Thirunarayan, K Sheth, AP Rindflesch, TC AF Cameron, Delroy Bodenreider, Olivier Yalamanchili, Hima Tu Danh Vallabhaneni, Sreeram Thirunarayan, Krishnaprasad Sheth, Amit P. Rindflesch, Thomas C. TI A graph-based recovery and decomposition of Swanson's hypothesis using semantic predications SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Literature-Based Discovery (LBD); Swanson's hypothesis; Semantic predications; Semantic associations; Subgraph creation; Background knowledge ID LITERATURE-BASED DISCOVERY; UNDISCOVERED PUBLIC KNOWLEDGE; FISH-OIL; RAYNAUDS; PROSTACYCLIN; LITERATURES; CONNECTIONS; MAGNESIUM; MIGRAINE; MEDLINE AB Objectives: This paper presents a methodology for recovering and decomposing Swanson's Raynaud Syndrome-Fish Oil hypothesis semi-automatically. The methodology leverages the semantics of assertions extracted from biomedical literature (called semantic predications) along with structured background knowledge and graph-based algorithms to semi-automatically capture the informative associations originally discovered manually by Swanson. Demonstrating that Swanson's manually intensive techniques can be undertaken semi-automatically, paves the way for fully automatic semantics-based hypothesis generation from scientific literature. Methods: Semantic predications obtained from biomedical literature allow the construction of labeled directed graphs which contain various associations among concepts from the literature. By aggregating such associations into informative subgraphs, some of the relevant details originally articulated by Swanson have been uncovered. However, by leveraging background knowledge to bridge important knowledge gaps in the literature, a methodology for semi-automatically capturing the detailed associations originally explicated in natural language by Swanson, has been developed. Results: Our methodology not only recovered the three associations commonly recognized as Swanson's hypothesis, but also decomposed them into an additional 16 detailed associations, formulated as chains of semantic predications. Altogether, 14 out of the 19 associations that can be attributed to Swanson were retrieved using our approach. To the best of our knowledge, such an in-depth recovery and decomposition of Swanson's hypothesis has never been attempted. Conclusion: In this work therefore, we presented a methodology to semi-automatically recover and decompose Swanson's RS-DFO hypothesis using semantic representations and graph algorithms. Our methodology provides new insights into potential prerequisites for semantics-driven Literature-Based Discovery (LBD). Based on our observations, three critical aspects of LBD include: (1) the need for more expressive representations beyond Swanson's ABC model; (2) an ability to accurately extract semantic information from text; and (3) the semantic integration of scientific literature and structured background knowledge. Published by Elsevier Inc. C1 [Cameron, Delroy; Thirunarayan, Krishnaprasad; Sheth, Amit P.] Wright State Univ, Ohio Ctr Excellence Knowledge Enabled Comp Knoesi, Dayton, OH 45435 USA. [Yalamanchili, Hima; Tu Danh; Vallabhaneni, Sreeram] Wright State Univ, Div Biomed Sci, Dayton, OH 45435 USA. [Bodenreider, Olivier; Rindflesch, Thomas C.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Cameron, D (reprint author), Wright State Univ, Ohio Ctr Excellence Knowledge Enabled Comp Knoesi, Dayton, OH 45435 USA. EM delroy@knoesis.org FU Intramural Research Program of the National Library of Medicine (NLM), National Institutes of Health (NIH); NIH Grant [R21 DA030571-01A1]; Center for Treatment, Interventions and Addictions Research (CITAR) at Wright State University; ORISE program FX This research was supported in part by the Intramural Research Program of the National Library of Medicine (NLM), National Institutes of Health (NIH) and NIH Grant No. R21 DA030571-01A1 awarded to the Ohio Center of Excellence in Knowledge-enabled Computing (Kno.e.sis) and the Center for Treatment, Interventions and Addictions Research (CITAR) at Wright State University. We would also like to thank Dongwook Shin and the ORISE program for their support, as well as Cartic Ramakrishnan, Pablo N. Mendes and Ramakanth Kavuluru for their intuitive ideas. NR 41 TC 10 Z9 11 U1 2 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD APR PY 2013 VL 46 IS 2 BP 238 EP 251 DI 10.1016/j.jbi.2012.09.004 PG 14 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 122MP UT WOS:000317322500004 PM 23026233 ER PT J AU Lodish, MB AF Lodish, Maya B. TI Kinase Inhibitors: Adverse Effects Related to the Endocrine System SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID CHRONIC MYELOID-LEUKEMIA; RENAL-CELL CARCINOMA; METASTATIC BREAST-CANCER; GASTROINTESTINAL STROMAL TUMOR; CHRONIC MYELOGENOUS LEUKEMIA; SUNITINIB INDUCES HYPOTHYROIDISM; PHASE-III TRIAL; IMATINIB MESYLATE; THYROID-DYSFUNCTION; SECONDARY HYPERPARATHYROIDISM AB Context: The use of kinase inhibitors (KIs) in the treatment of cancer has become increasingly common, and practitioners must be familiar with endocrine-related side effects associated with these agents. This review provides an update to the clinician regarding the management of potential endocrinological effects of KIs. Evidence Acquisition: PubMed was employed to identify relevant manuscripts. A review of the literature was conducted, and data were summarized and incorporated. Evidence Synthesis: KIs, including small molecule KIs and monoclonal antibodies directed against kinases, have emerged over the past decade as an important class of anticancer agents. KIs specifically interfere with signaling pathways that are dysregulated in certain types of cancers and also target common mechanisms of growth, invasion, metastasis, and angiogenesis. Currently, at least 20 KIs are approved as cancer therapeutics. However, KIs may affect a broad spectrum of targets and may have additional, unidentified mechanisms of action at the cellular level due to overlap between signaling pathways in the tumor cell and endocrine system. Recent reports in the literature have identified side effects associated with KIs, including alterations in thyroid function, bone metabolism, linear growth, gonadal function, fetal development, adrenal function, and glucose metabolism. Conclusions: Clinicians need to monitor the thyroid functions of patients on KIs. In addition, bone density and vitamin D status should be assessed. Special care should be taken to follow linear growth and development in children taking these agents. Clinicians should counsel patients appropriately on the potential adverse effects of KIs on fetal development. (J Clin Endocrinol Metab 98: 1333-1342, 2013) C1 [Lodish, Maya B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Lodish, Maya B.] NIH, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. RP Lodish, MB (reprint author), 10 Ctr Dr,CRC Room 1-3330, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU intramural research division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported by the intramural research division of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 115 TC 16 Z9 16 U1 0 U2 12 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2013 VL 98 IS 4 BP 1333 EP 1342 DI 10.1210/jc.2012-4085 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 120TJ UT WOS:000317195600034 PM 23450053 ER PT J AU Adler-Wailes, DC Periwal, V Ali, AH Brady, SM McDuffie, JR Uwaifo, GI Tanofsky-Kraff, M Salaita, CG Hubbard, VS Reynolds, JC Chow, CC Sumner, AE Yanovski, JA AF Adler-Wailes, Diane C. Periwal, Vipul Ali, Asem H. Brady, Sheila M. McDuffie, Jennifer R. Uwaifo, Gabriel I. Tanofsky-Kraff, Marian Salaita, Christine G. Hubbard, Van S. Reynolds, James C. Chow, Carson C. Sumner, Anne E. Yanovski, Jack A. TI Sex-Associated Differences in Free Fatty Acid Flux of Obese Adolescents SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; INSULIN-RESISTANCE; GLUCOSE-METABOLISM; ENERGY-EXPENDITURE; BODY-COMPOSITION; VISCERAL FAT; IN-VIVO; SENSITIVITY; PUBERTY; LIPOLYSIS AB Context: In obesity, increases in free fatty acid (FFA) flux can predict development of insulin resistance. Adult women release more FFA relative to resting energy expenditure (REE) and have greater FFA clearance rates than men. In adolescents, it is unknown whether sex differences in FFA flux occur. Objective: Our objective was to determine the associations of sex, REE, and body composition with FFA kinetics in obese adolescents. Participants: Participants were from a convenience sample of 112 non-Hispanic white and black adolescents (31% male; age range, 12-18 years; body mass index SD score range, 1.6-3.1) studied before initiating obesity treatment. Main Outcome Measures: Glucose, insulin, and FFA were measured during insulin-modified frequently sampled iv glucose tolerance tests. Minimal models for glucose and FFA calculated insulin sensitivity index (SI) and FFA kinetics, including maximum (I-0 + I-2) and insulin-suppressed (I-2) lipolysis rates, clearance rate constant (c(f)), and insulin concentration for 50% lipolysis suppression (ED50). Relationships of FFA measures to sex, REE, fat mass (FM), lean body mass (LBM) and visceral adipose tissue (VAT) were examined. Results: In models accounting for age, race, pubertal status, height, FM, and LBM, we found sex, pubertal status, age, and REE independently contributed to the prediction of I-2 and I-0 + I-2 (P < .05). Sex and REE independently predicted ED50 (P < .05). Sex, FM/VAT, and LBM were independent predictors of c(f). Girls had greater I-2, I-0 + I-2 and ED50 (P < .05, adjusted for REE) and greater c(f) (P < .05, adjusted for FM or VAT) than boys. Conclusion: Independent of the effects of REE and FM, FFA kinetics differ significantly in obese adolescent girls and boys, suggesting greater FFA flux among girls. (J Clin Endocrinol Metab 98: 1676-1684, 2013) C1 [Adler-Wailes, Diane C.; Ali, Asem H.; Brady, Sheila M.; McDuffie, Jennifer R.; Uwaifo, Gabriel I.; Tanofsky-Kraff, Marian; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Periwal, Vipul; Chow, Carson C.] NIDDKD, Math Cell Modeling Sect, Bethesda, MD 20892 USA. [Salaita, Christine G.] NIDDKD, Div Extramural Act, Bethesda, MD 20892 USA. [Hubbard, Van S.] NIDDKD, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Sumner, Anne E.] NIDDKD, Lab Endocrinol & Receptor Biol, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, US Dept HHS, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Obes, Program Dev Endocrinol & Genet, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1E 3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov RI Periwal, Vipul/I-1728-2012; Uwaifo, Gabriel/M-2361-2016; OI Uwaifo, Gabriel/0000-0002-6962-9304; Yanovski, Jack/0000-0001-8542-1637 FU Intramural Research Program, NIH [Z1AHD00641]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Minority Health and Health Disparities, NIH FX This work was supported by the Intramural Research Program, NIH (Grant Z1AHD00641 to J.A.Y.), from the Eunice Kennedy Shriver National Institute of Child Health and Human Development with supplemental funding from National Institute on Minority Health and Health Disparities, NIH. J.A.Y. is a Commissioned Officer in the U. S. Public Health Service, Department of Health and Human Services. NR 40 TC 8 Z9 8 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2013 VL 98 IS 4 BP 1676 EP 1684 DI 10.1210/jc.2012-3817 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 120TJ UT WOS:000317195600073 PM 23450055 ER PT J AU Piaggi, P Thearle, MS Bogardus, C Krakoff, J AF Piaggi, Paolo Thearle, Marie S. Bogardus, Clifton Krakoff, Jonathan TI Lower Energy Expenditure Predicts Long-Term Increases in Weight and Fat Mass SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID RESTING METABOLIC-RATE; BODY-COMPOSITION; CARBOHYDRATE OXIDATION; RESPIRATORY CHAMBER; FUEL UTILIZATION; DIETARY-FAT; GAIN; OBESITY; DETERMINANTS; BALANCES AB Context: The relevance of the contribution of energy expenditure (EE) and substrate oxidation to weight change has not been fully confirmed. Objective: The objective of the study was to determine whether metabolic parameters measured in a whole room indirect calorimeter are predictive of long-term body weight change. Setting: The study was conducted at a clinical research unit in Phoenix, Arizona, from 1985 to 2005. Participants: A total of 612 healthy subjects (384 males and 228 females; aged 29.5 +/- 8.1 years; body mass index 33.0 +/- 8.7 kg/m(2); percent body fat 30.9 +/- 9.6%), including 422 Native Americans and 190 whites. Follow-up data were available for 292 Native Americans with a median follow-up time of 6.7 years (interquartile range 3.9-10.5). Main Outcome Measures: Twenty-four-hour EE, sleeping metabolic rate, daily (fed) and sleeping (fasting) respiratory quotient, and carbohydrate and fat oxidation rates were measured during a 24-hour respiratory chamber. Body composition was assessed by underwater weighing or dual-energy x-ray absorptiometry. Results: After accounting for demographic and body composition measures, the remaining variance of 24-hour EE was inversely related to the rate of weight change (rho = -0.158, P = .007) and fat mass change (rho = -0.179, P = .012), such that 100 kcal below the expected 24-hour EE corresponded to 0.2 kg/y weight gain, of which 0.1 kg/y was fat mass. Deviations from the predicted values of the sleeping metabolic rate (rho = -0.121, P = .039) and fed respiratory quotient (rho = 0.119, P = .042) were also associated with future weight change, whereas the fat oxidation rate was inversely associated with weight change in men(rho = -0.174, P = .024) but not in women(rho = 0.018, P = .853). Conclusions: Measures of energy expenditure and substrate oxidation are predictors of long-term weight change, indicating a small but significant role for reduced metabolic rate in weight gain. (J Clin Endocrinol Metab 98: E703-E707, 2013) C1 [Piaggi, Paolo; Thearle, Marie S.; Bogardus, Clifton; Krakoff, Jonathan] NIDDKD, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ 85016 USA. [Piaggi, Paolo] Univ Hosp Pisa, Endocrinol Unit, Obes Res Ctr, I-56124 Pisa, Italy. RP Piaggi, P (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Obes & Diabet Clin Res Sect, Phoenix, AZ 85016 USA. EM paolo.piaggi@gmail.com OI Piaggi, Paolo/0000-0003-2774-9161 FU Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 20 TC 15 Z9 15 U1 1 U2 14 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2013 VL 98 IS 4 BP E703 EP E707 DI 10.1210/jc.2012-3529 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 120TJ UT WOS:000317195600012 PM 23418317 ER PT J AU Roberts, ML Kino, T Nicolaides, NC Hurt, DE Katsantoni, E Sertedaki, A Komianou, F Kassiou, K Chrousos, GP Charmandari, E AF Roberts, Michael L. Kino, Tomoshige Nicolaides, Nicolas C. Hurt, Darrell E. Katsantoni, Eleni Sertedaki, Amalia Komianou, Filadelfia Kassiou, Korina Chrousos, George P. Charmandari, Evangelia TI A Novel Point Mutation in the DNA-Binding Domain (DBD) of the Human Glucocorticoid Receptor Causes Primary Generalized Glucocorticoid Resistance by Disrupting the Hydrophobic Structure of its DBD SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NUCLEAR-LOCALIZATION; MOLECULAR-DYNAMICS AB Context: Primary generalized glucocorticoid resistance is a rare genetic condition characterized by partial end-organ insensitivity to glucocorticoids. Most affected subjects present with clinical manifestations of mineralocorticoid and androgen excess. The condition has been associated with inactivating mutations in the human glucocorticoid receptor (hGR) gene, which impair the molecular mechanisms of hGR alpha action, thereby reducing tissue sensitivity to glucocorticoids. Objective: The aim of our study was to investigate the molecular mechanisms through which one previously described natural heterozygous V423A mutation, the second mutation detected in the DNA-binding domain (DBD) of the hGR alpha, affects glucocorticoid signal transduction. Design and Results: Compared with the wild-type receptor, hGR alpha V423A demonstrated a 72% reduction in its ability to transactivate the glucocorticoid-inducible mouse mammary tumor virus promoter in response to dexamethasone. The hGR alpha V423A receptor showed a significant reduction in its ability to bind to glucocorticoid-response elements of glucocorticoid-responsive genes, owing to structural alterations of the DBD confirmed by computer-based structural analysis. In addition, hGR alpha V423A demonstrated a 2.6-fold delay in nuclear translocation following exposure to the ligand, although it did not exert a dominant negative effect on the wild-type hGR alpha, had a similar affinity to the ligand with the wild-type receptor, and displayed a normal interaction with the GRIP1 coactivator in vitro. Conclusions: The natural mutant receptor hGR alpha V423A causes primary generalized glucocorticoid resistance by affecting multiple steps in the cascade of glucocorticoid receptor action, which primarily involve decreased ability to bind to target glucocorticoid response elements and delayed translocation into the nucleus. (J Clin Endocrinol Metab 98: E790-E795, 2013) C1 [Roberts, Michael L.; Nicolaides, Nicolas C.; Sertedaki, Amalia; Chrousos, George P.; Charmandari, Evangelia] Univ Athens, Sch Med, Div Endocrinol Metab & Diabet, Aghia Sophia Childrens Hosp,Dept Pediat 1, GR-11527 Athens, Greece. [Komianou, Filadelfia; Kassiou, Korina] Aghia Sophia Childrens Hosp, Dept Pediat 1, Athens 11527, Greece. [Roberts, Michael L.; Nicolaides, Nicolas C.; Sertedaki, Amalia; Chrousos, George P.; Charmandari, Evangelia] Acad Athens, Div Endocrinol & Metab, Clin Res Ctr, Biomed Res Fdn, Athens 11527, Greece. [Katsantoni, Eleni] Acad Athens, Div Hematol Oncol, Clin Res Ctr, Biomed Res Fdn, Athens 11527, Greece. [Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Hurt, Darrell E.] NIAID, Bioinformat & Computat Biosci Branch, Off Cyber Infrastruct & Computat Biol, NIH, Bethesda, MD 20892 USA. RP Charmandari, E (reprint author), Univ Athens, Sch Med, Div Endocrinol Metab & Diabet, Aghia Sophia Childrens Hosp,Dept Pediat 1, Thivon & Papadiamantopoulou St, GR-11527 Athens, Greece. EM evangelia.charmandari@googlemail.com RI Charmandari, Evangelia/B-6701-2011; OI Roberts, Michael/0000-0001-7387-1155 FU University of Athens Medical School, Athens, Greece; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland FX This work was supported in part by the University of Athens Medical School, Athens, Greece, the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. NR 20 TC 8 Z9 8 U1 0 U2 11 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD APR PY 2013 VL 98 IS 4 BP E790 EP E795 DI 10.1210/jc.2012-3549 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 120TJ UT WOS:000317195600026 PM 23426617 ER PT J AU Chatterjee, S Ganini, D Tokar, EJ Kumar, A Das, S Corbett, J Kadiiska, MB Waalkes, MP Diehl, AM Mason, RP AF Chatterjee, Saurabh Ganini, Douglas Tokar, Erik J. Kumar, Ashutosh Das, Suvarthi Corbett, Jean Kadiiska, Maria B. Waalkes, Michael P. Diehl, Anna Mae Mason, Ronald P. TI Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental non-alcoholic steatohepatitis SO JOURNAL OF HEPATOLOGY LA English DT Article DE Adipocytokines; Kupffer cell; Oxidative stress; Tyrosine nitration; NADPH oxidase; ob/ob mice ID HEPATIC STELLATE CELLS; NITRIC-OXIDE; TNF-ALPHA; INDUCTION; RADICALS; RATS AB Background & Aims: Progression from steatosis to steatohepatitic lesions is hypothesized to require a second hit. These lesions have been associated with increased oxidative stress, often ascribed to high levels of leptin and other proinflammatory mediators. Here we have examined the role of leptin in inducing oxidative stress and Kupffer cell activation in CCl4-mediated steatohepatitic lesions of obese mice. Methods: Male C57BL/6 mice fed with a high-fat diet (60% kcal) at 16 weeks were administered CCl4 to induce steatohepatitic lesions. Approaches included use of immuno-spin trapping for measuring free radical stress, gene-deficient mice for leptin, p47 phox, iNOS and adoptive transfer of leptin primed macrophages in vivo. Results: Diet-induced obese (DIO) mice, treated with CCl4 increased serum leptin levels. Oxidative stress was significantly elevated in the DIO mouse liver, but not in ob/ob mice, or in DIO mice treated with leptin antibody. In ob/ob mice, leptin supplementation restored markers of free radical generation. Markers of free radical formation were significantly decreased by the peroxynitrite decomposition catalyst FeTPPS, the iNOS inhibitor 1400W, the NADPH oxidase inhibitor apocynin, or in iNOS or p47 phox-deficient mice. These results correlated with the decreased expression of TNF-alpha and MCP-1. Kupffer cell depletion eliminated oxidative stress and inflammation, whereas in macrophage-depleted mice, the adoptive transfer of leptinprimed macrophages significantly restored inflammation. Conclusions: These results, for the first time, suggest that leptin action in macrophages of the steatotic liver, through induction of iNOS and NADPH oxidase, causes peroxynitrite-mediated oxidative stress thus activating Kupffer cells. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Chatterjee, Saurabh; Das, Suvarthi] Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. [Chatterjee, Saurabh; Ganini, Douglas; Kumar, Ashutosh; Corbett, Jean; Kadiiska, Maria B.; Mason, Ronald P.] NIEHS, Free Radical Metab Grp, Labs Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Toxicol Grp, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Diehl, Anna Mae] Duke Univ, Div Gastroenterol, Durham, NC 27707 USA. RP Chatterjee, S (reprint author), Univ S Carolina, Dept Environm Hlth Sci, Environm Hlth & Dis Lab, Columbia, SC 29208 USA. EM schatt@mailbox.sc.edu FU NIH [4R00ES019875-02]; Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES050139-13]; NIH Institutes of Health; [K99-R00] FX This work has been supported by a K99-R00, NIH pathway to Independence Award (4R00ES019875-02 to Saurabh Chatterjee) and the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences (Z01 ES050139-13 to Ronald P. Mason).; The underlying research reported in the study was funded by the NIH Institutes of Health. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 28 TC 35 Z9 36 U1 1 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2013 VL 58 IS 4 BP 778 EP 784 DI 10.1016/j.jhep.2012.11.035 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 123GE UT WOS:000317375600021 PM 23207144 ER PT J AU Cantor, F Heiss, J AF Cantor, F. Heiss, J. TI Migraine, Chiari malformation and cervical muscles SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Cantor, F.; Heiss, J.] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2013 VL 14 IS 4 SU 1 BP S29 EP S29 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 126RR UT WOS:000317639400114 ER PT J AU Lebovitz, E Keller, J Kaszas, K Iadarola, M Mannes, A AF Lebovitz, E. Keller, J. Kaszas, K. Iadarola, M. Mannes, A. TI Exploring the actions of TRPV1 positive allosteric modulators in a peripheral inflammation model SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Lebovitz, E.; Keller, J.; Kaszas, K.; Iadarola, M.; Mannes, A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2013 VL 14 IS 4 SU 1 BP S69 EP S69 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 126RR UT WOS:000317639400272 ER PT J AU Low, L Thompson, S Martinez, S Stone, L Bushnell, M AF Low, L. Thompson, S. Martinez, S. Stone, L. Bushnell, M. TI Environmental enrichment introduced 3 months after a nerve injury does not affect sensory hypersensitivity or exploratory behaviors in the rat SO JOURNAL OF PAIN LA English DT Meeting Abstract C1 [Low, L.; Thompson, S.; Martinez, S.; Stone, L.; Bushnell, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD APR PY 2013 VL 14 IS 4 SU 1 BP S43 EP S43 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 126RR UT WOS:000317639400170 ER PT J AU Woods, AS Jackson, SN Lewis, EK Egan, T Muller, L Tabet, JC Schultz, JA AF Woods, Amina S. Jackson, Shelley N. Lewis, Ernest K. Egan, Thomas Muller, Ludovic Tabet, Jean-Claude Schultz, J. Albert TI MALDI/Post Ionization-Ion Mobility Mass Spectrometry of Noncovalent Complexes of Dopamine Receptors' Epitopes SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE noncovalent interactions; ion-mobility; disordered proteins; dopamine receptor; heteromers ID ASSISTED-LASER-DESORPTION/IONIZATION; ELECTROSTATIC INTERACTION; ADENOSINE A(2A); DISORDERED PROTEIN; AMAZING STABILITY; PHOSPHATE; HETEROMERIZATION; PEPTIDES; ARGININE; RESIDUES AB Protein domains involved in receptor heterorner formation are disordered and rich in the amino acids necessary for the formation of noncovalent complexes (NCX). We present mass spectral NCX data from proteins and protein receptors' epitopes obtained by combining ion mobility (IM) and MALDI. We focus on NCX involved in heteromer formation occurring between epitopes of the Dopamine D-2 (D2R) and Adenosine A(2A) receptors (A(2A)R) as well as D2R and the alpha 2 nicotinic (NR) receptor's subunit. The IM data yield information on the gas phase conformation of the singly charged NCX which are observed either directly from MALDI or as codesorbed neutrals that are subsequently postionized by a time delayed excimer laser pulse directed onto a portion of the neutral plume created by the MALDI desorption laser. Imaging mass spectrometry of the matrix/epitope dried droplet surface shows that the acidic and basic epitopes and their NCX are found to be spatially collocated within regions as small as 25 X 50 mu m(2). Subtle differences in the relative abundance of protonated and cationized NCX and epitopes are measured in spatial regions near the sodium-rich outer border of the droplet. C1 [Woods, Amina S.; Jackson, Shelley N.; Muller, Ludovic] NIDA, IRP, Struct Biol Unit, Cellular Neurobiol Branch,NIH, Baltimore, MD 21224 USA. [Tabet, Jean-Claude] Univ Paris 06, Paris, France. [Lewis, Ernest K.; Egan, Thomas; Schultz, J. Albert] Ionwerks Inc, Houston, TX USA. RP Woods, AS (reprint author), NIDA, IRP, Struct Biol Unit, Cellular Neurobiol Branch,NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH; Office of National Drug Control Policy (ONDCP); National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services [HHSN271200900009C, IRC3DA031431-01] FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. The authors thank Dr. Damon Barbacci for helpful comments and the Office of National Drug Control Policy (ONDCP) for instrumentation funding, without which this and other projects could not have been accomplished. This project has also been funded in part at Ionwerks with federal funds from the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, under SBIR Phase II Contract No. HHSN271200900009C and SBIR Phase II Grant No. IRC3DA031431-01 NR 39 TC 1 Z9 1 U1 0 U2 19 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 APR PY 2013 VL 12 IS 4 BP 1668 EP 1677 DI 10.1021/pr301004w PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 122ON UT WOS:000317327500012 PM 23469763 ER PT J AU Hung, EW Mayes, MD Sharif, R Assassi, S Machicao, VI Hosing, C St Clair, EW Furst, DE Khanna, D Forman, S Mineishi, S Phillips, K Seibold, JR Bredeson, C Csuka, ME Nash, RA Wener, MH Simms, R Ballen, K Leclercq, S Storek, J Goldmuntz, E Welch, B Keyes-Elstein, L Castina, S Crofford, LJ Mcsweeney, P Sullivan, KM AF Hung, Emily W. Mayes, Maureen D. Sharif, Roozbeh Assassi, Shervin Machicao, Victor I. Hosing, Chitra St Clair, E. William Furst, Daniel E. Khanna, Dinesh Forman, Stephen Mineishi, Shin Phillips, Kristine Seibold, James R. Bredeson, Christopher Csuka, Mary Ellen Nash, Richard A. Wener, Mark H. Simms, Robert Ballen, Karen Leclercq, Sharon Storek, Jan Goldmuntz, Ellen Welch, Beverly Keyes-Elstein, Lynette Castina, Sharon Crofford, Leslie J. Mcsweeney, Peter Sullivan, Keith M. TI Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE GASTRIC ANTRAL VASCULAR ECTASIA; GAVE; SYSTEMIC SCLEROSIS; VASCULOPATHY; ENDOSCOPY ID WATERMELON STOMACH; GAVE; CYCLOPHOSPHAMIDE AB Objective. To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; "watermelon stomach") in early diffuse systemic sclerosis (SSc). Methods. Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests. Results. Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Sc170) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003). Conclusion. Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Sc170 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc. (J Rheurnatol First Release Feb 15 2013; doi:10.3899/jrheum.121087) C1 [Hung, Emily W.] Rheumatol Associates Houston, Houston, TX USA. [Mayes, Maureen D.; Assassi, Shervin; Machicao, Victor I.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Sharif, Roozbeh] Univ Texas Med Branch, Galveston, TX 77555 USA. [Hosing, Chitra] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [St Clair, E. William; Sullivan, Keith M.] Duke Univ, Durham, NC USA. [Furst, Daniel E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Khanna, Dinesh; Mineishi, Shin; Phillips, Kristine] Univ Michigan, Ann Arbor, MI 48109 USA. [Forman, Stephen] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Seibold, James R.] Scleroderma Res Consultants LLC, Avon, CT USA. [Bredeson, Christopher] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Csuka, Mary Ellen] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Nash, Richard A.; Mcsweeney, Peter] Colorado Blood Canc Inst, Rocky Mt Blood & Marrow Transplant Program, Denver, CO USA. [Wener, Mark H.] Univ Washington, Seattle, WA 98195 USA. [Simms, Robert] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ballen, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Leclercq, Sharon; Storek, Jan] Univ Calgary, Calgary, AB, Canada. [Goldmuntz, Ellen; Welch, Beverly] NIAID, NIH, Bethesda, MD 20892 USA. [Keyes-Elstein, Lynette; Castina, Sharon] Rho, Chapel Hill, NC USA. [Crofford, Leslie J.] Univ Kentucky, Lexington, KY USA. RP Mayes, MD (reprint author), Univ Texas Hlth Sci Ctr Houston, 6431 Fannin St,Med Sch Bldg 5-270, Houston, TX 77030 USA. EM Maureen.d.mayes@uth.unc.edu RI Crofford, Leslie/J-8010-2013; OI Simms, Robert/0000-0002-0101-1807; Hosing, Chitra/0000-0003-0409-5556 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases (USA) [A1-05419, HHSN272201100025C] FX Supported by awards A1-05419 and HHSN272201100025C from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (USA). NR 15 TC 16 Z9 16 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD APR PY 2013 VL 40 IS 4 BP 455 EP 460 DI 10.3899/jrheum.121087 PG 6 WC Rheumatology SC Rheumatology GA 125LF UT WOS:000317540600018 PM 23418384 ER PT J AU LaMere, BJ Castle, PE Fetterman, B Poitras, N Stanley, M Shieh, J Lorey, T Kinney, W Schiffman, M AF LaMere, Brandon J. Castle, Philip E. Fetterman, Barbara Poitras, Nancy Stanley, Mark Shieh, Jen Lorey, Thomas Kinney, Walter Schiffman, Mark TI A study of borderline positive Hybrid Capture 2 tests in the Kaiser Permanente Northern California cervical screening program: Evidence against retesting SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HPV; Borderline; Hybrid Capture 2; Cervical cancer screening ID HUMAN-PAPILLOMAVIRUS; CANCER; RISK C1 [LaMere, Brandon J.] Kaiser Permanente Northern Calif, Womens Hlth Res Inst, Div Res, Oakland, CA USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY USA. [Fetterman, Barbara; Poitras, Nancy; Stanley, Mark; Shieh, Jen; Lorey, Thomas] Kaiser Permanente TPMG Reg Lab, Berkeley, CA 94710 USA. [Kinney, Walter] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP LaMere, BJ (reprint author), Kaiser Permanente TPMG Reg Lab, 1725 Eastshore Highway, Berkeley, CA 94710 USA. EM brandon.j.lamere@kp.org FU Intramural NIH HHS [ZIA CP010206-01] NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD APR PY 2013 VL 189 IS 1 BP 77 EP 79 DI 10.1016/j.jviromet.2013.01.011 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 124HT UT WOS:000317455100013 PM 23384678 ER PT J AU Gilstrap, LG Malhotra, R Peltier-Saxe, D Slicas, D Pineda, E Culhane-Hermann, C Cook, N Fernandez-Golarz, C Wood, M AF Gilstrap, Lauren Gray Malhotra, Rajeev Peltier-Saxe, Donna Slicas, Donna Pineda, Eliana Culhane-Hermann, Catherine Cook, Nakela Fernandez-Golarz, Carina Wood, Malissa TI Community-Based Primary Prevention Programs Decrease the Rate of Metabolic Syndrome Among Socioeconomically Disadvantaged Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID AMERICAN-HEART-ASSOCIATION; CARDIOVASCULAR-DISEASE; LIFE-STYLE; RISK; METAANALYSIS; PREVALENCE; HEALTH; TRENDS AB Background: Metabolic Syndrome (MetSyn) is one of the strongest predictors of type 2 diabetes (DM2) and cardiovascular disease (CVD). It is associated with a 4- to 10-fold increased risk of DM2 and a 2- to 3-fold increased risk of CVD. Low income and minority women have some of the highest rates of MetSyn. This study examines the effect of a unique, community based, primary prevention program on the rates of MetSyn and health habits. Methods: Sixty-four low income and minority women were enrolled in the HAPPY (Health Awareness and Primary Prevention in Your neighborhood) Heart Program in an eastern suburb of Boston. Over these 2 years, patients were evaluated by an interdisciplinary medical team: their primary physician, cardiologist, nutritionist, physical therapist, and health coach. The rate of MetSyn was measured at baseline, year 1, and year 2. Comparisons were made either using the paired t test for normally distributed variables or the Wilcoxon Sign test for non-normal variables. Results: The rate of MetSyn fell from 64.7% at baseline to 34.9% at year 1 (p = 0.01) and 28.2% at year 2 (p < 0.001). This was driven by increases in high-density lipoprotein (HDL-C) (p < 0.001) and decreases in blood pressure (p = 0.05). Fasting blood glucose trended down, but the hemoglobin A1c (HbA1c) reached significance (decreasing from 6 to 5.8, p < 0.01). Nutrition and exercise habits trended toward improvement. There were significant decreases in anxiety (p < 0.001), depression (p = 0.006) and stress (p = 0.002). Conclusion: This lifestyle intervention program is effective at decreasing MetSyn in a socioeconomically disadvantaged, largely minority, female population. This program also decreases anxiety, stress, and depression among participants. C1 [Gilstrap, Lauren Gray; Malhotra, Rajeev; Fernandez-Golarz, Carina] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Malhotra, Rajeev; Wood, Malissa] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Peltier-Saxe, Donna; Slicas, Donna; Pineda, Eliana; Culhane-Hermann, Catherine] Massachusetts Gen Hosp, Revere Hlth Ctr, Boston, MA 02114 USA. [Cook, Nakela] NHLBI, NIH, Bethesda, MD 20892 USA. RP Gilstrap, LG (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM lgilstrap@partners.org OI Malhotra, Rajeev/0000-0003-0120-4630 NR 36 TC 3 Z9 3 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD APR PY 2013 VL 22 IS 4 BP 322 EP 329 DI 10.1089/jwh.2012.3854 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 126FZ UT WOS:000317599700006 PM 23540328 ER PT J AU Schwartz, GK Tap, WD Qin, LX Livingston, MB Undevia, SD Chmielowski, B Agulnik, M Schuetze, SM Reed, DR Okuno, SH Ludwig, JA Keedy, V Rietschel, P Kraft, AS Adkins, D Van Tine, BA Brockstein, B Yim, V Bitas, C Abdullah, A Antonescu, CR Condy, M Dickson, MA Vasudeva, SD Ho, AL Doyle, LA Chen, HX Maki, RG AF Schwartz, Gary K. Tap, William D. Qin, Li-Xuan Livingston, Michael B. Undevia, Samir D. Chmielowski, Bartosz Agulnik, Mark Schuetze, Scott M. Reed, Damon R. Okuno, Scott H. Ludwig, Joseph A. Keedy, Vicki Rietschel, Petra Kraft, Andrew S. Adkins, Douglas Van Tine, Brian A. Brockstein, Bruce Yim, Vincent Bitas, Christiana Abdullah, Abdul Antonescu, Cristina R. Condy, Mercedes Dickson, Mark A. Vasudeva, Shyamprasad Deraje Ho, Alan L. Doyle, L. Austin Chen, Helen X. Maki, Robert G. TI Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial SO LANCET ONCOLOGY LA English DT Article ID REFRACTORY EWING SARCOMA; FACTOR-I RECEPTOR; INSULIN; ANTIBODY; TUMORS; INHIBITOR; RAPAMYCIN; AKT; ACTIVATION; EXPRESSION AB Background Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center. C1 [Schwartz, Gary K.; Tap, William D.; Yim, Vincent; Bitas, Christiana; Abdullah, Abdul; Dickson, Mark A.; Vasudeva, Shyamprasad Deraje; Ho, Alan L.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Qin, Li-Xuan] Mem Sloan Kettering Canc Ctr, Dept Epidemiol Biostat, New York, NY 10021 USA. [Antonescu, Cristina R.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Condy, Mercedes] Mem Sloan Kettering Canc Ctr, Dept Nursing, New York, NY 10021 USA. [Livingston, Michael B.] Levine Canc Inst, Dept Med, Charlotte, NC USA. [Undevia, Samir D.] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Chmielowski, Bartosz] Univ Calif Los Angeles, Dept Med, Los Angeles, CA USA. [Agulnik, Mark; Brockstein, Bruce] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Schuetze, Scott M.] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Reed, Damon R.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Sarcoma, Tampa, FL 33682 USA. [Okuno, Scott H.] Mayo Clin, Dept Oncol, Rochester, MN USA. [Ludwig, Joseph A.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. [Keedy, Vicki] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Rietschel, Petra] Albert Einstein Canc Ctr, Dept Med, Bronx, NY USA. [Kraft, Andrew S.] Med Univ S Carolina, Dept Med, Hollings Canc Ctr, Charleston, SC 29425 USA. [Adkins, Douglas; Van Tine, Brian A.] Washington Univ, Dept Med, St Louis, MO USA. [Doyle, L. Austin; Chen, Helen X.] NCI, Invest Drugs Branch, Bethesda, MD 20892 USA. [Maki, Robert G.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. RP Schwartz, GK (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM schwartg@mskcc.org OI Chmielowski, Bartosz/0000-0002-2374-3320 FU Pfizer; Imclone; National Cancer Institute [RC2 CA148260, R01 CA140331]; CycleforSurvival from MSKCC; CycleforSurvival Fund; Memorial Sloan-Kettering Cancer Center FX GKS has received a consultancy fee from Pfizer and a speaker honorarium from Imclone. WDT is the study chair (uncompensated) of a clinical trial funded by Imclone. MAD has received a consultancy fee from Pfizer and is a study chair (uncompensated) of a clinical trial funded by Pfizer. RGM has received a consultancy fee from Imclone. All other authors declare that they have no conflicts of interest.; We thank all collaborators on this study and all the patients who participated. We also acknowledge the funding provided by the National Cancer Institute under grants RC2 CA148260 (RGM and GKS) and R01 CA140331 (GKS), and CycleforSurvival funding from MSKCC. We thank Noah Goodman-Davis and Jerusa Altema (MSKCC), who contributed substantially to the preparation of the data for this manuscript.; Funding National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center. NR 21 TC 68 Z9 70 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2013 VL 14 IS 4 BP 371 EP 382 DI 10.1016/S1470-2045(13)70049-4 PG 12 WC Oncology SC Oncology GA 123LD UT WOS:000317390300045 PM 23477833 ER PT J AU Morhason-Bello, IO Odedina, F Rebbeck, TR Harford, J Dangou, JM Denny, L Adewole, IF AF Morhason-Bello, Imran O. Odedina, Folakemi Rebbeck, Timothy R. Harford, Joe Dangou, Jean-Marie Denny, Lynette Adewole, Isaac F. TI Challenges and opportunities in cancer control in Africa: a perspective from the African Organisation for Research and Training in Cancer SO LANCET ONCOLOGY LA English DT Article ID CERVICAL-CANCER; PROSTATE-CANCER; BREAST-CANCER; HEALTH-CARE; NIGERIA; KNOWLEDGE; AWARENESS; MALIGNANCIES; UNIVERSITY; HOSPITALS AB Sub-Saharan Africa has a disproportionate burden of disease and faces a major public-health challenge from non-communicable diseases. Although infectious diseases continue to afflict Africa, the proportion of the overall disease burden in sub-Saharan Africa attributable to cancer is rising. The region is predicted to have a greater than 85% increase in cancer burden by 2030. Approaches to minimise the burden of cancer in sub-Saharan Africa in the past few years have had little success because of low awareness of the cancer burden and a poor understanding of the potential for cancer prevention. Success will not be easy, and will need partnerships and bridges to be built across countries, economies, and professions. A strategic approach to cancer control in sub-Saharan Africa is needed to build on what works there and what is unique to the region. It should ideally be situated within strong, robust, and sustainable health-care systems that off er quality health care to all people, irrespective of their social or economic standing. However, to achieve this will need new leadership, critical thinking, investment, and understanding. We discuss the present situation in sub-Saharan Africa and propose ideas to advance cancer control in the region, including the areas of cancer awareness, advocacy, research, workforce, care, training, and funding. C1 [Morhason-Bello, Imran O.; Adewole, Isaac F.] Univ Ibadan, Dept Obstet & Gynaecol, Coll Med, Ibadan, Oyo State, Nigeria. [Adewole, Isaac F.] African Org Res & Training Canc, Cape Town, South Africa. [Odedina, Folakemi] Univ Florida, Dept Pharmaceut Outcomes & Policy & Radiat Oncol, Gainesville, FL USA. [Rebbeck, Timothy R.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Harford, Joe] NCI, Ctr Global Hlth, NIH, Bethesda, MD 20892 USA. [Dangou, Jean-Marie] WHO Reg Off Africa, Brazzaville, Congo. [Denny, Lynette] Univ Cape Town, Dept Obstet & Gynaecol, Cape Town, South Africa. RP Adewole, IF (reprint author), Univ Ibadan, Dept Obstet & Gynaecol, Coll Med, Ibadan, Oyo State, Nigeria. EM if.adewole@mail.ui.edu.ng FU GlaxoSmithKline; Merck/MSA FX IFA has received honoraria from GlaxoSmithKline for participation in various speaker forums, and for serving on the independent data safety monitoring committee for a multinational study. LD has received honoraria for appearing at various speaker forums for GlaxoSmithKline and Merck/MSA, and has worked on clinical trials supported by both companies. IOM-B, FO, TRR, JH, and J-MD declare that they have no conflicts of interest. NR 78 TC 33 Z9 33 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD APR PY 2013 VL 14 IS 4 BP E142 EP E151 PG 10 WC Oncology SC Oncology GA 123LD UT WOS:000317390300011 PM 23561745 ER PT J AU de Larrea, CF Kyle, RA Durie, BGM Ludwig, H Usmani, S Vesole, DH Hajek, R San Miguel, JF Sezer, O Sonneveld, P Kumar, SK Mahindra, A Comenzo, R Palumbo, A Mazumber, A Anderson, KC Richardson, PG Badros, AZ Caers, J Cavo, M Leleu, X Dimopoulos, MA Chim, CS Schots, R Noeul, A Fantl, D Mellqvist, UH Landgren, O Chanan-Khan, A Moreau, P Fonseca, R Merlini, G Lahuerta, JJ Blade, J Orlowski, RZ Shah, JJ AF Fernandez de Larrea, C. Kyle, R. A. Durie, B. G. M. Ludwig, H. Usmani, S. Vesole, D. H. Hajek, R. San Miguel, J. F. Sezer, O. Sonneveld, P. Kumar, S. K. Mahindra, A. Comenzo, R. Palumbo, A. Mazumber, A. Anderson, K. C. Richardson, P. G. Badros, A. Z. Caers, J. Cavo, M. Leleu, X. Dimopoulos, M. A. Chim, C. S. Schots, R. Noeul, A. Fantl, D. Mellqvist, U-H Landgren, O. Chanan-Khan, A. Moreau, P. Fonseca, R. Merlini, G. Lahuerta, J. J. Blade, J. Orlowski, R. Z. Shah, J. J. CA Int Myeloma Working Grp TI Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group SO LEUKEMIA LA English DT Review DE plasma cell leukemia; cytogenetics; bortezomib; transplantation; myeloma; prognosis ID BONE-MARROW MICROENVIRONMENT; IN-SITU HYBRIDIZATION; OF-THE-LITERATURE; C-MYC ONCOGENE; MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; GENETIC ABERRATIONS; CLINICAL-FEATURES; SINGLE-CENTER AB Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (>= 20%) and absolute number (>= 2 x 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL. Leukemia (2013) 27, 780-791; doi:10.1038/leu.2012.336 C1 [Fernandez de Larrea, C.; Blade, J.] Hosp Clin Barcelona, Dept Hematol, Amyloidosis & Myeloma Unit, IDIBAPS, E-08036 Barcelona, Spain. [Kyle, R. A.; Kumar, S. K.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Durie, B. G. M.] Samuel Oschin Comprehens Canc Inst, Cedars Sinai Outpatient Canc Ctr, Southwest Oncol Grp, Int Myeloma Fdn, Los Angeles, CA USA. [Ludwig, H.] Wilhelminenspital Stadt Wien, Dept Med, Ctr Oncol & Hematol, Vienna, Austria. [Usmani, S.] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. [Vesole, D. H.] Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Hajek, R.] Univ Hosp Ostrava, Dept Haematooncol, Ostrava, Czech Republic. [Hajek, R.] Sch Med Univ, Ostrava, Czech Republic. [San Miguel, J. F.] Hosp Univ Salamanca, Serv Hematol, CIC, IBMCC USAL CSIC, Salamanca, Spain. [Sezer, O.] Univ Hamburg, Univ Med Ctr, Hamburg, Germany. [Sonneveld, P.] Erasmus Univ, Dept Hematol, Med Ctr, Rotterdam, Netherlands. [Mahindra, A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Comenzo, R.] Tufts Med Ctr, Boston, MA USA. [Palumbo, A.] Univ Turin, Myeloma Unit, Div Hematol, Turin, Italy. [Mazumber, A.] NYU Comprehens Canc Ctr, New York, NY USA. [Anderson, K. C.; Richardson, P. G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Badros, A. Z.] Univ Maryland, Dept BMT, Baltimore, MD 21201 USA. [Caers, J.] Ctr Hosp Univ Liege, Dept Hematol, Liege, Belgium. [Cavo, M.] S Orsolas Univ Hosp, Bologna Sch Med, Seragnoli Inst Haematol, Bologna, Italy. [Leleu, X.] Hosp Claude Huriez, Dept Hematol, Lille, France. [Dimopoulos, M. A.] Univ Athens, Dept Clin Therapeut, Sch Med Athens, GR-10679 Athens, Greece. [Chim, C. S.] Queen Mary Hosp, Div Haematol & Med Oncol, Hong Kong, Hong Kong, Peoples R China. [Schots, R.] Univ Ziekenhuis Brussels, Dept Clin Hematol, Brussels, Belgium. [Noeul, A.] Hospital Ruiz & Paez, Bolivar, Venezuela. [Fantl, D.] Hosp Italiano Buenos Aires, Caba, Argentina. [Mellqvist, U-H] Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden. [Landgren, O.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Chanan-Khan, A.] Mayo Clin, Div Hematol Oncol, Jacksonville, FL 32224 USA. [Moreau, P.] Univ Hosp, Dept Clin Hematol, Nantes, France. [Fonseca, R.] Mayo Clin Scottsdale, Div Hematol Oncol, Scottsdale, AZ USA. [Merlini, G.] Univ Pavia, Dept Biochem, I-27100 Pavia, Italy. [Lahuerta, J. J.] Hosp Univ 12 Octubre, Dept Hematol, Madrid, Spain. [Orlowski, R. Z.; Shah, J. J.] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Div Canc Med, Houston, TX 77030 USA. RP de Larrea, CF (reprint author), Hosp Clin Barcelona, Dept Hematol, Villarroel 170, E-08036 Barcelona, Spain. EM cfernan1@clinic.ub.es; jjshah@mdanderson.org RI Kumar, Shaji/A-9853-2008; richard, chrystelle/K-8595-2015; Garcia-Sanz, Ramon/B-7986-2017; OI Kumar, Shaji/0000-0001-5392-9284; Garcia-Sanz, Ramon/0000-0003-4120-2787; SAN MIGUEL, JESUS/0000-0002-9183-4857; Fonseca, Rafael/0000-0002-5938-3769; CAVO, MICHELE/0000-0003-4514-3227; Merlini, Giampaolo/0000-0001-7680-3254; nahi, hareth/0000-0003-4711-5094 FU Hospital Clinic de Barcelona; Instituto de Salud Carlos III, Spain [RD12/0036/0046] FX This work has been supported in part by 'Josep Font' Grant from Hospital Clinic de Barcelona and RD12/0036/0046 from Instituto de Salud Carlos III, Spain. Meeting on Plasma Cell Leukemia was supported by the International Myeloma Foundation. NR 92 TC 39 Z9 41 U1 0 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD APR PY 2013 VL 27 IS 4 BP 780 EP 791 DI 10.1038/leu.2012.336 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 124NT UT WOS:000317472200005 ER PT J AU MacKenzie, KF Van den Bosch, MWM Naqvi, S Elcombe, SE McGuire, VA Reith, AD Blackshear, PJ Dean, JLE Arthur, JSC AF MacKenzie, Kirsty F. Van den Bosch, Mirjam W. M. Naqvi, Shaista Elcombe, Suzanne E. McGuire, Victoria A. Reith, Alastair D. Blackshear, Perry J. Dean, Jonathan L. E. Arthur, J. Simon C. TI MSK1 and MSK2 Inhibit Lipopolysaccharide-Induced Prostaglandin Production via an Interleukin-10 Feedback Loop SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CYCLOOXYGENASE-2 MESSENGER-RNA; NECROSIS-FACTOR-ALPHA; STRESS-INDUCED PHOSPHORYLATION; RAW 264.7 MACROPHAGES; P38 MAPK PATHWAY; NF-KAPPA-B; GENE-TRANSCRIPTION; BINDING-PROTEIN; 3'-UNTRANSLATED REGION AB Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E-2 (PGE(2)) levels following intraperitoneal injection of LPS. C1 [MacKenzie, Kirsty F.; Van den Bosch, Mirjam W. M.; Naqvi, Shaista; Elcombe, Suzanne E.; McGuire, Victoria A.; Arthur, J. Simon C.] Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat Unit, Dundee, Scotland. [Reith, Alastair D.] GlaxoSmithKline China R&D Co Ltd, External Alliances & Dev, Med Res Ctr, Stevenage, Herts, England. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Dean, Jonathan L. E.] Univ Oxford, Kennedy Inst Rheumatol, London, England. [Arthur, J. Simon C.] Univ Dundee, Sch Life Sci, Div Cell Signalling & Immunol, Dundee, Scotland. RP Arthur, JSC (reprint author), Univ Dundee, Sch Life Sci, MRC Prot Phosphorylat Unit, Sir James Black Complex, Dundee, Scotland. EM j.s.c.arthur@dundee.ac.uk OI Arthur, Simon/0000-0002-8135-1958; McGuire, Victoria/0000-0002-7808-3278 FU UK Medical Research Council; Arthritis Research UK; AstraZeneca; Boehringer-Ingelheim; GlaxoSmithKline; Merck KgaA; Janssen Pharmaceutica; Pfizer; Wellcome Trust FX These studies were supported by the UK Medical Research Council, Arthritis Research UK, and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica, and Pfizer). S.E.E. was funded by a Wellcome Trust Clinical Ph.D. studentship. NR 72 TC 17 Z9 18 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2013 VL 33 IS 7 BP 1456 EP 1467 DI 10.1128/MCB.01690-12 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121UF UT WOS:000317269200016 PM 23382072 ER PT J AU Tang, ZW Feng, MQ Gao, W Phung, Y Chen, WZ Chaudhary, A St Croix, B Qian, M Dimitrov, DS Ho, M AF Tang, Zhewei Feng, Mingqian Gao, Wei Phung, Yen Chen, Weizao Chaudhary, Amit St Croix, Brad Qian, Min Dimitrov, Dimiter S. Ho, Mitchell TI A Human Single-Domain Antibody Elicits Potent Antitumor Activity by Targeting an Epitope in Mesothelin Close to the Cancer Cell Surface SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; HIGH-AFFINITY; IN-VITRO; OVARIAN CANCERS; IMMUNOTHERAPY; CYTOTOXICITY; IMMUNOTOXIN; THERAPY; DISPLAY; VIVO AB Monoclonal antibodies against mesothelin are being evaluated for the treatment of mesothelioma and multiple forms of cancers, and show great promise for clinical development for solid cancers. Antibodies against mesothelin have been shown to act via immunotoxin-based inhibition of tumor growth and induction of antibody-dependent cell-mediated cytotoxicity (ADCC). However, complement-dependent cytotoxicity (CDC), considered an important additional mechanism of therapeutic antibodies against tumors, is inactive for such antibodies. Here, we used phage display antibody engineering technology and synthetic peptide screening to identify SD1, a human single-domain antibody to mesothelin. SD1 recognizes a conformational epitope at the C-terminal end (residues 539-588) of mesothelin close to the cell surface. To investigate SD1 as a potential therapeutic agent, we generated a recombinant human Fc (SD1-hFc) fusion protein. Interestingly, the SD1-hFc protein exhibits strong CDC activity, in addition to ADCC, against mesothelin-expressing tumor cells. Furthermore, it causes growth inhibition of human tumor xenografts in nude mice as a single agent. SD1 is the first human single-domain antibody targeting mesothelin-expressing tumors, shows potential as a cancer therapeutic candidate, and may improve current antibody therapy targeting mesothelin-expressing tumors. Mol Cancer Ther; 12(4); 416-26. (C) 2013 AACR. C1 [Tang, Zhewei; Qian, Min] E China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai 200062, Peoples R China. [Tang, Zhewei; Feng, Mingqian; Gao, Wei; Phung, Yen; Ho, Mitchell] NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Chen, Weizao; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCR Nanobiol Program, Frederick, MD 21701 USA. [Chaudhary, Amit; St Croix, Brad] NCI, Tumor Angiogenesis Sect, Mouse Canc Genet Program, Frederick Natl Lab Canc Res, Frederick, MD 21701 USA. RP Ho, M (reprint author), NCI, Antibody Therapy Sect, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5002C, Bethesda, MD 20892 USA. EM homi@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU NIH, NCI, Center for Cancer Research [Z01 BC 010891, ZIA BC010891]; NCI FX This research was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research (Z01 BC 010891 and ZIA BC010891) and by the 2011 NCI Director's Intramural Innovation Award (Principal Investigator Award) to M. Ho. This work was also possible due to a Mesothelioma Applied Research Foundation Craig Kozicki Memorial Grant to M. Ho. NR 38 TC 13 Z9 14 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD APR PY 2013 VL 12 IS 4 BP 416 EP 426 DI 10.1158/1535-7163.MCT-12-0731 PG 11 WC Oncology SC Oncology GA 123NB UT WOS:000317395800008 PM 23371858 ER PT J AU Schwartz-Roberts, JL Shajahan, AN Cook, KL Warri, A Abu-Asab, M Clarke, R AF Schwartz-Roberts, Jessica L. Shajahan, Ayesha N. Cook, Katherine L. Waerri, Anni Abu-Asab, Mones Clarke, Robert TI GX15-070 (Obatoclax) Induces Apoptosis and Inhibits Cathepsin D- and L-Mediated Autophagosomal Lysis in Antiestrogen-Resistant Breast Cancer Cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID BCL-2 PROTEIN FAMILY; ESTROGEN-RECEPTOR; PROGNOSTIC VALUE; LINE MCF-7; FULVESTRANT; TAMOXIFEN; DEATH; RESPONSIVENESS; CHEMOTHERAPY; SENSITIVITY AB In estrogen receptor-positive (ER+) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and autophagy, yet the underlying cell death mechanisms have yet to be elucidated. Here, we show that GX15-070 is more effective in reducing the cell density of antiestrogen-resistant breast cancer cells versus sensitive cells and that this increased sensitivity of resistant cells to GX15-070 correlates with an accumulation of autophagic vacuoles. Formation of autophagosomes in GX15-070-treated cells was verified by changes in expression of the lipidation of microtubule-associated protein-1 light chain-3 and both confocal and transmission electron microscopy. While GX15-070 treatment promotes autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulate. Moreover, GX15-070 exposure leads to a reduction in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo. Thus, GX15-070 has dual roles in promoting cell death: (i) directly inhibiting antiapoptotic BCL2 family members, thereby inducing apoptosis; and (ii) inhibiting downstream CTSD and CTSL1 protein expression to limit the ability of cells to use degraded material to fuel cellular metabolism and restore homeostasis. Our data highlight a new mechanism of GX15-070-induced cell death that could be used to design novel therapeutic interventions for antiestrogen resistant breast cancer. Mol Cancer Ther; 12(4); 448-59. (C) 2013 AACR. C1 [Schwartz-Roberts, Jessica L.; Shajahan, Ayesha N.; Cook, Katherine L.; Waerri, Anni; Clarke, Robert] Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Schwartz-Roberts, Jessica L.; Clarke, Robert] Georgetown Univ, Sch Med, Dept Physiol & Biophys, Washington, DC 20057 USA. [Abu-Asab, Mones] NEI, Sect Immunopathol, NIH, Bethesda, MD 20892 USA. [Abu-Asab, Mones] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Clarke, R (reprint author), Georgetown Univ, Sch Med, Dept Oncol, Res Bldg W405A,3970 Reservoir Rd NW, Washington, DC 20057 USA. EM clarker@georgetown.edu RI Clarke, Robert/A-6485-2008; OI Clarke, Robert/0000-0002-9278-0854; Cook, Katherine/0000-0001-6241-0214; Abu-Asab, Mones/0000-0002-4047-1232 FU NIH [F31CA165514-01A1]; Public Health Service [U54-CA149147, R01-CA131465]; Susan G. Komen Grant [KG090245]; National Cancer Institute [P30CA051008] FX J.L. Schwartz-Roberts is the recipient of a NIH training grant (grant no. F31CA165514-01A1). This research was supported by Public Health Service Awards U54-CA149147, R01-CA131465, and Susan G. Komen Grant KG090245 (to R. Clarke). The project described earlier was supported by Award Number P30CA051008 from the National Cancer Institute. NR 45 TC 29 Z9 31 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD APR PY 2013 VL 12 IS 4 BP 448 EP 459 DI 10.1158/1535-7163.MCT-12-0617 PG 12 WC Oncology SC Oncology GA 123NB UT WOS:000317395800011 PM 23395885 ER PT J AU Mokhtari, A Blancato, VS Repizo, GD Henry, C Pikis, A Bourand, A Alvarez, MD Immel, S Mechakra-Maza, A Hartke, A Thompson, J Magni, C Deutscher, J AF Mokhtari, Abdelhamid Blancato, Victor S. Repizo, Guillermo D. Henry, Celine Pikis, Andreas Bourand, Alexa de Fatima Alvarez, Maria Immel, Stefan Mechakra-Maza, Aicha Hartke, Axel Thompson, John Magni, Christian Deutscher, Josef TI Enterococcus faecalis utilizes maltose by connecting two incompatible metabolic routes via a novel maltose 6-phosphate phosphatase (MapP) SO MOLECULAR MICROBIOLOGY LA English DT Article ID GRAM-POSITIVE BACTERIA; FUSOBACTERIUM-MORTIFERUM ATCC-25557; BACILLUS-SUBTILIS; CATABOLITE REPRESSION; LACTOBACILLUS-CASEI; INDUCER EXCLUSION; KLEBSIELLA-PNEUMONIAE; LACTOCOCCUS-LACTIS; ESCHERICHIA-COLI; TRANSPORT AB Similar to Bacillus subtilis, Enterococcus faecalis transports and phosphorylates maltose via a phosphoenolpyruvate (PEP):maltose phosphotransferase system (PTS). The maltose-specific PTS permease is encoded by the malT gene. However, E.faecalis lacks a malA gene encoding a 6-phospho--glucosidase, which in B.subtilis hydrolyses maltose 6-P into glucose and glucose 6-P. Instead, an operon encoding a maltose phosphorylase (MalP), a phosphoglucomutase and a mutarotase starts upstream from malT. MalP was suggested to split maltose 6-P into glucose 1-P and glucose 6-P. However, purified MalP phosphorolyses maltose but not maltose 6-P. We discovered that the gene downstream from malT encodes a novel enzyme (MapP) that dephosphorylates maltose 6-P formed by the PTS. The resulting intracellular maltose is cleaved by MalP into glucose and glucose 1-P. Slow uptake of maltose probably via a maltodextrin ABC transporter allows poor growth for the mapP but not the malP mutant. Synthesis of MapP in a B.subtilis mutant accumulating maltose 6-P restored growth on maltose. MapP catalyses the dephosphorylation of intracellular maltose 6-P, and the resulting maltose is converted by the B.subtilis maltose phosphorylase into glucose and glucose 1-P. MapP therefore connects PTS-mediated maltose uptake to maltose phosphorylase-catalysed metabolism. Dephosphorylation assays with a wide variety of phospho-substrates revealed that MapP preferably dephosphorylates disaccharides containing an O--glycosyl linkage. C1 [Mokhtari, Abdelhamid; Henry, Celine; Bourand, Alexa; Deutscher, Josef] INRA, Microbiol Alimentat Serv Sante Humaine MICALIS, UMR1319, F-78350 Jouy En Josas, France. [Mokhtari, Abdelhamid; Henry, Celine; Bourand, Alexa; Deutscher, Josef] AgroParisTech, MICALIS, UMR1319, F-78350 Jouy En Josas, France. [Mokhtari, Abdelhamid; Mechakra-Maza, Aicha] Univ Mentouri, Fac Nat Sci & Life, Dept Biochem Microbiol, Lab Environm Biol, Constantine 25017, Algeria. [Blancato, Victor S.; Repizo, Guillermo D.; Magni, Christian] Univ Nacl Rosario, Inst Biol Mol & Celular Rosario IBR CONICET, Fac Ciencias Bioquim & Farmaceut, RA-2000 Rosario, Santa Fe, Argentina. [Blancato, Victor S.; Repizo, Guillermo D.; Magni, Christian] Univ Nacl Rosario, Dept Microbiol, Fac Ciencias Bioquim & Farmaceut, RA-2000 Rosario, Santa Fe, Argentina. [Pikis, Andreas] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. [Bourand, Alexa; Deutscher, Josef] CNRS, MICALIS, SNC9130, F-78350 Jouy En Josas, France. [de Fatima Alvarez, Maria] Univ Nacl Tucuman, Fac Bioquim Quim & Farm, Inst Super Invest Biol INSIBIO UNT CONICET, RA-4000 San Miguel De Tucuman, Argentina. [de Fatima Alvarez, Maria] Univ Nacl Tucuman, Fac Bioquim Quim & Farm, Dept Biol Desarrollo, RA-4000 San Miguel De Tucuman, Argentina. [Immel, Stefan] Tech Univ Darmstadt, Inst Organ Chem, D-64287 Darmstadt, Germany. [Hartke, Axel] Univ Caen Basse Normandie, EA4655, Stress Virulence U2RM, F-14032 Caen, France. [Thompson, John] NIDCR, Microbial Biochem & Genet Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Deutscher, J (reprint author), INRA, Microbiol Alimentat Serv Sante Humaine MICALIS, UMR1319, F-78350 Jouy En Josas, France. EM josef.deutscher@grignon.inra.fr OI Blancato, Victor/0000-0003-3945-2859 FU MinCyt/ECOS-Sud programme [A09B03]; Agencia Nacional de Promocion y Tecnologica (AN-PCyT, Argentina) [2010-1828, 2008-1562]; NIDCR, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland [20892] FX We thank Tarek Msadek and Dusko Ehrlich for vectors pAC7 and pMUTIN respectively, and Eliane Milohanic for providing us with a plasmid containing the promoter and Shine-Dalgarno box of B. subtilis ptsH. We are grateful to Isabelle Rince for technical assistance during construction of the mapP mutant. This work was supported by grants from the MinCyt/ECOS-Sud programme (Action No. A09B03) (C. M and J.D), the Agencia Nacional de Promocion y Tecnologica (AN-PCyT, contract 2010-1828 and 2008-1562; Argentina) (C. M.), and the Intramural Research Program of the NIDCR, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892 (J.T.). G. R. is a fellow researcher of CONICET (Argentina), and V. B and C. M. are Career Investigators of CONICET (Argentina). NR 47 TC 5 Z9 7 U1 1 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2013 VL 88 IS 2 BP 234 EP 253 DI 10.1111/mmi.12183 PG 20 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 126CG UT WOS:000317588300003 PM 23490043 ER PT J AU Ozdemir, V Badr, KF Dove, ES Endrenyi, L Geraci, CJ Hotez, PJ Milius, D Neves-Pereira, M Pang, T Rotimi, CN Sabra, R Sarkissian, CN Srivastava, S Tims, H Zgheib, NK Kickbusch, I AF Oezdemir, Vural Badr, Kamal F. Dove, Edward S. Endrenyi, Laszlo Geraci, Christy Jo Hotez, Peter J. Milius, Djims Neves-Pereira, Maria Pang, Tikki Rotimi, Charles N. Sabra, Ramzi Sarkissian, Christineh N. Srivastava, Sanjeeva Tims, Hesther Zgheib, Nathalie K. Kickbusch, Ilona TI Crowd-Funded Micro-Grants for Genomics and "Big Data": An Actionable Idea Connecting Small (Artisan) Science, Infrastructure Science, and Citizen Philanthropy SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID NEGLECTED TROPICAL DISEASES; AMERICAN DIPLOMACY; CIVILIAN POWER; PUBLIC-HEALTH; GLOBAL HEALTH; NEED; 21ST-CENTURY; DISCOVERY; MEDICINE; SOCIETY AB Biomedical science in the 21st century is embedded in, and draws from, a digital commons and "Big Data" created by high-throughput Omics technologies such as genomics. Classic Edisonian metaphors of science and scientists (i.e., "the lone genius" or other narrow definitions of expertise) are ill equipped to harness the vast promises of the 21st century digital commons. Moreover, in medicine and life sciences, experts often under-appreciate the important contributions made by citizen scholars and lead users of innovations to design innovative products and co-create new knowledge. We believe there are a large number of users waiting to be mobilized so as to engage with Big Data as citizen scientists-only if some funding were available. Yet many of these scholars may not meet the meta-criteria used to judge expertise, such as a track record in obtaining large research grants or a traditional academic curriculum vitae. This innovation research article describes a novel idea and action framework: micro-grants, each worth $1000, for genomics and Big Data. Though a relatively small amount at first glance, this far exceeds the annual income of the "bottom one billion"-the 1.4 billion people living below the extreme poverty level defined by the World Bank ($1.25/day). We describe two types of micro-grants. Type 1 micro-grants can be awarded through established funding agencies and philanthropies that create micro-granting programs to fund a broad and highly diverse array of small artisan labs and citizen scholars to connect genomics and Big Data with new models of discovery such as open user innovation. Type 2 micro-grants can be funded by existing or new science observatories and citizen think tanks through crowd-funding mechanisms described herein. Type 2 micro-grants would also facilitate global health diplomacy by co-creating crowd-funded micro-granting programs across nation-states in regions facing political and financial instability, while sharing similar disease burdens, therapeutics, and diagnostic needs. We report the creation of ten Type 2 micro-grants for citizen science and artisan labs to be administered by the nonprofit Data-Enabled Life Sciences Alliance International (DELSA Global, Seattle). Our hope is that these micro-grants will spur novel forms of disruptive innovation and genomics translation by artisan scientists and citizen scholars alike. We conclude with a neglected voice from the global health frontlines, the American University of Iraq in Sulaimani, and suggest that many similar global regions are now poised for micro-grant enabled collective innovation to harness the 21st century digital commons. C1 [Oezdemir, Vural] Data Enabled Life Sci Alliance Int DELSA Global, Seattle, WA USA. [Oezdemir, Vural] McGill Univ, Fac Management, Res Grp Complex Collaborat, Montreal, PQ, Canada. [Oezdemir, Vural; Dove, Edward S.; Milius, Djims] McGill Univ, Ctr Genom & Policy, Fac Med, Dept Human Genet, Montreal, PQ, Canada. [Badr, Kamal F.] Amer Univ Beirut, Dept Internal Med, Fac Med, Beirut, Lebanon. [Dove, Edward S.] Columbia Law Sch LLM Program, New York, NY USA. [Endrenyi, Laszlo] Univ Toronto, Fac Med, Dept Pharmacol, Toronto, ON, Canada. [Geraci, Christy Jo] Amer Univ Iraq, Dept Math & Nat Sci, Sulaimani, Iraq. [Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Houston, TX 77030 USA. [Hotez, Peter J.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Hotez, Peter J.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Hotez, Peter J.] Sabin Vaccine Inst, Houston, TX USA. [Hotez, Peter J.] Texas Childrens Hosp, Ctr Vaccine Dev, Houston, TX 77030 USA. [Hotez, Peter J.] Rice Univ, James A Baker III Inst Publ Policy, Houston, TX USA. [Milius, Djims] Univ Cape Town, Dept Private & Business Law, ZA-7925 Cape Town, South Africa. [Pang, Tikki] Natl Univ Singapore, Lee Kuan Yew Sch Publ Policy, Singapore 117548, Singapore. [Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, Bethesda, MD 20892 USA. [Sabra, Ramzi; Zgheib, Nathalie K.] Amer Univ Beirut, Dept Pharmacol & Toxicol, Fac Med, Beirut, Lebanon. [Sarkissian, Christineh N.] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada. [Sarkissian, Christineh N.] Montreal Childrens Hosp, Res Inst, Montreal, PQ H3H 1P3, Canada. [Srivastava, Sanjeeva] Indian Inst Technol, Dept Biosci & Bioengn, Prote Lab, Bombay, Maharashtra, India. [Kickbusch, Ilona] Grad Inst Int & Dev Studies, Global Hlth Programme, Geneva, Switzerland. RP Ozdemir, V (reprint author), McGill Univ, Fac Med, Montreal, PQ, Canada. EM vural.ozdemir@alumni.utoronto.ca OI Hotez, Peter/0000-0001-8770-1042 FU NIMHD NIH HHS [P20 MD006899] NR 59 TC 12 Z9 14 U1 4 U2 103 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 EI 1557-8100 J9 OMICS JI OMICS PD APR PY 2013 VL 17 IS 4 BP 161 EP 172 DI 10.1089/omi.2013.0034 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 124OZ UT WOS:000317475700001 PM 23574338 ER PT J AU Dvir-Ginzberg, M Oppenheimer, H Meir, H Gabay, O Zaal, K Sanchez, C Haze, A Kandel, L Leibergall, M AF Dvir-Ginzberg, M. Oppenheimer, H. Meir, H. Gabay, O. Zaal, K. Sanchez, C. Haze, A. Kandel, L. Leibergall, M. TI DECIPHERING THE ROLE OF 75KDA SIRT1 FRAGMENT IN OSTEOARTHRITIS SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) CY APR 18-21, 2013 CL Philadelphia, PA SP OsteoArthritis Res Soc Int (OARSI) C1 [Dvir-Ginzberg, M.; Oppenheimer, H.; Meir, H.] Hebrew Univ Jerusalem, Jerusalem, Israel. [Gabay, O.; Zaal, K.] NIAMS, NIH, Bethesda, MD 20892 USA. [Sanchez, C.] Univ Liege, Hebrew Univ Jerusalem, Liege, Belgium. [Haze, A.; Kandel, L.; Leibergall, M.] Hebrew Univ Jerusalem, Hadassah Med Ctr, Jerusalem, Israel. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2013 VL 21 SU S BP S49 EP S49 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 130TF UT WOS:000317942300109 ER PT J AU Gabay, OH Zaal, KJ Sanchez, C Dvir-Ginzberg, M Gagarina, V Song, Y He, X McBurney, M AF Gabay, O. H., Jr. Zaal, K. J., Jr. Sanchez, C., Jr. Dvir-Ginzberg, M., Jr. Gagarina, V., Jr. Song, Y., Jr. He, X., Jr. McBurney, M., Sr. TI ALTERED CARTILAGE PHENOTYPE IN MICE LACKING SIRT 1 GENE SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) CY APR 18-21, 2013 CL Philadelphia, PA SP OsteoArthritis Res Soc Int (OARSI) C1 [Gabay, O. H., Jr.; Zaal, K. J., Jr.; Gagarina, V., Jr.] NIH, Bethesda, MD 20892 USA. [Sanchez, C., Jr.] BCRU Univ Liege, Liege, Belgium. [Dvir-Ginzberg, M., Jr.] Hebrew Univ Haddassah Ein Kerem, Jerusalem, Israel. [Song, Y., Jr.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [He, X., Jr.; McBurney, M., Sr.] Ottawa Hasp, Res Inst, Ottawa, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2013 VL 21 SU S BP S168 EP S168 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 130TF UT WOS:000317942300350 ER PT J AU Kaneko, H Sadatsuki, R Culley, KL Otero, M Futami, I Hada, S Hirasawa-Arikawa, E Yamada, Y Kaneko, K Goldring, MB Ishijima, M AF Kaneko, H. Sadatsuki, R. Culley, K. L. Otero, M. Futami, I. Hada, S. Hirasawa-Arikawa, E. Yamada, Y. Kaneko, K. Goldring, M. B. Ishijima, M. TI PERLECAN IS REQUIRED FOR CHONDROGENIC DIFFERENTIATION OF MESENCHYMAL SYNOVIAL CELLS SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) CY APR 18-21, 2013 CL Philadelphia, PA SP OsteoArthritis Res Soc Int (OARSI) C1 [Kaneko, H.; Sadatsuki, R.; Futami, I.; Hada, S.; Kaneko, K.; Ishijima, M.] Juntendo Univ, Grad Sch Med, Dept Orthoped & Med Motor Organ, Tokyo, Japan. Weill Cornell Med Coll, Tissue Engn Regenerat & Repair Program, Div Res, Hosp Special Surg, New York, NY USA. [Culley, K. L.; Otero, M.; Goldring, M. B.] Hosp Special Surg, Weill Cornell Med Coll, Tissue Engn Regenerat & Repair Program, Div Res, New York, NY 10021 USA. [Hirasawa-Arikawa, E.] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo, Japan. [Yamada, Y.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2013 VL 21 SU S BP S43 EP S43 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 130TF UT WOS:000317942300099 ER PT J AU Sigurdardottir, S Olafsdottir, S Aspelund, T Harris, TB Gudnason, V Jonsson, H AF Sigurdardottir, S. Olafsdottir, S. Aspelund, T. Harris, T. B. Gudnason, V. Jonsson, H. TI TOTAL JOINT REPLACEMENT DUE TO OSTEOARTHRITIS: THE EFFECT OF OCCUPATIONAL HISTORY, EDUCATION AND PHYSICAL ACTIVITY. THE AGES-REYKJAVIK STUDY SO OSTEOARTHRITIS AND CARTILAGE LA English DT Meeting Abstract CT World Congress of the Osteoarthritis-Research-Society-International (OARSI) CY APR 18-21, 2013 CL Philadelphia, PA SP OsteoArthritis Res Soc Int (OARSI) C1 [Sigurdardottir, S.; Olafsdottir, S.; Aspelund, T.; Gudnason, V.; Jonsson, H.] Univ Iceland, Reykjavik, Iceland. [Aspelund, T.; Gudnason, V.] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, T. B.] NIA, Bethesda, MD 20892 USA. [Jonsson, H.] Landspitalinn Univ Hosp, Reykjavik, Iceland. RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD APR PY 2013 VL 21 SU S BP S164 EP S164 PG 1 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 130TF UT WOS:000317942300340 ER PT J AU Xu, Y Wang, H Nussinov, R Ma, BY AF Xu, Yu Wang, Hong Nussinov, Ruth Ma, Buyong TI Protein charge and mass contribute to the spatio-temporal dynamics of protein-protein interactions in a minimal proteome SO PROTEOMICS LA English DT Article DE Bioinformatics; Diffusion collision; Macromolecular crowding; Minimal genome; Minimalproteome; Proteinprotein interaction network ID ESCHERICHIA-COLI; INTERACTION NETWORK; BASIC-PROTEINS; DIELECTRIC-SPECTROSCOPY; BROWNIAN DYNAMICS; BINDING CASCADES; FOLDING FUNNELS; GLOBAL ANALYSIS; WHOLE PROTEOME; NET CHARGE AB We constructed and simulated a minimal proteome model using Langevin dynamics. It contains 206 essential protein types that were compiled from the literature. For comparison, we generated six proteomes with randomized concentrations. We found that the net charges and molecular weights of the proteins in the minimal genome are not random. The net charge of a protein decreases linearly with molecular weight, with small proteins being mostly positively charged and large proteins negatively charged. The protein copy numbers in the minimal genome have the tendency to maximize the number of proteinprotein interactions in the network. Negatively charged proteins that tend to have larger sizes can provide a large collision cross-section allowing them to interact with other proteins; on the other hand, the smaller positively charged proteins could have higher diffusion speed and are more likely to collide with other proteins. Proteomes with random charge/mass populations form less stable clusters than those with experimental protein copy numbers. Our study suggests that proper populations of negatively and positively charged proteins are important for maintaining a proteinprotein interaction network in a proteome. It is interesting to note that the minimal genome model based on the charge and mass of Escherichia coli may have a larger proteinprotein interaction network than that based on the lower organism Mycoplasma pneumoniae. C1 [Xu, Yu; Wang, Hong] Minzu Univ China, Inst Chinese Minor Tradit Med, Beijing, Peoples R China. [Nussinov, Ruth; Ma, Buyong] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program,Frederick Natl Lab, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Ma, BY (reprint author), NCI, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick Natl Lab, Frederick, MD 21702 USA. EM mabuyong@mail.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; China Scholarship Council [[2009]3009]; NIH, NCI, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. Y. Xu thanks China Scholarship Council [2009]3009. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. All simulations were performed using the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH, Bethesda, MD (http://biowulf.nih.gov). NR 71 TC 4 Z9 4 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD APR PY 2013 VL 13 IS 8 SI SI BP 1339 EP 1351 DI 10.1002/pmic.201100540 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127GD UT WOS:000317684800012 PM 23420643 ER PT J AU Wang, HH Xi, SH Xu, YY Wang, F Zheng, Y Li, B Li, X Zheng, QM Sun, GF AF Wang, Huihui Xi, Shuhua Xu, Yuanyuan Wang, Fei Zheng, Yi Li, Bing Li, Xin Zheng, Quanmei Sun, Guifan TI Sodium arsenite induces cyclooxygenase-2 expression in human uroepithelial cells through MAPK pathway activation and reactive oxygen species induction SO TOXICOLOGY IN VITRO LA English DT Article DE Human uroepithelial cell; Arsenite; Cyclooxygenase-2 (COX-2); Mitogen-activated protein kinase (MAPK); Reactive oxygen species (ROS) ID HUMAN BLADDER CELLS; MONOMETHYLARSONOUS ACID; SIGNAL-TRANSDUCTION; CARCINOGENESIS; CANCER; INFLAMMATION; COX-2; KERATINOCYTES; INHIBITION; KINASES AB Arsenic can induce reactive oxygen species (ROS) leading to oxidative stress and carcinogenesis. Bladder is one of the major target organs of arsenic, and cyclooxygenase-2 (COX-2) may play an important role in arsenic-induced bladder cancer. However, the mechanism by which arsenic induces COX-2 in bladder cells remains unclear. This study aimed at investigating arsenic-mediated intracellular redox status and signaling cascades leading to COX-2 induction in human uroepithelial cells (SV-HUC-1). SV-HUC-1 cells were exposed to sodium arsenite and COX-2 expression, mitogen-activated protein kinase (MAPK) phosphorylation, glutathione (GSH) levels, ROS induction and Nrf2 expression were quantified. Our results demonstrate that arsenite (1-10 mu M) elevates COX-2 expression, GSH levels, ROS and Nrf2 expression. Arsenite treatment for 24 h stimulates phosphorylation of ERK and p38, but not JNK in SV-HUC-1 cells. Induction of Cox-2 mRNA levels by arsenite was attenuated by inhibitors of ERR, p38 and JNK. Arsenite-induced ROS generation and COX-2 expression were significantly attenuated by treatment with melatonin (a ROS scavenger), but enhanced by DL-buthionine-(S, R)-sulfoximine (BSO, an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS) resulting in lower GSH and increased ROS levels). These data indicate that arsenite promotes an induction of ROS, which results in an induction of COX-2 expression through activation of the MAPK pathway. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Wang, Huihui; Xi, Shuhua; Wang, Fei; Zheng, Yi; Li, Bing; Li, Xin; Zheng, Quanmei; Sun, Guifan] China Med Univ, Sch Publ Hlth, Dept Occupat & Environm Hlth, Shenyang, Liaoning, Peoples R China. [Xu, Yuanyuan] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Sun, GF (reprint author), 92 Bei Er Rd, Shenyang 110001, Peoples R China. EM sungf@mail.cmu.edu.cn FU National Natural Science Foundation of China (NSFC) [30771865]; National Science and Technology Pillar Program of China during the 11th Five-Year Plan Period [2006BAI06B04] FX This work was supported by the grant (No. 30771865) from the National Natural Science Foundation of China (NSFC) and National Science and Technology Pillar Program of China during the 11th Five-Year Plan Period (No. 2006BAI06B04). This project was conducted in the Key Laboratory of Liaoning Province (Biological effects of arsenic and arsenic poisoning Laboratory). NR 35 TC 12 Z9 15 U1 0 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD APR PY 2013 VL 27 IS 3 SI SI BP 1043 EP 1048 DI 10.1016/j.tiv.2013.01.012 PG 6 WC Toxicology SC Toxicology GA 124EL UT WOS:000317446500007 PM 23376440 ER PT J AU Sherman, AC Trehanpati, N Daucher, M Davey, RT Masur, H Sarin, SK Kottilil, S Kohli, A AF Sherman, Amy C. Trehanpati, Nirupama Daucher, Marybeth Davey, Richard T. Masur, Henry Sarin, Shiv Kumar Kottilil, Shyam Kohli, Anita TI Augmentation of Hepatitis B Virus-Specific Cellular Immunity with Programmed Death Receptor-1/Programmed Death Receptor-L1 Blockade in Hepatitis B Virus and HIV/Hepatitis B Virus Coinfected Patients Treated with Adefovir SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID REGULATORY T-CELLS; LAMIVUDINE THERAPY; VIRAL-HEPATITIS; LIVER-DISEASE; C VIRUS; INFECTION; EXPRESSION; HBV; LYMPHOCYTES; METAANALYSIS AB The immunological parameters leading to viral persistence in chronic hepatitis B (CHB) are not clearly established. We analyzed HBV-specific immunoregulatory mechanisms in HIV-infected and HIV-uninfected HBeAg+ CHB patients to determine (1) the roles of immunoregulatory pathways, (2) the effect of anti-HBV therapy on immunoregulatory pathways, and (3) the role of immunomodulatory therapy to overcome the effect of T regulatory cells (Tregs, CD4(+)CD25(+)FoxP3(+)) in HBV-infected individuals. A prospective, double blind, randomized, placebo-controlled trial treated HBV (HIV+/-)-infected patients with adefovir 10mg daily or placebo for 48 weeks. HBV viral load (VL), immunophenotying, and functional studies were performed at multiple time points. Suppression of HBV VL with adefovir leads to decreased peripheral expansion of Tregs. While declining, Tregs significantly inhibit cytokine-secreting HBV-specific CD8(+) T cell responses over 48 weeks of anti-HBV adefovir therapy (p < 0.05). A large proportion of these Tregs express programmed death receptor-1 (PD-1), blockade of which in vitro leads to improved cytokine-secreting HBV-specific CD8(+) T cell responses, particularly in HIV/HBV-coinfected patients (p < 0.05). Peripheral expansion of Treg levels correlated with HBV viral load and decreased HBV-specific CD8(+) T cells. PD-1 blockade increased survival of HBV-specific CD8(+) T cells, removing the inhibitory effect of PD-1(+) peripheral Tregs. Hence therapies involving PD-1 blockade in combination with directly acting antivirals should be investigated to reduce the need for life-long directly acting antiviral therapy. C1 [Sherman, Amy C.; Daucher, Marybeth; Davey, Richard T.; Kottilil, Shyam; Kohli, Anita] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Trehanpati, Nirupama; Sarin, Shiv Kumar] Inst Liver & Biliary Sci, New Delhi, India. [Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. [Kohli, Anita] SAIC Frederick Inc, Clin Res Directorate CMRP, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kohli, A (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM kohlia@niaid.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; National Institute of Allergy and Infectious Diseases FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. NR 39 TC 14 Z9 14 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD APR PY 2013 VL 29 IS 4 BP 665 EP 672 DI 10.1089/aid.2012.0320 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 119RO UT WOS:000317115300005 PM 23259453 ER PT J AU De Matteis, S Consonni, D Pesatori, AC Bergen, AW Bertazzi, PA Caporaso, NE Lubin, JH Wacholder, S Landi, MT AF De Matteis, Sara Consonni, Dario Pesatori, Angela C. Bergen, Andrew W. Bertazzi, Pier Alberto Caporaso, Neil E. Lubin, Jay H. Wacholder, Sholom Landi, Maria Teresa TI Are Women Who Smoke at Higher Risk for Lung Cancer Than Men Who Smoke? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; lung cancer; sex differences; smoking ID CIGARETTE-SMOKING; SEX-DIFFERENCES; HISTOLOGIC TYPE; FEMALE SMOKERS; TOBACCO; GENDER; POPULATION; MORTALITY; COHORT; SUSCEPTIBILITY AB Worldwide lung cancer incidence is decreasing or leveling off among men, but rising among women. Sex differences in associations of tobacco carcinogens with lung cancer risk have been hypothesized, but the epidemiologic evidence is conflicting. We tested sex-smoking interaction in association with lung cancer risk within a population-based case-control study, the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study (Lombardy, Italy, 2002-2005). Detailed lifetime smoking histories were collected by personal interview in 2,100 cases with incident lung cancer and 2,120 controls. Odds ratios and 95% confidence intervals for pack-years of cigarette smoking were estimated by logistic regression, adjusted for age, residence area, and time since quitting smoking. To assess sex-smoking interaction, we compared the slopes of odds ratios for logarithm of pack-years in a model for men and women combined. Overall, the slope for pack-years was steeper in men (odds ratio for female-smoking interaction = 0.39, 95% confidence interval: 0.24, 0.62; P < 0.0001); after restriction to ever smokers, the difference in slopes was much smaller (odds ratio for interaction = 0.63, 95% confidence interval: 0.29, 1.37; P = 0.24). Similar results were found by histological type. Results were unchanged when additional confounders were evaluated (e.g., tobacco type, inhalation depth, Fagerstrom-assessed nicotine dependence). These findings do not support a higher female susceptibility to tobacco-related lung cancer. C1 [De Matteis, Sara; Bergen, Andrew W.; Caporaso, Neil E.; Lubin, Jay H.; Wacholder, Sholom; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [De Matteis, Sara; Consonni, Dario; Pesatori, Angela C.; Bertazzi, Pier Alberto] Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Dept Prevent Med, Epidemiol Unit, Milan, Italy. [De Matteis, Sara; Pesatori, Angela C.; Bertazzi, Pier Alberto] Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Mol Genet Program, Menlo Pk, CA 94025 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Consonni, Dario/K-7943-2016; bertazzi, pietro alberto/D-5039-2017; OI Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 FU US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland; Lombardy Region, Direzione Generale Sanita, Environmental Epidemiology Program, Milan, Italy [14013-1/5/2010, 8956-7/6/2006]; CARIPLO Foundation, Milan, Italy; Ministero della Salute and Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy [PMS/42/06] FX This work was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland; the Lombardy Region, Direzione Generale Sanita, Environmental Epidemiology Program, Milan, Italy (grants 14013-1/5/2010 and 8956-7/6/2006); the CARIPLO Foundation, Milan, Italy; and the Ministero della Salute and Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, Rome, Italy (grant PMS/42/06). NR 39 TC 19 Z9 19 U1 0 U2 10 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 APR 1 PY 2013 VL 177 IS 7 BP 601 EP 612 DI 10.1093/aje/kws445 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120CH UT WOS:000317147700002 PM 23425629 ER PT J AU Qu, SM Wen, WQ Shu, XO Chow, WH Xiang, YB Wu, J Ji, BT Rothman, N Yang, G Cai, QY Gao, YT Zheng, W AF Qu, Shimian Wen, Wanqing Shu, Xiao-Ou Chow, Wong-Ho Xiang, Yong-Bing Wu, Jie Ji, Bu-Tian Rothman, Nathaniel Yang, Gong Cai, Qiuyin Gao, Yu-Tang Zheng, Wei TI Association of Leukocyte Telomere Length With Breast Cancer Risk: Nested Case-Control Findings From the Shanghai Women's Health Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast cancer; biomarkers; epidemiology; genetic factors; telomere ID MULTIPLEX QUANTITATIVE PCR; BLOOD-CELLS; STRESS; DAMAGE AB Telomeres are specialized chromatin structures essential for the maintenance of chromosomal integrity and stability. Telomere shortening has been linked to multiple aging-related diseases, including cancer. Evidence associating telomere length with breast cancer risk most of which has been from retrospective case-control studies is conflicting. We conducted a nested case-control study based on the Shanghai Women's Health Study (1997-2009) in which we evaluated the association of telomere length and breast cancer risk using peripheral blood samples collected before cancer diagnosis (601 cases and 695 controls). We used monochrome multiplex quantitative polymerase chain reaction to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios with 95% confidence intervals as the measure of association. Telomere length was inversely correlated with age (r=-0.22). Women with moderately long telomeres (those in the fourth quintile) had the lowest breast cancer risk. Risk increased in a dose-response manner with decreasing quintile of telomere length; odds ratios were 1.39 (95% confidence interval (Cl): 0.95, 2.04), 1.79 (95% Cl: 1.17, 2.75), and 2.39 (95% Cl: 1.45, 3.92), respectively, for the third, second, and first quintiles compared with the fourth quintile. A slightly elevated risk of breast cancer (odds ratio = 1.35, 95% Cl: 0.90, 2.04), although one that was not statistically significant, was found in the top quintile (longest telomeres). Our results support the hypothesis that telomere shortening is associated with increased risk of breast cancer and suggest a possible elevated risk associated with long telomeres. C1 [Qu, Shimian; Wen, Wanqing; Shu, Xiao-Ou; Wu, Jie; Yang, Gong; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Div Epidemiol, Dept Med, Med Ctr, Nashville, TN 37203 USA. [Qu, Shimian; Wen, Wanqing; Shu, Xiao-Ou; Wu, Jie; Yang, Gong; Cai, Qiuyin; Zheng, Wei] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Chow, Wong-Ho; Ji, Bu-Tian; Rothman, Nathaniel] NCI, Occupat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Xiang, Yong-Bing; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, 2525 West End Ave,8th Floor, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu FU National Institutes of Health [R37 CA 070867]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX Funding for this work was provided by the National Institutes of Health (grant R37 CA 070867). Sample preparations and telomere length assays were performed at the Survey and Biospecimen Shared Resource, which is supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 28 TC 25 Z9 25 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2013 VL 177 IS 7 BP 617 EP 624 DI 10.1093/aje/kws291 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120CH UT WOS:000317147700004 PM 23444102 ER PT J AU Schliep, KC Schisterman, EF Mumford, SL Perkins, NJ Ye, AJ Pollack, AZ Zhang, CL Porucznik, CA VanDerslice, JA Stanford, JB Wactawski-Wende, J AF Schliep, Karen C. Schisterman, Enrique F. Mumford, Sunni L. Perkins, Neil J. Ye, Aijun Pollack, Anna Z. Zhang, Cuilin Porucznik, Christina A. VanDerslice, James A. Stanford, Joseph B. Wactawski-Wende, Jean TI Validation of Different Instruments for Caffeine Measurement Among Premenopausal Women in the BioCycle Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE beverages; caffeine; diet; mental recall; nutrition assessment; questionnaires; validation studies; women ID FOOD-FREQUENCY QUESTIONNAIRE; HORMONE CONCENTRATIONS; DIETARY QUESTIONNAIRE; POSTMENOPAUSAL WOMEN; HEALTH; COFFEE; CONSUMPTION; VALIDITY; ALCOHOL; REPRODUCIBILITY AB Effects of caffeine on women's health are inconclusive, in part because of inadequate exposure assessment. In this study we determined 1) validity of a food frequency questionnaire compared with multiple 24-hour dietary recalls (24HDRs) for measuring monthly caffeine and caffeinated beverage intakes; and 2) validity of the 24HDR compared with the prior day's diary record for measuring daily caffeinated coffee intake. BioCycle Study (2005-2007) participants, women (n=259) aged 18-44 years from western New York State, were followed for 2 menstrual cycles. Participants completed a food frequency questionnaire at the end of each cycle, four 24HDRs per cycle, and daily diaries. Caffeine intakes reported for the food frequency questionnaires were greater than those reported for the 24HDRs (mean = 114.1 vs. 92.6mg/day, P = 0.01) but showed high correlation (r = 0.73, P < 0.001) and moderate agreement (K = 0.51, 95% confidence interval: 0.43, 0.57). Women reported less caffeinated coffee intake in their 24HDRs compared with their corresponding diary days (mean = 0.51 vs. 0.80 cups/day, P < 0.001) (1 cup = 237 mL). Although caffeine and coffee exposures were highly correlated, absolute intakes differed significantly between measurement tools. These results highlight the importance of considering potential misclassification of caffeine exposure. C1 [Schliep, Karen C.; Schisterman, Enrique F.; Mumford, Sunni L.; Perkins, Neil J.; Ye, Aijun; Pollack, Anna Z.; Zhang, Cuilin] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. [Schliep, Karen C.; Porucznik, Christina A.; VanDerslice, James A.; Stanford, Joseph B.] Univ Utah, Div Publ Hlth, Dept Family & Prevent Med, Salt Lake City, UT USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, 6100 Execut Blvd,7B03M, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 29 TC 9 Z9 10 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2013 VL 177 IS 7 BP 690 EP 699 DI 10.1093/aje/kws283 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120CH UT WOS:000317147700013 PM 23462965 ER PT J AU Yu, BB AF Yu, Binbing TI A Class of Transformation Covariate Regression Models for Estimating the Excess Hazard in Relative Survival Analysis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE additive hazards; multiplicative hazards; relative survival; transformation hazards ID CANCER; MORTALITY AB Relative survival is the standard measure of excess mortality due to cancer in population-based cancer survival studies. In relative survival analysis, the observed hazard for cancer patients is the sum of the expected hazard for the general cancer-free population and the excess hazard associated with a cancer diagnosis. Previous models for relative survival analysis have assumed that the excess hazard rate is related to covariates by additive or multiplicative regression models. In this paper, a transformation covariate regression model is developed for estimation of the excess hazard rate, which includes both the additive and the multiplicative regression models as special cases. The baseline excess hazard rate and time-dependent hazard ratios can be approximated by means of regression splines, and the parameter estimates can be obtained using a standard statistical package. As is demonstrated through simulation, the proposed transformation hazards model provides a reasonably good fit to typical relative survival data. For illustration purposes, the sex difference in relative survival for lung and bronchus cancer patients is examined using data from population-based cancer registries (1973-2003). C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), NIA, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309,7201, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU National Institute on Aging, National Institutes of Health FX This research was partly supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 22 TC 1 Z9 1 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2013 VL 177 IS 7 BP 708 EP 717 DI 10.1093/aje/kws288 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120CH UT WOS:000317147700015 PM 23492766 ER PT J AU Lin, SW Qiao, YL Abnet, CC AF Lin, Shih-Wen Qiao, You-Lin Abnet, Christian C. TI RE: "PROSPECTIVE STUDY OF SERUM 25-HYDROXYVITAMIN D CONCENTRATION AND MORTALITY IN A CHINESE POPULATION" REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 [Lin, Shih-Wen; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. RP Lin, SW (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM lins4@mail.nih.gov RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2013 VL 177 IS 7 BP 726 EP 727 DI 10.1093/aje/kwt034 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 120CH UT WOS:000317147700018 PM 23662309 ER PT J AU St Peter, WL Weinhandl, ED Fiessner, ME AF St. Peter, Wendy L. Weinhandl, Eric D. Fiessner, Michael E. TI Sitagliptin-Another Option for Managing Type 2 Diabetes in Dialysis Patients? SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID GLUCOSE CONTROL; EFFICACY C1 [St. Peter, Wendy L.] Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. [Weinhandl, Eric D.] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA. [Fiessner, Michael E.] NIH, Washington, DC USA. RP St Peter, WL (reprint author), Univ Minnesota, Coll Pharm, 7-176 WDH,308 Harvard St SE, Minneapolis, MN 55455 USA. EM stpet002@umn.edu OI St Peter, Wendy/0000-0002-2201-3019 NR 17 TC 6 Z9 6 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2013 VL 61 IS 4 BP 532 EP 535 DI 10.1053/j.ajkd.2013.01.004 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 121WG UT WOS:000317274900344 PM 23497767 ER PT J AU Holmes, KW Maslen, CL Kindem, M Kroner, BL Song, HK Ravekes, W Dietz, HC Weinsaft, JW Roman, MJ Devereux, RB Pyeritz, RE Bavaria, J Milewski, K Milewicz, D LeMaire, SA Hendershot, T Eagle, KA Tolunay, HE Desvigne-Nickens, P Silberbach, M AF Holmes, Kathryn W. Maslen, Cheryl L. Kindem, Mark Kroner, Barbara L. Song, Howard K. Ravekes, William Dietz, H. C. Weinsaft, Jonathan W. Roman, Mary J. Devereux, Richard B. Pyeritz, Reed E. Bavaria, Joseph Milewski, Karianna Milewicz, Dianna LeMaire, Scott A. Hendershot, Tabitha Eagle, Kim A. Tolunay, H. Eser Desvigne-Nickens, Patrice Silberbach, Michael CA GenTAC Registry Consortium TI GenTAC registry report: Gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE aorta; aneurysm; dissection; gender ID HEART-FAILURE; MANAGEMENT AB Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR=0.65, P<0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR=0.68, P<0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events. (c) 2013 Wiley Periodicals, Inc. C1 [Holmes, Kathryn W.; Maslen, Cheryl L.; Song, Howard K.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Holmes, Kathryn W.; Ravekes, William; Dietz, H. C.; Silberbach, Michael] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Kindem, Mark; Kroner, Barbara L.; Hendershot, Tabitha] RTI Int, Rockville, MD USA. [Weinsaft, Jonathan W.; Roman, Mary J.; Devereux, Richard B.] Weill Cornell Med Coll, New York, NY USA. [Pyeritz, Reed E.; Bavaria, Joseph; Milewski, Karianna] Univ Penn, Raymond & Ruth Perelman Sch Med, Philadelphia, PA 19104 USA. [Milewicz, Dianna] Univ Texas Houston, Med Ctr, Houston, TX USA. [LeMaire, Scott A.] St Lukes Episcopal Hosp, Baylor Coll Med, Houston, TX 77030 USA. [LeMaire, Scott A.] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Eagle, Kim A.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Tolunay, H. Eser; Desvigne-Nickens, Patrice] NIH, Bethesda, MD 20892 USA. RP Holmes, KW (reprint author), Oregon Hlth & Sci Univ, MC CDRC P, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM holmesk@ohsu.edu FU National Heart Lung and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases [HHSN268200648199C, HHSN268201000048C]; US Federal Government [HHSN268200648199C, HHSN268201000048C] FX Grant sponsor: National Heart Lung and Blood Institute; Grant sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases; Grant numbers: HHSN268200648199C, HHSN268201000048C.; The GenTAC Registry has been supported by US Federal Government contracts HHSN268200648199C andHHSN268201000048C from the National Heart Lung and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Bethesda, MD). NR 17 TC 12 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2013 VL 161A IS 4 BP 779 EP 786 DI 10.1002/ajmg.a.35836 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 112YM UT WOS:000316631300021 PM 23444191 ER PT J AU Pazmino, PA AF Pazmino, Patricio A. TI Dabigatran: A Nephrological Way Out SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter C1 [Pazmino, Patricio A.] Texas Tech Univ, Hlth Sci Ctr, Nephrol Internal Med & Hypertens NIH Ctr, El Paso, TX 79905 USA. [Pazmino, Patricio A.] Texas Tech Univ, Hlth Sci Ctr, Paul Foster Sch Med, El Paso, TX USA. RP Pazmino, PA (reprint author), Texas Tech Univ, Hlth Sci Ctr, Nephrol Internal Med & Hypertens NIH Ctr, El Paso, TX 79905 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD APR PY 2013 VL 126 IS 4 BP E21 EP E21 DI 10.1016/j.amjmed.2012.10.017 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 115IR UT WOS:000316806300010 PM 23507214 ER PT J AU Romero, R Korzeniewski, SJ AF Romero, Roberto Korzeniewski, Steven J. TI Are infants born by elective cesarean delivery without labor at risk for developing immune disorders later in life? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID GUT MICROBIOTA; SENSITIVITY-ANALYSIS; INTESTINAL MICROBIOTA; COMMENSAL MICROBIOTA; MOLECULAR ANALYSIS; BIAS FORMULAS; DISEASE; RESPONSES; SECTION; OBESITY C1 [Romero, Roberto; Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Korzeniewski, Steven J.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Korzeniewski, Steven J.] Wayne State Univ, Sch Med, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, Hutzel Womens Hosp, NICHD,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov FU Intramural NIH HHS [ZIA HD002400-22] NR 57 TC 18 Z9 18 U1 0 U2 17 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2013 VL 208 IS 4 BP 243 EP 246 DI 10.1016/j.ajog.2012.12.026 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 116DR UT WOS:000316863300005 PM 23273890 ER PT J AU Chaiworapongsa, T Romero, R Korzeniewski, SJ Kusanovic, JP Soto, E Lam, J Dong, Z Than, NG Yeo, L Hernandez-Andrade, E Conde-Agudelo, A Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Korzeniewski, Steven J. Pedro Kusanovic, Juan Soto, Eleazar Lam, Jennifer Dong, Zhong Than, Nandor G. Yeo, Lami Hernandez-Andrade, Edgar Conde-Agudelo, Agustin Hassan, Sonia S. TI Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 59th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 21-24, 2012 CL San Diego, CA SP Soc Gynecol Invest DE fetal death; placental growth factor (PlGF); small-for-gestational-age (SGA); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) ID ENDOTHELIAL GROWTH-FACTOR; UTERINE ARTERY DOPPLER; CIRCULATING ANGIOGENIC FACTORS; LATE-ONSET PREECLAMPSIA; FOR-GESTATIONAL-AGE; HUMAN CHORIONIC-GONADOTROPIN; UNEXPLAINED FETAL-DEATH; TYROSINE KINASE 1; FACTOR RECEPTOR-1 CONCENTRATION; HYPERTENSIVE DISORDERS AB OBJECTIVE: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) at 30-34 weeks of gestation can identify patients at risk for stillbirth, late preeclampsia, and delivery of small-for-gestational-age (SGA) neonates. STUDY DESIGN: A prospective cohort study included 1269 singleton pregnant women from whom blood samples were obtained at 30-34 weeks of gestation and who delivered at >34 weeks of gestation. Plasma concentrations of PlGF, sEng, and sVEGFR-1 were determined by enzyme-linked immunosorbent assay. RESULTS: The prevalence of late (>34 weeks of gestation) preeclampsia, severe late preeclampsia, stillbirth, and SGA was 3.2% (n = 40), 1.8% (n = 23), 0.4% (n = 5), and 8.5% (n = 108), respectively. A plasma concentration of PlGF/sEng <0.3 MoM was associated with severe late preeclampsia (adjusted odds ratio, 16); the addition of PlGF/sEng to clinical risk factors increased the area under the receiver-operating characteristic curve from 0.76 to 0.88 (P = .03). The ratio of PlGF/sEng or PlGF/sVEGFR-1 in the third trimester outperformed those obtained in the first or second trimester and uterine artery Doppler velocimetry at 20-25 weeks of gestation for the prediction of severe late preeclampsia (comparison of areas under the receiver-operating characteristic curve; each P <= .02). Both PlGF/sEng and PlGF/sVEGFR-1 ratios achieved a sensitivity of 74% with a fixed false-positive rate of 15% for the identification of severe late preeclampsia. A plasma concentration of PlGF/sVEGFR-1 <0.12 MoM at 30-34 weeks of gestation had a sensitivity of 80%, a specificity of 94%, and a likelihood ratio of a positive test of 14 for the identification of subsequent stillbirth. Similar findings (sensitivity 80%; specificity 93%) were observed in a separate case-control study. CONCLUSION: Risk assessment for stillbirth and severe late preeclampsia in the third trimester is possible with the determination of maternal plasma concentrations of angiogenic and antiangiogenic factors at 30-34 weeks of gestation. C1 [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Soto, Eleazar; Lam, Jennifer; Dong, Zhong; Than, Nandor G.; Yeo, Lami; Hernandez-Andrade, Edgar; Conde-Agudelo, Agustin; Hassan, Sonia S.] NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Chaiworapongsa, Tinnakorn; Romero, Roberto; Korzeniewski, Steven J.; Soto, Eleazar; Lam, Jennifer; Dong, Zhong; Than, Nandor G.; Yeo, Lami; Hernandez-Andrade, Edgar; Conde-Agudelo, Agustin; Hassan, Sonia S.] NICHHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Korzeniewski, Steven J.; Soto, Eleazar; Lam, Jennifer; Than, Nandor G.; Yeo, Lami; Hernandez-Andrade, Edgar; Hassan, Sonia S.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Pedro Kusanovic, Juan] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Ctr Res & Innovat Maternal Fetal Med CIMAF, Sotero del Rio Hosp, Santiago, Chile. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch,NIH,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM tchaiwor@med.wayne.edu; romeror@mail.nih.gov FU Intramural NIH HHS [ZIA HD002400-22] NR 159 TC 10 Z9 11 U1 0 U2 16 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 APR PY 2013 VL 208 IS 4 AR 287.e1 DI 10.1016/j.ajog.2013.01.016 PG 15 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 116DR UT WOS:000316863300017 PM 23333542 ER PT J AU Whitten, AE Romero, R Korzeniewski, SJ Tarca, AL Schwartz, AG Yeo, L Dong, Z Hassan, SS Chaiworapongsa, T AF Whitten, Amy E. Romero, Roberto Korzeniewski, Steven J. Tarca, Adi L. Schwartz, Alyse G. Yeo, Lami Dong, Zhong Hassan, Sonia S. Chaiworapongsa, Tinnakorn TI Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 59th Annual Scientific Meeting of the Society-for-Gynecological-Investigation CY MAR 21-24, 2012 CL San Diego, CA SP Soc Gynecol Invest DE flt-1; fms-like tyrosine kinase-1; placental growth factor; recurrent pregnancy loss; soluble endoglin; soluble vascular endothelial growth factor receptor ID ENDOTHELIAL-GROWTH-FACTOR; ANTI-ANGIOGENIC FACTORS; FOR-GESTATIONAL-AGE; CIRCULATING ANTIANGIOGENIC FACTORS; FACTOR RECEPTOR-1 CONCENTRATION; LATE-ONSET PREECLAMPSIA; SOLUBLE ENDOGLIN; TYROSINE KINASE-1; AMNIOTIC-FLUID; PLASMA-CONCENTRATIONS AB OBJECTIVE: Massive perivillous fibrin deposition (MPFD) is associated with serious complications of pregnancy including recurrent spontaneous abortion, fetal growth restriction, and fetal demise. The aim of this study was to determine whether maternal plasma concentrations of angiogenic/antiangiogenic factors in MPFD differ from those of uncomplicated pregnancies. STUDY DESIGN: This retrospective longitudinal case-control study included MPFD cases (n = 10) and control patients (n = 175) with uncomplicated pregnancies who were enrolled in a longitudinal study and delivered at term. Serial plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor (sVEGFR)-1 and -2 were determined by an enzyme-linked immunosorbent assay (cases, n = 28 samples; controls, n = 723 samples). Individual analyte concentrations were averaged across gestational age at specimen collection intervals. Linear mixed models were used to test for differences in log-transformed mean analyte concentrations both overall and as a function of time. RESULTS: The following results were found: (1) patients with MPFD had a lower mean plasma PlGF concentration (P = .03) and higher mean plasma concentrations of sVEGFR-1 and sEng (both P < .01) than controls, adjusted for potential confounders; (2) the mean plasma concentration of PlGF differed further among cases and controls as a function of gestational age interval (P < .0001); however, mean sVEGFR-1 and sEng group differences as a function of gestational age interval approached but did not reach significance (P = .09 and P = .11, respectively); (3) patients with MPFD had lower mean plasma concentrations of PlGF/sVEGFR-1 (P < .0001) and PlGF/sEng (P < .001): both of these relationships differed further as a function of gestational age interval (both P < .0001); and (4) differences in mean sVEGFR-1, sEng, and the ratios of PlGF to sVEGFR-1 and PlGF to sEng were observed before 20 weeks of gestation. CONCLUSION: An imbalance of angiogenic/antiangiogenic factors is present in patients with MPFD prior to the diagnosis. We propose that these changes participate in the mechanisms responsible for adverse pregnancy outcomes in patients with MPFD. C1 [Whitten, Amy E.; Romero, Roberto; Korzeniewski, Steven J.; Tarca, Adi L.; Schwartz, Alyse G.; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Whitten, Amy E.; Romero, Roberto; Korzeniewski, Steven J.; Tarca, Adi L.; Schwartz, Alyse G.; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. [Whitten, Amy E.; Korzeniewski, Steven J.; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Obstet, Detroit, MI 48201 USA. [Whitten, Amy E.; Korzeniewski, Steven J.; Yeo, Lami; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn] Wayne State Univ, Dept Gynecol, Detroit, MI 48201 USA. [Tarca, Adi L.] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,Dept Hlth & Human Serv,Hutzel Womens Hosp, 3990 John R,Box 4, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; tchaiwor@med.wayne.edu FU Intramural NIH HHS [ZIA HD002400-21] NR 119 TC 11 Z9 11 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2013 VL 208 IS 4 AR 310.e1 DI 10.1016/j.ajog.2013.01.017 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 116DR UT WOS:000316863300026 PM 23333548 ER PT J AU Carrington, LB Seifert, SN Armijos, MV Lambrechts, L Scott, TW AF Carrington, Lauren B. Seifert, Stephanie N. Armijos, M. Veronica Lambrechts, Louis Scott, Thomas W. TI Reduction of Aedes aegypti Vector Competence for Dengue Virus under Large Temperature Fluctuations SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LARVAL ENVIRONMENTAL-TEMPERATURE; EXTRINSIC INCUBATION; DIPTERA-CULICIDAE; MOSQUITO VECTORS; OCKELBO VIRUS; TRANSMISSION; SUSCEPTIBILITY; INFECTION; ENCEPHALITIS; THAILAND AB Diurnal temperature fluctuations can fundamentally alter mosquito biology and mosquito-virus interactions in ways that impact pathogen transmission. We investigated the effect of two daily fluctuating temperature profiles on Aedes aegypti vector competence for dengue virus (DENV) serotype-1. A large diurnal temperature range of 18.6 degrees C around a 26 degrees C mean, corresponding with the low DENV transmission season in northwestern Thailand, reduced midgut infection rates and tended to extend the virus extrinsic incubation period. Dissemination was first observed at day 7 under small fluctuations (7.6 degrees C; corresponding with high DENV transmission) and constant control temperature, but not until Day 11 for the large diurnal temperature range. Results indicate that female Ae. aegypti in northwest Thailand are less likely to transmit DENV during the low than high transmission season because of reduced DENV susceptibility and extended virus extrinsic incubation period. Better understanding of DENV transmission dynamics will come with improved knowledge of temperature effects on mosquito-virus interactions. C1 [Carrington, Lauren B.; Armijos, M. Veronica; Scott, Thomas W.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Lambrechts, Louis] Inst Pasteur, CNRS, Unite Rech Associee 3012, Paris, France. [Scott, Thomas W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Carrington, Lauren B.] Univ Melbourne, Nossal Inst Global Hlth, Carlton, Vic 3053, Australia. [Seifert, Stephanie N.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. RP Carrington, LB (reprint author), Univ Calif Davis, Dept Entomol, 1 Shields Ave, Davis, CA 95616 USA. EM lbcarrington@ucdavis.edu; seifst@sas.upenn.edu; mvarmijos@ucdavis.edu; louis.lambrechts@pasteur.fr; twscott@ucdavis.edu RI Lambrechts, Louis/A-2057-2010; OI Lambrechts, Louis/0000-0001-5958-2138; Carrington, Lauren Bree/0000-0001-9273-7912 FU Ecology of Infectious Disease Program of the National Science Foundation [EF-0914384]; Research and Policy for Infectious Disease Dynamics Program FX The study was supported by grant EF-0914384 from the Ecology of Infectious Disease Program of the National Science Foundation. Thomas W. Scott acknowledges funding from the Research and Policy for Infectious Disease Dynamics Program. NR 28 TC 32 Z9 34 U1 1 U2 33 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD APR PY 2013 VL 88 IS 4 BP 689 EP 697 DI 10.4269/ajtmh.12-0488 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 118KP UT WOS:000317024700014 PM 23438766 ER PT J AU Busse, PJ Cohn, RD Salo, PM Zeldin, DC AF Busse, Paula J. Cohn, Richard D. Salo, Paivi M. Zeldin, Darryl C. TI Characteristics of allergic sensitization among asthmatic adults older than 55 years: results from the National Health and Nutrition Examination Survey, 2005-2006 SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID IMMUNOGLOBULIN-E LEVELS; SKIN-TEST REACTIVITY; IGE LEVELS; EXPOSURE; AGE; POPULATION; SEVERITY; SEX; HYPERRESPONSIVENESS; UNDERDIAGNOSIS AB Background: Approximately 60% to 80% of children and young adults with asthma are sensitized to at least one allergen. In contrast, previous studies from specific subpopulations of older patients with asthma suggest that allergic sensitization is significantly lower in this age group. The prevalence and patterns of IgE-mediated sensitization have not been compared among a broad population of younger and older patients with asthma. Objective: To determine the prevalence and patterns of IgE-mediated sensitization among a broad population of younger and older patients with asthma. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 to compare IgE-mediated sensitization rates between younger (20-40 years) and older (>= 55 years) patients with current asthma. Atopy was defined as a detectable serum IgE to at least 1 allergen in a panel of 19 allergens. The associations among sensitization, current asthma, and asthma control measures (health care use and symptoms) were examined by logistic regression. Results: In a group of 2,573 patients, either 20 to 40 years of age or 55 years or older, 108 (6.7%) and 43 (4.5%) patients with current asthma were identified, respectively. Allergic sensitization rates among the adults with asthma differed only moderately and not statistically significantly between the age groups; 75.4% of the younger and 65.2% of the older asthmatic patients were sensitized to at least 1 allergen. The association between sensitization and markers of asthma control did not appear to differ among the age groups. Conclusion: Allergic sensitization in older patients with asthma may be more common than previously reported. (C) 2013 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. C1 [Busse, Paula J.] Mt Sinai Sch Med, Dept Med, Div Clin Immunol, New York, NY USA. [Cohn, Richard D.] SRA Int Inc, Durham, NC USA. [Salo, Paivi M.; Zeldin, Darryl C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Busse, PJ (reprint author), Mt Sinai Hosp, 1425 Madison Ave, New York, NY 10029 USA. EM paula.busse@mssm.edu FU Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health [Z01 025041] FX This research was supported in part by grant Z01 025041 from the Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health. NR 37 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD APR PY 2013 VL 110 IS 4 BP 247 EP 252 DI 10.1016/j.anai.2013.01.016 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 121VY UT WOS:000317274000007 PM 23535087 ER PT J AU Bornstein, MH Hahn, CS Suwalsky, JTD AF Bornstein, Marc H. Hahn, Chun-Shin Suwalsky, Joan T. D. TI Developmental Pathways Among Adaptive Functioning and Externalizing and Internalizing Behavioral Problems: Cascades From Childhood Into Adolescence SO APPLIED DEVELOPMENTAL SCIENCE LA English DT Article ID LIMITED ANTISOCIAL PATHWAYS; LIFE-COURSE-PERSISTENT; EPIDEMIOLOGIC SAMPLE; DEPRESSIVE SYMPTOMS; SOCIAL COMPETENCE; CONDUCT DISORDER; FIT INDEXES; FOLLOW-UP; CHILDREN; PSYCHOPATHOLOGY AB Here, a 3-wave multivariate design and developmental cascade analysis were used to investigate pathways among adaptive functioning and externalizing and internalizing behavioral problems in a community sample of 134 children seen at 4, 10, and 14 years. Adaptive functioning in early adolescence was predicted by early childhood adaptive functioning and externalizing behavioral problems, with both effects mediated by late childhood adaptive functioning and internalizing behavioral problems; externalizing behavioral problems in early adolescence were predicted by early childhood internalizing behavioral problems with the effect mediated by late childhood externalizing behavioral problems. These developmental cascades were obtained independent of child intelligence. Strategically timed and targeted interventions designed to address young children's behavioral problems may return investment in terms of an enhanced epidemiology of adaptively functioning teens. C1 [Bornstein, Marc H.; Hahn, Chun-Shin; Suwalsky, Joan T. D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-25] NR 72 TC 3 Z9 3 U1 2 U2 20 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1088-8691 J9 APPL DEV SCI JI Appl. Dev. Sci. PD APR 1 PY 2013 VL 17 IS 2 BP 76 EP 87 DI 10.1080/10888691.2013.774875 PG 12 WC Psychology, Developmental SC Psychology GA 121ZC UT WOS:000317283400003 PM 23585713 ER PT J AU Chan, L Sandel, ME Jette, AM Appelman, J Brandt, DE Cheng, PF TeSelle, M Delmonico, R Terdiman, JF Rasch, EK AF Chan, Leighton Sandel, M. Elizabeth Jette, Alan M. Appelman, Jed Brandt, Diane E. Cheng, Pengfei TeSelle, Marian Delmonico, Richard Terdiman, Joseph F. Rasch, Elizabeth K. TI Does Postacute Care Site Matter? A Longitudinal Study Assessing Functional Recovery After a Stroke SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Disability evaluation; Outcome assessment; Rehabilitation; Stroke ID INPATIENT REHABILITATION FACILITIES; CLINICAL-TRIALS; HIP FRACTURE; OUTCOMES; PATIENT; RELIABILITY; SETTINGS; VALIDITY; SCALE AB Objective: To determine the impact of postacute care site on stroke outcomes. Design: Prospective cohort study. Setting: Four northern California hospitals that are part of a single health maintenance organization. Participants: Patients with stroke (N=222) enrolled between February 2008 and July 2010. Intervention: Not applicable. Main Outcome Measure: Baseline and 6-month assessments were performed using the Activity Measure for Post Acute Care (AM-PAC), a test of self-reported function in 3 domains: Basic Mobility, Daily Activities, and Applied Cognition. Results: Of the 222 patients analyzed, 36% went home with no treatment, 22% received home health/outpatient care, 30% included an inpatient rehabilitation facility (IRF) in their care trajectory, and 13% included a skilled nursing facility (but not IRF) in their care trajectory. At 6 months, after controlling for important variables such as age, functional status at acute care discharge, and total hours of rehabilitation, patients who went to an IRF had functional scores that were at least 8 points higher (twice the minimally detectable change for the AM-PAC) than those who went to a skilled nursing facility in all 3 domains and in 2 of 3 functional domains compared with those who received home health/outpatient care. Conclusions: Patients with stroke may make more functional gains if their postacute care includes an IRF. This finding may have important implications as postacute care delivery is reshaped through health care reform. Archives of Physical Medicine and Rehabilitation 2013;94:622-9 (C) 2013 by the American Congress of Rehabilitation Medicine C1 [Chan, Leighton; Brandt, Diane E.; Rasch, Elizabeth K.] NIH, Mark O Hatfield Clin Res Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. [Sandel, M. Elizabeth; Appelman, Jed; Delmonico, Richard] Kaiser Fdn Rehabil Ctr, Vallejo, CA USA. [Jette, Alan M.] Hlth & Disabil Res Inst, Sch Publ Hlth, Boston, MA USA. [Cheng, Pengfei; Terdiman, Joseph F.] Kaiser Permanente Northern Calif, Permanente Med Grp, Div Res, Oakland, CA USA. [TeSelle, Marian] Kaiser Permanente, Capital Serv Area, Sacramento, CA USA. RP Chan, L (reprint author), NIH, Mark O Hatfield Clin Res Ctr, Dept Rehabil Med, Bldg 10,Room 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM chanle@cc.nih.gov OI Jette, Alan/0000-0002-2117-9973 FU National Institutes of Health Intramural Research Program; National Institute for Neurologic Diseases and Stroke [5RC1NS068397] FX Supported by the National Institutes of Health Intramural Research Program and by the National Institute for Neurologic Diseases and Stroke (grant no. 5RC1NS068397). NR 30 TC 20 Z9 20 U1 0 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD APR PY 2013 VL 94 IS 4 BP 622 EP 629 DI 10.1016/j.apmr.2012.09.033 PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 120LN UT WOS:000317171900004 PM 23124133 ER PT J AU Averbeck, BB Djamshidian, A O'Sullivan, SS Housden, CR Roiser, JP AF Averbeck, Bruno B. Djamshidian, Atbin O'Sullivan, Sean S. Housden, Charlotte R. Roiser, Jonathan P. TI Uncertainty About Mapping Future Actions Into Rewards May Underlie Performance on Multiple Measures of Impulsivity in Behavioral Addiction: Evidence From Parkinson's Disease SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE dopamine; Parkinson's disease; impulsivity; Markov decision process; sequential decision making ID STRIATAL DOPAMINE RELEASE; CONTROL DISORDERS; DECISION-MAKING; INTERTEMPORAL CHOICE; COMPULSIVE BEHAVIORS; REFLECTION-IMPULSIVITY; NOVELTY SEEKING; RISK; HUMANS; CONCLUSIONS AB A subset of patients with Parkinson's disease (PD) develops behavioral addictions, which may be due to their dopamine replacement therapy. Recently, several groups have been comparing PD patients with and without behavioral addictions on tasks that are thought to measure aspects of impulsivity. Several of these experiments, including information sampling, a bias toward novel stimuli and temporal discounting, have shown differences between PD patients with and without behavioral addictions. We have developed a unifying theoretical framework that allows us to model behavior in all three of these tasks. By exploring the performance of the patient groups on the three tasks with a single framework, we can ask questions about common mechanisms that underlie all three. Our results suggest that the effects seen in all three tasks can be accounted for by uncertainty about the ability to map future actions into rewards. More specifically, the modeling is consistent with the hypothesis that the group with behavioral addictions behaves as if they cannot use information provided within the experimental context to improve future reward guided actions. Future studies will be necessary to more firmly establish (or refute) this hypothesis. We discuss this result in light of what is known about the pathology that underlies the behavioral addictions in the PD patients. C1 [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Djamshidian, Atbin; O'Sullivan, Sean S.; Roiser, Jonathan P.] Univ London, Dept Mol Neurosci, London, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Roiser, Jonathan P.] Univ London, Reta Lila Weston Inst Neurol Studies, London, England. [Housden, Charlotte R.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Roiser, Jonathan P.] UCL, Inst Cognit Neurosci, London, England. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM bruno.averbeck@nih.gov RI Lees, Andrew/A-6605-2009; O'Sullivan, Sean/C-9333-2012 OI O'Sullivan, Sean/0000-0002-0583-7956 FU Intramural Research Program of the National Institute of Mental Health FX This work was supported in part by the Intramural Research Program of the National Institute of Mental Health. NR 68 TC 14 Z9 14 U1 3 U2 20 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2013 VL 127 IS 2 BP 245 EP 255 DI 10.1037/a0032079 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 119VY UT WOS:000317128600011 PM 23565936 ER PT J AU Merten, JA Shapiro, JF Gulbis, AM Rao, KV Bubalo, J Lanum, S Engemann, AM Shayani, S Williams, C Leather, H Walsh-Chocolaad, T AF Merten, Julianna A. Shapiro, Jamie F. Gulbis, Alison M. Rao, Kamakshi V. Bubalo, Joseph Lanum, Scott Engemann, Ashley Morris Shayani, Sepideh Williams, Casey Leather, Helen Walsh-Chocolaad, Tracey TI Utilization of Collaborative Practice Agreements between Physicians and Pharmacists as a Mechanism to Increase Capacity to Care for Hematopoietic Stem Cell Transplant Recipients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Hematopoietic cell transplantation; Collaborative drug therapy management; Pharmaceutical services; Medication Therapy Management; Physician capacity; National Marrow Donor Program ID DRUG-THERAPY MANAGEMENT; COMMUNITY PHARMACISTS; PATIENT SATISFACTION; MEDICATION ADHERENCE; SERVICES; IMPACT; OUTCOMES; PROTOCOL; PROGRAM; ANTICOAGULATION AB Survival after hematopoietic stem cell transplantation (HSCT) has improved and the number of allogeneic HSCTs performed annually in the United States is expected to reach 10,000 by 2015. The National Marrow Donor Program created the System Capacity Initiative to formulate mechanisms to care for the growing number of HSCT recipients. One proposed method to increase capacity is utilization of pharmacists to manage drug therapy via collaborative practice agreements (CPAs). Pharmacists have managed drug therapy in oncology patients with CPAs for decades; however, there are limited HSCT centers that employ this practice. Engaging in collaborative practice and billing agreements with credentialed pharmacists to manage therapeutic drug monitoring, chronic medical conditions, and supportive care in HSCT recipients may be cost-effective and enable physicians to spend more time on new or more complex patients. The goal of this paper is to provide a framework for implementation of a CPA and address how it may improve HSCT program capacity. (C) 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. C1 [Merten, Julianna A.] Mayo Clin, Dept Pharm, Rochester, MN USA. [Shapiro, Jamie F.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Pharm, Tampa, FL 33682 USA. [Gulbis, Alison M.] Univ Texas MD Anderson Canc Ctr, Div Pharm, Houston, TX 77030 USA. [Rao, Kamakshi V.] Univ North Carolina Hosp & Clin, Dept Pharm, Chapel Hill, NC USA. [Bubalo, Joseph] Oregon Hlth & Sci Univ, Dept Pharm, Portland, OR 97201 USA. [Lanum, Scott] Univ Washington, Med Ctr, Dept Pharm, Seattle, WA 98195 USA. [Engemann, Ashley Morris] Duke Univ, Med Ctr, Div Cellular Therapy, Durham, NC USA. [Shayani, Sepideh] City Hope Natl Med Ctr, Dept Pharm Serv, Duarte, CA 91010 USA. [Williams, Casey] Sanford Res USD, Edith Sanford Breast Canc Initiat, Sioux Falls, SD USA. [Leather, Helen] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL USA. [Walsh-Chocolaad, Tracey] NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. RP Merten, JA (reprint author), Rochester Methodist Hosp, Dept Pharm, 201 West Ctr St,Ei 1 420B, Rochester, MN 55905 USA. EM merten.julianna@mayo.edu FU Intramural NIH HHS [Z99 CL999999] NR 63 TC 4 Z9 4 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2013 VL 19 IS 4 BP 509 EP 518 DI 10.1016/j.bbmt.2012.12.022 PG 10 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 120IH UT WOS:000317163500003 PM 23419976 ER PT J AU Baird, K Steinberg, SM Grkovic, L Pulanic, D Cowen, EW Mitchell, SA Williams, KM Datiles, MB Bishop, R Bassim, CW Mays, JW Edwards, D Cole, K Avila, DN Taylor, T Urban, A Joe, GO Comis, LE Berger, A Stratton, P Zhang, D Shelhamer, JH Gea-Banacloche, JC Sportes, C Fowler, DH Gress, RE Pavletic, SZ AF Baird, Kristin Steinberg, Seth M. Grkovic, Lana Pulanic, Drazen Cowen, Edward W. Mitchell, Sandra A. Williams, Kirsten M. Datiles, Manuel B. Bishop, Rachel Bassim, Carol W. Mays, Jacqueline W. Edwards, Dean Cole, Kristen Avila, Daniele N. Taylor, Tiffany Urban, Amanda Joe, Galen O. Comis, Leora E. Berger, Ann Stratton, Pamela Zhang, Dan Shelhamer, James H. Gea-Banacloche, Juan C. Sportes, Claude Fowler, Daniel H. Gress, Ronald E. Pavletic, Steven Z. TI National Institutes of Health Chronic Graft-versus-Host Disease Staging in Severely Affected Patients: Organ and Global Scoring Correlate with Established Indicators of Disease Severity and Prognosis SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Institutes of Health; Chronic graft-versus-host disease; Consensus Criteria; Lung dysfunction; Sclerotic skin; Stem cell transplant ID CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; CLINICAL-TRIALS; BLOOD EOSINOPHILIA; CRITERIA; DIAGNOSIS; THERAPY; SCALE AB Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus <= 49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/mu L, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Baird, Kristin] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grkovic, Lana; Pulanic, Drazen; Williams, Kirsten M.; Cole, Kristen; Avila, Daniele N.; Taylor, Tiffany; Urban, Amanda; Zhang, Dan; Gea-Banacloche, Juan C.; Sportes, Claude; Fowler, Daniel H.; Gress, Ronald E.; Pavletic, Steven Z.] NCI, Expt Immunol & Transplantat Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Grkovic, Lana; Pulanic, Drazen] Clin Hosp Ctr Zagreb, Dept Internal Med, Div Hematol, Zagreb, Croatia. [Cowen, Edward W.] NIH, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Mitchell, Sandra A.] NIH, Div Canc Control & Populat Sci, Ctr Canc Res, Bethesda, MD 20892 USA. [Williams, Kirsten M.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders Blood & Marrow Transpl, Washington, DC 20010 USA. [Datiles, Manuel B.; Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Bassim, Carol W.; Mays, Jacqueline W.; Edwards, Dean] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Joe, Galen O.; Comis, Leora E.] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. [Berger, Ann] NIH, Dept Pain & Palliat Care, Ctr Clin, Bethesda, MD 20892 USA. [Stratton, Pamela] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD USA. [Shelhamer, James H.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Pulanic, Drazen] JJ Strossmayer Univ Osijek, Fac Med Osijek, Osijek, Croatia. RP Baird, K (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 1W-3940, Bethesda, MD 20892 USA. EM kbaird@mail.nih.gov OI Datiles, Manuel III B./0000-0003-4660-1664 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. The authors are employees of the United States Government, and, as such, this work was done in that capacity. The views expressed do not necessarily represent the views of the National Institutes of Health or the United States Government. There are no conflicts of interest to report. NR 33 TC 24 Z9 24 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2013 VL 19 IS 4 BP 632 EP 639 DI 10.1016/j.bbmt.2013.01.013 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 120IH UT WOS:000317163500019 PM 23340040 ER PT J AU Yuen, TJ Johnson, KR Miron, VE Zhao, C Quandt, J Harrisingh, MC Swire, M Williams, A McFarland, HF Franklin, RJM Ffrench-Constant, C AF Yuen, Tracy J. Johnson, Kory R. Miron, Veronique E. Zhao, Chao Quandt, Jacqueline Harrisingh, Marie C. Swire, Matthew Williams, Anna McFarland, Henry F. Franklin, Robin J. M. Ffrench-Constant, Charles TI Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination SO BRAIN LA English DT Article DE remyelination; inflammation; oligodendrocytes; endothelin; regeneration; multiple sclerosis ID CNS REMYELINATION; OLIGODENDROCYTE DIFFERENTIATION; RECEPTOR ANTAGONIST; SCHWANN-CELLS; OPTIC-NERVE; MYELINATION; DEMYELINATION; BRAIN; REGENERATION; EXPRESSION AB The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration. C1 [Yuen, Tracy J.; Miron, Veronique E.; Harrisingh, Marie C.; Swire, Matthew; Williams, Anna; Ffrench-Constant, Charles] Univ Edinburgh, Ctr Translat Res, MS Soc, Edinburgh EH16 4TJ, Midlothian, Scotland. [Yuen, Tracy J.; Zhao, Chao; Franklin, Robin J. M.] Univ Cambridge, Wellcome Trust MRC Cambridge Stem Cell Inst, Cambridge, England. [Yuen, Tracy J.; Zhao, Chao; Franklin, Robin J. M.] Univ Cambridge, Dept Vet Med, Cambridge, England. [Yuen, Tracy J.; Quandt, Jacqueline; McFarland, Henry F.] NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, Bioinformat Sect, Informat Technol & Bioinformat Program, NIH, Bethesda, MD 20892 USA. RP Ffrench-Constant, C (reprint author), Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4TJ, Midlothian, Scotland. EM cffc@ed.ac.uk FU United Kingdom Multiple Sclerosis Society; National Multiple Sclerosis Society; Wellcome Trust; National Institutes of Health-University of Cambridge; International Biomedical Research Alliance FX This work was supported by the United Kingdom Multiple Sclerosis Society (to C.ff.C., R.J.M.F.); National Multiple Sclerosis Society (to C.ff.C., R.J.M.F.); and the Wellcome Trust (to C.ff.C.) T.J.Y. was supported by the National Institutes of Health-University of Cambridge Graduate Partnerships Program and the International Biomedical Research Alliance. NR 50 TC 23 Z9 24 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2013 VL 136 BP 1035 EP 1047 DI 10.1093/brain/awt024 PN 4 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 123OW UT WOS:000317400700007 PM 23518706 ER PT J AU Milton, JN Rooks, H Drasar, E McCabe, EL Baldwin, CT Melista, E Gordeuk, VR Nouraie, M Kato, GR Minniti, C Taylor, J Campbell, A Luchtman-Jones, L Rana, S Castro, O Zhang, YZ Thein, SL Sebastiani, P Gladwin, MT Steinberg, MH AF Milton, Jacqueline N. Rooks, Helen Drasar, Emma McCabe, Elizabeth L. Baldwin, Clinton T. Melista, Efi Gordeuk, Victor R. Nouraie, Mehdi Kato, Gregory R. Minniti, Caterina Taylor, James Campbell, Andrew Luchtman-Jones, Lori Rana, Sohail Castro, Oswaldo Zhang, Yingze Thein, Swee Lay Sebastiani, Paola Gladwin, Mark T. Steinberg, Martin H. CA Walk-PHAAST Investigators TI Genetic determinants of haemolysis in sickle cell anaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE haemolysis; sickle cell anaemia; haemolytic anaemia; genetic analysis; thalassaemia ID REGULATORY ELEMENT HS-40; GENOME-WIDE ASSOCIATION; ALPHA-THALASSEMIA; GLOBIN GENE; FETAL-HEMOGLOBIN; HUMAN-DISEASE; NITRIC-OXIDE; POLYMORPHISM; POPULATION; MORTALITY AB Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13 center dot 3) (P=6 center dot 04x1007). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r2=1) and in strong LD with rs7197554 (r2=0 center dot 75) and rs13336641 (r2=0 center dot 77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the 3 center dot 7thalassaemia gene deletion. When adjusting for HbF and thalassaemia, the association of NPRL3 with the haemolytic score was significant (P=0 center dot 00375) and remained significant when examining only cases without gene deletion thalassaemia (P=0 center dot 02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia. C1 [Milton, Jacqueline N.; McCabe, Elizabeth L.; Sebastiani, Paola] Boston Univ, Boston, MA 02118 USA. [Rooks, Helen; Drasar, Emma; Thein, Swee Lay] Kings Coll Sch Med, London, England. [Drasar, Emma; Thein, Swee Lay] Kings Coll London, London WC2R 2LS, England. [Baldwin, Clinton T.; Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Melista, Efi] Boston Univ, Ctr Human Genet, Boston, MA 02118 USA. [Gordeuk, Victor R.; Nouraie, Mehdi; Rana, Sohail; Castro, Oswaldo] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Kato, Gregory R.; Minniti, Caterina; Taylor, James; Castro, Oswaldo] NHLBI, Sickle Cell Vasc Dis Sect, Hematol Branch, Bethesda, MD 20892 USA. [Campbell, Andrew] Univ Michigan, Ann Arbor, MI 48109 USA. [Luchtman-Jones, Lori] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Zhang, Yingze; Gladwin, Mark T.; Walk-PHAAST Investigators] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. RP Steinberg, MH (reprint author), Boston Univ, Sch Med, Dept Med, 72 E Concord St, Boston, MA 02118 USA. EM mhsteinb@bu.edu RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; sebastiani, paola/0000-0001-6419-1545; Steinberg, Martin/0000-0001-8800-8020; Schraufnagel, Dean/0000-0003-0063-7223; Taylor, James/0000-0002-4421-1809 FU National Institutes of Health [R01 HL87681, RC2 L101212, 5T32HL007501, 2R25 HL003679-8, R01 HL079912, 2M01 RR10284-10, R01HL098032, R01HL096973, P01HL103455, 5T32]; Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania; Medical Research Grant (UK) [G0001249 ID 56477] FX This work was supported by National Institutes of Health Grants R01 HL87681 (MHS), RC2 L101212 (MHS), 5T32HL007501 (JNM), 2R25 HL003679-8 (VRG), R01 HL079912 (VRG), 2M01 RR10284-10 (VRG), R01HL098032 (MTG), R01HL096973 (MTG), P01HL103455 (MTG), the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania (MTG), Medical Research Grant (UK) G0001249 ID 56477 (SLT). Monika Kowalczyk and Douglas Higgs kindly provided their unpublished results and very important input.This work was supported by National Institutes of Health Grants R01 HL87681 (MHS), RC2 L101212 (MHS), 5T32 NR 35 TC 16 Z9 17 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2013 VL 161 IS 2 BP 270 EP 278 DI 10.1111/bjh.12245 PG 9 WC Hematology SC Hematology GA 119UN UT WOS:000317124200015 PM 23406172 ER PT J AU Park, SR Speranza, G Piekarz, R Wright, JJ Kinders, RJ Wang, LH Pfister, T Trepel, JB Lee, MJ Alarcon, S Steinberg, SM Collins, J Doroshow, JH Kummar, S AF Park, Sook Ryun Speranza, Giovanna Piekarz, Richard Wright, John J. Kinders, Robert J. Wang, Lihua Pfister, Thomas Trepel, Jane B. Lee, Min-Jung Alarcon, Sylvia Steinberg, Seth M. Collins, Jerry Doroshow, James H. Kummar, Shivaani TI A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Fostamatinib; R406; R935788; Solid tumors; Angiogenesis ID SPLEEN TYROSINE KINASE; CIRCULATING ENDOTHELIAL-CELLS; RHEUMATOID-ARTHRITIS; PROGENITOR CELLS; BREAST-CANCER; INHIBITOR; SYK; BEVACIZUMAB; ANGIOGENESIS; LYMPHOMA AB A multi-cohort phase II study of fostamatinib, an oral multi-kinase inhibitor, was conducted to determine the response rate in patients with advanced colorectal (CRC), thyroid, non-small cell lung, head and neck, and renal cell carcinomas, and pheochromocytomas. Patients received 200 mg fostamatinib BID in 4-week cycles with response assessed every 2 cycles. Blood was collected for pharmacokinetic analysis and measurements of circulating tumor cells and circulating endothelial (progenitor) cells (CE(P)Cs). A total of 37 patients (22 CRC), median of 4 prior therapies, were enrolled. Due to toxicities in four of the first five patients, the study was amended to incorporate a dose escalation phase for each histology. The maximum-tolerated dose was established at 50 mg BID in CRC but was not established for the other cancers. Common grade 3/4 toxicities included transaminitis, hyperbilirubinemia, and hypertension. Pharmacokinetic profile was similar to previous reports. Seventy-three percent of CRC patients had liver involvement and 91 % had prior anti-angiogenic therapy. Patients with abnormal liver tests at baseline were more likely to experience grade a parts per thousand yen2 hepatotoxicity than those with normal tests (44 vs. 0 %). No responses were observed; disease stabilization rate was 27 % in CRC. Reduction in CECs following treatment was associated with a better disease stabilization rate (75 vs. 0 %) in CRC. Fostamatinib had limited anti-tumor activity in this first clinical trial in patients with advanced refractory solid tumors; reduction in CECs and CEPs was indicative of anti-angiogenic effects. Abnormal liver testing at baseline appeared to influence drug tolerability. C1 [Park, Sook Ryun; Speranza, Giovanna; Piekarz, Richard; Wright, John J.; Collins, Jerry; Doroshow, James H.; Kummar, Shivaani] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kinders, Robert J.; Wang, Lihua; Pfister, Thomas] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Appl Dev Res Directorate, Frederick, MD USA. [Trepel, Jane B.; Lee, Min-Jung; Alarcon, Sylvia; Steinberg, Seth M.; Doroshow, James H.; Kummar, Shivaani] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Div Canc Treatment & Diag, 31 Ctr Dr,3A44, Bethesda, MD 20892 USA. EM kummars@mail.nih.gov FU National cancer institute, National institutes of health [HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National cancer institute, National institutes of health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the department of health and human services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. NR 24 TC 11 Z9 11 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD APR PY 2013 VL 71 IS 4 BP 981 EP 990 DI 10.1007/s00280-013-2091-3 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 114MM UT WOS:000316745500017 PM 23404627 ER PT J AU Stumpf, JD Saneto, RP Copeland, WC AF Stumpf, Jeffrey D. Saneto, Russell P. Copeland, William C. TI Clinical and Molecular Features of POLG-Related Mitochondrial Disease SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID DNA-POLYMERASE-GAMMA; PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; SENSORY ATAXIC NEUROPATHY; MTDNA MUTATOR MICE; SACCHAROMYCES-CEREVISIAE; ALPERS-SYNDROME; W748S MUTATION; AUTOSOMAL-DOMINANT; STATUS EPILEPTICUS; ACCESSORY SUBUNIT AB The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol gamma) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol gamma, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG- related disease: (1) clinical symptoms that identify and distinguish POLGrelated diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol gamma exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol gamma replication. C1 [Stumpf, Jeffrey D.; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Saneto, Russell P.] Univ Washington, Div Pediat Neurol, Seattle Childrens Hosp, Seattle, WA 98105 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [ES 065078]; Mitochondrial Research Guild at Seattle Children's Hospital FX We and the rest of the POLG field are indebted to the hard work of Margaret Humble for maintaining and updating the pol gamma mutation database (http://tools.niehs.nih.gov/polg). We also thank Drs. Richard Gradman and Tammy Collins for comments and suggestions from their critical reading of this manuscript. This work is supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Environmental Health Sciences (ES 065078), and the Mitochondrial Research Guild at Seattle Children's Hospital. NR 91 TC 16 Z9 16 U1 0 U2 19 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD APR PY 2013 VL 5 IS 4 AR a011395 DI 10.1101/cshperspect.a011395 PG 17 WC Cell Biology SC Cell Biology GA 120MT UT WOS:000317175200009 PM 23545419 ER PT J AU Ivankov, DN Payne, SH Galperin, MY Bonissone, S Pevzner, PA Frishman, D AF Ivankov, Dmitry N. Payne, Samuel H. Galperin, Michael Y. Bonissone, Stefano Pevzner, Pavel A. Frishman, Dmitrij TI How many signal peptides are there in bacteria? SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI K-12; N-TERMINAL PEPTIDES; COMBINED TRANSMEMBRANE TOPOLOGY; TANDEM MASS-SPECTRA; SUBCELLULAR-LOCALIZATION; GENOME ANNOTATION; SORTING SIGNALS; CLEAVAGE SITES; PREDICTION; IDENTIFICATION AB Over the last 5 years proteogenomics (using mass spectroscopy to identify proteins predicted from genomic sequences) has emerged as a promising approach to the high-throughput identification of protein N-termini, which remains a problem in genome annotation. Comparison of the experimentally determined N-termini with those predicted by sequence analysis tools allows identification of the signal peptides and therefore conclusions on the cytoplasmic or extracytoplasmic (periplasmic or extracellular) localization of the respective proteins. We present here the results of a proteogenomic study of the signal peptides in Escherichia coliK-12 and compare its results with the available experimental data and predictions by such software tools as SignalP and Phobius. A single proteogenomics experiment recovered more than a third of all signal peptides that had been experimentally determined during the past three decades and confirmed at least 31 additional signal peptides, mostly in the known exported proteins, which had been previously predicted but not validated. The filtering of putative signal peptides for the peptide length and the presence of an eight-residue hydrophobic patch and a typical signal peptidase cleavage site proved sufficient to eliminate the false-positive hits. Surprisingly, the results of this proteogenomics study, as well as a re-analysis of the E.coli genome with the latest version of SignalP program, show that the fraction of proteins containing signal peptides is only about 10%, or half of previous estimates. C1 [Ivankov, Dmitry N.; Frishman, Dmitrij] Tech Univ Munich, Dept Genome Oriented Bioinformat, D-85354 Freising Weihenstephan, Germany. [Payne, Samuel H.] Pacific NW Natl Lab, Biol Sci Div, Richland, WA 99352 USA. [Galperin, Michael Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Bonissone, Stefano; Pevzner, Pavel A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Frishman, Dmitrij] Helmholtz Zentrum Munich, Natl Res Ctr Environm & Hlth, Inst Bioinformat, D-85764 Neuherberg, Germany. RP Frishman, D (reprint author), Tech Univ Munich, Dept Genome Oriented Bioinformat, D-85354 Freising Weihenstephan, Germany. EM d.frishman@wzw.tum.de OI Payne, Samuel/0000-0002-8351-1994; Galperin, Michael/0000-0002-2265-5572 FU DFG International Training and Research Group RECESS (Regulation and Evolution of Cellular Systems); NSF [EF-0949047]; NIH Intramural Research Program at the National Library of Medicine; NIAID [IAA-Y1-A1-8401]; U.S. Department of Energy/Biological and Environmental Research national scientific user facility; DOE by Battelle [DEAC05-76RLO 1830] FX We thank Natalya Bogatyreva for assistance. D. N. I. was supported by the DFG International Training and Research Group RECESS (Regulation and Evolution of Cellular Systems). S. H. P. was supported by an NSF award EF-0949047. M. Y. G. was supported by the NIH Intramural Research Program at the National Library of Medicine. Data from the Pacific Northwest National Laboratory were obtained with funding from NIAID IAA-Y1-A1-8401 in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy/Biological and Environmental Research national scientific user facility. Pacific Northwest National Laboratory is operated for the DOE by Battelle under Contract DEAC05-76RLO 1830. NR 47 TC 11 Z9 12 U1 2 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-2912 EI 1462-2920 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD APR PY 2013 VL 15 IS 4 BP 983 EP 990 DI 10.1111/1462-2920.12105 PG 8 WC Microbiology SC Microbiology GA 122AM UT WOS:000317287200001 PM 23556536 ER PT J AU Roman, E Lightfoot, T Smith, AG Forman, MR Linet, MS Robison, L Simpson, J Kaatsch, P Grell, K Frederiksen, K Schuz, J AF Roman, Eve Lightfoot, Tracy Smith, Alexandra G. Forman, Michele R. Linet, Martha S. Robison, Les Simpson, Jill Kaatsch, Peter Grell, Kathrine Frederiksen, Kirsten Schuz, Joachim TI Childhood acute lymphoblastic leukaemia and birthweight: Insights from a pooled analysis of case-control data from Germany, the United Kingdom and the United States SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Childhood Cancer; Low birth weight; Epidemiology; Perinatal mortality ID GROWTH-FACTOR-I; CONGENITAL LEUKEMIA; MAGNETIC-FIELDS; GESTATIONAL-AGE; PRETERM BIRTH; FETAL-GROWTH; BRAIN-TUMORS; RISK-FACTOR; CANCER; PREGNANCY AB Background: Heavy birthweight is one of the few established risk factors for childhood acute lymphoblastic leukaemia (ALL). To provide new insight into this relationship, particularly at the extremes (<1500 and >4500 g), we pooled data from three of the largest childhood cancer case-control studies ever conducted. Methods: Birthweight and gestational age on 4075 children with ALL and 12,065 controls were collected during the course of three studies conducted in the USA, the UK and Germany in the 1990s. Information was obtained from mothers at interview, and the impact of bias was evaluated using the UK study which accessed birth registrations of participants and non-participants. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. Results: Children with ALL were, on average, heavier than controls at all gestations, the disparity being driven by a deficit of low-birthweight at all gestations and an excess of high-birth-weight at >= 40 weeks. Overall, a 1.2 (95% CI 1.1-1.3) increase in ALL risk per kg increase in birthweight was observed; the ORs rising from 0.2 (0.1-0.7) at <= 1500 g through to 1.2 (0.9-1.6) at >= 4500 g; and 0.8 (0.7-0.9) <10th centile through to 1.3 (1.1-1.4) >= 90th centile. Conclusion: Our findings demonstrate the importance of looking across the full birthweight spectrum when examining associations with disease risk. The new observation of a deficit of very-low-birthweight cases at all gestations has aetiological and study design implications for future work examining not only the in utero origins of ALL, but also other childhood and adult cancers. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Roman, Eve; Lightfoot, Tracy; Smith, Alexandra G.; Simpson, Jill] Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, York YO10 5DD, N Yorkshire, England. [Forman, Michele R.] Univ Texas, Coll Nat Sci, Dell Pediat Inst, Dept Nutr Sci, Austin, TX USA. [Linet, Martha S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Robison, Les] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Kaatsch, Peter] Johannes Gutenberg Univ Mainz, German Childhood Canc Registry, Mainz, Germany. [Grell, Kathrine; Frederiksen, Kirsten] Danish Canc Soc Res Ctr, Stat Bioinformat & Registry, Copenhagen, Denmark. [Schuz, Joachim] Sect Environm & Radiat, Int Agcy Res Canc, Lyon, France. RP Roman, E (reprint author), Univ York, Dept Hlth Sci, Epidemiol & Canc Stat Grp, Area 3,Seebohm Rowntree Bldg, York YO10 5DD, N Yorkshire, England. EM eve.roman@york.ac.uk RI sebastianovitsch, stepan/G-8507-2013 FU UK's Leukaemia Lymphoma Research; National Cancer Institute [CA 48051]; Children's Cancer Research Fund; German Ministry for the Environment; Leukaemia & Lymphoma Research FX The present analysis was supported by the UK's Leukaemia Lymphoma Research. The original US study was supported in part by Grant CA 48051 from the National Cancer Institute and a grant from the Children's Cancer Research Fund; the German study by a grant from the German Ministry for the Environment; and the UK study is sponsored and administered by Leukaemia & Lymphoma Research. None of the funders had any role in the design of the study, the collection, analysis and interpretation of the data, the writing of the manuscript, or the decision to publish. The corresponding author had full access to all data and the final responsibility for the decision to submit the manuscript for publication. NR 45 TC 12 Z9 13 U1 0 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD APR PY 2013 VL 49 IS 6 BP 1437 EP 1447 DI 10.1016/j.ejca.2012.11.017 PG 11 WC Oncology SC Oncology GA 120RF UT WOS:000317188600028 PM 23266048 ER PT J AU Simpson, CL Cropp, CD Wahlfors, T George, A Jones, MS Harper, U Ponciano-Jackson, D Tammela, T Schleutker, J Bailey-Wilson, JE AF Simpson, Claire L. Cropp, Cheryl D. Wahlfors, Tiina George, Asha Jones, MaryPat S. Harper, Ursula Ponciano-Jackson, Damaris Tammela, Teuvo Schleutker, Johanna Bailey-Wilson, Joan E. TI Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE linkage analysis; ordered subset analysis; prostate cancer ID COMPARATIVE GENOMIC HYBRIDIZATION; AUTOSOMAL-DOMINANT INHERITANCE; WIDE LINKAGE SCAN; CHROMOSOME 8Q24; SUSCEPTIBILITY LOCUS; GERMLINE MUTATIONS; COMMON VARIANTS; RISK LOCUS; AMPLIFICATION UNIT; AFRICAN-AMERICANS AB Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (Delta LOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, Delta LOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, Delta LOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families. European Journal of Human Genetics (2013) 21, 437-443; doi:10.1038/ejhg.2012.185; published online 5 September 2012 C1 [Simpson, Claire L.; Cropp, Cheryl D.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. [Wahlfors, Tiina; Schleutker, Johanna] Univ Tampere, BioMediTech, Inst Biomed Technol, FIN-33101 Tampere, Finland. [Wahlfors, Tiina; Schleutker, Johanna] Fimlab Labs, Tampere, Finland. [George, Asha] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Jones, MaryPat S.; Harper, Ursula; Ponciano-Jackson, Damaris] NHGRI, Genom Core, Genome Technol Branch, NIH, Rockville, MD USA. [Tammela, Teuvo] Univ Tampere, Dept Urol, Tampere Univ Hosp, FIN-33101 Tampere, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. RP Bailey-Wilson, JE (reprint author), NHGRI, Inherited Dis Res Branch, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM jebw@nhgri.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural Program of the National Human Genome Research Institute, National Institutes of Health; Academy of Finland [116437, 251074]; Sigrid Juselius Foundation; Finnish Cancer Organizations; Tampere University Hospital [9M094]; NHGRI Health Disparities Research Fellowship; National Institutes of Health [U01 CA89600]; Center for Inherited Disease Research (NIH) [N01-HG-65403] FX We would like to express our gratitude to the families who participated in this study. This work was supported in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health, the Academy of Finland (116437, 251074), the Sigrid Juselius Foundation, the Finnish Cancer Organizations and the Competitive Research Funding of the Tampere University Hospital (9M094). CDC is the recipient of an NHGRI Health Disparities Research Fellowship. The International Consortium for Prostate Cancer Genetics (ICPCG), including the consortium's Data Coordinating Center (DCC), is made possible by a grant from the National Institutes of Health U01 CA89600 (to William B Isaacs). SNP genotyping services were provided by the Center for Inherited Disease Research (NIH Contract: N01-HG-65403). NR 83 TC 2 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD APR PY 2013 VL 21 IS 4 BP 437 EP 443 DI 10.1038/ejhg.2012.185 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 119HV UT WOS:000317089300015 PM 22948022 ER PT J AU Huang, J Liu, EY Welch, R Willer, C Hindorff, LA Li, Y AF Huang, Jie Liu, Eric Y. Welch, Ryan Willer, Cristen Hindorff, Lucia A. Li, Yun TI WikiGWA: an open platform for collecting and using genome-wide association results SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE genome-wide association; open platform; bioinformatics AB The number of discovered genetic variants from genome-wide association (GWA) studies (GWAS) has been growing rapidly. Centralized efforts such as the National Human Genome Research Institute's GWAS catalog provide regular updates and a convenient interface for quick lookup. However, the catalog entries are manually curated and rely on data from published articles. Other tools such as SNPedia (http://www.snpedia.com) collect published results regarding functional consequences of genetic variations. Here, we propose an approach that allows individual investigators to share their GWA results through an open platform. Unlike GWAS catalog or SNPedia, wikiGWA collects first-hand GWAS results and in a much larger scale. Investigators are not only able to post a much larger amount of results, but also post results from unpublished studies, which could alleviate publication bias and facilitate identification of weak signals. Our interface allows for flexible and fast queries, and the query results are formatted to work seamlessly with the Locus Zoom program for visualization and annotation. We here describe wikiGWA, made publically available at http://www.wikiGWA.org. European Journal of Human Genetics (2013) 21, 471-473; doi:10.1038/ejhg.2012.187; published online 29 August 2012 C1 [Huang, Jie] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge CB10 1SA, England. [Liu, Eric Y.; Li, Yun] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. [Welch, Ryan] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Willer, Cristen] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Hindorff, Lucia A.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. [Li, Yun] Univ N Carolina, Dept Biostat, Dept Genet, Chapel Hill, NC 27599 USA. RP Huang, J (reprint author), Wellcome Trust Sanger Inst, Dept Human Genet, Genome Campus, Cambridge CB10 1SA, England. EM jh21@sanger.ac.uk; yunli@med.unc.edu RI Liu, Eric Yi/B-6221-2016; OI Willer, Cristen/0000-0001-5645-4966 FU NIH [R01-HG006292, R01-HG006703-01, 3-R01-CA082659-11S1] FX We thank the Consortium of GIANT and MAGIC for making a few their GWA results publically available. We thank the users who signed up and uploaded their GWA findings to our beta version website. YL is supported by the NIH grant R01-HG006292, R01-HG006703-01, and 3-R01-CA082659-11S1. NR 9 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD APR PY 2013 VL 21 IS 4 BP 471 EP 473 DI 10.1038/ejhg.2012.187 PG 3 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 119HV UT WOS:000317089300022 PM 22929026 ER PT J AU Gatton, ML Chitnis, N Churcher, T Donnelly, MJ Ghani, AC Godfray, HCJ Gould, F Hastings, I Marshall, J Ranson, H Rowland, M Shaman, J Lindsay, SW AF Gatton, Michelle L. Chitnis, Nakul Churcher, Thomas Donnelly, Martin J. Ghani, Azra C. Godfray, H. Charles J. Gould, Fred Hastings, Ian Marshall, John Ranson, Hilary Rowland, Mark Shaman, Jeff Lindsay, Steve W. TI THE IMPORTANCE OF MOSQUITO BEHAVIOURAL ADAPTATIONS TO MALARIA CONTROL IN AFRICA SO EVOLUTION LA English DT Review DE Anopheles; indoor residual spraying; insecticidal nets; resistance ID ANOPHELES-GAMBIAE COMPLEX; INSECTICIDE-TREATED NETS; CULEX-QUINQUEFASCIATUS MOSQUITOS; EXPERIMENTAL HUT EVALUATION; ARABIENSIS PATTON DIPTERA; HOST-SEEKING BEHAVIOR; BED NETS; PYRETHROID-RESISTANT; FEEDING-BEHAVIOR; VECTOR CONTROL AB Over the past decade the use of long-lasting insecticidal nets (LLINs), in combination with improved drug therapies, indoor residual spraying (IRS), and better health infrastructure, has helped reduce malaria in many African countries for the first time in a generation. However, insecticide resistance in the vector is an evolving threat to these gains. We review emerging and historical data on behavioral resistance in response to LLINs and IRS. Overall the current literature suggests behavioral and species changes may be emerging, but the data are sparse and, at times unconvincing. However, preliminary modeling has demonstrated that behavioral resistance could have significant impacts on the effectiveness of malaria control. We propose seven recommendations to improve understanding of resistance in malaria vectors. Determining the public health impact of physiological and behavioral insecticide resistance is an urgent priority if we are to maintain the significant gains made in reducing malaria morbidity and mortality. C1 [Gatton, Michelle L.; Godfray, H. Charles J.; Gould, Fred; Shaman, Jeff; Lindsay, Steve W.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Gatton, Michelle L.] Queensland Inst Med Res, Malaria Drug Resistance & Chemotherapy Lab, Brisbane, Qld 4006, Australia. [Chitnis, Nakul] Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland. [Chitnis, Nakul] Univ Basel, CH-4003 Basel, Switzerland. [Churcher, Thomas; Marshall, John] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 IPG, England. [Donnelly, Martin J.; Ranson, Hilary] Univ Liverpool, Liverpool Sch Trop Med, Vector Grp, Liverpool L3 5QA, Merseyside, England. [Ghani, Azra C.] Univ London Imperial Coll Sci Technol & Med, Dept Dis Epidemiol, MRC Ctr Outbreak Anal & Modelling, London W2 1PG, England. [Godfray, H. Charles J.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Hastings, Ian] Univ Liverpool, Liverpool Sch Trop Med, Mol & Biochem Parasitol Grp, Liverpool L3 5QA, Merseyside, England. [Rowland, Mark] Univ London London Sch Hyg & Trop Med, Dept Dis Control, London WC1E 7HT, England. [Shaman, Jeff] Columbia Univ, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Lindsay, Steve W.] Univ Durham, Sch Biol & Biomed Sci, Durham DH 3LE, England. RP Gatton, ML (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM m.gatton@qut.edu.au RI Ghani, Azra/B-8560-2009; Chitnis, Nakul/B-3105-2013; OI Gatton, Michelle/0000-0003-1188-609X; Churcher, Thomas/0000-0002-8442-0525; Ranson, Hilary/0000-0003-2332-8247 FU Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security; Fogarty International Center, National Institutes of Health; NHMRC; Bill and Melinda Gates Foundation FX The authors thank K. Shea, L. White, and U. Kitron for insightful discussions and review of the manuscript. This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. MLG was supported by an NHMRC Career Development Award. NC was supported by a grant from the Bill and Melinda Gates Foundation. The authors have no competing interests. NR 104 TC 63 Z9 67 U1 3 U2 70 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-3820 EI 1558-5646 J9 EVOLUTION JI Evolution PD APR PY 2013 VL 67 IS 4 BP 1218 EP 1230 DI 10.1111/evo.12063 PG 13 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 119XT UT WOS:000317133800026 PM 23550770 ER PT J AU Andersen, JB Thorgeirsson, SS AF Andersen, Jesper B. Thorgeirsson, Snorri S. TI Genomic Decoding of Intrahepatic Cholangiocarcinoma Reveals Therapeutic Opportunities SO GASTROENTEROLOGY LA English DT Editorial Material ID HEPATOCELLULAR-CARCINOMA; GENE; RECURRENCE C1 [Andersen, Jesper B.; Thorgeirsson, Snorri S.] NIH, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Bldg 37,Room 4146A,37 Convent Dr, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov OI Andersen , Jesper B/0000-0003-1760-5244 NR 25 TC 4 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2013 VL 144 IS 4 BP 687 EP 690 DI 10.1053/j.gastro.2013.02.018 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 114JB UT WOS:000316735800022 PM 23462122 ER PT J AU Peters, U Jiao, S Schumacher, FR Hutter, CM Aragaki, AK Baron, JA Berndt, SI Bezieau, S Brenner, H Butterbach, K Caan, BJ Campbell, PT Carlson, CS Casey, G Chan, AT Chang-Claude, J Chanock, SJ Chen, LS Coetzee, GA Coetzee, SG Conti, DV Curtis, KR Duggan, D Edwards, T Fuchs, CS Gallinger, S Giovannucci, EL Gogarten, SM Gruber, SB Haile, RW Harrison, TA Hayes, RB Henderson, BE Hoffmeister, M Hopper, JL Hudson, TJ Hunter, DJ Jackson, RD Jee, SH Jenkins, MA Jia, WH Kolonel, LN Kooperberg, C Kuery, S Lacroix, AZ Laurie, CC Laurie, CA Le Marchand, L Lemire, M Levine, D Lindor, NM Liu, Y Ma, J Makar, KW Matsuo, K Newcomb, PA Potter, JD Prentice, RL Qu, CH Rohan, T Rosse, SA Schoen, RE Seminara, D Shrubsole, M Shu, XO Slattery, ML Taverna, D Thibodeau, SN Ulrich, CM White, E Xiang, YB Zanke, BW Zeng, YX Zhang, B Zheng, W Hsu, L AF Peters, Ulrike Jiao, Shuo Schumacher, Fredrick R. Hutter, Carolyn M. Aragaki, Aaron K. Baron, John A. Berndt, Sonja I. Bezieau, Stephane Brenner, Hermann Butterbach, Katja Caan, Bette J. Campbell, Peter T. Carlson, Christopher S. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen J. Chen, Lin S. Coetzee, Gerhard A. Coetzee, Simon G. Conti, David V. Curtis, Keith R. Duggan, David Edwards, Todd Fuchs, Charles S. Gallinger, Steven Giovannucci, Edward L. Gogarten, Stephanie M. Gruber, Stephen B. Haile, Robert W. Harrison, Tabitha A. Hayes, Richard B. Henderson, Brian E. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Hunter, David J. Jackson, Rebecca D. Jee, Sun Ha Jenkins, Mark A. Jia, Wei-Hua Kolonel, Laurence N. Kooperberg, Charles Kuery, Sebastien Lacroix, Andrea Z. Laurie, Cathy C. Laurie, Cecelia A. Le Marchand, Loic Lemire, Mathieu Levine, David Lindor, Noralane M. Liu, Yan Ma, Jing Makar, Karen W. Matsuo, Keitaro Newcomb, Polly A. Potter, John D. Prentice, Ross L. Qu, Conghui Rohan, Thomas Rosse, Stephanie A. Schoen, Robert E. Seminara, Daniela Shrubsole, Martha Shu, Xiao-Ou Slattery, Martha L. Taverna, Darin Thibodeau, Stephen N. Ulrich, Cornelia M. White, Emily Xiang, Yongbing Zanke, Brent W. Zeng, Yi-Xin Zhang, Ben Zheng, Wei Hsu, Li CA Colon Canc Family Registry Genetics Epidemiology Colorectal TI Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis SO GASTROENTEROLOGY LA English DT Article DE Colon Cancer; Genetics; Risk Factors; SNP ID STRANDED-DNA-BINDING; BASE-LINE CHARACTERISTICS; CANCER SCREENING TRIAL; REPLICATION PROTEIN-A; ASSOCIATION SCAN; COLON-CANCER; WOMENS HEALTH; EPITHELIAL-CELLS; RANDOMIZED-TRIAL; MEAT CONSUMPTION AB BACKGROUND & AIMS: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 X 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 X 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 X 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 X 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 X 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 X 10(-7)). CONCLUSIONS: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to beta-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation. C1 [Peters, Ulrike; Hutter, Carolyn M.; Aragaki, Aaron K.; Carlson, Christopher S.; Curtis, Keith R.; Harrison, Tabitha A.; Kooperberg, Charles; Lacroix, Andrea Z.; Makar, Karen W.; Newcomb, Polly A.; Potter, John D.; Prentice, Ross L.; Qu, Conghui; Rosse, Stephanie A.; Ulrich, Cornelia M.; White, Emily; Hsu, Li] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Gogarten, Stephanie M.; Laurie, Cathy C.; Laurie, Cecelia A.; Levine, David] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Peters, Ulrike; Hutter, Carolyn M.; Carlson, Christopher S.; Newcomb, Polly A.; Rosse, Stephanie A.; Ulrich, Cornelia M.; White, Emily] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Schumacher, Fredrick R.; Casey, Graham; Coetzee, Gerhard A.; Coetzee, Simon G.; Conti, David V.; Gruber, Stephen B.; Haile, Robert W.; Henderson, Brian E.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Baron, John A.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Berndt, Sonja I.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bezieau, Stephane; Kuery, Sebastien] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France. [Brenner, Hermann; Butterbach, Katja; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. [Campbell, Peter T.] Amer Canc Soc, Atlanta, GA 30329 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.; Ma, Jing] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.; Fuchs, Charles S.; Giovannucci, Edward L.; Ma, Jing] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chen, Lin S.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Duggan, David; Taverna, Darin] Translat Genom Res Inst, Phoenix, AZ USA. [Edwards, Todd; Shrubsole, Martha; Shu, Xiao-Ou; Zhang, Ben] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gallinger, Steven] Toronto Gen Hosp, Dept Surg, Toronto, ON, Canada. [Giovannucci, Edward L.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melborne Sch Populat Hlth, Melbourne, Vic, Australia. [Hudson, Thomas J.; Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Jee, Sun Ha] Yonsei Univ, Inst Hlth Promot, Seoul 120749, South Korea. [Jia, Wei-Hua; Zeng, Yi-Xin] Sun Yat Sen Univ, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Lindor, Noralane M.] Mayo Clin Scottsdale, Dept Hlth Sci Res, Scottsdale, AZ USA. [Liu, Yan] Stephens & Associates, Carrollton, GA USA. [Matsuo, Keitaro] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Rohan, Thomas] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Epidemiol, Pittsburgh, PA USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Thibodeau, Stephen N.] Mayo Clin, Dept Lab Genet, Rochester, MN USA. [Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany. [Ulrich, Cornelia M.] German Canc Res Ctr, Heidelberg, Germany. [Xiang, Yongbing] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Zanke, Brent W.] Univ Ottawa, Fac Med, Div Hematol, Ottawa, ON, Canada. [Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North,M4-B402,POB 19024, Seattle, WA 98109 USA. EM upeters@fhcrc.org; lih@fhcrc.org RI Gallinger, Steven/E-4575-2013; Hoffmeister, Michael/B-5745-2012; KURY, Sebastien/G-5971-2015; Shrubsole, Martha/K-5052-2015; Bezieau, stephane/G-5621-2015; Jenkins, Mark/P-7803-2015; Brenner, Hermann/B-4627-2017; Coetzee, Simon/C-1218-2014; OI Gogarten, Stephanie/0000-0002-7231-9745; Hayes, Richard/0000-0002-0918-661X; Matsuo, Keitaro/0000-0003-1761-6314; Hoffmeister, Michael/0000-0002-8307-3197; KURY, Sebastien/0000-0001-5497-0465; Shrubsole, Martha/0000-0002-5591-7575; Bezieau, stephane/0000-0003-0095-1319; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Coetzee, Simon/0000-0003-4267-5930; Potter, John/0000-0001-5439-1500 FU National Cancer Institute, National Institutes of Health; US Department of Health and Human Services [U01 CA137088, R01 CA059045]; Japanese Ministry of Education, Culture, Sports, Science and Technology [17015018, 221S0001]; Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte Contre le Cancer; Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer; National Institutes of Health [U01 CA074783, R01 CA60987, RFA CA-95-011, R37CA070867, R01CA082729, R01CA124558, R01CA148667, R01CA122364, P50CA95103, R01CA121060, K05 CA154337]; Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research; National Cancer Institute, National Institutes of Health [U01 CA122839]; Vanderbilt University School of Medicine; Vanderbilt-Ingram Cancer Center [P30 CA 68485]; 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 Genetics and Epidemiology of Colorectal Cancer Consortium study was supported by the National Cancer Institute, National Institutes of Health, and the US Department of Health and Human Services (U01 CA137088; R01 CA059045). The Asian Consortium was supported by a Grant-in-aid for Cancer Research, the Grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (17015018 and 221S0001). The french Association STudy Evaluating RISK for sporadic colorectal cancer was supported by a Hospital Clinical Research Program (PHRC) and by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte Contre le Cancer, the Association Anne de Bretagne Genetique, and the Ligue Regionale Contre le Cancer. The Assessment of Risk in Colorectal Tumours in Canada study was supported by the National Institutes of Health through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783; see the Colon Cancer Family Registry support section below); and by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, by a Cancer Risk Evaluation Program grant from the Canadian Cancer Society Research Institute, and by Senior Investigator Awards (T.J.H. and B.W.Z.) from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Economic Development and Innovation. The Hawaii Colorectal Cancer Studies 2 and 3 studies were supported by the National Institutes of Health (R01 CA60987). The Colon Cancer Family Registry was supported by the 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 (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 centers in the cancer family registries, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the cancer family registries. The following colon cancer family registries centers contributed data to this article and were supported by National Institutes of Health: the Australasian Colorectal Cancer Family Registry (U01 CA097735), Seattle Colorectal Cancer Family Registry (U01 CA074794), and the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783). The Darmkrebs: Chancen der Verhutung durch Screening study was supported by the 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). The Diet, Activity, and Lifestyle Study was supported by the National Institutes of Health (R01 CA48998 to M. L. S.); Guangzhou-1 was supported by the National Key Scientific and Technological Project (2011ZX09307-001-04) and the National Basic Research Program (2011CB504303) was supported by the People's Republic of China.; The Health Professionals Follow-up Study was supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), the Nurses' Health Study was supported by the National Institutes of Health (R01 137178, P01 CA 087969, and P50 CA 127003), and the Physicians' Health Study was supported by the National Institutes of Health (CA42182). The Korean Cancer Prevention Study-II study was supported by the National R&D Program for cancer control (1220180), and the Seoul R&D Program (10526, Republic of Korea). The Multiethnic Cohort study was supported by the National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). The Prostate, Lung, Colorectal Cancer, and Ovarian Cancer Screening Trial was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility prostate cancer scan, supported by the Intramural Research Program of the National Cancer Institute. The data sets used in this analysis were accessed with appropriate approval through the dbGaP online resource (http://www.cgems.cancer.gov/data_acess.html) through dbGaP accession number 000207v.1p1. Control samples also were genotyped as part of the GWAS of Lung Cancer and Smoking (Yeager, M et al. Nat Genet 2008;124:161-170). Support for this work was provided through the National Institutes of Health, Genes, Environment and Health Initiative (Z01 CP 010200). The human subjects participating in the genome-wide association study were derived from the Prostate, Lung, Colon, and Ovarian Screening Trial and the study was supported by intramural resources of the National Cancer Institute. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, Geneva Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institutes of Health, Genes, Environment and Health Initiative (U01 HG 004438). The data sets used for the analyses described in this article were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000093 v2.p2. The Postmenopausal Hormone Study was supported by the National Institutes of Health (R01 CA076366 to P.A.N.). The Shanghai-1 and Shanghai-2 studies were supported by the National Institutes of Health (R37CA070867, R01CA082729, R01CA124558, R01CA148667, and R01CA122364), as well as an Ingram Professorship and Research Reward funds from the Vanderbilt University School of Medicine. The Tennessee Colorectal Polyp Study was supported by the National Institutes of Health (P50CA95103 and R01CA121060) and was conducted by the Survey and Biospecimen Shared Resource, which was supported in part by the Vanderbilt-Ingram Cancer Center (P30 CA 68485). The VITamins And Lifestyle study was supported by the National Institutes of Health (K05 CA154337).; The Women's Health Initiative program was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. NR 106 TC 121 Z9 122 U1 4 U2 47 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2013 VL 144 IS 4 BP 799 EP + DI 10.1053/j.gastro.2012.12.020 PG 33 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 114JB UT WOS:000316735800039 PM 23266556 ER PT J AU Cao, ZX Mulvihill, MM Mukhopadhyay, P Xu, H Erdelyi, K Hao, EK Holovac, E Hasko, G Cravatt, BF Nomura, DK Pacher, P AF Cao, Zongxian Mulvihill, Melinda M. Mukhopadhyay, Partha Xu, Huan Erdelyi, Katalin Hao, Enkui Holovac, Eileen Hasko, Gyoergy Cravatt, Benjamin F. Nomura, Daniel K. Pacher, Pal TI Monoacylglycerol Lipase Controls Endocannabinoid and Eicosanoid Signaling and Hepatic Injury in Mice SO GASTROENTEROLOGY LA English DT Article DE Mouse Model; Endocannabinoid Signaling; Eicosanoid Production; Surgery ID ISCHEMIA-REPERFUSION INJURY; CANNABINOID CB2 RECEPTORS; ISCHEMIA/REPERFUSION INJURY; LIVER-INJURY; CYCLOOXYGENASE-2; ANTAGONISM; BLOCKADE; PROTECTS; SYSTEM; ACTIVATION AB BACKGROUND & AIMS: The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. METHODS: We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll(-/-) mice, fatty acid amide hydrolase(-/-) mice, and in cannabinoid receptor type 1(-/-) (CB1-/-) and cannabinoid receptor type 2(-/-) (CB2-/-). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. RESULTS: Wild-type mice given JZL184 and Mgll(-/-) mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB2 and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl4. CONCLUSIONS: MAGL modulates hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat conditions that expose the liver to oxidative stress and inflammatory damage. C1 [Cao, Zongxian; Mukhopadhyay, Partha; Xu, Huan; Erdelyi, Katalin; Hao, Enkui; Holovac, Eileen; Pacher, Pal] NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. [Mulvihill, Melinda M.; Nomura, Daniel K.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Program Metab Biol, Berkeley, CA 94720 USA. [Hao, Enkui] Shandong Univ, Jinan Cent Hosp, Dept Cardiol, Jinan 250100, Shandong, Peoples R China. [Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Cravatt, Benjamin F.] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Physiol Chem, La Jolla, CA 92037 USA. RP Pacher, P (reprint author), NIAAA, NIH, 5625 Fishers Lane,MSC 9413,Room 2N-17, Rockville, MD 20852 USA. EM pacher@mail.nih.gov RI Pacher, Pal/B-6378-2008; MUKHOPADHYAY, PARTHA/G-3890-2010 OI Pacher, Pal/0000-0001-7036-8108; MUKHOPADHYAY, PARTHA/0000-0002-1178-1274 FU Intramural Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism; University of California Berkeley/Department of Nutritional Sciences and Toxicology start-up funds; National Institute on Drug Abuse [R00DA030908, DA017259]; Skaggs Institute for Chemical Biology FX Supported by the Intramural Program of the National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (P. P.), University of California Berkeley/Department of Nutritional Sciences and Toxicology start-up funds (D.K.N., M. M. M.), National Institute on Drug Abuse (R00DA030908 to D.K.N. and M. M. M., and DA017259 to B. F. C.), and the Skaggs Institute for Chemical Biology (B.F.C.). NR 34 TC 37 Z9 40 U1 0 U2 20 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2013 VL 144 IS 4 BP 808 EP + DI 10.1053/j.gastro.2012.12.028 PG 25 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 114JB UT WOS:000316735800040 PM 23295443 ER PT J AU Scott, BH Mishkin, M Yin, PB AF Scott, Brian H. Mishkin, Mortimer Yin, Pingbo TI Effect of acoustic similarity on short-term auditory memory in the monkey SO HEARING RESEARCH LA English DT Article ID CEBUS-APELLA; TEMPORAL CORTEX; PITCH; MACAQUE; TIMBRE; INFORMATION; HIPPOCAMPUS; RETENTION; PRIMATES; AMYGDALA AB Recent evidence suggests that the monkey's short-term memory in audition depends on a passively retained sensory trace as opposed to a trace reactivated from long-term memory for use in working memory. Reliance on a passive sensory trace could render memory particularly susceptible to confusion between sounds that are similar in some acoustic dimension. If so, then in delayed matching-to-sample, the monkey's performance should be predicted by the similarity in the salient acoustic dimension between the sample and subsequent test stimulus, even at very short delays. To test this prediction and isolate the acoustic features relevant to short-term memory, we examined the pattern of errors made by two rhesus monkeys performing a serial, auditory delayed match-to-sample task with interstimulus intervals of 1 s. The analysis revealed that false-alarm errors did indeed result from similarity-based confusion between the sample and the subsequent nonmatch stimuli. Manipulation of the stimuli showed that removal of spectral cues was more disruptive to matching behavior than removal of temporal cues. In addition, the effect of acoustic similarity on false-alarm response was stronger at the first nonmatch stimulus than at the second one. This pattern of errors would be expected if the first nonmatch stimulus overwrote the sample's trace, and suggests that the passively retained trace is not only vulnerable to similarity-based confusion but is also highly susceptible to overwriting. (C) 2013 Elsevier B.V. All rights reserved. C1 [Scott, Brian H.; Mishkin, Mortimer; Yin, Pingbo] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Yin, Pingbo] Univ Maryland, Syst Res Inst, Neural Syst Lab, College Pk, MD 20742 USA. RP Scott, BH (reprint author), NIMH, Neuropsychol Lab, NIH, 49 Convent Dr,Room 1B80, Bethesda, MD 20892 USA. EM brianscott@mail.nih.gov; mishkinm@mail.nih.gov; pyin@umd.edu OI Scott, Brian/0000-0003-3949-9737 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, National Institutes of Health, Department of Health and Human Services FX We thank Helen Tak, Kathleen Moorhead, Peter Sergo, and Holly Vinal for assistance with animal training and data collection, and Alexander Kloth for programming assistance as well as data collection. This work was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services. NR 32 TC 10 Z9 10 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD APR PY 2013 VL 298 BP 36 EP 48 DI 10.1016/j.heares.2013.01.011 PG 13 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 120GP UT WOS:000317159100005 PM 23376550 ER PT J AU Oikawa, T Kamiya, A Zeniya, M Chikada, H Hyuck, AD Yamazaki, Y Wauthier, E Tajiri, H Miller, LD Wang, XW Reid, LM Nakauchi, H AF Oikawa, Tsunekazu Kamiya, Akihide Zeniya, Mikio Chikada, Hiromi Hyuck, Ahn Dong Yamazaki, Yuji Wauthier, Eliane Tajiri, Hisao Miller, Lance D. Wang, Xin Wei Reid, Lola M. Nakauchi, Hiromitsu TI Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers SO HEPATOLOGY LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; STEM/PROGENITOR CELLS; THERAPEUTIC TARGET; SIGNAL TRANSDUCER; GASTRIC-CARCINOMA; OKIHIRO-SYNDROME; GENE-EXPRESSION; BILIARY TREE; FETAL; DIFFERENTIATION AB Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4s expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2). Conclusion: SALL4s expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers. (HEPATOLOGY 2013) C1 [Oikawa, Tsunekazu; Tajiri, Hisao] Jikei Univ, Div Gastroenterol & Hepatol, Dept Internal Med, Sch Med, Tokyo, Japan. [Oikawa, Tsunekazu; Wauthier, Eliane; Reid, Lola M.] Univ N Carolina, Sch Med, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA. [Kamiya, Akihide; Chikada, Hiromi] Tokai Univ, Inst Innovat Sci & Technol, Isehara, Kanagawa 2591193, Japan. [Zeniya, Mikio] Jikei Univ, Grad Sch Med, Tokyo, Japan. [Hyuck, Ahn Dong; Yamazaki, Yuji; Nakauchi, Hiromitsu] Univ Tokyo, Inst Med Sci, Div Stem Cell Therapy, Ctr Stem Cell & Regenerat Med, Tokyo 1088639, Japan. [Miller, Lance D.] Wake Forest Sch Med, Dept Canc Biol, Winston Salem, NC USA. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Reid, Lola M.] Univ N Carolina, Sch Med, Program Mol Biol & Biotechnol, Chapel Hill, NC 27599 USA. RP Kamiya, A (reprint author), Tokai Univ, Inst Innovat Sci & Technol, 143 Shiomokasuya, Isehara, Kanagawa 2591193, Japan. EM kamiyaa@tokai-u.jp; Lola.M.Reid@gmail.com; nakauchi@ims.u-tokyo.ac.jp RI Wang, Xin/B-6162-2009 FU Ministry of Education, Culture, Sports, Science and Technology in Japan [22790674, 23689040]; Vertex Pharmaceuticals (Cambridge, MA); Vesta Therapeutics (Bethesda, MD); NCI [CA016086]; Intramural Research Program of the Center for Cancer Research, the National Cancer Institute [Z01 BC 010876]; American Cancer Society [RSG-12198-01-TBG] FX The laboratories in Japan were supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (22790674 and 23689040). Lola M. Reid and associates were funded by sponsored research grants from Vertex Pharmaceuticals (Cambridge, MA) and Vesta Therapeutics (Bethesda, MD) and by an NCI grant (CA016086). Xin Wei Wang was supported by the Intramural Research Program of the Center for Cancer Research, the National Cancer Institute (Z01 BC 010876). Lance D. Miller was funded by a grant from the American Cancer Society (RSG-12198-01-TBG). NR 50 TC 71 Z9 78 U1 3 U2 42 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2013 VL 57 IS 4 BP 1469 EP 1483 DI 10.1002/hep.26159 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 123BQ UT WOS:000317363600021 PM 23175232 ER PT J AU Yamashita, T Honda, M Nakamoto, Y Baba, M Nio, K Hara, Y Zeng, SS Hayashi, T Kondo, M Takatori, H Yamashita, T Mizukoshi, E Ikeda, H Zen, Y Takamura, H Wang, XW Kaneko, S AF Yamashita, Taro Honda, Masao Nakamoto, Yasunari Baba, Masayo Nio, Kouki Hara, Yasumasa Zeng, Sha Sha Hayashi, Takehiro Kondo, Mitsumasa Takatori, Hajime Yamashita, Tatsuya Mizukoshi, Eishiro Ikeda, Hiroko Zen, Yoh Takamura, Hiroyuki Wang, Xin Wei Kaneko, Shuichi TI Discrete nature of EpCAM+ and CD90+cancer stem cells in human hepatocellular carcinoma SO HEPATOLOGY LA English DT Article ID TUMOR-INITIATING CELLS; HUMAN LIVER-CANCER; PROGENITOR CELLS; SELF-RENEWAL; DIFFERENTIATION; EXPRESSION; IDENTIFICATION; PROMOTE; GROWTH AB Recent evidence suggests that hepatocellular carcinoma (HCC) is organized by a subset of cells with stem cell features (cancer stem cells; CSCs). CSCs are considered a pivotal target for the eradication of cancer, and liver CSCs have been identified by the use of various stem cell markers. However, little information is known about the expression patterns and characteristics of marker-positive CSCs, hampering the development of personalized CSC-targeted therapy. Here, we show that CSC markers EpCAM and CD90 are independently expressed in liver cancer. In primary HCC, EpCAM+ and CD90+ cells resided distinctively, and gene-expression analysis of sorted cells suggested that EpCAM+ cells had features of epithelial cells, whereas CD90+ cells had those of vascular endothelial cells. Clinicopathological analysis indicated that the presence of EpCAM+ cells was associated with poorly differentiated morphology and high serum alpha-fetoprotein (AFP), whereas the presence of CD90+ cells was associated with a high incidence of distant organ metastasis. Serial xenotransplantation of EpCAM+/CD90+ cells from primary HCCs in immune-deficient mice revealed rapid growth of EpCAM+ cells in the subcutaneous lesion and a highly metastatic capacity of CD90+ cells in the lung. In cell lines, CD90+ cells showed abundant expression of c-Kit and in vitro chemosensitivity to imatinib mesylate. Furthermore, CD90+ cells enhanced the motility of EpCAM+ cells when cocultured in vitro through the activation of transforming growth factor beta (TGF-) signaling, whereas imatinib mesylate suppressed TGFB1 expression in CD90+ cells as well as CD90+ cell-induced motility of EpCAM+ cells. Conclusion: Our data suggest the discrete nature and potential interaction of EpCAM+ and CD90+ CSCs with specific gene-expression patterns and chemosensitivity to molecular targeted therapy. The presence of distinct CSCs may determine the clinical outcome of HCC. (HEPATOLOGY 2013) C1 [Yamashita, Taro; Honda, Masao; Nakamoto, Yasunari; Baba, Masayo; Nio, Kouki; Hara, Yasumasa; Zeng, Sha Sha; Hayashi, Takehiro; Kondo, Mitsumasa; Takatori, Hajime; Yamashita, Tatsuya; Mizukoshi, Eishiro; Ikeda, Hiroko; Zen, Yoh; Takamura, Hiroyuki; Kaneko, Shuichi] Kanazawa Univ Hosp, Ctr Liver, Kanazawa, Ishikawa 9208641, Japan. [Wang, Xin Wei] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yamashita, T (reprint author), Kanazawa Univ Hosp, Dept Gen Med, 13-1 Takara Machi, Kanazawa, Ishikawa 9208641, Japan. EM taroy@m-kanazawa.jp RI Wang, Xin/B-6162-2009 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [23590967]; Japanese Society of Gastroenterology; Ministry of Health, Labor, and Welfare; National Cancer Center Research and Development Fund of Japan [23-B-5]; Intramural Research Program of the Center for Cancer Research, U.S. National Cancer Institute FX This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23590967), a grant from the Japanese Society of Gastroenterology, a grant from the Ministry of Health, Labor, and Welfare, and a grant from the National Cancer Center Research and Development Fund (23-B-5) of Japan. X.W.W. is supported by the Intramural Research Program of the Center for Cancer Research, U.S. National Cancer Institute. NR 25 TC 87 Z9 99 U1 1 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2013 VL 57 IS 4 BP 1484 EP 1497 DI 10.1002/hep.26168 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 123BQ UT WOS:000317363600022 PM 23174907 ER PT J AU Squires, RH Dhawan, A Alonso, E Narkewicz, MR Shneider, BL Rodriguez-Baez, N Olio, DD Karpen, S Bucuvalas, J Lobritto, S Rand, E Rosenthal, P Horslen, S Ng, V Subbarao, G Kerkar, N Rudnick, D Lopez, MJ Schwarz, K Romero, R Elisofon, S Doo, E Robuck, PR Lawlor, S Belle, SH AF Squires, Robert H. Dhawan, Anil Alonso, Estella Narkewicz, Michael R. Shneider, Benjamin L. Rodriguez-Baez, Norberto Olio, Dominic Dell Karpen, Saul Bucuvalas, John Lobritto, Steven Rand, Elizabeth Rosenthal, Philip Horslen, Simon Ng, Vicky Subbarao, Girish Kerkar, Nanda Rudnick, David Lopez, M. James Schwarz, Kathleen Romero, Rene Elisofon, Scott Doo, Edward Robuck, Patricia R. Lawlor, Sharon Belle, Steven H. CA Pediat Acute Liver Failure Study TI Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: A placebo-controlled clinical trial SO HEPATOLOGY LA English DT Article ID FULMINANT HEPATIC-FAILURE; TRANSLATIONAL SYSTEMS BIOLOGY; ACETAMINOPHEN-PROTEIN ADDUCTS; CHILDREN; TRANSPLANTATION; GLUTATHIONE; SURVIVAL; INFLAMMATION; DYSFUNCTION; EXPERIENCE AB N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE. Conclusion: NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults. (HEPATOLOGY 2013) C1 [Squires, Robert H.; Shneider, Benjamin L.] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA USA. [Dhawan, Anil] Kings Coll London, London WC2R 2LS, England. [Alonso, Estella] Northwestern Univ, Evanston, IL USA. [Narkewicz, Michael R.] Univ Colorado SOM, Boulder, CO USA. [Narkewicz, Michael R.] Childrens Hosp Colorado, Boulder, CO USA. [Rodriguez-Baez, Norberto] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Olio, Dominic Dell] Birmingham Childrens Hosp, Birmingham, W Midlands, England. [Karpen, Saul] Baylor Coll Med, Houston, TX 77030 USA. [Bucuvalas, John] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Lobritto, Steven] Columbia Univ, New York, NY USA. [Rand, Elizabeth] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Rosenthal, Philip] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Horslen, Simon] Univ Washington, Seattle, WA 98195 USA. [Ng, Vicky] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Subbarao, Girish] Indiana Univ, Indianapolis, IN 46204 USA. [Kerkar, Nanda] Mt Sinai Med Ctr, New York, NY 10029 USA. [Rudnick, David] Washington Univ, St Louis, MO USA. [Lopez, M. James] Univ Michigan, Ann Arbor, MI 48109 USA. [Schwarz, Kathleen] Johns Hopkins Univ, Baltimore, MD USA. [Romero, Rene] Emory Univ, Atlanta, GA 30322 USA. [Elisofon, Scott] Childrens Hosp Boston, Boston, MA USA. [Doo, Edward; Robuck, Patricia R.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Lawlor, Sharon; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Squires, RH (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, UPMC, 4401 Penn Ave, Pittsburgh, PA 15224 USA. EM squiresr@upmc.edu RI Dhawan, Anil/B-6730-2009 FU NCATS NIH HHS [UL1 TR000077, UL1 TR000150]; NCRR NIH HHS [M01 RR000037, M01 RR000069, M01 RR008084, M01 RR08084, M01-RR00037, M01-RR00069]; NIDDK NIH HHS [P30 DK026743, U01 DK058369, U01 DK072146, U01-DK58369] NR 38 TC 34 Z9 35 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2013 VL 57 IS 4 BP 1542 EP 1549 DI 10.1002/hep.26001 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 123BQ UT WOS:000317363600027 PM 22886633 ER PT J AU Tian, ZG Chen, YY Gao, B AF Tian, Zhigang Chen, Yongyan Gao, Bin TI Natural killer cells in liver disease SO HEPATOLOGY LA English DT Review ID HEPATIC STELLATE CELLS; C VIRUS-INFECTION; EXPERIMENTAL BILIARY ATRESIA; NK CELLS; HEPATOCELLULAR-CARCINOMA; T-CELLS; INCREASED SUSCEPTIBILITY; CIRCULATING LYMPHOCYTES; CELLS/INTERFERON-GAMMA; NEGATIVE REGULATION AB Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including tumor necrosis factorrelated apoptosis-inducing ligand-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors through their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis, but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease, but has also revealed new therapeutic targets for managing this disease. (HEPATOLOGY 2013;57:16541662) C1 [Tian, Zhigang; Chen, Yongyan] Univ Sci & Technol China, Sch Life Sci, Dept Microbiol & Immunol, Hefei 230027, Peoples R China. [Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. RP Tian, ZG (reprint author), Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Peoples R China. EM tzg@ustc.edu.cn; bgao@mail.nih.gov RI Tian, Zhigang/J-3512-2013 FU Chinese Natural Science Foundation [91029303, 30911120480, 31021061]; Ministry of Science and Technology [973-2012CB519004]; National Science and Technology Major Projects [2012ZX10002006]; intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health FX The work described from Dr. Zhigang Tian's lab was supported by the Chinese Natural Science Foundation (91029303, 30911120480, and 31021061), the Ministry of Science and Technology (973-2012CB519004), and the National Science and Technology Major Projects (2012ZX10002006), and the work described from Dr. Bin Gao's lab was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 81 TC 58 Z9 67 U1 2 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD APR PY 2013 VL 57 IS 4 BP 1654 EP 1662 DI 10.1002/hep.26115 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 123BQ UT WOS:000317363600038 PM 23111952 ER PT J AU Chung, JY Kitano, H Takikita, M Cho, H Noh, KH Kim, TW Ylaya, K Hanaoka, J Fukuoka, J Hewitt, SM AF Chung, Joon-Yong Kitano, Haruhisa Takikita, Mikiko Cho, Hanbyoul Noh, Kyung Hee Kim, Tae Woo Ylaya, Kris Hanaoka, Jun Fukuoka, Junya Hewitt, Stephen M. TI Synaptonemal complex protein 3 as a novel prognostic marker in early stage non-small cell lung cancer SO HUMAN PATHOLOGY LA English DT Article DE Immunohistochemistry; Non-small cell lung cancer; Prognostic marker; Synaptonemal complex protein 3; Tissue microarray ID BIOMARKERS; OVEREXPRESSION; LOCALIZATION; EXPRESSION; DIAGNOSIS; SYCP3; CORE AB Synaptonemal complex protein 3 is a marker for cell transformation that has prognostic significance in various cancers. However, the prognostic significance of synaptonemal complex protein 3 has not been studied in non-small cell lung cancer. To investigate the potential correlation between synaptonemal complex protein 3 and various clinicopathologic parameters, we assessed the expression of synaptonemal complex protein 3 in archival tumor tissues from 258 patients with non-small cell lung cancer by immunohistochemical staining. By immunofluorescence, synaptonemal complex protein 3 was detected in both the cytoplasmic and nuclear fractions of NCI-H1299 cell. In tumor samples, synaptonemal complex protein 3 is detected as cytoplasmic expression pattern and observed in 50 clinical samples (19.4%) by immunohistochemical staining. Synaptonemal complex protein 3 expression was correlated with T status (P = .008), lymph node metastasis (P = .010), tumor types (P = .019), and pleural invasion (P = .005). In multivariate analysis of patients with early stage disease, increased synaptonemal complex protein 3 expression predicted worse overall survival in early stage (stage I and II) with pT1 status (P = .041). These results suggest that positive synaptonemal complex protein 3 expression is a portent of poor outcome and may be a potential biomarker in the early stages of the non-small cell lung cancer for survival and may provide clues in the identification of patients for adjuvant therapy. Published by Elsevier Inc. C1 [Chung, Joon-Yong; Kitano, Haruhisa; Takikita, Mikiko; Cho, Hanbyoul; Ylaya, Kris; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong; Kitano, Haruhisa; Takikita, Mikiko; Cho, Hanbyoul; Ylaya, Kris; Hewitt, Stephen M.] NCI, Appl Mol Pathol Lab, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Kitano, Haruhisa; Hanaoka, Jun] Shiga Univ Med Sci, Dept Thorac Surg, Otsu, Shiga 5202192, Japan. [Takikita, Mikiko] Shiga Univ Med Sci, Div Diagnost Pathol, Otsu, Shiga 5202192, Japan. [Cho, Hanbyoul] Yonsei Univ, Coll Med, Gangnam Severance Hosp, Dept Obstet & Gynecol, Seoul 135720, South Korea. [Noh, Kyung Hee; Kim, Tae Woo] Korea Univ, Grad Sch Med, Dept Biomed Sci, Seoul 425707, South Korea. [Fukuoka, Junya] Toyama Univ Hosp, Pathol Lab, Toyama 9300194, Japan. RP Hewitt, SM (reprint author), NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 7 Z9 7 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD APR PY 2013 VL 44 IS 4 BP 472 EP 479 DI 10.1016/j.humpath.2012.06.018 PG 8 WC Pathology SC Pathology GA 121LQ UT WOS:000317246700002 PM 23069255 ER PT J AU Harnof, S Zibly, Z Cohen, Z Shaw, A Schlaff, C Kassel, NF AF Harnof, Sagi Zibly, Zion Cohen, Zvi Shaw, Andrew Schlaff, Cody Kassel, Neal F. TI Cranial Nerve Threshold for Thermal Injury Induced by MRI-Guided High-Intensity Focused Ultrasound (MRgHIFU): Preliminary Results on an Optic Nerve Model SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID NONINVASIVE FUNCTIONAL NEUROSURGERY; UTERINE FIBROIDS; SURGERY; BRAIN; FEASIBILITY; ABLATION AB Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies. We sought to validate the production, safety, and efficacy of thermal injury to cranial nerves generated by MRgHIFU. In this study, five female domestic pigs underwent a standard bifrontal craniectomy under general anesthesia. Treatment was then given using an MRgHIFU system to induce hyperthermic ablative sonication (6 to 10 s; 50 to 2000 J.) Histological analyses were done to confirm nerve damage; temperature measured on the optic nerve was approximately 53.4 degrees C (range: 39 degrees C to 70 degrees C.) Histology demonstrated a clear definition between a necrotic, transitional zone, and normal tissue. MRgHIFU induces targeted thermal injury to nervous tissue within a specific threshold of 50 degrees C to 60 degrees C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation. C1 [Harnof, Sagi; Zibly, Zion; Cohen, Zvi] Chaim Sheba Med Ctr, Dept Neurosurg, IL-52621 Tel Hashomer, Israel. [Zibly, Zion; Schlaff, Cody] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Shaw, Andrew] Ohio State Univ, Dept Neurol Surg, Columbus, OH 43210 USA. [Kassel, Neal F.] Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA. RP Harnof, S (reprint author), Chaim Sheba Med Ctr, Dept Neurosurg, IL-52621 Tel Hashomer, Israel. EM sagi.harnof@sheba.health.gov.il FU Focused Ultrasound Surgery Foundation FX The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Z. Zibly was supported by the Focused Ultrasound Surgery Foundation. NR 12 TC 3 Z9 3 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD APR PY 2013 VL 60 IS 4 BP 702 EP 705 DI 10.1109/TUFFC.2013.2618 PG 4 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 118FU UT WOS:000317010200006 PM 23549530 ER PT J AU Levin, AM Mathias, RA Huang, LL Roth, LA Daley, D Myers, RA Himes, BE Romieu, I Yang, M Eng, C Park, JE Zoratti, K Gignoux, CR Torgerson, DG Galanter, JM Huntsman, S Nguyen, EA Becker, AB Chan-Yeung, M Kozyrskyj, AL Kwok, PY Gilliland, FD Gauderman, WJ Bleecker, ER Raby, BA Meyers, DA London, SJ Martinez, FD Weiss, ST Burchard, EG Nicolae, DL Ober, C Barnes, KC Williams, LK AF Levin, Albert M. Mathias, Rasika A. Huang, Lili Roth, Lindsey A. Daley, Denise Myers, Rachel A. Himes, Blanca E. Romieu, Isabelle Yang, Mao Eng, Celeste Park, Julie E. Zoratti, Karla Gignoux, Christopher R. Torgerson, Dara G. Galanter, Joshua M. Huntsman, Scott Nguyen, Elizabeth A. Becker, Allan B. Chan-Yeung, Moira Kozyrskyj, Anita L. Kwok, Pui-Yan Gilliland, Frank D. Gauderman, W. James Bleecker, Eugene R. Raby, Benjamin A. Meyers, Deborah A. London, Stephanie J. Martinez, Fernando D. Weiss, Scott T. Burchard, Esteban G. Nicolae, Dan L. Ober, Carole Barnes, Kathleen C. Williams, L. Keoki TI A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Meta-analysis; genome-wide association study; total IgE; race-ethnicity; continental population groups ID CHILDHOOD ASTHMA; AFRICAN-AMERICAN; AIRWAY RESPONSIVENESS; COMPONENTS-ANALYSIS; LATINO POPULATIONS; GENETIC ANCESTRY; IMMUNOGLOBULIN-E; LUNG-FUNCTION; CHILDREN; DISEASE AB Background: IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE. Objective: We sought to identify the genetic predictors of serum total IgE levels. Methods: We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. Results: We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P < 5.0 x 10(-6)) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P = .007 and 2.45 x 10(-7), respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. Conclusion: This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects. (J Allergy Clin Immunol 2013;131:1176-84.) C1 [Levin, Albert M.] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. [Mathias, Rasika A.] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, Baltimore, MD USA. [Mathias, Rasika A.; Huang, Lili; Barnes, Kathleen C.] Johns Hopkins Univ, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD USA. [Roth, Lindsey A.; Eng, Celeste; Gignoux, Christopher R.; Torgerson, Dara G.; Galanter, Joshua M.; Huntsman, Scott; Nguyen, Elizabeth A.; Burchard, Esteban G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Daley, Denise] Univ British Columbia, James Hogg Res Ctr, Inst Heart & Lung Hlth, Vancouver, BC V5Z 1M9, Canada. [Myers, Rachel A.; Nicolae, Dan L.; Ober, Carole] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Himes, Blanca E.; Raby, Benjamin A.; Weiss, Scott T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Romieu, Isabelle] WHO, Int Agcy Res Canc, Lyon, France. [Yang, Mao; Zoratti, Karla; Williams, L. Keoki] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA. [Park, Julie E.] Univ British Columbia, Providence Hlth Care Res Inst, Vancouver, BC V5Z 1M9, Canada. [Becker, Allan B.] Univ Manitoba, Dept Pediat & Child Hlth, Winnipeg, MB R3T 2N2, Canada. [Becker, Allan B.] Univ Manitoba, Manitoba Inst Child Hlth, Winnipeg, MB, Canada. [Chan-Yeung, Moira] Univ British Columbia, Occupat & Environm Lung Dis Unit, Vancouver, BC V5Z 1M9, Canada. [Kozyrskyj, Anita L.] Univ Alberta, Dept Pediat, Edmonton, AB, Canada. [Kozyrskyj, Anita L.] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. [Kwok, Pui-Yan] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Kwok, Pui-Yan] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Gilliland, Frank D.; Gauderman, W. James] Univ So Calif, Keck Sch Med, Dept Preventat Med, Los Angeles, CA 90033 USA. [Bleecker, Eugene R.; Meyers, Deborah A.] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [London, Stephanie J.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Martinez, Fernando D.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Martinez, Fernando D.] Univ Arizona, Inst BIO5, Tucson, AZ USA. [Burchard, Esteban G.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Nicolae, Dan L.] Univ Chicago, Dept Stat, Chicago, IL 60637 USA. [Williams, L. Keoki] Henry Ford Hlth Syst, Dept Internal Med, Detroit, MI USA. RP Williams, LK (reprint author), Henry Ford Hlth Syst, Ctr Hlth Serv Res, 1 Ford Pl,3A, Detroit, MI USA. EM kbarnes@jhmi.edu; kwillia5@hfhs.org RI Kwok, Pui-Yan/F-7725-2014; OI Kwok, Pui-Yan/0000-0002-5087-3059; Nguyen, Elizabeth/0000-0002-8070-6382; London, Stephanie/0000-0003-4911-5290 FU National Heart, Lung, and Blood Institute [HL085197, HL087665, HL072414, HL49596, HL064307, HL064313, HL075419, HL65899, HL083069, HL066289, HL101543, HL101651, HL079055, HL087699, HL049612, HL075417, HL04266, HL072433, HL061768, HL076647, HL087680, HL078885, HL088133, HL069167]; National Institutes of Allergy and Infectious Disease [AI070503, AI079139, AI061774, AI050024, AI044840, AI041040, AI077439]; National Institute of Diabetes and Digestive and Kidney Diseases [DK064695]; National Institutes of Environmental Health Sciences [ES09606, ES018176, ES015903, ES007048, ES009581, R826708, RD831861, ES011627, ES015794]; National Institutes of Environmental Health Sciences, Division of Intramural Research [Z01 ES049019]; National Center for Research Resources [RR03048]; Environmental Protection Agency [83213901, R-826724]; American Asthma Foundation; Fund for Henry Ford Hospital; Mary Beryl Patch Turnbull Scholar Program; National Council of Science and Technology (Mexico) [26206-M]; Centers for Disease Control, US; Flight Attendant Medical Research Institute (FAMRI); RWJF Amos Medical Faculty Development Award; Sandler Foundation; AllerGen NCE (the Allergy, Genes and Environment Network); Canadian Institutes for Health Research; Tier II Canadian Research Chair; Michael Smith Foundation for Health Research FX Supported by grants from the National Heart, Lung, and Blood Institute (HL101651 to C.O. and D.L.N.; HL087665 to D.L.N.; HL085197, HL087665, HL072414, and HL49596 to C.O.; HL064307 and HL064313 to F. D. M.; HL075419, HL65899, HL083069, HL066289, HL087680, HL101543, and HL101651 to S. T. W.; HL079055 to L. K. W.; HL087699, HL049612, HL075417, HL04266, and HL072433 to K. C. B.; HL061768, HL076647, to F. D. G.; HL087680 to W.J.G.; HL078885 and HL088133 to E. G. B.; HL087665 to D. A. M.; and HL069167 to E. R. B), the National Institutes of Allergy and Infectious Disease (AI070503 to C.O.; AI079139 and AI061774 to L. K. W.; AI050024, AI044840, and AI041040 to K. C. B.; and AI077439 to E. G. B.), the National Institute of Diabetes and Digestive and Kidney Diseases to L. K. W. (DK064695); the National Institutes of Environmental Health Sciences (ES09606, ES018176, and ES015903 to K. C. B.; ES007048, ES009581, R826708, RD831861, and ES011627 to F. D. G.; ES015794 to E. G. B.; and the Division of Intramural Research, Z01 ES049019, to S.J.L.); the National Center for Research Resources (RR03048 to K. C. B.), the Environmental Protection Agency (83213901 and R-826724 to K. C. B.), the American Asthma Foundation and the Fund for Henry Ford Hospital (to L. K. W.), Mary Beryl Patch Turnbull Scholar Program (to K. C. B.), the National Council of Science and Technology (Mexico; 26206-M to I. R.), the Centers for Disease Control, US (to I. R.); and the Flight Attendant Medical Research Institute (FAMRI), RWJF Amos Medical Faculty Development Award, the American Asthma Foundation, and the Sandler Foundation (to E. G. B.). The Canadian studies (SAGE and CAPPS) were supported by AllerGen NCE (the Allergy, Genes and Environment Network, which is a member of the Networks of Centres of Excellence) and by a grant from the Canadian Institutes for Health Research. D. D. is supported by a Tier II Canadian Research Chair and a scholar award from the Michael Smith Foundation for Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 18 Z9 19 U1 0 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD APR PY 2013 VL 131 IS 4 BP 1176 EP 1184 DI 10.1016/j.jaci.2012.10.002 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 120QT UT WOS:000317187200028 PM 23146381 ER PT J AU Smrz, D Bandara, G Zhang, SL Mock, BA Beaven, MA Metcalfe, DD Gilfillan, AM AF Smrz, Daniel Bandara, Geethani Zhang, Shuling Mock, Beverly A. Beaven, Michael A. Metcalfe, Dean D. Gilfillan, Alasdair M. TI A novel KIT-deficient mouse mast cell model for the examination of human KIT-mediated activation responses SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Degranulation; Fc epsilon RI; KIT; Mast cells; KIT; SCF ID EPSILON-RI AGGREGATION; SIGNALING PATHWAYS; C-KIT; KINASE; RELEASE; GROWTH; CHEMOTAXIS; INDUCTION; MIGRATION; RECEPTOR AB Activation of KIT, by its ligand, stem cell factor (SCF), results in the initiation of signal transduction pathways that influence mast cell survival and proliferation. Activating mutations in KIT have thus been linked to clonal MC proliferation associated with systemic mastocytosis. SCF also modulates MC function by inducing MC chemotaxis and by potentiating antigen (Ag)/IgE-mediated MC degranulation. Thus, mutations in KIT also have the potential to affect these processes in allergic and other mast cell-related diseases. Studies to determine how native and mutated KIT may modulate MC chemotaxis and activation have, however, been limited due to the lack of availability of a suitable functional MC line lacking native KIT which would allow transduction of KIT constructs. Here we describe a novel mouse MC line which allows the study of normal and mutated KIT constructs. These cells originated from a bone marrow-derived mouse MC culture out of which a rapidly dividing mast cell sub-population spontaneously arose. Over time, these cells lost KIT expression while continuing to express functional high affinity receptors for IgE (Fc epsilon RI). As a consequence, these cells degranulated in response to Ag/IgE but did not migrate nor show any evidence of potentiation of Ag/IgE degranulation in response to SCF. Retroviral transduction of the cells with a human (hu)KIT construct resulted in surface expression of huKIT which responded to huSCF by potentiation of Ag/IgE-induced degranulation and chemotaxis. This cell line thus presents a novel system to delineate how MC function is modulated by native and mutated KIT and for the identification of novel inhibitors of these processes. Published by Elsevier B.V. C1 [Smrz, Daniel; Bandara, Geethani; Metcalfe, Dean D.; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Zhang, Shuling; Mock, Beverly A.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Smrz, D (reprint author), Charles Univ Prague, Sch Med 2, Inst Immunol, V Uvalu 84, Prague 15006 5, Czech Republic. EM daniel.smrz@lfmotol.cuni.cz RI Smrz, Daniel/D-4853-2014; Mock, Beverly/B-3110-2015 OI Smrz, Daniel/0000-0003-0143-8744; Mock, Beverly/0000-0003-2479-4549 FU NIAID; NHLBI; NCI FX Research was supported by funding from the Intramural Research programs within NIAID (D.S., A.M.G., D.D.M.), and NHLBI (M.A.B) and NCI (S.Z. and B.A.M.). We would like to thank Biological Imaging Facility (RTB/NIAID/NIH) for the technical support in confocal image acquisition including Juraj Kabat for assistance in image post processing and analysis. NR 39 TC 4 Z9 4 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD APR PY 2013 VL 390 IS 1-2 BP 52 EP 62 DI 10.1016/j.jim.2013.01.008 PG 11 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 123IB UT WOS:000317380500007 PM 23357051 ER PT J AU Bekisz, J Sato, Y Johnson, C Husain, SR Puri, RK Zoon, KC AF Bekisz, Joseph Sato, Yuki Johnson, Chase Husain, Syed R. Puri, Raj K. Zoon, Kathryn C. TI Immunomodulatory Effects of Interferons in Malignancies SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Review ID TRAIL-INDUCED APOPTOSIS; OVARIAN-CANCER CELLS; ACTIVATED MACROPHAGES; IFN-ALPHA; ADOPTIVE IMMUNOTHERAPY; TUMORICIDAL ACTIVITY; BLOOD MONOCYTES; IN-VITRO; PHASE-I; GAMMA AB Investigation of the antitumor and immunomodulatory activities of interferon (IFN) began shortly after the cytokine was discovered in 1957. Early work showed a direct correlation between administration of IFN and inhibition of symptoms associated with virally induced leukemia in mice as well as an increase in their survival time. Subsequent studies with purified IFNs confirmed the direct and indirect stimulation of immune cells, resulting in antitumor activities of IFN. Clinically, IFN-alphas (alpha s) have been shown to have activity against a variety of tumors. Initially, the U.S. Food and Drug Administration licensed 2 recombinant IFN-alpha s for the treatment of hairy-cell leukemia and then later for several other cancers. The success rate seen with IFNs and certain tumors has been varied. Unfortunately, some neoplasms show no response to IFN. Monocytes/macrophages play an important role in cancer progression. Monocytes in combination with IFN may be an important therapy for several cancers. This article focuses on the role of IFN and monocytes alone or in combination in affecting malignancies. C1 [Bekisz, Joseph; Johnson, Chase; Zoon, Kathryn C.] NIAID, Cytokine Biol Sect, NIH, Bethesda, MD 20892 USA. [Sato, Yuki; Husain, Syed R.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Zoon, KC (reprint author), NIAID, Div Intramural Res, NIH, Bldg 33,Rm 2N09G2,33 North Dr, Bethesda, MD 20892 USA. EM kzoon@niaid.nih.gov NR 50 TC 19 Z9 19 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD APR PY 2013 VL 33 IS 4 SI SI BP 154 EP 161 DI 10.1089/jir.2012.0167 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 124KY UT WOS:000317463400003 PM 23570381 ER PT J AU Guenther, PM Casavale, KO Reedy, J Kirkpatrick, SI Hiza, HAB Kuczynski, KJ Kahle, LL Krebs-Smith, SM AF Guenther, Patricia M. Casavale, Kellie O. Reedy, Jill Kirkpatrick, Sharon I. Hiza, Hazel A. B. Kuczynski, Kevin J. Kahle, Lisa L. Krebs-Smith, Susan M. TI Update of the Healthy Eating Index: HEI-2010 SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Healthy Eating Index; Diet quality; Diet assessment tool ID NUTRIENT-RICH FOODS; ONE 24-HOUR RECALL; DIET-QUALITY; COLORECTAL-CANCER; BLOOD-PRESSURE; OLDER-ADULTS; UNITED-STATES; WEIGHT STATUS; DASH-SODIUM; RISK AB The Healthy Eating Index (HEI) is a measure of diet quality in terms of conformance with federal dietary guidance. Publication of the 2010 Dietary Guidelines for Americans prompted an interagency working group to update the HEI. The HEI-2010 retains several features of the 2005 version: (a) it has 12 components, many unchanged, including nine adequacy and three moderation components; (b) it uses a density approach to set standards, eg, per 1,000 calories or as a percentage of calories; and (c) it employs least-restrictive standards; ie, those that are easiest to achieve among recommendations that vary by energy level, sex, and/or age. Changes to the index include: (a) the Greens and Beans component replaces Dark Green and Orange Vegetables and Legumes; (b) Seafood and Plant Proteins has been added to capture specific choices from the protein group; (c) Fatty Acids, a ratio of polyunsaturated and monounsaturated to saturated fatty acid's, replaces Oils and Saturated Fat to acknowledge the recommendation to replace, saturated fat with monounsaturated and polyunsaturated fatty acids; and (d) a moderation component, Refined Grains, replaces the adequacy component, Total Grains, to assess overconsumption. The HEI-2010 captures the key recommendations of the 2010 Dietary Guidelines and, like earlier versions, will be used to assess the diet quality of the US population and subpopulations, evaluate interventions, research dietary patterns, and evaluate various aspects of the food environment. J Acad Nutr Diet. 2013;113:569-580. C1 [Guenther, Patricia M.; Casavale, Kellie O.; Hiza, Hazel A. B.; Kuczynski, Kevin J.] USDA, Ctr Nutr Policy & Promot, Alexandria, VA 22302 USA. [Casavale, Kellie O.] US Dept HHS, Off Dis Prevent & Hlth Promot, Rockville, MD USA. [Reedy, Jill; Kirkpatrick, Sharon I.; Krebs-Smith, Susan M.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kahle, Lisa L.] Informat Management Serv Inc, Calverton, MD USA. RP Guenther, PM (reprint author), USDA, Ctr Nutr Policy & Promot, 3101 Pk Ctr Dr,Suite 1034, Alexandria, VA 22302 USA. EM Patricia.Guenther@cnpp.usda.gov OI Kirkpatrick, Sharon/0000-0001-9896-5975 FU Intramural NIH HHS [Z99 CA999999] NR 67 TC 242 Z9 242 U1 5 U2 67 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD APR PY 2013 VL 113 IS 4 BP 569 EP 580 DI 10.1016/j.jand.2012.12.016 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 121PS UT WOS:000317257300013 PM 23415502 ER PT J AU Olfson, M He, JP Merikangas, KR AF Olfson, Mark He, Jian-ping Merikangas, Kathleen Ries TI Psychotropic Medication Treatment of Adolescents: Results From the National Comorbidity Survey-Adolescent Supplement SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE psychotropic medications; DSM-IV disorders; National Comorbidity Survey -Adolescent Supplement (NCS-A) ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; RANDOMIZED CONTROLLED-TRIALS; SURVEY REPLICATION; US CHILDREN; ETHNIC-DIFFERENCES; MENTAL-DISORDERS; CLINICAL-TRIAL; NCS-A; DEPRESSION AB Objective: To examine the 12-month prevalence of psychotropic medication use among adolescents, and the match between mental disorder diagnoses and past-year antidepressant and stimulant use. Method: Data are from the National Comorbidity Survey Adolescent Supplement (2002-2004), a nationally representative survey of 10,123 adolescents aged 13 to 18 years that assesses DSM-IV disorders using a fully structured diagnostic interview, a modified version of the World Health Organization Composite International Diagnostic Interview (CIDI). Rates of 12-month psychotropic medication use are stratified by respondent socio-demographic characteristics, and the distribution of 12-month DSM-IV CIDI disorders is estimated among past-12-month use of antidepressants and stimulants. Results: During a 1-year period, 7.0% of adolescents used at least one psychotropic medication; these medications were most commonly antidepressants (3.9%), followed by stimulants (2.8%), anxiolytics (0.8%), antipsychotics (0.5%), and mood stabilizers (0.4%). Nearly three-quarters (74.1%) of adolescents with any past-year psychotropic medication use had at least one CIDI mental disorder, and many had disorders for which the specific medication class is clinically indicated. Among adolescents using antidepressants, 48.8% had a past-12-month depressive or anxiety disorder, and an additional 20.3% had a lifetime depressive or anxiety disorder. Nearly one-half (49.1%) of adolescents using stimulants met past-12-month attention-deficit/hyperactivity disorder (ADHD) criteria, and an additional 13.1% met lifetime criteria for ADHD. Conclusions: Most adolescents who are treated with psychotropic medications have one or more psychiatric disorders and many, albeit far from all, have mental disorders for which the specific medications are clinically indicated. J. Am. Acad. Child Adolesc. Psychiatry; 2013;52(4):378-388. C1 [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Olfson, Mark] Columbia Univ, New York, NY 10027 USA. [He, Jian-ping; Merikangas, Kathleen Ries] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Bldg 35,Room 1A201,35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. FU Intramural Research Program of NIMH; Agency for Healthcare Research and Quality [U18-HS016097]; Eli Lilly and Co. FX This work was supported by the Intramural Research Program of NIMH and by U18-HS016097 from the Agency for Healthcare Research and Quality.; Dr. Olfson has received research support to Columbia University from Eli Lilly and Co. Dr. Merikangas and.Ms. He report no biomedical financial interests or potential conflicts of interest. NR 43 TC 16 Z9 16 U1 2 U2 14 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 APR PY 2013 VL 52 IS 4 BP 378 EP 388 DI 10.1016/j.jaac.2012.12.006 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 122LL UT WOS:000317319500007 PM 23582869 ER PT J AU Callahan, K Kritchevsky, S Yaffe, K Miller, ME Hire, D Ayonayon, H Cawthon, P Duncan, P Harris, T Rosano, C Satterfield, S Williamson, J AF Callahan, K. Kritchevsky, S. Yaffe, K. Miller, M. E. Hire, D. Ayonayon, H. Cawthon, P. Duncan, P. Harris, T. Rosano, C. Satterfield, S. Williamson, J. TI Preclinical Cognitive Impairment: a Risk Factor for Rehospitalization. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 03-05, 2013 CL Grapevine, TX SP Amer Geriatr Soc C1 [Callahan, K.; Kritchevsky, S.; Duncan, P.; Williamson, J.] Wake Forest Sch Med, Winston Salem, NC USA. [Miller, M. E.; Hire, D.] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Yaffe, K.; Ayonayon, H.; Cawthon, P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Rosano, C.] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee Heatlh Sci, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 SU 1 SI SI BP S106 EP S106 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 120QW UT WOS:000317187600301 ER PT J AU Hassett, H Simonsick, E Ko, S Hicks, G Ferrucci, L AF Hassett, H. Simonsick, E. Ko, S. Hicks, G. Ferrucci, L. TI Does lumbopelvic pain alter gait patterns in older adults? Findings from the Baltimore Longitudinal Study of Aging (BLSA). SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 03-05, 2013 CL Grapevine, TX SP Amer Geriatr Soc C1 [Hassett, H.] Univ New England, Coll Osteopath Med, Biddeford, ME USA. [Hassett, H.; Simonsick, E.; Ferrucci, L.] Johns Hopkins Med Sch, Baltimore, MD USA. [Simonsick, E.; Ferrucci, L.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Ko, S.] Chonnam Natl Univ, Kwangju, Jeonnam, South Korea. [Hicks, G.] Univ Delaware, Newark, DE USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 SU 1 SI SI BP S122 EP S123 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 120QW UT WOS:000317187600349 ER PT J AU Marcum, ZA Zheng, Y Hanlon, J Strotmeyer, E Newman, A Shorr, R Simonsick, E Bauer, D Boudreau, R Donohue, J Perera, S AF Marcum, Z. A. Zheng, Y. Hanlon, J. Strotmeyer, E. Newman, A. Shorr, R. Simonsick, E. Bauer, D. Boudreau, R. Donohue, J. Perera, S. TI Gastroprotective agent use in older NSAID users: a pre-post analysis. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 03-05, 2013 CL Grapevine, TX SP Amer Geriatr Soc C1 [Marcum, Z. A.; Zheng, Y.; Hanlon, J.; Strotmeyer, E.; Newman, A.; Boudreau, R.; Donohue, J.; Perera, S.] Univ Pittsburgh, Pittsburgh, PA USA. [Shorr, R.] VA GRECC, Gainesville, FL USA. [Simonsick, E.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Bauer, D.] UCSF, San Francisco, CA USA. RI Perera, Subashan/D-7603-2014; Strotmeyer, Elsa/F-3015-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 SU 1 SI SI BP S36 EP S37 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 120QW UT WOS:000317187600103 ER PT J AU Meziab, O Yaffe, K Brach, J Simonsick, EM Harris, TB Barnes, DE AF Meziab, O. Yaffe, K. Brach, J. Simonsick, E. M. Harris, T. B. Barnes, D. E. TI Changes in Physical Activity Before and After Development of Pre-Clinical Cognitive Impairment. SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 03-05, 2013 CL Grapevine, TX SP Amer Geriatr Soc C1 [Meziab, O.] Univ Arizona, Coll Med, Tucson, AZ USA. [Yaffe, K.; Barnes, D. E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Brach, J.] Univ Pittsburgh, Pittsburgh, PA USA. [Simonsick, E. M.; Harris, T. B.] NIA, Baltimore, MD 21224 USA. [Yaffe, K.; Barnes, D. E.] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 SU 1 SI SI BP S115 EP S115 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 120QW UT WOS:000317187600327 ER PT J AU Peron, EP Perera, S Boudreau, R Donohue, JM Gray, SL Ruby, C Newman, AB Shorr, RI Bauer, D Simonsick, E Studenski, SA Hanlon, JT AF Peron, E. P. Perera, S. Boudreau, R. Donohue, J. M. Gray, S. L. Ruby, C. Newman, A. B. Shorr, R. I. Bauer, D. Simonsick, E. Studenski, S. A. Hanlon, J. T. TI Appropriateness of antihypertensive prescribing after Medicare Part D SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Meeting Abstract CT Annual Scientific Meeting of the American-Geriatrics-Society CY MAY 03-05, 2013 CL Grapevine, TX SP Amer Geriatr Soc C1 [Peron, E. P.] VCU, Richmond, VA USA. [Perera, S.; Boudreau, R.; Donohue, J. M.; Ruby, C.; Newman, A. B.; Studenski, S. A.; Hanlon, J. T.] Univ Pittsburgh, Pittsburgh, PA USA. [Gray, S. L.] Univ Washington, Seattle, WA 98195 USA. [Shorr, R. I.] VA GRECC, Gainesville, FL USA. [Bauer, D.] UCSF, San Francisco, CA USA. [Simonsick, E.] NIA, Bethesda, MD 20892 USA. RI Perera, Subashan/D-7603-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD APR PY 2013 VL 61 SU 1 SI SI BP S52 EP S52 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 120QW UT WOS:000317187600146 ER PT J AU Pilotto, A Gallina, P Fontana, A Sancarlo, D Bazzano, S Copetti, M Maggi, S Paroni, G Marcato, F Pellegrini, F Donato, D Ferrucci, L AF Pilotto, Alberto Gallina, Pietro Fontana, Andrea Sancarlo, Daniele Bazzano, Salvatore Copetti, Massimiliano Maggi, Stefania Paroni, Giulia Marcato, Francesco Pellegrini, Fabio Donato, Daniele Ferrucci, Luigi TI Development and Validation of a Multidimensional Prognostic Index for Mortality Based on a Standardized Multidimensional Assessment Schedule (MPI-SVaMA) in Community-Dwelling Older Subjects SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Comprehensive geriatric assessment; prognosis; mortality; elderly ID COMPREHENSIVE GERIATRIC ASSESSMENT; HOSPITALIZED ELDERLY-PATIENTS; LONG-TERM MORTALITY; PREDICTION; ADULTS; DEATH; PEOPLE AB Objectives: To develop and validate a Multidimensional Prognostic Index (MPI) for mortality based on information collected by the Multidimensional Assessment Schedule (SVaMA), the recommended standard tool for multidimensional assessment of community-dwelling older subjects in seven Italian regions. Design: Prospective cohort study. Participants: Community-dwelling subjects older than 65 years who underwent an SVaMA evaluation from 2004 to 2010 in Padova Health District, Veneto, Italy. Measurements: The MPI-SVaMA was calculated as a weighted (weights were derived from multivariate Cox regressions) linear combination of the following nine domains: age, sex, main diagnosis, and six scores, ie, the Short Portable Mental Status Questionnaire, the Barthel index (contains two domains: activities of daily living and mobility), the Exton-Smith scale, the Nursing Care Needs, and the Social Network Support by a structured interview. Subjects were followed for a median of 2 years; those who had not died were followed for at least 1 year. The MPI-SVaMA score ranged from 0 to 1 and 3 grades of severity of the MPI-SVaMA were calculated on the basis of estimated cutoffs. Discriminatory power and calibration were further assessed. Results: A total of 12,020 subjects (mean age 81.84 +/- 7.97 years) were included. Two random cohorts were selected: (1) a development cohort, ie, 7876 subjects (mean age 81.79 +/- 8.05, % females: 63.1) and (2) a validation cohort, ie, 4144 subjects (mean age: 81.95 +/- 7.83, % females: 63.7). The discriminatory power for mortality of MPI-SVaMA was 0.828 (95% CI 0.817-0.838) and 0.832 (95% CI 0.818-0.845) at 1 month and 0.791 (95% CI 0.784-0.798) and 0.792 (95% CI 0.783-0.802) at 1 year in development and validation cohorts, respectively. MPI-SVaMA results were well calibrated showing lower than 10% differences between predicted and observed mortality, both in development and validation cohorts. Conclusions: The MPI-SVaMA is an accurate and well-calibrated prognostic tool for mortality in community-dwelling older subjects, and can be used in clinical decision making. Copyright (C) 2013 - American Medical Directors Association, Inc. C1 [Pilotto, Alberto; Bazzano, Salvatore] S Antonio Hosp, Geriatr Unit, Azienda ULSS 16 Padova, I-35127 Padua, Italy. [Gallina, Pietro; Marcato, Francesco; Donato, Daniele] Azienda ULSS 16 Padova, Hlth Serv Directorate, Padua, Italy. [Fontana, Andrea; Copetti, Massimiliano; Pellegrini, Fabio] IRCCS Casa Sollievo Sofferenza, Biostat Unit, San Giovanni Rotondo, FG, Italy. [Sancarlo, Daniele; Paroni, Giulia] IRCCS Casa Sollievo Sofferenza, Gerontol & Geriatr Res Lab, San Giovanni Rotondo, FG, Italy. [Maggi, Stefania] CNR, Aging Sect, Padua, Italy. [Pellegrini, Fabio] Consorzio Mario Negri Sud, Lab Clin Epidemiol Diabet & Chron Dis, Chieti, Italy. [Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. RP Pilotto, A (reprint author), S Antonio Hosp, Geriatr Unit, Azienda ULSS 16 Padova, Via Jacopo Facciolati 71, I-35127 Padua, Italy. EM alberto.pilotto@sanita.padova.it RI sebastianovitsch, stepan/G-8507-2013; Fontana, Andrea/J-8584-2016; Copetti, Massimiliano/K-3186-2016; Sancarlo, Daniele/C-1056-2017; Paroni, Giulia/C-3768-2017 OI Fontana, Andrea/0000-0002-6660-5315; Copetti, Massimiliano/0000-0002-7960-5947; Sancarlo, Daniele/0000-0001-9541-6364; Paroni, Giulia/0000-0003-0240-8475 FU Ministero della Salute, Italy; National Institute of Aging, Baltimore, MD FX This work was supported by the Ministero della Salute, Italy, IRCCS Research Program 2009-2011, Line 2: "Malattie complesse" and by the Intramural Research Program of the National Institute of Aging, Baltimore, MD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 14 Z9 14 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD APR PY 2013 VL 14 IS 4 BP 287 EP 292 DI 10.1016/j.jamda.2013.01.005 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 121YI UT WOS:000317281200013 PM 23402948 ER PT J AU Pellikka, PA Douglas, PS Miller, JG Abraham, TP Baumann, R Buxton, DB Byrd, BF Chen, P Cook, NL Gardin, JM Hansen, G Houle, HC Husson, S Kaul, S Klein, AL Lang, RM Leong-Poi, H Lopez, H Mahmoud, TM Maslak, S McCulloch, ML Metz, S Nagueh, SF Pearlman, AS Pibarot, P Picard, MH Porter, TR Prater, D Rodriguez, R Sarano, ME Scherrer-Crosbie, M Shirali, GS Sinusas, A Slosky, JJ Sugeng, L Tatpati, A Villanueva, FS von Ramm, OT Weissman, NJ Zamani, S AF Pellikka, Patricia A. Douglas, Pamela S. Miller, James G. Abraham, Theodore P. Baumann, Rolf Buxton, Denis B. Byrd, Benjamin F., III Chen, Peter Cook, Nakela L. Gardin, Julius M. Hansen, Gunnar Houle, Helene C. Husson, Stefan Kaul, Sanjiv Klein, Allan L. Lang, Roberto M. Leong-Poi, Howard Lopez, Hector Mahmoud, Tamer M. Maslak, Sam McCulloch, Marti L. Metz, Steve Nagueh, Sherif F. Pearlman, Alan S. Pibarot, Philippe Picard, Michael H. Porter, Thomas R. Prater, David Rodriguez, Rudy Sarano, Maurice E. Scherrer-Crosbie, Marielle Shirali, Girish S. Sinusas, Albert Slosky, Jack J. Sugeng, Lissa Tatpati, Anand Villanueva, Flordeliza S. von Ramm, Olaf T. Weissman, Neil J. Zamani, Shaun TI American Society of Echocardiography Cardiovascular Technology and Research Summit: A Roadmap for 2020 SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Editorial Material DE Echocardiography; Cardiac imaging; Cardiovascular imaging; Cardiovascular technology; Cardiovascular technology development; Research; Clinical Research; Myocardial deformation; Three-dimensional imaging; Doppler; Contrast echocardiography; Valvular heart disease; Therapeutic ultrasound; Research infrastructure; Research training ID VALVULAR HEART-DISEASE; REGIONAL MYOCARDIAL-FUNCTION; 3-DIMENSIONAL ECHOCARDIOGRAPHY; DIAGNOSTIC ULTRASOUND; IN-VIVO; EAE/ASE RECOMMENDATIONS; MICROBUBBLES; STRAIN; QUANTIFICATION; INVESTIGATORS C1 [Pellikka, Patricia A.; Sarano, Maurice E.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Douglas, Pamela S.; von Ramm, Olaf T.] Duke Univ, Sch Med, Duke Clin Res Inst, Durham, NC USA. [Miller, James G.] Washington Univ, Dept Phys, St Louis, MO 63130 USA. [Abraham, Theodore P.] Johns Hopkins Univ, Baltimore, MD USA. [Baumann, Rolf] TomTec Imaging Syst GmbH, Munich, Germany. [Buxton, Denis B.; Cook, Nakela L.] NHLBI, Bethesda, MD 20892 USA. [Byrd, Benjamin F., III] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Chen, Peter] GE Healthcare Med Diagnost, Chicago, IL USA. [Gardin, Julius M.] Hackensack Univ Med Ctr, Hackensack, NJ USA. [Hansen, Gunnar] GE Healthcare, Horten, Norway. [Houle, Helene C.] Siemens Med Solut USA Inc, Mountain View, CA USA. [Husson, Stefan] GE Ultrasound, Milwaukee, WI USA. [Kaul, Sanjiv] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Klein, Allan L.] Cleveland Clin, Cleveland, OH 44106 USA. [Lang, Roberto M.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Leong-Poi, Howard] Univ Toronto, St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Lopez, Hector] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Mahmoud, Tamer M.] Abbott Vasc Struct Heart, Menlo Pk, CA USA. [McCulloch, Marti L.; Nagueh, Sherif F.] Methodist Hosp, Methodist DeBakey Heart & Vasc Ctr, Houston, TX 77030 USA. [Metz, Steve] Philips Healthcare, Seattle, WA USA. [Pearlman, Alan S.] Univ Washington, Seattle, WA 98195 USA. [Pibarot, Philippe] Univ Laval, Quebec Heart Inst, Quebec City, PQ, Canada. [Picard, Michael H.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Picard, Michael H.; Scherrer-Crosbie, Marielle] Harvard Univ, Sch Med, Boston, MA USA. [Porter, Thomas R.] Univ Nebraska Med Ctr, Omaha, NE USA. [Prater, David] Philips Healthcare, Andover, MA USA. [Rodriguez, Rudy; Zamani, Shaun] Edwards Lifesci, Irvine, CA USA. [Shirali, Girish S.] Childrens Mercy Hosp, Kansas City, MO 64108 USA. [Sinusas, Albert; Sugeng, Lissa] Yale Univ, New Haven, CT USA. [Slosky, Jack J.] Lantheus Med Imaging, North Billerica, MA USA. [Tatpati, Anand] Siemens Med Solut, San Francisco, CA USA. [Villanueva, Flordeliza S.] Univ Pittsburgh, Pittsburgh, PA USA. [Weissman, Neil J.] Washington Hosp Ctr, MedStar Res Inst, Washington, DC 20010 USA. RP Pellikka, PA (reprint author), Amer Soc Echocardiog, 2100 Gateway Ctr Blvd,Suite 310, Morrisville, NC 27560 USA. EM ase@asecho.org OI Buxton, Denis/0000-0003-3077-6435; Picard, Michael/0000-0002-9264-3243 NR 37 TC 15 Z9 15 U1 0 U2 15 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD APR PY 2013 VL 26 IS 4 BP 325 EP 338 DI 10.1016/j.echo.2013.02.003 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 122UM UT WOS:000317343600001 PM 23537771 ER PT J AU Arimbasseri, AG Maraia, RJ AF Arimbasseri, Aneeshkumar G. Maraia, Richard J. TI Distinguishing Core and Holoenzyme Mechanisms of Transcription Termination by RNA Polymerase III SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MASS-SPECTROMETRY; CLEAVAGE ACTIVITY; STRUCTURAL BASIS; ELONGATION; DNA; ARCHITECTURE; SUBCOMPLEX; COMPLEX; MAF1; BACKTRACKING AB Transcription termination by RNA polymerase (Pol) III serves multiple purposes; it delimits interference with downstream genes, forms 3' oligo(U) binding sites for the posttranscriptional processing factor, La protein, and resets the polymerase complex for reinitiation. Although an interplay of several Pol III subunits is known to collectively control these activities, how they affect molecular function of the active center during termination is incompletely understood. We have approached this using immobilized Pol III-nucleic acid scaffolds to examine the two major components of termination, transcription pausing and RNA release. This allowed us to distinguish two mechanisms of termination by isolated Saccharomyces cerevisiae Pol III. A core mechanism can operate in the absence of C53/37 and C11 subunits but requires synthesis of 8 or more 3' U nucleotides, apparently reflecting inherent sensitivity to an oligo(rU.dA) hybrid that is the termination signal proper. The holoenzyme mechanism requires fewer U nucleotides but uses C53/37 and C11 to slow elongation and prevent terminator arrest. N-terminal truncation of C53 or point mutations that disable the cleavage activity of C11 impair their antiarrest activities. The data are consistent with a model in which C53, C37, and C11 activities are functionally integrated with the active center of Pol III during termination. C1 [Arimbasseri, Aneeshkumar G.; Maraia, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA. RP Maraia, RJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Intramural Res Program, NIH, Bethesda, MD USA. EM maraiar@mail.nih.gov OI Arimbasseri, Gopalakrishnan Aneeshkumar/0000-0001-5266-2688 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. R.J.M. is a member of the U.S. Public Health Service Commissioned Corps. NR 53 TC 6 Z9 7 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR PY 2013 VL 33 IS 8 BP 1571 EP 1581 DI 10.1128/MCB.01733-12 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 121VK UT WOS:000317272500008 PM 23401852 ER PT J AU Ferreira, Z Seixas, S Andres, AM Kretzschmar, WW Mullikin, JC Cherukuri, PF Cruz, P Swanson, WJ Clark, AG Green, ED Hurle, B AF Ferreira, Zelia Seixas, Susana Andres, Aida M. Kretzschmar, Warren W. Mullikin, James C. Cherukuri, Praveen F. Cruz, Pedro Swanson, Willie J. Clark, Andrew G. Green, Eric D. Hurle, Belen CA NISC Comparative Sequencing TI Reproduction and Immunity-Driven Natural Selection in the Human WFDC Locus SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE WFDC; semenogelins; natural selection; innate immunity; serine protease inhibitors; reproduction ID HUMAN SEMINAL PLASMA; SECRETORY LEUCOPROTEASE INHIBITOR; FALSE DISCOVERY RATES; SEMENOGELIN-I; HUMAN GENOME; POSITIVE SELECTION; HAPLOTYPE RECONSTRUCTION; MOLECULAR EVOLUTION; STATISTICAL-METHOD; GENETIC-VARIATION AB The whey acidic protein (WAP) four-disulfide core domain (WFDC) locus located on human chromosome 20q13 spans 19 genes with WAP and/or Kunitz domains. These genes participate in antimicrobial, immune, and tissue homoeostasis activities. Neighboring SEMG genes encode seminal proteins Semenogelin 1 and 2 (SEMG1 and SEMG2). WFDC and SEMG genes have a strikingly high rate of amino acid replacement (d(N)/d(S))(,) indicative of responses to adaptive pressures during vertebrate evolution. To better understand the selection pressures acting on WFDC genes in human populations, we resequenced 18 genes and 54 noncoding segments in 71 European (CEU), African (YRI), and Asian (CHB + JPT) individuals. Overall, we identified 484 single-nucleotide polymorphisms (SNPs), including 65 coding variants (of which 49 are nonsynonymous differences). Using classic neutrality tests, we confirmed the signature of short-term balancing selection on WFDC8 in Europeans and a signature of positive selection spanning genes PI3, SEMG1, SEMG2, and SLPI. Associated with the latter signal, we identified an unusually homogeneous-derived 100-kb haplotype with a frequency of 88% in Asian populations. A putative candidate variant targeted by selection is Thr56Ser in SEMG1, which may alter the proteolytic profile of SEMG1 and antimicrobial activities of semen. All the well-characterized genes residing in the WDFC locus encode proteins that appear to have a role in immunity and/or fertility, two processes that are often associated with adaptive evolution. This study provides further evidence that the WFDC and SEMG loci have been under strong adaptive pressure within the short timescale of modern humans. C1 [Ferreira, Zelia; Green, Eric D.; Hurle, Belen] NHGRI, NIH, Bethesda, MD 20892 USA. [Ferreira, Zelia; Seixas, Susana] Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal. [Ferreira, Zelia] Univ Porto, Fac Sci, Dept Biol, P-4100 Oporto, Portugal. [Andres, Aida M.] Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, Leipzig, Germany. [Kretzschmar, Warren W.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Mullikin, James C.; Cherukuri, Praveen F.; Cruz, Pedro; NISC Comparative Sequencing] NHGRI, NISC, NIH, Rockville, MD USA. [Swanson, Willie J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. RP Ferreira, Z (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM zferreira@ipatimup.pt RI Seixas, Susana /I-5084-2013; Andres, Aida/B-4088-2014; OI Seixas, Susana /0000-0002-7035-7422; Andres, Aida/0000-0002-8590-9672; Kretzschmar, Warren/0000-0002-2575-0807 FU Intramural Research Program of the National Human Genome Research Institute; Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/45907/2008]; POPH-QREN-Promotion of scientific employment; European Social Fund and national funds of the Portuguese Ministry of Education and Science; Wellcome Trust Centre for Human Genetics [WT097307]; FCT FX The authors acknowledge Anh-Dao Nguyen for the help inferring the ancestral allele state of each SNP and Guillaume Laval for making available the scripts for the DIND test. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute, by the SFRH/BD/45907/2008 fellowship from the Portuguese Foundation for Science and Technology (FCT) to Z.F., by the POPH-QREN-Promotion of scientific employment to Z. F. and S. S., supported by the European Social Fund and national funds of the Portuguese Ministry of Education and Science, and by the Wellcome Trust Centre for Human Genetics (WT097307) to W. W. K. IPATIMUP is an Associated Laboratory of the Portuguese Ministry of Education and Science and is partially supported by FCT. NR 89 TC 8 Z9 8 U1 0 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD APR PY 2013 VL 30 IS 4 BP 938 EP 950 DI 10.1093/molbev/mss329 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 118DF UT WOS:000317002300021 PM 23292442 ER PT J AU Airenne, KJ Hu, YC Kost, TA Smith, RH Kotin, RM Ono, C Matsuura, Y Wang, S Yla-Herttuala, S AF Airenne, Kari J. Hu, Yu-Chen Kost, Thomas A. Smith, Richard H. Kotin, Robert M. Ono, Chikako Matsuura, Yoshiharu Wang, Shu Yla-Herttuala, Seppo TI Baculovirus: an Insect-derived Vector for Diverse Gene Transfer Applications SO MOLECULAR THERAPY LA English DT Review ID NUCLEAR POLYHEDROSIS-VIRUS; MESENCHYMAL STEM-CELLS; ROTATING-SHAFT BIOREACTOR; GROWTH-FACTOR EXPRESSION; MAMMALIAN-CELLS; RECOMBINANT BACULOVIRUS; IN-VIVO; TRANSGENE EXPRESSION; ADENOASSOCIATED VIRUS; ANTITUMOR IMMUNITY AB Insect-derived baculoviruses have emerged as versatile and safe workhorses of biotechnology. Baculovirus expression vectors (BEVs) have been applied widely for crop and forest protection, as well as safe tools for recombinant protein production in insect cells. However, BEVs ability to efficiently transduce noninsect cells is still relatively poorly recognized despite the fact that efficient baculovirus-mediated in vitro and ex vivo gene delivery into dormant and dividing vertebrate cells of diverse origin has been described convincingly by many authors. Preliminary proof of therapeutic potential has also been established in preclinical studies. This review summarizes the advantages and current status of baculovirus-mediated gene delivery. Stem cell transduction, preclinical animal studies, tissue engineering, vaccination, cancer gene therapy, viral vector production, and drug discovery are covered. Received 15 August 2012; accepted 11 December 2012; advance online publication 26 February 2013. doi:10.1038/mt.2012.286 C1 [Airenne, Kari J.; Yla-Herttuala, Seppo] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland. [Hu, Yu-Chen] Natl Tsing Hua Univ, Dept Chem Engn, Hsinchu, Taiwan. [Hu, Yu-Chen] Natl Tsing Hua Univ, Inst Biomed Engn, Hsinchu, Taiwan. [Kost, Thomas A.] GlaxoSmithKline R&D, Biol Reagents & Assay Dev, Res Triangle Pk, NC USA. [Smith, Richard H.; Kotin, Robert M.] NHLBI, Mol Virol & Gene Therapy Lab, NIH, Bethesda, MD 20892 USA. [Ono, Chikako; Matsuura, Yoshiharu] Osaka Univ, Microbial Dis Res Inst, Dept Mol Virol, Suita, Osaka 565, Japan. [Wang, Shu] Inst Bioengn & Nanotechnol, Singapore, Singapore. [Wang, Shu] Natl Univ Singapore, Dept Biol Sci, Singapore 117548, Singapore. [Yla-Herttuala, Seppo] Kuopio Univ Hosp, Res Unit, SF-70210 Kuopio, Finland. [Yla-Herttuala, Seppo] Kuopio Univ Hosp, Gene Therapy Unit, SF-70210 Kuopio, Finland. RP Airenne, KJ (reprint author), Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, POB 1627, Kuopio 70211, Finland. EM Kari.Airenne@uef.fi; Seppo.Ylaherttuala@uef.fi RI wang, shu /H-6744-2012; sebastianovitsch, stepan/G-8507-2013 FU Division of Intramural Research of the National Heart, Lung, and Blood Institute (National Institutes of Health (NIH)); International Collaborative Effort (ICE) for Duchenne Muscular Dystrophy comprised of the French Duchenne Parent Project; Association Monogasque contre les Myopathies; U.S. Government; NIH policy FX R.H.S., R.M.K. funding was provided by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (National Institutes of Health (NIH)). Additional funding was provided by the International Collaborative Effort (ICE) for Duchenne Muscular Dystrophy comprised of the French Duchenne Parent Project and the Association Monogasque contre les Myopathies. Portions of the technology described in this report are covered by United States and European patents assigned to the Secretary of the Department of Health and Human Services. A fraction of the licensing fees made to the NIH is distributed to the inventors in accordance with U.S. Government and NIH policy. The authors declared no conflict of interest. NR 150 TC 64 Z9 66 U1 6 U2 66 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD APR PY 2013 VL 21 IS 4 BP 739 EP 749 DI 10.1038/mt.2012.286 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 119PR UT WOS:000317110300005 PM 23439502 ER PT J AU Kranz, G Shamim, EA Lin, PT Kranz, GS Hallett, M AF Kranz, Gottfried Shamim, Ejaz A. Lin, Peter T. Kranz, George S. Hallett, Mark TI Long-term depression-like plasticity of the blink reflex for the treatment of blepharospasm SO MOVEMENT DISORDERS LA English DT Article DE blepharospasm; dystonia; plasticity; clinical trials randomized controlled; blink reflex ID TRANSCRANIAL MAGNETIC STIMULATION; BRAIN-STIMULATION; RECOVERY; POTENTIATION; EXCITABILITY; DYSTONIA AB Our previous work showed a beneficial therapeutic effect on blepharospasm using slow repetitive transcranial magnetic stimulation, which produces a long-term depression (LTD)-like effect. High-frequency supraorbital electrical stimulation, asynchronous with the R2 component of the blink reflex, can also induce LTD-like effects on the blink reflex circuit in healthy subjects. Patients with blepharospasm have reduced inhibition of their blink recovery curves; therefore, a LTD-like intervention might normalize the blink reflex recovery (BRR) and have a favorable therapeutic effect. This is a randomized, sham-controlled, observer-blinded prospective study. In 14 blepharospasm patients, we evaluated the effects of high-frequency supraorbital stimulation on three separate treatment days. We applied 28 trains of nine stimuli, 400 Hz, either before or after the R2 or used sham stimulation. The primary outcome was the blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after and 1 hour after stimulation while resting, reading, and talking; secondary outcome was the BRR. Stimulation before and after the R2 both showed a similar improvement as sham stimulation in physician rating, but patients felt significantly better with the before condition. Improvement in recovery of the blink reflex was noted only in the before condition. Clinical symptoms differed in the three baseline conditions (resting, reading, and talking). Stimulation before R2 increased inhibition in trigeminal blink reflex circuits in blepharospasm toward normal values and produced subjective, but not objective, improvement. Inhibition of the blink reflex pathway by itself appeared to be insufficient for a useful therapeutic effect. (c) 2013 Movement Disorder Society C1 [Kranz, Gottfried; Shamim, Ejaz A.; Lin, Peter T.; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Kranz, Gottfried] Med Univ Vienna, Dept Neurol, A-1090 Vienna, Austria. [Shamim, Ejaz A.] Midatlantic Permanente Med Grp, Midatlantic Permanente Res Inst, Dept Neurol, Rockville, MD USA. [Lin, Peter T.] Santa Clara Valley Med Ctr, Dept Neurol, San Jose, CA 95128 USA. [Kranz, George S.] Med Univ Vienna, Dept Psychiat & Psychotherapy, A-1090 Vienna, Austria. RP Kranz, G (reprint author), Med Univ Vienna, Dept Neurol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM gottfried.kranz@meduniwien.ac.at FU National Institutes of Health/National Institute for Neurological Disorders and Stroke Human Motor Control Section; Max Kade Foundation (New York, New York, USA) FX This work was supported by the National Institutes of Health/National Institute for Neurological Disorders and Stroke Human Motor Control Section and the Max Kade Foundation (New York, New York, USA; to G.K.). NR 17 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2013 VL 28 IS 4 BP 498 EP 503 DI 10.1002/mds.25329 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 123CO UT WOS:000317366100019 PM 23401198 ER PT J AU Kulkarni, O LaFaver, K Papavassiliou, E Tarsy, D Shih, LC AF Kulkarni, Omesh LaFaver, Kathrin Papavassiliou, Efstathios Tarsy, Daniel Shih, Ludy C. TI Thalamic and subthalamic deep brain stimulation for parkinsonian tremor: Are two circuits involved? SO MOVEMENT DISORDERS LA English DT Letter C1 [Kulkarni, Omesh; Tarsy, Daniel; Shih, Ludy C.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Papavassiliou, Efstathios] Beth Israel Deaconess Med Ctr, Dept Surg, Div Neurosurg, Boston, MA 02215 USA. [LaFaver, Kathrin] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. RP Shih, LC (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave,KS 228, Boston, MA 02215 USA. EM lshih@caregroup.harvard.edu NR 6 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR PY 2013 VL 28 IS 4 BP 554 EP 554 DI 10.1002/mds.25299 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 123CO UT WOS:000317366100031 PM 23389961 ER PT J AU Afonin, KA Viard, M Martins, AN Lockett, SJ Maciag, AE Freed, EO Heldman, E Jaeger, L Blumenthal, R Shapiro, BA AF Afonin, Kirill A. Viard, Mathias Martins, Angelica N. Lockett, Stephen J. Maciag, Anna E. Freed, Eric O. Heldman, Eliahu Jaeger, Luc Blumenthal, Robert Shapiro, Bruce A. TI Activation of different split functionalities on re-association of RNA-DNA hybrids SO NATURE NANOTECHNOLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; PROTEIN INTERACTIONS; EMERGING FIELD; NANOPARTICLES; INTERFERENCE; SIRNA; DICER; DELIVERY; NANOTECHNOLOGY; HYBRIDIZATION AB Split-protein systems, an approach that relies on fragmentation of proteins with their further conditional re-association to form functional complexes, are increasingly used for various biomedical applications. This approach offers tight control of protein functions and improved detection sensitivity. Here we report a similar technique based on a pair of RNA-DNA hybrids that can be used generally for triggering different split functionalities. Individually, each hybrid is inactive but when two cognate hybrids re-associate, different functionalities are triggered inside mammalian cells. As a proof of concept, this work mainly focuses on the activation of RNA interference. However, the release of other functionalities (such as resonance energy transfer and RNA aptamer) is also shown. Furthermore, in vivo studies demonstrate a significant uptake of the hybrids by tumours together with specific gene silencing. This split-functionality approach presents a new route in the development of 'smart' nucleic acid-based nanoparticles and switches for various biomedical applications. C1 [Afonin, Kirill A.; Viard, Mathias; Blumenthal, Robert; Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. [Viard, Mathias; Maciag, Anna E.; Heldman, Eliahu] NCI, Basic Sci Program, SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Martins, Angelica N.; Freed, Eric O.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Lockett, Stephen J.] NCI, Adv Technol Program, SAIC Frederick, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Maciag, Anna E.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Heldman, Eliahu] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. [Jaeger, Luc] Univ Calif Santa Barbara, Dept Chem & Biochem, Biomol Sci & Engn Program, Santa Barbara, CA 93106 USA. RP Afonin, KA (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. EM shapirbr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Federal funds from the Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E]; NIH [R01GM-079604] FX The authors acknowledge help with ex vivo imaging from the Pathology Histology Laboratory of SAIC-Frederick at the Frederick National Laboratory for Cancer Research Thanks also go to C.J. Westlake at the Frederick National Laboratory for Cancer Research for providing plasmids expressing GFP-Rab5 or GFP-Rab7. The authors thank P.S. Steeg at the National Cancer Institute for providing GFP-expressing cells for in vivo experiments. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work was funded, in whole or in part, by Federal funds from the Frederick National Laboratory for Cancer Research, NIH (contract no. HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was also supported by an NIH grant no. R01GM-079604 to L.J.). NR 50 TC 27 Z9 28 U1 4 U2 64 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD APR PY 2013 VL 8 IS 4 BP 296 EP 304 DI 10.1038/NNANO.2013.44 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 118ST UT WOS:000317046800018 PM 23542902 ER PT J AU Pennacchio, LA Bickmore, W Dean, A Nobrega, MA Bejerano, G AF Pennacchio, Len A. Bickmore, Wendy Dean, Ann Nobrega, Marcelo A. Bejerano, Gill TI Enhancers: five essential questions SO NATURE REVIEWS GENETICS LA English DT Article ID LONG-RANGE INTERACTION; LOCUS-CONTROL REGION; GENE ACTIVATION; HUMAN GENOME; TRANSCRIPTIONAL ENHANCERS; REGULATORY SEQUENCES; HUMAN-CELLS; PROMOTER; EVOLUTION; ELEMENTS AB It is estimated that the human genome contains hundreds of thousands of enhancers, so understanding these gene-regulatory elements is a crucial goal. Several fundamental questions need to be addressed about enhancers, such as how do we identify them all, how do they work, and how do they contribute to disease and evolution? Five prominent researchers in this field look at how much we know already and what needs to be done to answer these questions. C1 [Pennacchio, Len A.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Bickmore, Wendy] Univ Edinburgh, MRC Human Genet Unit, IGMM, Edinburgh EH4 2XU, Midlothian, Scotland. [Dean, Ann] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. [Nobrega, Marcelo A.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Bejerano, Gill] Stanford Univ, Beckman Ctr B300, Stanford, CA 94305 USA. RP Nobrega, MA (reprint author), Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. EM lapennacchio@lbl.gov; wendy.bickmore@igmm.ed.ac.uk; anndean@helix.nih.gov; nobrega@uchicago.edu; bejerano@stanford.edu RI Bickmore, Wendy/C-7314-2013 OI Bickmore, Wendy/0000-0001-6660-7735 FU US National Human Genome Research Institute [R01HG003988, U54HG006997]; US Department of Energy, University of California [DE-AC02-05CH11231]; Intramural Program of the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH); US National Institutes of Health [R01DK093972, R01HL114010] FX L.A.P. was supported by US National Human Genome Research Institute grants R01HG003988 and U54HG006997. Research was conducted at the E.O. Lawrence Berkeley National Laboratory and carried out under US Department of Energy Contract DE-AC02-05CH11231, University of California. A.D. acknowledges support for research in her laboratory by the Intramural Program of the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH). M.A.N. is currently supported by the US National Institutes of Health, grants R01DK093972 and R01HL114010. G.B. thanks members of his laboratory, past and present, for their wisdom and company. NR 74 TC 70 Z9 73 U1 3 U2 75 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD APR PY 2013 VL 14 IS 4 BP 288 EP 295 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 117TF UT WOS:000316975300012 PM 23503198 ER PT J AU Weidensteiner, C Reichardt, W Shami, PJ Saavedra, JE Keefer, LK Baumer, B Werres, A Jasinski, R Osterberg, N Weyerbrock, A AF Weidensteiner, Claudia Reichardt, Wilfried Shami, Paul J. Saavedra, Joseph E. Keefer, Larry K. Baumer, Brunhilde Werres, Anna Jasinski, Robert Osterberg, Nadja Weyerbrock, Astrid TI Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE Nitric oxide; JS-K; cGMP; Blood-tumor barrier; DCE-MRI; U87 glioma ID GROWTH-FACTOR RECEPTOR; CELLS IN-VITRO; BRAIN-BARRIER; MATRIX METALLOPROTEINASES; ANTINEOPLASTIC ACTIVITY; MALIGNANT GLIOMAS; TYROSINE KINASE; C6 GLIOMAS; DCE-MRI; CANCER AB Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI). In vitro experiments showed dose-dependent antiproliferative and cytotoxic effects in U87 cells. In addition, treatment of U87 cells with JS-K resulted in a dose-dependent activation of soluble guanylate cyclase and intracellular accumulation of cyclic guanosine monophosphate (cGMP) which was irreversibly inhibited by the selective inhibitor of soluble guanylate cyclase ODQ (1H-[1,2,4]oxadiazolo(4,3a)quinoxaline-1-one). Using dynamic contrast enhanced MRI (DCE-MRI) as a minimally invasive technique, we demonstrated for the first time a significant increase in the DCE-MRI read-out initial area under the concentration curve (iAUC(60)) indicating an acute increase in blood-tumor barrier permeability after i.v. treatment with JS-K. Repeated MR imaging of animals with intracranial U87 gliomas under treatment with JS-K (3.5 mu mol/kg JS-K 3 x/week) and of untreated controls on day 12 and 19 after tumor inoculation revealed no significant changes in tumor growth, edema formation or tumor perfusion. Immunohistochemical workup of the brains showed a significant antiproliferative effect of JS-K in the gliomas. Taken together, in vitro and in vivo data suggest that JS-K has antiproliferative effects in U87 gliomas and opens the blood-tumor barrier by activation of the NO/cGMP signaling pathway. This might be a novel approach to facilitate entry of therapeutic drugs into brain tumors. DCE-MRI is a non-invasive, repeatable imaging modality to monitor biological effects of NO donors and other experimental therapeutics in intracranial tumor models. (c) 2013 Elsevier Inc. All rights reserved. C1 [Weidensteiner, Claudia; Reichardt, Wilfried] Univ Med Ctr Freiburg, Dept Radiol Med Phys, D-79106 Freiburg, Germany. [Reichardt, Wilfried] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Reichardt, Wilfried] Deutsch Konsortium Translat Krebsforsch DKTK, Freiburg, Germany. [Shami, Paul J.] Univ Utah, Huntsman Canc Inst, Div Med Oncol, Salt Lake City, UT 84112 USA. [Saavedra, Joseph E.] NCI Frederick, SAIC Frederick, Frederick, MD 21702 USA. [Keefer, Larry K.] NCI Frederick, Biol Chem Lab, Frederick, MD 21702 USA. [Baumer, Brunhilde; Werres, Anna; Jasinski, Robert; Osterberg, Nadja; Weyerbrock, Astrid] Univ Med Ctr Freiburg, Dept Neurosurg, D-79106 Freiburg, Germany. RP Weidensteiner, C (reprint author), Univ Med Ctr Freiburg, Dept Radiol Med Phys, Breisacher Str 60A, D-79106 Freiburg, Germany. EM claudia.weidensteiner@uniklinik-freiburg.de RI Reichardt, Wilfried/K-6727-2013; Weyerbrock, Astrid/E-8493-2014; Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; ENCITE; European Commission FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (JS) and by Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. It was also supported in part by ENCITE which is co-funded by the European Commission under the 7th Framework Programme. NR 55 TC 3 Z9 4 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD APR 1 PY 2013 VL 30 BP 17 EP 25 DI 10.1016/j.niox.2013.01.003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 122LV UT WOS:000317320500003 PM 23370169 ER PT J AU Hudson, AG Reeves, KW Modugno, F Wilson, JW Evans, RW Vogel, VG Gierach, GL Simpson, J Weissfeld, JL AF Hudson, Alana G. Reeves, Katherine W. Modugno, Francesmary Wilson, John W. Evans, Rhobert W. Vogel, Victor G. Gierach, Gretchen L. Simpson, Jennifer Weissfeld, Joel L. TI Erythrocyte Omega-6 and Omega-3 Fatty Acids and Mammographic Breast Density SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID FATTY-ACIDS; CANCER RISK; DIETARY; PATTERNS; JAPANESE; WOMEN; N-3; MARKERS; COHORT; LIPIDS AB Diets low in omega-6 (n-6) polyunsaturated fatty acids (PUFAs) and high in omega-3 (n-3) PUFAs may protect against breast cancer development. Associations of PUFA intake with mammographic density, an intermediate marker of breast cancer risk, have been inconsistent; however, prior studies have relied on self-reported dietary PUFA intake. We examined the association between circulating erythrocyte n-6 and n-3 PUFAs with mammographic density in 248 postmenopausal women who were not taking exogenous hormones. PUFAs in erythrocytes were measured by gas-liquid chromatography, and mammographic density was assessed quantitatively by planimetry. Spearman's correlation coefficients and generalized linear models were used to evaluate the relationships between PUFA measures and mammographic density. None of the erythrocyte n-6 or n-3 PUFA measures were associated with percent density or dense breast area. C1 [Hudson, Alana G.] West Virginia Dept Hlth & Human Resources, Div Canc Epidemiol, Bur Publ Hlth, Charleston, WV USA. [Hudson, Alana G.; Reeves, Katherine W.; Modugno, Francesmary; Evans, Rhobert W.; Gierach, Gretchen L.; Simpson, Jennifer; Weissfeld, Joel L.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Reeves, Katherine W.] Univ Massachusetts, Dept Publ Hlth, Amherst, MA 01003 USA. [Wilson, John W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Vogel, Victor G.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Gierach, Gretchen L.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Simpson, Jennifer] ImClone Syst, Bridgewater, NJ USA. [Weissfeld, Joel L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. RP Hudson, AG (reprint author), 350 Capitol St,Room 125, Charleston, WV 25301 USA. EM Alana.L.Hudson@wv.gov RI Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU NIH [R25-CA57703, K07-CA80668, R21-CA95113, P20 CA103730-02]; Department of Defense [DAMD17-02-1-0553, W81 XWH-06-1-0532]; Pennsylvania Department of Health [P2777693]; NIH/National Center for Research Resources/General Clinical Research Center [MO1-RR000056] FX This article was supported by NIH grants R25-CA57703, K07-CA80668, R21-CA95113, and P20 CA103730-02; Department of Defense grants DAMD17-02-1-0553 and W81 XWH-06-1-0532; and Pennsylvania Department of Health grant P2777693. Additional support was provided by funds received from the NIH/National Center for Research Resources/General Clinical Research Center grant MO1-RR000056. NR 26 TC 4 Z9 4 U1 0 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PD APR 1 PY 2013 VL 65 IS 3 BP 410 EP 416 DI 10.1080/01635581.2013.760744 PG 7 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 113GX UT WOS:000316655700010 PM 23530640 ER PT J AU Ferris, FL Wilkinson, CP Bird, A Chakravarthy, U Chew, E Csaky, K Sadda, SR AF Ferris, Frederick L., III Wilkinson, C. P. Bird, Alan Chakravarthy, Usha Chew, Emily Csaky, Karl Sadda, SriniVas R. CA Beckman Initiative Macular Res TI Clinical Classification of Age-related Macular Degeneration SO OPHTHALMOLOGY LA English DT Article ID RAND-LIKE METHODOLOGY; GLAUCOMA MANAGEMENT; PANEL ASSESSMENT; SEVERITY SCALE; MACULOPATHY; PROGRESSION; RISK; OPHTHALMOLOGY; ROTTERDAM; CONSENSUS AB Objective: To develop a clinical classification system for age-related macular degeneration (AMD). Design: Evidence-based investigation, using a modified Delphi process. Participants: Twenty-six AMD experts, 1 neuro-ophthalmologist, 2 committee chairmen, and 1 methodologist. Methods: Each committee member completed an online assessment of statements summarizing current AMD classification criteria, indicating agreement or disagreement with each statement on a 9-step scale. The group met, reviewed the survey results, discussed the important components of a clinical classification system, and defined new data analyses needed to refine a classification system. After the meeting, additional data analyses from large studies were provided to the committee to provide risk estimates related to the presence of various AMD lesions. Main Outcome Measures: Delphi review of the 9-item set of statements resulting from the meeting. Results: Consensus was achieved in generating a basic clinical classification system based on fundus lesions assessed within 2 disc diameters of the fovea in persons older than 55 years. The committee agreed that a single term, age-related macular degeneration, should be used for the disease. Persons with no visible drusen or pigmentary abnormalities should be considered to have no signs of AMD. Persons with small drusen (<63 mu m), also termed drupelets, should be considered to have normal aging changes with no clinically relevant increased risk of late AMD developing. Persons with medium drusen (>= 63-<125 mu m), but without pigmentary abnormalities thought to be related to AMD, should be considered to have early AMD. Persons with large drusen or with pigmentary abnormalities associated with at least medium drusen should be considered to have intermediate AMD. Persons with lesions associated with neovascular AMD or geographic atrophy should be considered to have late AMD. Five-year risks of progressing to late AMD are estimated to increase approximately 100 fold, ranging from a 0.5% 5-year risk for normal aging changes to a 50% risk for the highest intermediate AMD risk group. Conclusions: The proposed basic clinical classification scale seems to be of value in predicting the risk of late AMD. Incorporating consistent nomenclature into the practice patterns of all eye care providers may improve communication and patient care. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:844-851 (C) 2013 by the American Academy of Ophthalmology. C1 [Ferris, Frederick L., III; Chew, Emily] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Wilkinson, C. P.] Greater Baltimore Med Ctr, Baltimore, MD USA. [Bird, Alan] NHS Fdn Trust, Moorfields Eye Hosp, London, England. [Chakravarthy, Usha] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland. [Csaky, Karl] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Sadda, SriniVas R.] Doheny Eye Inst, Los Angeles, CA 90033 USA. RP Ferris, FL (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 3-2531, Bethesda, MD 20892 USA. EM RickFerris@nei.nih.gov FU Arnold and Mabel Beckman Initiative for Macular Research, Irvine, California FX Supported by the Arnold and Mabel Beckman Initiative for Macular Research, Irvine, California. NR 22 TC 168 Z9 170 U1 10 U2 48 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2013 VL 120 IS 4 BP 844 EP 851 DI 10.1016/j.ophtha.2012.10.036 PG 8 WC Ophthalmology SC Ophthalmology GA 122UL UT WOS:000317343500030 PM 23332590 ER PT J AU Phillips, SM McAuley, E AF Phillips, Siobhan M. McAuley, Edward TI Social cognitive influences on physical activity participation in long-term breast cancer survivors SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; physical activity; breast cancer survivors; social cognitive theory ID QUALITY-OF-LIFE; MAXIMUM-LIKELIHOOD-ESTIMATION; STRUCTURAL EQUATION MODELS; SELF-EFFICACY; OLDER-ADULTS; EXERCISE PARTICIPATION; MISSING DATA; FIT INDEXES; DIAGNOSIS; HEALTH AB Background Although physical activity is beneficial for breast cancer survivors, the majority do not meet public health physical activity recommendations. The purpose of this study was to test a social cognitive theory model of physical activity behavior in a sample of long-term breast cancer survivors using both self-report and objective measures of physical activity. Methods Participants (N=1527) completed measures of physical activity, self-efficacy, goals, outcome expectations, fatigue, and social support at baseline and 6-month follow-up. A subsample (n=370) was randomly selected to wear an accelerometer. It was hypothesized that self-efficacy directly and indirectly influences physical activity through goals, social support, fatigue, and outcome expectations. Relationships were examined using panel analysis within a covariance modeling framework. Results The hypothesized model provided a good model-data fit (2=1168.73, df=271, p=<0.001, CFI=0.96, SRMR=0.04) in the full sample when controlling for covariates. At baseline, self-efficacy directly and indirectly, via goals, outcome expectations, and social support, influenced physical activity. These relationships were also supported across time. Additionally, the hypothesized model was supported in the subsample with accelerometer data (2=656.88, df=330, p<0.001, CFI=0.95, SRMR=0.05). Conclusions This study validates a social cognitive model for understanding physical activity behavior in long-term breast cancer survivors. Future studies should be designed to replicate this model in other breast cancer survivor populations, and the findings should be applied to the development of future physical activity programs and studies for this population. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Phillips, Siobhan M.] NCI, Ctr Canc Training, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Phillips, Siobhan M.; McAuley, Edward] Univ Illinois, Dept Kinesiol & Community Hlth, Urbana, IL USA. RP Phillips, SM (reprint author), NCI, Ctr Canc Training, Canc Prevent Fellowship Program, 6120 Execut Blvd,Suite 150E, Bethesda, MD 20892 USA. EM smphillips19@gmail.com FU National Institute on Aging [F31AG034025, AG020118]; Shahid and Ann Carlson Khan endowed professorship FX This work was supported by award #F31AG034025 from the National Institute on Aging awarded to Siobhan M. (White) Phillips, and a Shahid and Ann Carlson Khan endowed professorship awarded to Edward McAuley who is also supported by grant #AG020118 from the National Institute on Aging. NR 52 TC 17 Z9 17 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD APR PY 2013 VL 22 IS 4 BP 783 EP 791 DI 10.1002/pon.3074 PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 122IQ UT WOS:000317312200009 PM 22451113 ER PT J AU Hamilton, JG Wu, LM Austin, JE Valdimarsdottir, H Basmajian, K Vu, A Rowley, SD Isola, L Redd, WH Rini, C AF Hamilton, Jada G. Wu, Lisa M. Austin, Jane E. Valdimarsdottir, Heiddis Basmajian, Katie Vu, AnnaMarie Rowley, Scott D. Isola, Luis Redd, William H. Rini, Christine TI Economic survivorship stress is associated with poor health-related quality of life among distressed survivors of hematopoietic stem cell transplantation SO PSYCHO-ONCOLOGY LA English DT Article DE psychological stress; finances; quality of life; stem cell transplantation; cancer survivors; oncology ID BONE-MARROW-TRANSPLANTATION; SOCIOECONOMIC-STATUS; CANCER SURVIVORS; FINANCIAL STRAIN; UNITED-STATES; RECOVERY; DETERMINANTS; DISEASE; IMPACT; SCALE AB Background Hematopoietic stem cell transplantation is a demanding cancer treatment associated with enduring physical and psychological complications. Survivors' well-being may be further compromised by exposure to chronic stressors common to this population, including difficulties arising from costly medical care, changes in employment status, and health insurance coverage. Thus, we hypothesized that financial, employment, and insurance stressors (collectively referred to as economic survivorship stressors) would be associated with poorer health-related quality of life (HRQOL) among hematopoietic stem cell transplantation survivors. Methods Survivors (n=181; M=640 days post-transplant) completed the measures of study variables through mailed questionnaires and telephone interviews. Hierarchical regression analyses were conducted to test the hypothesized associations between economic survivorship stressors and HRQOL, and to examine whether social and situational factors interact with survivors' stress perceptions to predict HRQOL. Results Greater financial and employment stress were associated with poorer functioning across multiple HRQOL domains, even after controlling for the effects of possible confounding sociodemographic and medical variables. Insurance stress was not associated with HRQOL. Some associations were moderated by situational factors including timing of the current financial crisis and portion of the transplant paid for by health insurance. Conclusions Hematopoietic stem cell transplantation survivors can face serious economic challenges during recovery. Results suggest the value of viewing these challenges as chronic stressors capable of reducing survivors' mental and physical well-being. Identifying resources and skills that help survivors cope with these demands is an important goal for clinicians and researchers. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Hamilton, Jada G.] NCI, Ctr Canc Training, Canc Prevent Fellowship Program, Rockville, MD 20892 USA. [Wu, Lisa M.; Valdimarsdottir, Heiddis; Basmajian, Katie; Vu, AnnaMarie; Redd, William H.; Rini, Christine] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Austin, Jane E.] William Paterson Univ, Dept Psychol, Wayne, NJ USA. [Rowley, Scott D.] Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA. [Isola, Luis] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Rini, Christine] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC USA. RP Hamilton, JG (reprint author), NCI, 6130 Execut Blvd,Room 4051C, Rockville, MD 20892 USA. EM hamiltonjg@mail.nih.gov FU American Cancer Society [RSGPB-07-285-01-CPPB] FX This research was supported by funding from the American Cancer Society (PI: Rini; grant #RSGPB-07-285-01-CPPB). NR 50 TC 14 Z9 15 U1 4 U2 19 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 APR PY 2013 VL 22 IS 4 BP 911 EP 921 DI 10.1002/pon.3091 PG 11 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 122IQ UT WOS:000317312200025 PM 22605430 ER PT J AU Lee, MR Wehring, HJ McMahon, RP Linthicum, J Cascella, N Liu, F Bellack, A Buchanan, RW Strauss, GP Contoreggi, C Kelly, DL AF Lee, Mary R. Wehring, Heidi J. McMahon, Robert P. Linthicum, Jared Cascella, Nicola Liu, Fang Bellack, Alan Buchanan, Robert W. Strauss, Gregory P. Contoreggi, Carlo Kelly, Deanna L. TI Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: Results from a randomized double blind placebo controlled pilot study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Oxytocin; Schizophrenia; Olfaction; Negative symptoms; Clinical trial; UPSIT ID DEFICIT SYNDROME SCHIZOPHRENIA; MONOZYGOTIC TWINS DISCORDANT; NEGATIVE SYMPTOMS; HUMAN BRAIN; ODOR IDENTIFICATION; VASOPRESSIN; PSYCHOSIS; DYSFUNCTION; RELATIVES; ABILITY AB Background: Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfactory identification as well as positive and negative symptoms in people with schizophrenia. Methods: Individuals with schizophrenia or schizoaffective disorder (n = 28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. Results: All 28 participants completed the clinical trial. Odor identification performance significantly improved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleasant smells. UPSIT score (F = 5.20, df = 1,23, p = 0.032) and subscore for pleasant smells (F = 4.56, df = 1,23, p = 0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxytocin was well tolerated during the three week trial. Conclusion: Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of positive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov). Published by Elsevier B.V. C1 [Lee, Mary R.] NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Wehring, Heidi J.; McMahon, Robert P.; Linthicum, Jared; Liu, Fang; Buchanan, Robert W.; Strauss, Gregory P.; Kelly, Deanna L.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Cascella, Nicola] Sheppard Pratt Hlth Syst, Baltimore, MD USA. [Bellack, Alan] Univ Maryland, Sch Med, Vet Affairs Med Ctr VISN5, Baltimore, MD 21201 USA. [Contoreggi, Carlo] NIDA, Chem Biol Res Branch, Intramural Res Program, Rockville, MD USA. RP Lee, MR (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, 251 Bayview Blvd 200, Baltimore, MD 21224 USA. EM leemary@mail.nih.gov RI McMahon, Robert/C-5462-2009 FU National Institutes on Drug Abuse (NIDA) Residential Research Services [HHSN271200599091CADB (N01DA-5-9909)]; Bristol Meyers Squibb; Ameritox FX This study was funded in part by the National Institutes on Drug Abuse (NIDA) Residential Research Services Contract HHSN271200599091CADB (N01DA-5-9909 Kelly, PI).; Dr. Kelly receives grant support from Bristol Meyers Squibb and Ameritox. NR 60 TC 33 Z9 33 U1 3 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2013 VL 145 IS 1-3 BP 110 EP 115 DI 10.1016/j.schres.2013.01.001 PG 6 WC Psychiatry SC Psychiatry GA 122RS UT WOS:000317336200017 PM 23415472 ER PT J AU Park, JP Raafat, A Feltracco, JA Blanding, WM Booth, BW AF Park, Jang Pyo Raafat, Ahmed Feltracco, Jessica A. Blanding, Walker M. Booth, Brian W. TI Differential Gene Expression in Nuclear Label-Retaining Cells in the Developing Mouse Mammary Gland SO STEM CELLS AND DEVELOPMENT LA English DT Article ID TEMPLATE DNA STRANDS; ESTROGEN-RECEPTOR-ALPHA; STEM-CELL; EPITHELIAL-CELLS; BREAST-CANCER; IN-VIVO; SELECTIVE SEGREGATION; NEURAL PROGENITORS; NERVOUS-SYSTEM; TRANSPLANTATION AB The immortal strand theory postulates stem cells protect themselves from DNA replication-associated mutations and subsequent cancer risk through selective segregation of template DNA strands. Stem cells self-renew by asymmetric cellular division. During asymmetric division, stem cells maintain their template DNA strands, while the newly synthesized DNA strands segregate to newly formed daughter cells. Previous studies have demonstrated that self-renewing mammary stem cells originate in the expanding mammary ducts during puberty-associated allometric growth. In this study, we labeled newly forming mammary stem cells with the thymidine analog 5-ethynl-2'-deoxyuridine for 2 weeks during allometric ductal expansion. Cells that incorporate and retain the nuclear label following extended chase periods are termed label-retaining cells (LRCs). A second nuclear label, 5-bromodeoxyuridine, was administered before euthanasia to identify cells traversing the cell cycle. Mammary cells collected following euthanasia were sorted based on nuclear label retention. Members of the Notch and Wnt signaling pathways were found differentially expressed by mammary LRCs. These pathways are involved in the regulation of stem cells in the mouse mammary gland. Upon further analysis, we found that in contrast to non-LRCs, Notch1 and Notch2 are expressed and localized in the nuclei of the LRCs. Expression of Notch-inducible genes, Hes1 and Hey2, was elevated in LRCs. Inhibition of Notch1 by shRNA reduced colony forming potential and label retention by mammary epithelial cells in vitro. These results indicate that genes are differentially regulated in the LRC population of mammary glands and Notch1 mediates asymmetric cell division of mammary progenitor cells. C1 [Park, Jang Pyo; Booth, Brian W.] Clemson Univ, Inst Biol Interfaces Engn, Clemson, SC 29634 USA. [Raafat, Ahmed] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Feltracco, Jessica A.; Blanding, Walker M.] Clemson Univ, Dept Biol Sci, Clemson, SC 29634 USA. RP Booth, BW (reprint author), Clemson Univ, Inst Biol Interfaces Engn, Rhodes Engn Res Ctr 401 1, Clemson, SC 29634 USA. EM brbooth@clemson.edu FU Institute for Biological Interfaces of Engineering of Clemson University FX The authors would like to acknowledge Dr. Meredith Morris at the Clemson University Genomics Institute and Dr. Julie Nelson at the University of Georgia Flow Cytometry Core Facility for their assistance with cell sorting, Ms. Tina Parker and the Clemson University Animal Services at Godley-Snell Research Facility for their help with in vivo studies, Miss Hiral Shah for assistance with the colony-forming assays, and Miss Aurora Booth and Miss Anja Booth for help with immunohistochemistry. Funding for the project was provided by the Institute for Biological Interfaces of Engineering of Clemson University. NR 61 TC 3 Z9 3 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD APR PY 2013 VL 22 IS 8 BP 1297 EP 1306 DI 10.1089/scd.2012.0496 PG 10 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 124OQ UT WOS:000317474500014 PM 23199335 ER PT J AU Xie-Zukauskas, H Das, J Short, BL Gutkind, JS Ray, PE AF Xie-Zukauskas, Hui Das, Jharna Short, Billie Lou Gutkind, J. Silvio Ray, Patricio E. TI Heparin inhibits angiotensin II-induced vasoconstriction on isolated mouse mesenteric resistance arteries through Rho-A- and PKA-dependent pathways SO VASCULAR PHARMACOLOGY LA English DT Article DE Ang II; Heparin; Resistance arteries; Rho-A/Rho kinase; Vascular tone ID MUSCLE-CELL-PROLIFERATION; FIBROBLAST-GROWTH-FACTOR; VASCULAR SMOOTH-MUSCLE; PROTEIN-KINASE; PULMONARY-HYPERTENSION; CEREBRAL-ARTERY; MYOGENIC TONE; CONTRACTION; ACTIVATION; PHOSPHORYLATION AB Heparin is commonly used to treat intravascular thrombosis in children undergoing extracorporeal membrane oxygenation or cardiopulmonary bypass. These clinical circumstances are associated with elevated plasma levels of angiotensin II (Ang II). However, the mechanisms by which heparin modulates vascular reactivity of Ang II remain unclear. We hypothesized that heparin may offset Ang II-induced vasoconstriction on mesenteric resistance arteries through modulating the Rho-A/Rho kinase pathway. Vascular contractility was studied by using pressurized, resistance-sized mesenteric arteries from mice. Rho-A activation was measured by pull-down assay, and myosin light chain or PICA phosphorylation by immunoblotting. We found that heparin significantly attenuated vasoconstriction induced by Ang II but not that by KCl. The combined effect of Ang II with heparin was almost abolished by a specific Rho kinase inhibitor Y27632. Ang II stimulated Rho-A activation and myosin light chain phosphorylation, both responses were antagonized by heparin. Moreover, the inhibitory effect of heparin on Ang II-induced vasoconstriction was reversed by Rp-cAMPS (cAMP-dependent PICA inhibitor), blunted by ODQ (soluble guanylate cyclase inhibitor), and mimicked by a cell-permeable cGMP analogue, 8-Br-cGMP, but not by a cAMP analogue. PKC and Src kinase were not involved. We conclude that heparin inhibits Ang II-induced vasoconstriction through Rho-A/Rho kinase- and cGMP/PKA-dependent pathways. (C) 2012 Elsevier Inc. All rights reserved. C1 [Short, Billie Lou] Childrens Natl Med Ctr, Div Neonatol, Washington, DC 20010 USA. [Short, Billie Lou; Ray, Patricio E.] George Washington Univ, Dept Pediat, Washington, DC 20010 USA. [Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Ray, PE (reprint author), Childrens Natl Med Ctr, Ctr Mol Physiol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM pray@cnmcresearch.org FU UPSHS [R01 HL-102497]; NIH (National Heart, Lung and Blood Institute) [R01 HL-55605] FX This work was supported by UPSHS awards R01 HL-102497 (to P.E.R), and the NIH (National Heart, Lung and Blood Institute grant) R01 HL-55605 (to P.E.R.). NR 38 TC 1 Z9 1 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1537-1891 J9 VASC PHARMACOL JI Vasc. Pharmacol. PD APR PY 2013 VL 58 IS 4 BP 313 EP 318 DI 10.1016/j.vph.2012.12.003 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 120JN UT WOS:000317166700009 PM 23268358 ER PT J AU Sabino, V Kwak, J Rice, KC Cottone, P AF Sabino, Valentina Kwak, Jina Rice, Kenner C. Cottone, Pietro TI Pharmacological Characterization of the 20% Alcohol Intermittent Access Model in Sardinian Alcohol-Preferring Rats: A Model of Binge-Like Drinking SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Naltrexone; Opioid; CRF or CRH or Corticotropin-Releasing; Ethanol; Addiction ID VOLUNTARY ETHANOL INTAKE; CROSS-FOSTERING ANALYSIS; C57BL/6J MICE; RECEPTOR ANTAGONIST; NUCLEUS-ACCUMBENS; DEPENDENT RATS; NALTREXONE TREATMENT; CRF1 ANTAGONIST; ANIMAL-MODELS; WISTAR RATS AB Background Binge drinking is defined as a pattern of alcohol drinking that brings blood alcohol levels to 80mg/dl or above. In this study, we pharmacologically characterized the intermittent access to 20% ethanol (EtOH) model (Wise, Psychopharmacologia 1973;29:203) in Sardinian alcohol-preferring (sP) rats to determine to which of the compounds known to reduce drinking in specific animal models this binge-like drinking was sensitive to. Methods Adult male sP rats were divided into 2 groups and allowed to drink either 20% v/v alcohol or water for 24hours on alternate days (Monday, Wednesday, and Friday) or 10% v/v alcohol and water for 24hours every day. After stabilization of their intake, both groups were administered 3 pharmacological agents with different mechanisms of action, naltrexonean opioid receptor antagonist, SCH 39166a dopamine D1 receptor antagonist, and R121919a Corticotropin-Releasing Factor 1 (CRF1) receptor antagonist, and their effects on alcohol and water intake were determined. Results Intermittent 20% alcohol (Wise) procedure in sP rats led to binge-like drinking. Alcohol drinking was suppressed by naltrexone and by SCH 39166, but not by R121919. Finally, naltrexone was more potent in reducing alcohol drinking in the intermittent 20% binge-drinking group than in the 10% continuous access drinking group. Conclusions The Wise procedure in sP rats induces binge-like drinking, which appears opioid- and dopamine-receptor mediated; the CRF1 system, on the other hand, does not appear to be involved. In addition, our results suggest that naltrexone is particularly effective in reducing binge drinking. Such different pharmacological responses may apply to subtypes of alcoholic patients who differ in their motivation to drink, and may eventually contribute to treatment response. C1 [Sabino, Valentina; Kwak, Jina; Cottone, Pietro] Boston Univ, Sch Med, Lab Addict Disorders, Dept Pharmacol & Expt Therapeut, Boston, MA 02118 USA. [Sabino, Valentina; Kwak, Jina; Cottone, Pietro] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, Bethesda, MD USA. RP Cottone, P (reprint author), Boston Univ, Sch Med, Lab Addict Disorders, 72 E Concord St,R-612, Boston, MA 02118 USA. EM vsabino@bu.edu RI Cottone, Pietro/F-5291-2012; Sabino, Valentina/F-5290-2012 OI Cottone, Pietro/0000-0003-1320-1672; Sabino, Valentina/0000-0002-6680-1279 FU National Institute on Alcohol Abuse and Alcoholism [AA016731, MH091944, MH091945, DA023680, DA030425]; National Institute of Mental Health; National Institute on Drug Abuse; Peter McManus Trust; Peter Paul Career Development Professorship; Boston University Undergraduate Research Opportunity Program; National Institutes of Health (NIH) Intramural Research Program of the NIDA; National Institutes of Health (NIH) Intramural Research Program of NIAAA FX We thank Stephen A. St Cyr, Aditi R. Narayan, Tamara Zeric, and Robert Pulido for excellent technical assistance. This publication was made possible by grant numbers AA016731, MH091944, MH091945, DA023680, and DA030425 from the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health, and the National Institute on Drug Abuse, by the Peter McManus Trust (VS), by the Peter Paul Career Development Professorship (PC), and by the Boston University Undergraduate Research Opportunity Program (JK). The research of the Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse (NIDA), and National Institute on Alcohol Abuse and Alcoholism (NIAAA), was supported by the National Institutes of Health (NIH) Intramural Research Programs of the NIDA and NIAAA. NR 58 TC 15 Z9 15 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD APR PY 2013 VL 37 IS 4 BP 635 EP 643 DI 10.1111/acer.12008 PG 9 WC Substance Abuse SC Substance Abuse GA 116TU UT WOS:000316906700012 PM 23126554 ER PT J AU Mbulaiteye, SM Clarke, CA Morton, LM Gibson, TM Pawlish, K Weisenburger, DD Lynch, CF Goodman, MT Engels, EA AF Mbulaiteye, Sam M. Clarke, Christina A. Morton, Lindsay M. Gibson, Todd M. Pawlish, Karen Weisenburger, Dennis D. Lynch, Charles F. Goodman, Marc T. Engels, Eric A. TI Burkitt lymphoma risk in US solid organ transplant recipients SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID UNITED-STATES; CANCER-RISK; CHILDREN; MALARIA; AGE; NEOPLASMS; PATTERNS; UGANDA; VIRUS; CELLS AB Case reports of Burkitt lymphoma (BL) in transplant recipients suggest that the risk is markedly elevated. Therefore, we investigated the incidence of BL in 203,557 solid organ recipients in the U.S. Transplant Cancer Match Study (19872009) and compared it with the general population using standardized incidence ratios. We also assessed associations with demographic and clinical characteristics, and treatments used to induce therapeutic immunosuppression. BL incidence was 10.8 per 100,000 person-years, representing 23-fold (95% confidence interval (CI) 1928) greater risk than in the general population, and it peaked 38 years after the time of transplantation. In adjusted analyses, BL incidence was higher in recipients transplanted when <18 vs. 35 years (incidence rate ratio [IRR] 3.49, 95% CI 2.085.68) and in those transplanted with a liver (IRR 2.91, 95% CI 1.685.09) or heart (IRR 2.39, 95% CI 1.304.31) compared with kidney. BL incidence was lower in females than males (IRR 0.45, 95% CI 0.280.71), in blacks than whites (IRR 0.33, 95% CI 0.120.74), in those with a baseline Epstein-Barr virus (EBV)-seropositive versus EBV-seronegative status (IRR 0.34, 95% CI 0.130.93), and in those treated with azathioprine (IRR 0.56, 95% CI 0.340.89) or corticosteroids (IRR 0.48, 95% CI 0.290.82). Tumors were EBV-positive in 69% of 32 cases with results. EBV positivity was 90% in those aged <18 years and 59% in those aged 18+ years. In conclusion, BL risk is markedly elevated in transplant recipients, and it is associated with certain demographic and clinical features. EBV was positive in most but not all BL cases with results. Am. J. Hematol. 88:245250, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Mbulaiteye, Sam M.; Morton, Lindsay M.; Gibson, Todd M.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Clarke, Christina A.] Canc Prevent Inst Calif, Fremont, CA USA. [Clarke, Christina A.] Stanford Univ, Dept Hlth Res & Policy & Med, Sch Med, Stanford, CA 94305 USA. [Pawlish, Karen] New Jersey Dept Hlth, Canc Epidemiol Serv, Trenton, NJ USA. [Weisenburger, Dennis D.] City Hope Natl Med Ctr, Dept Pathol, Duarte, CA 91010 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Goodman, Marc T.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Execut Plaza South,Rm 7080 MSC 7, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural NIH HHS [ZIA CP010176-11]; NCCDPHP CDC HHS [U58 DP000817, U58 DP000805, U58 DP000807, U58 DP000808, U58 DP000812, U58 DP000824, U58 DP000832, U58 DP000848]; NCI NIH HHS [HHSN261201000024C, HHSN261201000026C, HHSN261201000034C, HHSN261201000035I, HHSN261201000036C, HHSN261201000037C, N01PC35137, N01PC35139, N01PC35142, N01PC35143, N01PC54405, T32 CA126607]; None [HHSN261201000035C] NR 33 TC 9 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2013 VL 88 IS 4 BP 245 EP 250 DI 10.1002/joh.23385 PG 6 WC Hematology SC Hematology GA 115JQ UT WOS:000316808800001 PM 23386365 ER PT J AU Hawley, TS Riz, I Yang, WJ Wakabayashi, Y DePalma, L Chang, YT Peng, WQ Zhu, J Hawley, RG AF Hawley, Teresa S. Riz, Irene Yang, Wenjing Wakabayashi, Yoshiyuki DePalma, Louis Chang, Young-Tae Peng, Weiqun Zhu, Jun Hawley, Robert G. TI Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1 SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID P-GLYCOPROTEIN EXPRESSION; RISK MULTIPLE-MYELOMA; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; HEDGEHOG PATHWAY; ALDEHYDE DEHYDROGENASE; DOXORUBICIN RESISTANCE; T(4/14) TRANSLOCATION; EMBRYONIC STEM; GROWTH-FACTOR AB Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur. Am. J. Hematol. 88:265272, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Hawley, Teresa S.] George Washington Univ, Flow Cytometry Core Facil, Washington, DC 20037 USA. [Riz, Irene; DePalma, Louis; Peng, Weiqun; Hawley, Robert G.] George Washington Univ, Dept Anat & Regenerat Biol, Washington, DC 20037 USA. [Yang, Wenjing; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20037 USA. [Wakabayashi, Yoshiyuki; Zhu, Jun] NHLBI, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [DePalma, Louis] George Washington Univ, Dept Pathol, Washington, DC 20037 USA. [Chang, Young-Tae] Natl Univ Singapore, Dept Chem, Singapore 117548, Singapore. [DePalma, Louis] Natl Univ Singapore, Inst Life Sci, MedChem Program, Singapore 117548, Singapore. [Chang, Young-Tae] Agcy Sci Technol & Res, Lab Bioimaging Probe Dev, Singapore Bioimaging Consortium, Singapore, Singapore. [Hawley, Robert G.] Jining Med Univ, Sino US Joint Lab Translat Med, Affiliated Hosp, Jining, Shandong, Peoples R China. RP Hawley, RG (reprint author), George Washington Univ, Dept Anat & Regenerat Biol, 2300 I St NW, Washington, DC 20037 USA. EM rghawley@gwu.edu RI Chang, Young-Tae/B-2780-2010 OI Chang, Young-Tae/0000-0002-1927-3688 FU Dr. Cyrus and Myrtle Katzen Cancer Research Center at the George Washington University; Pilot Project Award from the Clinical and Translational Science Institute at Children's National Medical Center NIH; NIH [R01HL65519, R01HL66305]; [UL1RR031988] FX The Dr. Cyrus and Myrtle Katzen Cancer Research Center at the George Washington University (to R.G.H.) and Pilot Project Award from the Clinical and Translational Science Institute at Children's National Medical Center NIH; Contract grant number: UL1RR031988 (to I.R.); Contract grant sponsor: NIH; Contract grant numbers: R01HL65519; R01HL66305 (to R.G.H.). NR 80 TC 24 Z9 25 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2013 VL 88 IS 4 BP 265 EP 272 DI 10.1002/joh.23387 PG 8 WC Hematology SC Hematology GA 115JQ UT WOS:000316808800004 PM 23475625 ER PT J AU Costantine, MM Lai, YL Bloom, SL Soong, CY Varner, MW Rouse, DJ Ramin, SM Caritis, SN Peaceman, AM Sorokin, Y Sciscione, A Mercer, BM Thorp, JM Malone, FD Harper, M Iams, JD AF Costantine, Maged M. Lai, Yinglei Bloom, Steven L. Soong, Catherine Y. Varner, Michael W. Rouse, Dwight J. Ramin, Susan M. Caritis, Steve N. Peaceman, Alan M. Sorokin, Yoram Sciscione, Anthony Mercer, Brian M. Thorp, John M. Malone, Fergal D. Harper, Margaret Iams, Jay D. CA Eunice Kennedy Shriver Natl Inst Maternal Fetal Med Units Network TI Population versus Customized Fetal Growth Norms and Adverse Outcomes in an Intrapartum Cohort SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE customized norm; fetal growth; small for gestational age; adverse outcomes ID BIRTH-WEIGHT STANDARDS; MORTALITY; INFANTS; MORBIDITY AB Objective To compare population versus customized fetal growth norms in identifying neonates at risk for adverse outcomes (APO) associated with small for gestational age (SGA). Study Design Secondary analysis of an intrapartum fetal pulse oximetry trial in nulliparous women at term. Birth weight percentiles were calculated using ethnicity- and gender-specific population norms and customized norms (Gardosi). Results Of the studied neonates, 508 (9.9%) and 584 (11.3%) were SGA by population (SGApop) and customized (SGAcust) norms, respectively. SGApop infants were significantly associated with a composite adverse neonatal outcome, neonatal intensive care admission, low fetal oxygen saturation, and reduced risk of cesarean delivery; both SGApop and SGAcust infants were associated with a 5-minute Apgar score < 4. The ability of customized and population birth weight percentiles in predicting APO was poor (12 of 14 APOs had area under the curve of <0.6). Conclusion In this intrapartum cohort, neither customized nor normalized population norms adequately identified neonates at risk of APO related to SGA. C1 [Costantine, Maged M.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Bloom, Steven L.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Soong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Varner, Michael W.] Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. [Rouse, Dwight J.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Ramin, Susan M.] Univ Texas Houston, Hlth Sci Ctr Houston, Dept Obstet & Gynecol, Houston, TX USA. [Caritis, Steve N.] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Peaceman, Alan M.] Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Sorokin, Yoram] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Sciscione, Anthony] Drexel Univ, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Mercer, Brian M.] Case Western Reserve Univ, Dept Obstet & Gynecol, MetroHlth Med Ctr, Cleveland, OH 44106 USA. [Thorp, John M.] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Malone, Fergal D.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Harper, Margaret] Wake Forest Univ Hlth Sci, Dept Obstet & Gynecol, Winston Salem, NC USA. [Iams, Jay D.] Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. RP Costantine, MM (reprint author), 301 Univ Blvd, Galveston, TX 77555 USA. EM mmcostan@utmb.edu RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, HD36801] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD21410, HD27860, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, and HD36801) and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health. NR 25 TC 3 Z9 3 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD APR PY 2013 VL 30 IS 4 BP 335 EP 341 DI 10.1055/s-0032-1324708 PG 7 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 115SF UT WOS:000316831500012 PM 22893556 ER PT J AU Zhou, XM Wang, H Burg, MB Ferraris, JD AF Zhou, Xiaoming Wang, Hong Burg, Maurice B. Ferraris, Joan D. TI Inhibitory phosphorylation of GSK-3 beta by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP) SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE hypertonicity; p38 alpha; phosphorylation; transactivation; nuclear localization ID GLYCOGEN-SYNTHASE KINASE-3; ENHANCER-BINDING PROTEIN; DAMAGE-INDUCIBLE KINASE; NF-KAPPA-B; NUCLEAR-LOCALIZATION; GENE-EXPRESSION; STIMULATES TRANSCRIPTION; PHOSPHOLIPASE C-GAMMA-1; SKELETAL-MUSCLE; OSMOTIC-STRESS AB Zhou X, Wang H, Burg MB, Ferraris JD. Inhibitory phosphorylation of GSK-3 beta by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP). Am J Physiol Renal Physiol 304: F908-F917, 2013. First published January 16, 2013; doi:10.1152/ajprenal. 00591.2012.-High NaCl activates the transcription factor nuclear factor of activated T cells 5 (NFAT5), leading to increased transcription of osmoprotective target genes. Kinases PKA, PI3K, AKT1, and p38 alpha were known to contribute to the high NaCl-induced increase of NFAT5 activity. We now identify another kinase, GSK-3 beta. siRNA-mediated knock-down of GSK-3 beta increases NFAT5 transcriptional and transactivating activities without affecting high NaCl-induced nuclear localization of NFAT5 or NFAT5 protein expression. High NaCl increases phosphorylation of GSK-3 beta-S9, which inhibits GSK-3 beta. In GSK-3 beta-null mouse embryonic fibroblasts transfection of GSK-3 beta, in which serine 9 is mutated to alanine, so that it cannot be inhibited by phosphorylation at that site, inhibits high NaCl-induced NFAT5 transcriptional activity more than transfection of wild-type GSK-3 beta. High NaCl-induced phosphorylation of GSK-3 beta-S9 depends on PKA, PI3K, and AKT, but not p38 alpha. Overexpression of PKA catalytic subunit alpha or of catalytically active AKT1 reduces inhibition of NFAT5 by GSK-3 beta, but overexpression of p38 alpha together with its catalytically active upstream kinase, MKK6, does not. Thus, GSK-3 beta normally inhibits NFAT5 by suppressing its transactivating activity. When activated by high NaCl, PKA, PI3K, and AKT1, but not p38 alpha, increase phosphorylation of GSK-3 beta-S9, which reduces the inhibitory effect of GSK-3 beta on NFAT5, and thus contributes to activation of NFAT5. C1 [Zhou, Xiaoming; Wang, Hong] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Burg, Maurice B.; Ferraris, Joan D.] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Zhou, XM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM xiaoming.zhou@usuhs.edu FU Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services; National Kidney Foundation/National Capital Area FX This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, and by a grant-in-aid from National Kidney Foundation/National Capital Area. NR 75 TC 10 Z9 10 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD APR PY 2013 VL 304 IS 7 BP F908 EP F917 DI 10.1152/ajprenal.00591.2012 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 118DO UT WOS:000317003200008 PM 23324178 ER PT J AU Fradkin, JE Wallace, JA Rodgers, GP AF Fradkin, Judith E. Wallace, Julie A. Rodgers, Griffin P. TI Biomedical Research Paving a Pathway to Diabetes Prevention SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID LIFE-STYLE INTERVENTION; RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE; RISK-FACTORS; WEIGHT-LOSS; PROGRAM; METFORMIN; MELLITUS; US; PROGRESSION C1 [Fradkin, Judith E.; Wallace, Julie A.; Rodgers, Griffin P.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Fradkin, JE (reprint author), Bldg 2DEM,Room 683,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM fradkinj@mail.nih.gov NR 39 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2013 VL 44 IS 4 SU 4 BP S317 EP S323 DI 10.1016/j.amepre.2012.12.017 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 113NH UT WOS:000316674200005 PM 23498293 ER PT J AU Ben Dor, R Harsh, VL Fortinsky, P Koziol, DE Rubinow, DR Schmidt, PJ AF Ben Dor, Rivka Harsh, Veronica L. Fortinsky, Paige Koziol, Deloris E. Rubinow, David R. Schmidt, Peter J. TI Effects of Pharmacologically Induced Hypogonadism on Mood and Behavior in Healthy Young Women SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID HORMONE AGONIST THERAPY; MENOPAUSAL TRANSITION; PERIMENOPAUSAL WOMEN; DEPRESSIVE SYMPTOMS; GONADAL-STEROIDS; HOT FLASHES; ASSOCIATIONS; DISORDERS; INVENTORY; ESTRADIOL AB Objective: The relationship between depression and estrogen withdrawal remains controversial. The authors examined the effects of gonadotropin-releasing hormone agonist-induced ovarian suppression on mood, sleep, sexual function, and nighttime hot flushes. They focused on whether participating women experienced clinically significant depressive symptoms and whether specific symptoms associated with hypogonadism (nighttime hot flushes and disturbed sleep) increased susceptibility to depression. Method: Participants were 72 healthy premenopausal women, ages 19-52 years, with no current or past axis I psychiatric diagnosis or gynecological or other medical illness. After 2 months of baseline screening, women received monthly injections of leuprolide acetate (3.75 mg) for 2-3 months. Outcomes were measured using the Beck Depression Inventory (BDI) and a daily rating scale measuring the severity of several affective and behavioral symptoms. Data were analyzed by repeated-measures analysis of variance using PROC MIXED (for mixed models). Results: BDI scores >= 10 were reported in four of the 72 women (5.6%). Relative to baseline, induced hypogonadism was associated with significantly decreased sexual interest, disturbed sleep, and more severe nighttime hot flushes, but no significant change in any mood-related symptom score. Hot flush severity was significantly correlated with disturbed sleep. Conclusions: These data demonstrate that clinically significant depressive symptoms were rare accompaniments of short-term estradiol withdrawal and induced hypogonadism in healthy premenopausal women. Additionally, neither nighttime hot flushes nor disturbed sleep were sufficient to cause depressive symptoms in hypogonadal women. (Am J Psychiatry 2013; 170:426-433) C1 [Schmidt, Peter J.] NIMH, Sect Behav Endocrinol, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, BioStat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20892 USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. RP Schmidt, PJ (reprint author), NIMH, Sect Behav Endocrinol, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM peterschmidt@mail.nih.gov FU NIMH FX Supported by the Intramural Research Program of NIMH. NR 39 TC 6 Z9 6 U1 1 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X EI 1535-7228 J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2013 VL 170 IS 4 BP 426 EP 433 DI 10.1176/appi.ajp.2012.12010117 PG 8 WC Psychiatry SC Psychiatry GA 117AW UT WOS:000316925500013 PM 23545794 ER PT J AU Hasin, DS Auriacombe, M Borges, G Bucholz, K Budney, A Crowley, T Grant, BF O'Brien, C Petry, NM Schuckit, M Wall, MM AF Hasin, Deborah S. Auriacombe, Marc Borges, Guilherme Bucholz, Kathleen Budney, Alan Crowley, Thomas Grant, Bridget F. O'Brien, Charles Petry, Nancy M. Schuckit, Marc Wall, Melanie M. TI The DSM-5 Field Trials and Reliability of Alcohol Use Disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Letter ID PSYCHIATRIC DIAGNOSIS; MENTAL-DISORDERS; UNITED-STATES; INTERVIEW; SUBSTANCE; CANADA; IV C1 [Hasin, Deborah S.] Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Coll Phys & Surg, New York, NY 10027 USA. Bordeaux Segalen Univ, Dept Addict Psychiat, Bordeaux, France. Natl Inst Psychiat, Mexico City, DF, Mexico. Washington Univ, St Louis, MO 63130 USA. Univ Colorado, Dartmouth Univ, Addict Res Ctr, Dept Psychiat,Sch Med, Aurora, CO USA. NIAAA, Bethesda, MD USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Connecticut, Ctr Hlth, Dept Psychiat, Farmington, CT USA. San Diego VA Med Ctr, Dept Psychiat, San Diego, CA USA. Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10027 USA. RP Hasin, DS (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Psychiat, Coll Phys & Surg, New York, NY 10027 USA. RI Auriacombe, Marc/A-6197-2017; OI Auriacombe, Marc/0000-0002-8938-8683; Borges, Guilherme/0000-0002-3269-0507 FU NIAAA NIH HHS [P60 AA003510, K05 AA014223] NR 7 TC 8 Z9 8 U1 0 U2 7 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD APR PY 2013 VL 170 IS 4 BP 442 EP 443 DI 10.1176/appi.ajp.2013.13010032 PG 2 WC Psychiatry SC Psychiatry GA 117AW UT WOS:000316925500015 PM 23545795 ER PT J AU O'Reilly, EJ Wang, H Weisskopf, MG Fitzgerald, KC Falcone, G McCullough, ML Thun, M Park, Y Kolonel, LN Ascherio, A AF O'Reilly, Eilis J. Wang, Hao Weisskopf, Marc G. Fitzgerald, Kathryn C. Falcone, Guido McCullough, Marjorie L. Thun, Michael Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Premorbid body mass index and risk of amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Amyotrophic lateral sclerosis; body mass index; risk; epidemiology; cohort; nutrition ID BASE-LINE CHARACTERISTICS; CIGARETTE-SMOKING; PHYSICAL-ACTIVITY; ALCOHOL-CONSUMPTION; NUTRITIONAL-STATUS; ASSOCIATION; SURVIVAL; COHORT; DIET; ALS AB Our objective was to determine if amyotrophic lateral sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier. At baseline 537,968 females and 562,942 males in five ongoing cohorts reported height, current weight and weight at age 18/21 years. During 14-28 years of follow-up, 1153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random-effects models. Results showed that lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95% CI 14%-27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR = 0.76 (95% CI 0.62-0.93)) and obese (RR = 0.73 (95% CI 0.55-0.96)). Among never smokers the association persisted: RR = 0.75 (95% CI 0.65-0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of males and females had a healthy BMI at age 18/21 years, 15% of males and 8% of females were overweight or obese; there was no association with ALS although numbers with an unhealthy weight were small. In conclusion, these findings support an association between lower premorbid BMI and ALS. C1 [O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Weisskopf, Marc G.; Falcone, Guido; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [O'Reilly, Eilis J.; Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [O'Reilly, Eilis J.; Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Hao] Univ Groningen, Dept Pharmacoepidemiol & Pharmacoecon, Groningen, Netherlands. [McCullough, Marjorie L.; Thun, Michael] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr Hawaii, Canc Epidemiol Program, Honolulu, HI 96813 USA. RP O'Reilly, EJ (reprint author), 665 Huntington Ave,Bldg 2 Room 300, Boston, MA 02115 USA. EM eoreilly@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU NIH/National Institute of Neurological Diseases and Stroke; NIH FX This work was supported by a grant from the NIH/National Institute of Neurological Diseases and Stroke. Nurses' Health Study is funded by a NIH program project and Health Professional Follow-up Study also by a NIH program project. The funding agencies had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. NR 30 TC 43 Z9 43 U1 0 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LAT SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD APR PY 2013 VL 14 IS 3 BP 205 EP 211 DI 10.3109/21678421.2012.735240 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 117KT UT WOS:000316952900008 PM 23134505 ER PT J AU Micciolo, R Canal, L Minniti, A Mazzali, G Fantin, F Corzato, F Antonioli, A Harris, TB Zamboni, M AF Micciolo, Rocco Canal, Luisa Minniti, Alessia Mazzali, Gloria Fantin, Francesco Corzato, Francesca Antonioli, Angela Harris, Tamara B. Zamboni, Mauro TI The association between excess weight and comorbidity and self-rated health in the Italian population SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Aging; Comorbidity; Obesity; Self-rated health ID BODY-MASS INDEX; OLDER-ADULTS; WAIST CIRCUMFERENCE; REPORTED WEIGHT; US ADULTS; OBESITY; OVERWEIGHT; MORTALITY; RISK; DISEASE AB Purpose: To evaluate the association of obesity with comorbidity and with subjective health perception in a large sample representative of the Italian population and how the association differs by age and gender. Methods: Cross-sectional data were obtained from nine waves of the "Multipurpose Household Survey," conducted by the Italian National Institute of Statistics. Self-reported height and weight, six weight-associated diseases and self-rated health (SRH) were evaluated on 352,020 subjects aged 20 to 89 years. Comorbidity was defined as the presence of two or more diseases. Results: The prevalence of comorbidity was significantly different between obese and normal weight subjects in all age categories. SRH was worse in obese subjects than in those of normal weight; this difference persisted, at least in females, into older ages. Conclusions: Obesity is associated with comorbidity and self-rated health; this association varies across ages and genders. The results found for obese subjects of a given age category were similar to (or worse than) those found for older normal weight subjects of the next age class. For comorbidity, this was true both in males and in females of all the considered age categories; for SRH, this was true in particular for females and younger males. (c) 2013 Elsevier Inc. All rights reserved. C1 [Micciolo, Rocco; Canal, Luisa] Univ Trent, Dept Psychol & Cognit Sci, Trento, Italy. [Minniti, Alessia; Mazzali, Gloria; Fantin, Francesco; Corzato, Francesca; Antonioli, Angela; Zamboni, Mauro] Univ Verona, Dept Med, Geriatr Unit, I-37100 Verona, Italy. [Harris, Tamara B.] NIA, Off Geriatr Epidemiol, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. RP Micciolo, R (reprint author), Dept Psychol & Cognit Sci, Corso Bettini 31, I-38068 Rovereto, TN, Italy. EM rocco.micciolo@unitn.it OI ZAMBONI, Mauro/0000-0001-6961-9483 FU MIUR project "The role of intramuscular lipid infiltration: obesity, sarcopenia and aging" [2009KENS9K_002]; Intramural Research Program of NIA FX This study was supported by grants from the MIUR project 2009KENS9K_002 "The role of intramuscular lipid infiltration: obesity, sarcopenia and aging" and partly by the Intramural Research Program of NIA. NR 47 TC 6 Z9 6 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD APR PY 2013 VL 23 IS 4 BP 172 EP 178 DI 10.1016/j.annepidem.2013.02.003 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 117TO UT WOS:000316976200003 PM 23453383 ER PT J AU O'Shea, JJ Kontzias, A Yamaoka, K Tanaka, Y Laurence, A AF O'Shea, John J. Kontzias, Apostolos Yamaoka, Kunihiro Tanaka, Yoshiya Laurence, Arian TI Janus kinase inhibitors in autoimmune diseases SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACTIVE RHEUMATOID-ARTHRITIS; PLACEBO-CONTROLLED TRIAL; TOFACITINIB CP-690,550; JAK INHIBITOR; DOUBLE-BLIND; INADEQUATE RESPONSE; ULCERATIVE-COLITIS; RECEPTOR FAMILY; MYELOFIBROSIS AB Biological therapies directed at proinflammatory cytokines have irrevocably changed the landscape of treatment of rheumatoid arthritis (RA) and other autoimmune diseases. With the advances in our knowledge in cytokine signalling, the question emerges whether targeting intracellular signalling might also be a safe and efficacious strategy. Janus kinases or Jaks are critical for a large family of cytokines and the first Jak inhibitors has been approved by the FDA. It is therefore timely to consider this new category of drugs and reflect on their potential roles, present and future, in the treatment of RA and related disorders. C1 [O'Shea, John J.; Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Kontzias, Apostolos] NIAMSD, Pediat Rheumatol Branch, NIH, Bethesda, MD 20892 USA. [Yamaoka, Kunihiro; Tanaka, Yoshiya] Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 1, Kitakyushu, Fukuoka 807, Japan. RP O'Shea, JJ (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 FU Pfizer FX JJO'S and the National Institutes of Health (NIH) hold patents related to targeting JAKs as targets for immunomodulatory agents. JJO'S and the NIH have a Collaborative Research Agreement and Development Award with Pfizer. NR 50 TC 57 Z9 57 U1 2 U2 13 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD APR PY 2013 VL 72 SU 2 BP 111 EP 115 DI 10.1136/annrheumdis-2012-202576 PG 5 WC Rheumatology SC Rheumatology GA 115QF UT WOS:000316826300016 ER PT J AU Harlow, L Rosas, IO Gochuico, BR Mikuls, TR Dellaripa, PF Oddis, CV Ascherman, DP AF Harlow, Lisa Rosas, Ivan O. Gochuico, Bernadette R. Mikuls, Ted R. Dellaripa, Paul F. Oddis, Chester V. Ascherman, Dana P. TI Identification of Citrullinated Hsp90 Isoforms as Novel Autoantigens in Rheumatoid ArthritisAssociated Interstitial Lung Disease SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ISCHEMIC-HEART-DISEASE; EXTRAARTICULAR MANIFESTATIONS; PEPTIDE ANTIBODIES; INFLAMMATORY MYOPATHIES; PULMONARY INVOLVEMENT; SYSTEMIC-SCLEROSIS; ARTHRITIS; AUTOANTIBODIES; PROTEIN; CLASSIFICATION AB Objective Subsets of patients with rheumatoid arthritis (RA) develop extraarticular complications that include interstitial lung disease (ILD). Because standardized algorithms for identification of RA patients at risk of developing clinically significant ILD are lacking, the purpose of this study was to elucidate unique serologic markers of RA-associated ILD (RA-ILD). Methods Sera from RA patients with ILD and from RA patients without ILD were used to immunoprecipitate citrullinated and uncitrullinated proteins derived from K562 cell extracts. Mass spectrometry was performed to facilitate identification of citrullinated proteins differentially immunoprecipitated by RA-ILD patient sera. These candidate proteins were then used as substrate antigens in custom enzyme-linked immunosorbent assays (ELISAs) for high-throughput screening of sera obtained from cohorts of patients with RA, RA-ILD mixed connective tissue disease (MCTD), or idiopathic pulmonary fibrosis (IPF). Results Differential immunoprecipitation and subsequent mass spectrometric sequencing identified citrullinated Hsp90 and citrullinated Hsp90 as candidate autoantigens in patients with RA-ILD. ELISAs incorporating uncitrullinated and citrullinated isoforms of Hsp90 as substrate antigens demonstrated that sera from patients with RA-ILD preferentially recognized citrullinated versions of Hsp90 with moderate sensitivity (range 2030%) and great specificity (>95%) relative to sera derived from patients with RA alone (without ILD), patients with MCTD, or patients with IPF. Conclusion These studies demonstrate the utility of a novel autoantigen discovery method based on differential immunoprecipitation of citrullinated protein extracts. Application of these techniques identified citrullinated versions of Hsp90 and Hsp90 as autoantibody targets distinguishing RA-ILD from RA without ILD, MCTD, and IPF, suggesting that anticitrullinated Hsp90/ autoantibodies may serve as effective biomarkers for the potentially devastating pulmonary manifestations of RA-ILD. C1 [Harlow, Lisa; Ascherman, Dana P.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Rosas, Ivan O.; Dellaripa, Paul F.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gochuico, Bernadette R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Mikuls, Ted R.] Omaha VA Med Ctr, Omaha, NE USA. [Oddis, Chester V.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Ascherman, DP (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Rheumatol, RMSB 7152,1600 NW 10th Ave, Miami, FL 33136 USA. EM DAscherman@med.miami.edu FU National Human Genome Research Institute, NIH; Rheumatology Research Foundation of the American College of Rheumatology; VA Merit Review grant [1I01BX0007880] FX Supported in part by the Intramural Research Program of the National Human Genome Research Institute, NIH. Dr. Oddis' work was supported by a Within Our Reach grant from the Rheumatology Research Foundation of the American College of Rheumatology. Dr. Ascherman's work was supported by a Within Our Reach grant from the Rheumatology Research Foundation of the American College of Rheumatology and a VA Merit Review grant (1I01BX0007880). NR 41 TC 35 Z9 37 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD APR PY 2013 VL 65 IS 4 BP 869 EP 879 DI 10.1002/art.37881 PG 11 WC Rheumatology SC Rheumatology GA 117OE UT WOS:000316962000005 PM 23400887 ER PT J AU St Clair, EW Levesque, MC Prak, ETL Vivino, FB Alappatt, CJ Spychala, ME Wedgwood, J McNamara, J Sivils, KLM Fisher, L Cohen, P AF St Clair, E. William Levesque, Marc C. Prak, Eline T. Luning Vivino, Frederick B. Alappatt, Chacko J. Spychala, Meagan E. Wedgwood, Josiah McNamara, James Sivils, Kathy L. Moser Fisher, Lytia Cohen, Philip CA Autoimmunity Ctr Excellence TI Rituximab Therapy for Primary Sjogren's Syndrome: An Open-Label Clinical Trial and Mechanistic Analysis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RHEUMATOID-ARTHRITIS; DOUBLE-BLIND; RECEPTOR AUTOANTIBODIES; EFFICACY; BAFF; MULTICENTER; EXPRESSION; TOLERANCE; ANTI-CD20; BLOOD AB Objective To study the safety and clinical efficacy of rituximab therapy for primary Sjogren's syndrome, as well as to investigate its mechanisms. Methods Patients with primary Sjogren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression. Results Twelve female patients with primary Sjogren's syndrome were administered rituximab. They had a median age of 51 years (range 3469 years) and a median disease duration of 8.0 years (range 218 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and antitype 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature. Conclusion In patients with primary Sjogren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells. C1 [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Levesque, Marc C.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Prak, Eline T. Luning; Vivino, Frederick B.; Alappatt, Chacko J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Spychala, Meagan E.] Rho Inc, Chapel Hill, NC USA. [McNamara, James] NIAID, NIH, Bethesda, MD 20892 USA. [Sivils, Kathy L. Moser] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Fisher, Lytia; Cohen, Philip] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. RP St Clair, EW (reprint author), Duke Univ, Med Ctr, Dept Med, Box 3874 DUMC, Durham, NC 27710 USA. EM stcla003@mc.duke.edu FU Autoimmunity Centers of Excellence; National Institute of Allergy and Infectious Diseases, NIH [U19-AI-056363]; Genentech, Inc.; Pennsylvania Department of Health; Genentech; Biogen Idec; Amplimmune; Daiichi-Sankyo; Takeda; Novartis; Amgen; URL Pharma; National Institutes of Allergy and Infectious Diseases (NIAID) FX Supported by the Autoimmunity Centers of Excellence, a consortium funded by the National Institute of Allergy and Infectious Diseases, NIH (grant U19-AI-056363). Additional support was provided by Genentech, Inc., and the Pennsylvania Department of Health.; Dr. Levesque has received consulting fees from Genentech (less than $10,000) and grant support from Genentech. Dr. Luning Prak has received consulting fees, speaking fees, and/or honoraria from Biogen Idec (less than $10,000). Dr. Vivino has received consulting fees, speaking fees, and/or honoraria from Amplimmune and Daiichi-Sankyo (less than $10,000 each) and has provided expert testimony on behalf of Daiichi-Sankyo. Dr. Alappatt has received consulting fees, speaking fees, and/or honoraria from Takeda, Novartis, Amgen, and URL Pharma (less than $10,000 each).; The study was designed by the investigators and coordinated by the National Institutes of Allergy and Infectious Diseases (NIAID; the study sponsor) and Rho, Inc., which managed the collection and quality control of the data and performed the statistical analyses. Rituximab was provided at no cost by Genentech, which had no other role in the design, conduct, or analysis of the study. Publication of this article was not contingent upon approval by the NIAID, Rho, Inc., or Genentech. NR 36 TC 28 Z9 29 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD APR PY 2013 VL 65 IS 4 BP 1097 EP 1106 DI 10.1002/art.37850 PG 10 WC Rheumatology SC Rheumatology GA 117OE UT WOS:000316962000028 PM 23334994 ER PT J AU Bethi, S Dasgupta, A Weisman, MH Learch, TJ Gensler, LS Davis, JC Reveille, JD Ward, MM AF Bethi, Siddharth Dasgupta, Abhijit Weisman, Michael H. Learch, Thomas J. Gensler, Lianne S. Davis, John C., Jr. Reveille, John D. Ward, Michael M. TI Functional Limitations Due to Axial and Peripheral Joint Impairments in Patients With Ankylosing Spondylitis: Are Focused Measures More Informative? SO ARTHRITIS CARE & RESEARCH LA English DT Article ID QUALITY-OF-LIFE; DISEASE-ACTIVITY INDEX; PHYSICAL FUNCTION; PSORIATIC-ARTHRITIS; METROLOGY INDEX; HEALTH; PERFORMANCE; SPONDYLOARTHROPATHIES; DISABILITY; BASFI AB Objective Functional limitations in ankylosing spondylitis (AS) may be due to peripheral joint or axial involvement. To determine if the Bath Ankylosing Spondylitis Functional Index (BASFI), an axial-focused measure, can detect limitations related to peripheral joint involvement equally as well as the Health Assessment Questionnaire modified for the spondyloarthropathies (HAQ-S), a peripheral arthritisfocused measure, and vice versa, we compared associations of each questionnaire with spinal and hip range of motion, peripheral arthritis, and enthesitis in patients with AS. Methods We examined patients every 46 months in this prospective longitudinal study. We used mixed linear models to analyze the associations between 10 physical examination measures and the BASFI and HAQ-S. Results We studied 411 patients for a median of 1.5 years (median 3 visits). In multivariate analyses, cervical rotation, chest expansion, lateral thoracolumbar flexion, hip motion, tender joint count, and tender enthesis count were equally strongly associated with the BASFI and HAQ-S. Peripheral joint swelling was more strongly associated with the HAQ-S. Individual items of the BASFI were more likely than items of the HAQ-S to be associated with unrelated physical examination measures (e.g., the association between difficulty rising from a chair and cervical rotation), which may have diminished the axial/peripheral distinction for the BASFI. Conclusion The BASFI and HAQ-S had similar associations with impairments in axial measures, while the HAQ-S had stronger associations with the number of swollen peripheral joints. The HAQ-S should be considered for use in studies focused on spondyloarthritis with peripheral joint involvement. C1 [Bethi, Siddharth; Dasgupta, Abhijit; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Weisman, Michael H.; Learch, Thomas J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr, Houston, TX USA. RP Ward, MM (reprint author), NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [P01-052915, R01-AR048465]; Cedars-Sinai Medical Center [M01-RR00425]; University of Texas at Houston [M01-RR02558]; Rosalind Russell Center for Arthritis Research at the University of California, San Francisco; Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH FX Supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants P01-052915 and R01-AR048465); Cedars-Sinai Medical Center (grant M01-RR00425); the University of Texas at Houston (grant M01-RR02558); the Rosalind Russell Center for Arthritis Research at the University of California, San Francisco; and the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 39 TC 1 Z9 2 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD APR PY 2013 VL 65 IS 4 BP 607 EP 614 DI 10.1002/acr.21878 PG 8 WC Rheumatology SC Rheumatology GA 116UI UT WOS:000316908100016 PM 23097327 ER PT J AU Wang, P Hanover, JA AF Wang, Peng Hanover, John A. TI Nutrient-driven O-GlcNAc cycling influences autophagic flux and neurodegenerative proteotoxicity SO AUTOPHAGY LA English DT Editorial Material DE neurodegeneration; proteotoxicity; O-GlcNAc; proteostasis; autophagy; proteasome; insulin signaling AB O-GlcNAcylation is an abundant post-translational modification implicated in human neurodegenerative diseases. We showed that loss-of-function of OGT (O-linked GlcNAc transferase) alleviated, while loss of OGA (O-GlcNAc selective beta-N-acetyl-D-glucosaminidase) enhanced, the proteotoxicity of C. elegans neurodegenerative disease models including tauopathy, beta-amyloid peptide and polyglutamine expansion. The O-GlcNAc cycling mutants act, in part, by altering insulin signaling, proteasome activity and autophagy. In mutants lacking either of these enzymes of O-GlcNAc cycling, there is a striking accumulation of GFP::LGG-1 (C. elegans homolog of Atg8 and LC3) and increased phosphatidylethanolamine (PE)-modified GFP::LGG-1 upon starvation. We speculate that O-GlcNAc cycling is a key nutrient-responsive regulator of autophagic flux acting at multiple levels including direct modification of BECN1 and BCL2. C1 [Wang, Peng; Hanover, John A.] NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov NR 0 TC 8 Z9 10 U1 0 U2 10 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD APR PY 2013 VL 9 IS 4 BP 604 EP 606 DI 10.4161/auto.23459 PG 3 WC Cell Biology SC Cell Biology GA 114HR UT WOS:000316732200013 PM 23328586 ER PT J AU Shibata, Y Gvozdenovic-Jeremic, J Love, J Kloss, B White, JF Grisshammer, R Tate, CG AF Shibata, Yoko Gvozdenovic-Jeremic, Jelena Love, James Kloss, Brian White, Jim F. Grisshammer, Reinhard Tate, Christopher G. TI Optimising the combination of thermostabilising mutations in the neurotensin receptor for structure determination SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Neurotensin receptor; Thermostability; Membrane protein; Structure ID PROTEIN-COUPLED RECEPTOR; ADENOSINE A(2A) RECEPTOR; CRYSTAL-STRUCTURE; OPIOID RECEPTOR; AGONIST; ACTIVATION; STABILITY; COMPLEX; BETA(1)-ADRENOCEPTOR; PURIFICATION AB Conformational thermostabilisation of G protein-coupled receptors is a successful approach for their structure determination. We have recently determined the structure of a thermostabilised neurotensin receptor NTS1 in complex with its peptide agonist and here we describe the strategy for the identification and combination of the 6 thermostabilising mutations essential for crystallisation. First, thermostability assays were performed on a panel of 340 detergent-solubilised Ala/Leu NTS1 mutants and the best 16 thermostabilising mutations were identified. These mutations were combined pair-wise in nearly all combinations (119 out of a possible 120 combinations) and each mutant was expressed and its thermostability was experimentally determined. A theoretical stability score was calculated from the sum of the stabilities measured for each double mutant and applied to develop 24 triple mutants, which in turn led to the construction of 14 quadruple mutants. Use of the thermostability data for the double mutants to predict further mutant combinations resulted in a greater percentage of the triple and quadruple mutants showing improved thermostability than if only the thermostability data for the single mutations was considered. The best quadruple mutant (NTS1-Nag36k) was further improved by including an additional 2 mutations (resulting in NTS1-GW5) that were identified from a complete Ala/Leu scan of Nag36k by testing the thermostability of the mutants in situ in whole bacteria. NTS1-GW5 had excellent stability in short chain detergents and could be readily purified as a homogenous sample that ultimately allowed crystallisation and structure determination. (C) 2013 Elsevier B.V. All rights reserved. C1 [Shibata, Yoko; Tate, Christopher G.] MRC Lab Mol Biol, Cambridge CB2 0QH, England. [Gvozdenovic-Jeremic, Jelena; White, Jim F.; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Love, James; Kloss, Brian] New York Struct Biol Ctr, Prot Prod Facil New York Consortium Membrane Prot, New York, NY 10027 USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM reinhardg@helix.nih.gov; cgt@mrc-lmb.cam.ac.uk RI Grisshammer, Reinhard/C-3089-2015; OI Tate, Christopher/0000-0002-2008-9183 FU Pfizer Global Research and Development; UK Medical Research Council [MRC U105197215]; Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke; National Institutes of Health [U54GM075026]; MRCT Development Gap Fund FX This research was supported by a joint grant from Pfizer Global Research and Development and the MRCT Development Gap Fund in addition to core funding from the UK Medical Research Council MRC U105197215 (YS, CGT) and the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (JFW, JG-J, RG). The Protein Production Facility of the New York Consortium on Membrane Protein Structure was supported by the National Institutes of Health grant U54GM075026 (JL, BK). DNA sequence analysis was performed by the National Institute of Neurological Disorders and Stroke DNA Sequencing Facility. NR 37 TC 19 Z9 19 U1 0 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD APR PY 2013 VL 1828 IS 4 BP 1293 EP 1301 DI 10.1016/j.bbamem.2013.01.008 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 111LF UT WOS:000316522100013 PM 23337476 ER PT J AU Hek, K Demirkan, A Lahti, J Terracciano, A Teumer, A Cornelis, MC Amin, N Bakshis, E Baumert, J Ding, JZ Liu, YM Marciante, K Meirelles, O Nalls, MA Sun, YV Vogelzangs, N Yu, L Bandinelli, S Benjamin, EJ Bennett, DA Boomsma, D Cannas, A Coker, LH de Geus, E De Jager, PL Diez-Roux, AV Purcell, S Hu, FB Rimm, EB Hunter, DJ Jensen, MK Curhan, G Rice, K Penman, AD Rotter, JI Sotoodehnia, N Emeny, R Eriksson, JG Evans, DA Ferrucci, L Fornage, M Gudnason, V Hofman, A Illig, T Kardia, S Kelly-Hayes, M Koenen, K Kraft, P Kuningas, M Massaro, JM Melzer, D Mulas, A Mulder, CL Murray, A Oostra, BA Palotie, A Penninx, B Petersmann, A Pilling, LC Psaty, B Rawal, R Reiman, EM Schulz, A Shulman, JM Singleton, AB Smith, AV Sutin, AR Uitterlinden, AG Volzke, H Widen, E Yaffe, K Zonderman, AB Cucca, F Harris, T Ladwig, KH Llewellyn, DJ Raikkonen, K Tanaka, T van Duijn, CM Grabe, HJ Launer, LJ Lunetta, KL Mosley, TH Newman, AB Tiemeier, H Murabito, J AF Hek, Karin Demirkan, Ayse Lahti, Jari Terracciano, Antonio Teumer, Alexander Cornelis, Marilyn C. Amin, Najaf Bakshis, Erin Baumert, Jens Ding, Jingzhong Liu, Yongmei Marciante, Kristin Meirelles, Osorio Nalls, Michael A. Sun, Yan V. Vogelzangs, Nicole Yu, Lei Bandinelli, Stefania Benjamin, Emelia J. Bennett, David A. Boomsma, Dorret Cannas, Alessandra Coker, Laura H. de Geus, Eco De Jager, Philip L. Diez-Roux, Ana V. Purcell, Shaun Hu, Frank B. Rimm, Eric B. Hunter, David J. Jensen, Majken K. Curhan, Gary Rice, Kenneth Penman, Alan D. Rotter, Jerome I. Sotoodehnia, Nona Emeny, Rebecca Eriksson, Johan G. Evans, Denis A. Ferrucci, Luigi Fornage, Myriam Gudnason, Vilmundur Hofman, Albert Illig, Thomas Kardia, Sharon Kelly-Hayes, Margaret Koenen, Karestan Kraft, Peter Kuningas, Maris Massaro, Joseph M. Melzer, David Mulas, Antonella Mulder, Cornelis L. Murray, Anna Oostra, Ben A. Palotie, Aarno Penninx, Brenda Petersmann, Astrid Pilling, Luke C. Psaty, Bruce Rawal, Rajesh Reiman, Eric M. Schulz, Andrea Shulman, Joshua M. Singleton, Andrew B. Smith, Albert V. Sutin, Angelina R. Uitterlinden, Andre G. Voelzke, Henry Widen, Elisabeth Yaffe, Kristine Zonderman, Alan B. Cucca, Francesco Harris, Tamara Ladwig, Karl-Heinz Llewellyn, David J. Raikkonen, Katri Tanaka, Toshiko van Duijn, Cornelia M. Grabe, Hans J. Launer, Lenore J. Lunetta, Kathryn L. Mosley, Thomas H., Jr. Newman, Anne B. Tiemeier, Henning Murabito, Joanne TI A Genome-Wide Association Study of Depressive Symptoms SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis ID MAJOR DEPRESSION; CES-D; ATHEROSCLEROSIS RISK; VITAL EXHAUSTION; LIFE EVENTS; POPULATION; DISORDER; GENE; METAANALYSIS; LINKAGE AB Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 x 10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 x 10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 x 10(-3)). This 5q21 region reached genome-wide significance (p = 4.78 x 10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms. C1 [Hek, Karin; Mulder, Cornelis L.; Tiemeier, Henning] Erasmus MC, Res Ctr O3, Dept Psychiat, NL-3000 CA Rotterdam, Netherlands. [Hek, Karin; Hofman, Albert; Kuningas, Maris; Uitterlinden, Andre G.; Tiemeier, Henning] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Tanaka, Toshiko] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Cornelis, Marilyn C.; Hu, Frank B.; Rimm, Eric B.; Jensen, Majken K.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Bakshis, Erin; Diez-Roux, Ana V.; Kardia, Sharon] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Baumert, Jens; Emeny, Rebecca; Ladwig, Karl-Heinz] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Ding, Jingzhong] Wake Forest Univ, Dept Internal Med, Div Geriatr, Winston Salem, NC 27109 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Marciante, Kristin] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Terracciano, Antonio; Meirelles, Osorio; Sutin, Angelina R.] NIA, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Sun, Yan V.] Emory Univ, Dept Epidemiol, Atlanta, GA 30322 USA. [Vogelzangs, Nicole; Penninx, Brenda] Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Vogelzangs, Nicole; Penninx, Brenda] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Yu, Lei; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Bandinelli, Stefania] Geriatr Unit Azienda Sanitaria Firenze, Florence, Italy. [Benjamin, Emelia J.; Kelly-Hayes, Margaret; Massaro, Joseph M.; Lunetta, Kathryn L.; Murabito, Joanne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med & Publ Hlth, Sect Cardiol & Prevent Med, Dept Med, Boston, MA 02215 USA. [Boomsma, Dorret; de Geus, Eco] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Cannas, Alessandra; Mulas, Antonella] CNR, Ist Ric Genet & Biomed, Cagliari, Italy. [Coker, Laura H.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. [De Jager, Philip L.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp,Program Translat NeuroPsych, Boston, MA 02115 USA. [Purcell, Shaun] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Broad Inst, Cambridge, MA USA. [Hu, Frank B.; Rimm, Eric B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Penman, Alan D.] Univ Mississippi, Med Ctr, Ctr Biostat, Jackson, MS 39216 USA. [Penman, Alan D.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Sotoodehnia, Nona] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Eriksson, Johan G.] Univ Helsinki, Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Evans, Denis A.] Rush Univ, Med Ctr, Rush Inst Hlth Aging, Dept Internal Med, Chicago, IL 60612 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX USA. [Hofman, Albert; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Tiemeier, Henning] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Illig, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Kelly-Hayes, Margaret] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Koenen, Karestan] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA USA. [Melzer, David; Pilling, Luke C.; Llewellyn, David J.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Murray, Anna] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Exeter, Devon, England. [Mulder, Cornelis L.] Erasmus MC, Mental Hlth Ctr BavoEuropoort, NL-3000 CA Rotterdam, Netherlands. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Palotie, Aarno] Wellcome Trust Genome Campus, Wellcome Trust Sanger Inst, Cambridge, England. [Palotie, Aarno; Widen, Elisabeth] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. Univ Cent Hosp, Helsinki, Finland. [Palotie, Aarno] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA. [Penninx, Brenda] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Penninx, Brenda] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Petersmann, Astrid] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Psaty, Bruce] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rawal, Rajesh] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Reiman, Eric M.] Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ USA. [Reiman, Eric M.] Banner Alzheimers Inst, Phoenix, AZ USA. [Schulz, Andrea; Grabe, Hans J.] Univ Med Greifswald, Helios Hosp, Dept Psychiat & Psychotherapy, Stralsund, Germany. [Zonderman, Alan B.] NIA, Lab Behav Neurosci, Baltimore, MD 21224 USA. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Gudnason, Vilmundur; Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Murabito, Joanne] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Curhan, Gary] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Gudnason, Vilmundur; Smith, Albert V.] Univ Iceland, Dept Med, Reykjavik, Iceland. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Terracciano, Antonio; Sutin, Angelina R.] Florida State Univ, Coll Med, Tallahassee, FL 32306 USA. [Demirkan, Ayse; Amin, Najaf; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Demirkan, Ayse; Amin, Najaf; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Genet Epidemiol Unit, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Shulman, Joshua M.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Shulman, Joshua M.] Baylor Coll Med, Dept Human Genet, Houston, TX 77030 USA. RP Tiemeier, H (reprint author), Erasmus MC, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM h.tiemeier@erasmusmc.nl RI Smith, Albert/K-5150-2015; Pilling, Luke/E-4917-2013; terracciano, antonio/B-1884-2008; Singleton, Andrew/C-3010-2009; Ladwig, Karl-Heinz/B-5351-2014; Newman, Anne/C-6408-2013; Emeny, Rebecca/I-1100-2014; Gudnason, Vilmundur/K-6885-2015; de Geus, Eco/M-9318-2015; OI Zonderman, Alan B/0000-0002-6523-4778; Ware, Erin/0000-0003-4731-8158; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470; Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838; Tiemeier, Henning/0000-0002-4395-1397; Benjamin, Emelia/0000-0003-4076-2336; Eriksson, Johan/0000-0002-2516-2060; Smith, Albert/0000-0003-1942-5845; Pilling, Luke/0000-0002-3332-8454; Murabito, Joanne/0000-0002-0192-7516; Ladwig, Karl-Heinz/0000-0003-0710-1720; Massaro, Joseph/0000-0002-2682-4812; Lunetta, Kathryn/0000-0002-9268-810X; Newman, Anne/0000-0002-0106-1150; Emeny, Rebecca/0000-0002-8780-5439; Gudnason, Vilmundur/0000-0001-5696-0084; de Geus, Eco/0000-0001-6022-2666; Mulas, Antonella/0000-0002-6856-1483 FU Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; National Institutes of Health (NIH) [N01-AG-12100, HHSN268200625226C, UL1RR025005, HHSN268200782096C, R01 MH086498, CA65725, CA87969, CA49449, CA67262, CA50385, 5UO1CA098233]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL087641, R01-HL093029, R01-HL70825]; National Human Genome Research Institute [U01-HG004402]; NIH Roadmap for Medical Research; NIH, National Institute on Aging [NO1-AG-1-2109]; NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL105756, N01-HC-25195, N02-HL-6-4278, N01-HC-65226]; NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, R01AG15819, R01AG17917, K08AG34290, P30AG10161, R01AG30146]; Clinical and Translational Science Institute [UL1RR033176]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; European Community; European Network for Genetic and Genomic Epidemiology Consortium [HEALTHF-4-2007- 201413]; European Special Populations Research Network; European Commission [018947, LSHG-CT-2006-01947]; Netherlands Organisation for Scientific Research, Erasmus MC; Centre for Medical Systems Biology; Netherlands Brain Foundation (HersenStichting Nederland); Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Academy of Finland; Finnish Diabetes Research Society; Folkhalsan Research Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Wellcome Trust [WT098051]; Italian Ministry of Health [ICS 110.1RS97.71]; U.S. National Institute on Aging [N01]AG]916413, N01]AG]821336, 263 MD 9164 13, 263 MD 821336]; Helmholtz Zentrum Munchen; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research; Munich Center of Health Sciences as part of Ludwig-Maximilians-University; Netherlands Organisation of Scientific Research Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research [050-060-810]; Erasmus MC; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (Directorate-General XII); Municipality of Rotterdam; Vidi Grant of Netherlands Organization for the Health Research and Development [2009-017.106.370]; BavoEuropoort; German Bundesministerium fur Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; Translational Genomics Research Institute; Burroughs Wellcome Fund; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Research Foundation (DFG) [GR 1912/5-1]; Federal Ministry of Education and Research Germany; Humboldt Foundation; German Research Foundation; Lundbeck; Janssen-Cilag; Eli Lilly; Novartis; AstraZeneca; SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health; Sanofi-Aventis; Biotronik; [R01-AG29451]; [N01-HC-95159]; [N01-HC-95169]; [UL1-RR-024156]; [R01 HL101161] FX We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium in development and support of this manuscript. Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium members include the Netherland's Rotterdam Study, the National Heart, Lung, and Blood Institute's (NHLBI) Framingham Heart Study, Cardiovascular Health Study, the NHLBI's Atherosclerosis Risk in Communities Study, and the National Institute on Aging's (NIA) Iceland Age, Gene/Environment Susceptibility Study.; The Age, Gene/Environment Susceptibility Reykjavik Study has been funded by National Institutes of Health (NIH) contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament).; The Atherosclerosis Risk in Communities Study research is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 and Grants R01-HL087641, R01-HL093029, and R01-HL70825; National Human Genome Research Institute contract U01-HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the Atherosclerosis Risk in Communities 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.; The Baltimore Longitudinal Study of Aging research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.; This Cardiovascular Health Study research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133 and NHLBI Grants HL080295, HL075366, HL087652, and HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported, in part, by Clinical and Translational Science Institute Grant UL1RR033176 to the Cedars-Sinai General Clinical Research Center Genotyping core, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK063491 to the Southern California Diabetes Endocrinology Research Center, and the Governors' Chair in Medical Genetics (JIR).; The Erasmus Rucphen Family (ERF) research was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), European Network for Genetic and Genomic Epidemiology Consortium, Grant agreement HEALTHF-4-2007- 201413.; The genotyping for the ERF study was supported by European Special Populations Research Network and the European Commission FP6 STRP Grant (018947; LSHG-CT-2006-01947). The ERF study was further supported by Grants from the Netherlands Organisation for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology, and the Netherlands Brain Foundation (HersenStichting Nederland). We are grateful to all participating individuals and their relatives, general practitioners, and neurologists for their contributions and to P. Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work, and P. Snijders for his help in data collection.; Framingham Heart Study: The phenotype-genotype association analyses were supported by R01-AG29451. "This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. This work was partially 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). A portion of this research utilized the Linux Cluster for Genetic Analysis funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.''; 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, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (Grant number WT098051). We thank all study participants, as well as everybody involved in the Helsinki Birth Cohort Study.; The Health, Aging and Body Composition 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. Center for Inherited Disease Research 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. Dr. Yaffe is supported by NIH Grant R01 MH086498.; The Invechhiare in Chianti Study was supported as a targeted project (ICS 110.1RS97.71) by the Italian Ministry of Health, by the U.S. 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.; The Multi-Ethnic Study of Atherosclerosis (MESA) SNP Health Association Resource project is conducted and supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and UL1-RR-024156. Funding for genotyping was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. Funding for this project was also provided by #R01 HL101161.; The Monitoring of Trends and Determinants of Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by Grants from the German Federal Ministry of Education and Research. Furthermore, the research was supported within the Munich Center of Health Sciences as part of Ludwig-Maximilians-University.; The Nurses' Health Studies are supported by NIH Grants CA 65725, CA87969 (National Cancer Institute), CA49449, CA67262, CA50385, and 5UO1CA098233.; The generation and management of genome-wide association study genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research Investments (number 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015), the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research project number 050-060-810. The Rotterdam Study is funded by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Directorate-General XII), and the Municipality of Rotterdam. Henning Tiemeier was supported by the Vidi Grant of Netherlands Organization for the Health Research and Development (2009-017.106.370). Karin Hek was supported by a Grant from BavoEuropoort. We are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the genome-wide association study database, and Dr. Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. We thank Dr. Karol Estrada, Dr. Fernando Rivadeneira, Dr. Tobias A. Knoch, Anis Abuseiris, Luc V. de Zeeuw, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP and BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fur Forschung und Technology; Grants 01 AK 803 A-H, 01 IG 07015 G) for access to their grid computing resources.; The Rush Memory and Aging Project is supported by NIA Grants R01AG15819, R01AG17917, and K08AG34290 and the Translational Genomics Research Institute. The Rush Religious Orders Study is supported by NIA Grants P30AG10161, R01AG15819, R01AG30146, and K08AG34290 and the Translational Genomics Research Institute. We thank the study participants and the staff of the Rush Alzheimer's Disease Center. Joshua Shulman was additionally supported by a Career Award for Medical Scientists from Burroughs Wellcome Fund.; The SardiNIA research was supported, in part, by the Intramural Research Program of the NIH, National Institute on Aging. Funding was also provided through contract NO1-AG-1-2109 from the NIA-NIH.; Study of Health in Pomerania is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint Grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the Center of Knowledge Interchange program of the Siemens AG. This work was also funded by the German Research Foundation (DFG: GR 1912/5-1), Federal Ministry of Education and Research Germany, the Humboldt Foundation, and the German Research Foundation.; Study of Health in Pomerania: To HJG German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, and Servier; and travel funds from Lundbeck, Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca, and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. To HV research grants by Sanofi-Aventis, Biotronik, the Humboldt Foundation, the Federal Ministry of Education and Research (Germany), and the German Research Foundation. All other authors reported no biomedical financial interests or potential conflicts of interest. NR 75 TC 60 Z9 61 U1 1 U2 34 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 1 PY 2013 VL 73 IS 7 BP 667 EP 678 DI 10.1016/j.biopsych.2012.09.033 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 113RL UT WOS:000316685400013 PM 23290196 ER PT J AU Scheurer, ME Pritchett, JC Amirian, ES Zemke, NR Lusso, P Ljungman, P AF Scheurer, M. E. Pritchett, J. C. Amirian, E. S. Zemke, N. R. Lusso, P. Ljungman, P. TI HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis SO BONE MARROW TRANSPLANTATION LA English DT Review DE HHV-6; encephalitis; umbilical cord blood; hematopoietic; stem cell; transplantation ID STEM-CELL TRANSPLANTATION; HUMAN-HERPESVIRUS 6; BONE-MARROW-TRANSPLANTATION; ACUTE LIMBIC ENCEPHALITIS; CENTRAL-NERVOUS-SYSTEM; VERSUS-HOST-DISEASE; UNRELATED DONORS; PERIPHERAL-BLOOD; VIRAL LOAD; HUMAN-HERPESVIRUS-6 REACTIVATION AB Reactivation of human herpesvirus-6 (HHV-6) frequently occurs following hematopoietic SCT (HSCT), and has been associated with clinical consequences in many patient populations. HHV-6 reactivation and HHV-6 encephalitis seem to occur more frequently in patients undergoing HSCT with cord blood (CB) as the stem cell source. We have conducted a systematic literature review and meta-analysis to investigate the clinical significance of this correlation. A systematic review of publications indexed in PubMed was performed for HSCT studies published over the past 10 years that fit inclusion criteria. Data on prevalences of HHV-6 reactivation and HHV-6 encephalitis post HSCT were abstracted from 19 papers. Meta-analyses were conducted to calculate combined prevalence estimates. The prevalences of HHV-6 reactivation and encephalitis were compared among CB vs non-CB HSCT. Prevalences of HHV-6 reactivation and HHV-6 encephalitis were significantly higher in patients receiving CB as the stem cell source than in patients receiving another stem cell source (72.0% vs 37.4%, P<0.0001; 8.3% vs 0.50%, P<0.0001, respectively). HHV-6 reactivation and HHV-6 encephalitis are significant complications in the post-HSCT setting, particularly in patients receiving CB as the stem cell source. Thus, patients undergoing umbilical CB transplantation should be closely monitored for HHV-6 reactivation. Bone Marrow Transplantation (2013) 48, 574-580; doi: 10.1038/bmt.2012.180; published online 24 September 2012 C1 [Scheurer, M. E.] Baylor Coll Med, Sect Hematol Oncol, Dept Pediat, Houston, TX 77030 USA. [Scheurer, M. E.; Amirian, E. S.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Pritchett, J. C.; Zemke, N. R.] HHV 6 Fdn, Santa Barbara, CA USA. [Lusso, P.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Ljungman, P.] Karolinska Inst, Dept Med Huddinge, Div Hematol, Stockholm, Sweden. [Ljungman, P.] Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden. RP Scheurer, ME (reprint author), Baylor Coll Med, Sect Hematol Oncol, Dept Pediat, 1 Baylor Plaza MS BCM 305, Houston, TX 77030 USA. EM scheurer@bcm.edu OI Scheurer, Michael/0000-0002-8379-6088 NR 75 TC 38 Z9 38 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 IS 4 BP 574 EP 580 DI 10.1038/bmt.2012.180 PG 7 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 118NP UT WOS:000317032500016 PM 23000642 ER PT J AU St John, L Gordon, SM Childs, R Marquesen, M Pavletic, SZ Wu, TX Cozzarelli, T Schroeder, E Saria, MG Fall-Dickson, JM AF St John, L. Gordon, S. M. Childs, R. Marquesen, M. Pavletic, S. Z. Wu, T. X. Cozzarelli, T. Schroeder, E. Saria, M. G. Fall-Dickson, J. M. TI Topical thalidomide gel in oral chronic GVHD and role of in situ cytokine expression in monitoring biological activity SO BONE MARROW TRANSPLANTATION LA English DT Letter ID VERSUS-HOST-DISEASE; ALPHA C1 [St John, L.; Cozzarelli, T.; Schroeder, E.; Fall-Dickson, J. M.] NINR, Intramural Res Program, Symptom Management Branch, NIH, Bethesda, MD 20892 USA. [Gordon, S. M.] Univ Maryland, Baltimore Coll Dent Surg, Baltimore, MD 21201 USA. [Childs, R.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Marquesen, M.] NIAID, Bethesda, MD 20892 USA. [Pavletic, S. Z.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Wu, T. X.] NINDS, NIH, Bethesda, MD 20892 USA. [Saria, M. G.] Univ Calif San Diego, NIH Summer Intern Program 2009, San Diego, CA 92103 USA. RP St John, L (reprint author), NINR, Intramural Res Program, Symptom Management Branch, NIH, Bethesda, MD 20892 USA. EM stjohnl@mail.nih.gov FU Intramural NIH HHS [ZIA HL002345-13] NR 8 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 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD APR PY 2013 VL 48 IS 4 BP 610 EP 611 DI 10.1038/bmt.2012.178 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 118NP UT WOS:000317032500022 PM 23000649 ER PT J AU Kareva, I Morin, B Karev, G AF Kareva, Irina Morin, Benjamin Karev, Georgy TI Preventing the Tragedy of the Commons Through Punishment of Over-Consumers and Encouragement of Under-Consumers SO BULLETIN OF MATHEMATICAL BIOLOGY LA English DT Article DE Tragedy of the commons; Mathematical model; Reduction theorem; Adaptive dynamics ID DYNAMICS AB The conditions that can lead to the exploitative depletion of a shared resource, i.e., the tragedy of the commons, can be reformulated as a game of prisoner's dilemma: while preserving the common resource is in the best interest of the group, over-consumption is in the interest of each particular individual at any given point in time. One way to try and prevent the tragedy of the commons is through infliction of punishment for over-consumption and/or encouraging under-consumption, thus selecting against over-consumers. Here, the effectiveness of various punishment functions in an evolving consumer-resource system is evaluated within a framework of a parametrically heterogeneous system of ordinary differential equations (ODEs). Conditions leading to the possibility of sustainable coexistence with the common resource for a subset of cases are identified analytically using adaptive dynamics; the effects of punishment on heterogeneous populations with different initial composition are evaluated using the reduction theorem for replicator equations. Obtained results suggest that one cannot prevent the tragedy of the commons through rewarding of under-consumers alone-there must also be an implementation of some degree of punishment that increases in a nonlinear fashion with respect to over-consumption and which may vary depending on the initial distribution of clones in the population. C1 [Kareva, Irina; Morin, Benjamin] Arizona State Univ, Computat Modeling Sci Ctr, Tempe, AZ 85287 USA. [Kareva, Irina; Morin, Benjamin] Arizona State Univ, Sch Human Evolut & Social Changes, Tempe, AZ 85287 USA. [Karev, Georgy] NIH, Ctr Biotechnol Informat NCBI, Bethesda, MD 20892 USA. RP Kareva, I (reprint author), Arizona State Univ, Computat Modeling Sci Ctr, POB 871904, Tempe, AZ 85287 USA. EM Irina.Kareva@tufts.edu FU National Science Foundation (NSF) [DMPS-0838705]; National Security Agency (NSA) [H98230-09-1-0104]; Alfred P. Sloan Foundation; Office of the Provost of Arizona State University; National Science Foundation [DMS-1135663] FX The authors would like to thank Kalle Parvinen and John Nagy for their help with adaptive dynamics. This project has been supported by grants from the National Science Foundation (NSF-Grant DMPS-0838705), the National Security Agency (NSA-Grant H98230-09-1-0104), the Alfred P. Sloan Foundation, and the Office of the Provost of Arizona State University. This material is also based upon work partially supported by the National Science Foundation under Grant No. DMS-1135663. NR 18 TC 3 Z9 3 U1 0 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0092-8240 EI 1522-9602 J9 B MATH BIOL JI Bull. Math. Biol. PD APR PY 2013 VL 75 IS 4 BP 565 EP 588 DI 10.1007/s11538-012-9804-3 PG 24 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 113RC UT WOS:000316684500001 PM 23408009 ER PT J AU Lee, JM Hays, JL Noonan, AM Squires, J Minasian, L Annunziata, C Wood, BJ Yu, MS Calvo, KR Houston, N Azad, N Kohn, EC AF Lee, Jung-min Hays, John L. Noonan, Anne M. Squires, Jennifer Minasian, Lori Annunziata, Christina Wood, Bradford J. Yu, Minshu Calvo, Katherine R. Houston, Nicole Azad, Nilofer Kohn, Elise C. TI Feasibility and safety of sequential research-related tumor core biopsies in clinical trials SO CANCER LA English DT Article DE feasibility; safety; research biopsy; antiangiogenic agent; obesity ID OVARIAN-CANCER; ANTICANCER AGENTS; DRUG DEVELOPMENT; OBESE WOMEN; PHASE-II; THERAPY; LAPAROSCOPY; MODULATION AB BACKGROUND: There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed. METHODS: This institutional review board-approved, retrospective study included chart and interventional radiology case review from 6 phase 1/2 studies at the National Cancer Institute. RESULTS: One hundred forty-two of 150 protocol patients who were approached gave consent for research biopsies. Patients' median age was 56 years (range, 27-78 years), their median body mass index was 25.8 kg/m2 (range, 14.4-46.2 kg/m2), they had an Eastern Cooperative Oncology Group performance status of 0 or 1, and they had normal end-organ function. Baseline biopsies were collected from 138 of 142 patients (97%), and paired specimens were collected from 96 (70%). Most patients had metastatic gynecologic cancers (85%), and 78% had target disease below the diaphragm with a median size of 2.7 cm (range, 1-14.5 cm). Protocol therapies included kinase inhibitors (35%), angiogenesis inhibitors (54%), and olaparib/carboplatin (11%); therapy was not interrupted for biopsies. All adverse events were uncomplicated and were observed in 4 patients (liver subcapsular hematoma in 1 patient, vasovagal syncope in 2 patients, and pneumothorax in 1 patient). The complication rate in obese patients was similar to that in nonobese patients (3 of 108 patients vs 1 of 34 patients, respectively). Sixty-seven patients (48%) were receiving bevacizumab at the time of subsequent biopsies. The complication rate was not different between patients who were and were not receiving bevacizumab (3 of 67 patients vs 1 of 71 patients, respectively). Ninety-five percent of biopsies yielded useable material. CONCLUSIONS: Serial percutaneous core-needle biopsies can be obtained safely and yield material applicable for multiple translational applications. Obesity and/or concomitant antiangiogenic therapy and depth of disease did not increase the risk or preclude the successful acquisition of useful tissue. Cancer 2013. (c) 2012 American Cancer Society. C1 [Lee, Jung-min; Hays, John L.; Noonan, Anne M.; Squires, Jennifer; Minasian, Lori; Annunziata, Christina; Yu, Minshu; Houston, Nicole; Azad, Nilofer; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wood, Bradford J.] NIH, Ctr Intervent Radiol Radiol & Imaging Sci, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Calvo, Katherine R.] NIH, Dept Lab Med, Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Lee, JM (reprint author), 10 Ctr Dr,MSC1906,Bldg 10,Room 12N-226, Bethesda, MD 20892 USA. EM leej6@mail.nih.gov RI Calvo, Katherine/A-8109-2009; Hays, John/H-3968-2012; Annunziata, Christina/L-3219-2016; OI Annunziata, Christina/0000-0003-2033-6532; Calvo, Katherine/0000-0002-0771-4191 FU Intramural Program of the Center for Cancer Research, National Cancer Institute; Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health; Philips Healthcare FX This work was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, and the Center for Interventional Oncology, Radiology and Imaging Sciences, National Institutes of Health.; Dr. Wood has received research funding from Cooperative Research and Development Agreement with Philips Healthcare. NR 21 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2013 VL 119 IS 7 BP 1357 EP 1364 DI 10.1002/cncr.27916 PG 8 WC Oncology SC Oncology GA 115KU UT WOS:000316811900011 PM 23280317 ER PT J AU Banegas, MP Leng, M Graubard, BI Morales, LS AF Banegas, Matthew P. Leng, Mei Graubard, Barry I. Morales, Leo S. TI The risk of developing invasive breast cancer in Hispanic women SO CANCER LA English DT Article DE breast cancer; risk assessment; Hispanic; Latino; Breast Cancer Risk Assessment Tool ID POPULATIONS; ETHNICITY; LATINAS; WHITES; US AB BACKGROUND: Current evidence on breast cancer among US Hispanic women indicates a significant public health threat, although few studies have assessed the heterogeneity in breast cancer risk among Hispanics of different origin. METHODS: The 2000 and 2005 National Health Interview Survey Cancer Control Modules were used to examine the Breast Cancer Risk Assessment Tool (BCRAT) 5-year risk and lifetime risk of invasive breast cancer among Mexican/Mexican American, Puerto Rican, Cuban/Cuban American, Dominican (Republic), Central/South American, Other Hispanic, and non-Hispanic white (NHW) women ages 35 to 84 years. Multiple linear regression models were used to compare the BCRAT 5-year and lifetime breast cancer risk between 1) Hispanics and NHWs and 2) Hispanic subgroups. RESULTS: Hispanic women had significantly lower mean BCRAT 5-year and lifetime breast cancer risk compared with NHW women (P < .001). Among Hispanic subgroups, Cuban/Cuban Americans had a higher BCRAT 5-year risk (P < .05), whereas Dominicans had a higher lifetime risk (P < .001) compared with Mexican/Mexican Americans. Approximately 2.6% of Hispanic women were at high risk for breast cancer (BCRAT 5-year risk 1.67%), ranging from 1% of Central/South Americans to 3.7% of Puerto Ricans; few Hispanics (0.2%) had a lifetime risk 20%. CONCLUSIONS: The current findings indicate that Hispanic women have a significantly lower risk of breast cancer compared with NHW women, although the risk according to BCRAT differed significantly between specific Hispanic subgroups. We provide estimates of the number of US Hispanic women from six subgroups who may be eligible for prophylactic breast cancer chemoprevention. The authors concluded that future studies should further investigate the heterogeneity in breast cancer risk and risk factors between Hispanic women of different origins. Cancer 2013. (c) 2012 American Cancer Society. C1 [Banegas, Matthew P.; Morales, Leo S.] Univ Washington, Dept Hlth Serv, Sch Publ Hlth, Seattle, WA 98195 USA. [Banegas, Matthew P.; Morales, Leo S.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Leng, Mei] Univ Calif Los Angeles, Dept Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Graubard, Barry I.] NCI, Div Genet, Bethesda, MD 20892 USA. [Morales, Leo S.] Grp Hlth Res Inst, Seattle, WA USA. RP Banegas, MP (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4019B, Bethesda, MD 20892 USA. EM banegasmp@mail.nih.gov FU National Cancer Institute Biobehavioral Cancer Prevention and Control Training Program at the University of Washington [R25CA092408]; National Cancer Institute Center for Hispanic Health Promotion Training Program at the Fred Hutchinson Cancer Research Center [U54CA153502] FX Dr. Banegas conducted this work while he was at the University of Washington and Fred Hutchinson Cancer Research Center and was supported in part by the National Cancer Institute Biobehavioral Cancer Prevention and Control Training Program (grant R25CA092408) at the University of Washington and by the National Cancer Institute Center for Hispanic Health Promotion Training Program (grant U54CA153502) at the Fred Hutchinson Cancer Research Center. NR 31 TC 6 Z9 6 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2013 VL 119 IS 7 BP 1373 EP 1380 DI 10.1002/cncr.27896 PG 8 WC Oncology SC Oncology GA 115KU UT WOS:000316811900013 PM 23224859 ER PT J AU Schonfeld, SJ Hartge, P Pfeiffer, RM Freedman, DM Greenlee, RT Linet, MS Park, Y Schairer, C Visvanathan, K Lacey, JV AF Schonfeld, Sara J. Hartge, Patricia Pfeiffer, Ruth M. Freedman, D. Michal Greenlee, Robert T. Linet, Martha S. Park, Yikyung Schairer, Catherine Visvanathan, Kala Lacey, James V., Jr. TI An aggregated analysis of hormonal factors and endometrial cancer risk by parity SO CANCER LA English DT Article DE endometrial cancer; nulliparity; reproductive history; oral contraceptives; hormone; obesity ID ESTROGEN REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; ORAL-CONTRACEPTIVES; REPRODUCTIVE FACTORS; NATIONAL-INSTITUTES; BREAST-CANCER; AARP DIET; COHORT; HEALTH; PROGESTIN AB BACKGROUND: Nulliparity is associated with an increased risk of endometrial cancer. It is less clear whether nulliparity modifies the association between other established hormone-related risk factors. The proportion of nulliparous women has increased since the mid-1970s, but most individual studies to date have been too small to test the hypothesis that endometrial cancer risk factors may be associated more strongly with risk among nulliparous women compared with parous women. METHODS: Data were aggregated on 26,936 postmenopausal, Caucasian, nulliparous women (360 endometrial cancers) and 146,583 postmenopausal, Caucasian, parous women (1378 endometrial cancers) from 4 US prospective studies (1979-2006). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in stratified analyses. RESULTS: The risk of endometrial cancer was higher among nulliparous women than among parous women, as expected (nulliparous vs parous: HR, 1.42; 95% CI, 1.26-1.60). Stratified associations between endometrial cancer and hormone-related risk factors did not differ between nulliparous versus parous women: For both groups, oral contraceptives and earlier menopause were associated with reduced risk. The highest HRs were for obesity: A body mass index 30 kg/m2 (vs <25 kg/m2) increased the risk of endometrial cancer 3-fold among nulliparous women (HR, 3.04; 95% CI, 2.34-3.94) and parous women (HR, 2.88; 95% CI, 2.52-3.29). CONCLUSIONS: The results from this large, pooled analysis of data from 4 large prospective studies suggested that nulliparity does not modify the risks of endometrial cancer associated with established hormone-related risk factors. Cancer 2013. (c) 2012 American Cancer Society. C1 [Schonfeld, Sara J.; Hartge, Patricia; Pfeiffer, Ruth M.; Freedman, D. Michal; Linet, Martha S.; Park, Yikyung; Schairer, Catherine; Lacey, James V., Jr.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Schonfeld, Sara J.; Visvanathan, Kala] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Greenlee, Robert T.] Marshfield Clin Res Fdn, Epidemiol Res Ctr, Marshfield, WI USA. [Visvanathan, Kala] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Lacey, James V., Jr.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. RP Schonfeld, SJ (reprint author), Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM schonfelds@fellows.iarc.fr OI Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services; [N01-CN-25,518] FX This research was supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. Dr. Greenlee was supported in part by N01-CN-25,518. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 37 TC 12 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2013 VL 119 IS 7 BP 1393 EP 1401 DI 10.1002/cncr.27909 PG 9 WC Oncology SC Oncology GA 115KU UT WOS:000316811900016 PM 23280123 ER PT J AU McCarthy, SA Mufson, RA Pearce, EJ Rathmell, JC Howcroft, TK AF McCarthy, Susan A. Mufson, R. Allan Pearce, Edward J. Rathmell, Jeffrey C. Howcroft, T. Kevin TI Metabolic Reprogramming of the Immune Response in the Tumor Microenvironment SO CANCER BIOLOGY & THERAPY LA English DT Article DE metabolism; lymphocyte; immunotherapy; cancer; Warburg; mTOR; rapamycin ID T-CELL DIFFERENTIATION; MTOR AB A Division of Cancer Biology, NCI-sponsored workshop Metabolic Reprogramming of the Immune Response in the Tumor Microenvironment was held October 2nd, 2012 in Bethesda, MD. The purpose of the workshop was to bring together cancer cell biologists and immunologists to explore the mechanistic relationships between the metabolic pathways used by cancer cells and antitumor immune cells and how this information could be used to improve cancer immunotherapy. At the conclusion of the workshop a general discussion focused on defining the major challenges and opportunities concerning the impact of metabolism on antitumor immunity and cancer immunotherapy as well as what tools, technologies, resources or community efforts are required to accelerate research in this area. Overall, future studies need to consider how cancer cell metabolic pathways differ from activated lymphocytes in order to define a therapeutic window for cancer therapy. Further, studies aimed at reprogramming the metabolic qualities of T cells with the goal of improving immunotherapy were considered a promising avenue. C1 [McCarthy, Susan A.; Mufson, R. Allan; Howcroft, T. Kevin] NCI, Canc Immunol & Hematol Branch, Div Canc Biol, NIH, Bethesda, MD 20892 USA. [Pearce, Edward J.] Washington Univ, Sch Med, Dept Pathol & Immunol, Div Immunobiol, St Louis, MO USA. [Rathmell, Jeffrey C.] Duke Univ, Dept Pharmacol & Canc Biol, Dept Immunol, Sarah Stedman Nutr & Metab Ctr, Durham, NC USA. RP Howcroft, TK (reprint author), NCI, Canc Immunol & Hematol Branch, Div Canc Biol, NIH, Bethesda, MD 20892 USA. EM Howcrofk@mail.nih.gov FU NCI NIH HHS [R01 CA164062] NR 9 TC 1 Z9 1 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD APR PY 2013 VL 14 IS 4 BP 315 EP 318 DI 10.4161/cbt.23616 PG 4 WC Oncology SC Oncology GA 117KQ UT WOS:000316952500004 PM 23358474 ER PT J AU Bhardwaj, P Du, BH Zhou, XK Sue, E Harbus, MD Falcone, DJ Giri, D Hudis, CA Kopelovich, L Subbaramaiah, K Dannenberg, AJ AF Bhardwaj, Priya Du, Baoheng Zhou, Xi Kathy Sue, Erika Harbus, Michael D. Falcone, Domenick J. Giri, Dilip Hudis, Clifford A. Kopelovich, Levy Subbaramaiah, Kotha Dannenberg, Andrew J. TI Caloric Restriction Reverses Obesity-Induced Mammary Gland Inflammation in Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID ELEVATED AROMATASE EXPRESSION; TUMOR-NECROSIS-FACTOR; WHITE ADIPOSE-TISSUE; BODY-MASS INDEX; BREAST-CANCER; INSULIN-RESISTANCE; WEIGHT-LOSS; MACROPHAGE INFILTRATION; POSTMENOPAUSAL WOMEN; METABOLIC SYNDROME AB Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women. Estrogen synthesis is catalyzed by aromatase. Recently, we identified an obesity -> inflammation -> aromatase axis in mouse models and women. In mouse models of obesity, inflammatory foci characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages were found in the mammary gland. CLS of the breast were found in most overweight and obese women. CLS were associated with adipocyte hypertrophy, activation of NF-kappa B, elevated levels of proinflammatory mediators and aromatase, and increased expression of the progesterone receptor (PR). Collectively, these findings provide a plausible explanation for the link between obesity, chronic inflammation, and postmenopausal breast cancer. Here, we investigated whether caloric restriction (CR) reversed the inflammatory state and related molecular changes in the mammary gland of obese mice. Obese ovariectomized C57BL/6J mice were subjected to 30% CR for 7 or 14 weeks. Findings in CR mice were compared with the results in mice fed a high-fat diet ad libitum or with control mice fed a low-fat diet. CR was associated with more than a 75% decrease in mammary CLS/cm(2). Reduced histologic inflammation following CR was associated with decreased adipocyte diameter and monocyte chemoattractant protein-1 (MCP-1) levels, reduced NF-kappa B binding activity, and normalization of levels of proinflammatory mediators, aromatase, and PR. In summary, obesity-related inflammation of the mammary gland and elevated aromatase and PR levels were reversed with CR. Our results provide a rationale for determining whether weight loss can reverse breast inflammation associated with obesity in women. Cancer Prev Res; 6(4);282-9. (c) 2013 AACR. C1 [Bhardwaj, Priya; Du, Baoheng; Sue, Erika; Harbus, Michael D.; Subbaramaiah, Kotha; Dannenberg, Andrew J.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Zhou, Xi Kathy] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY 10065 USA. [Falcone, Domenick J.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Giri, Dilip] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Dannenberg, AJ (reprint author), Weill Cornell Med Coll, Dept Med, 525 East 68th St,Room F-206, New York, NY 10065 USA. EM ajdannen@med.cornell.edu FU NCI [1R01CA154481]; Breast Cancer Research Foundation; Botwinick-Wolfensohn Foundation FX This work was supported by NCI 1R01CA154481, the Breast Cancer Research Foundation, and the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick). NR 47 TC 17 Z9 18 U1 1 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2013 VL 6 IS 4 BP 282 EP 289 DI 10.1158/1940-6207.CAPR-12-0467 PG 8 WC Oncology SC Oncology GA 118QP UT WOS:000317040800005 PM 23430756 ER PT J AU Bodogai, M Chang, CL Wejksza, K Lai, JP Merino, M Wersto, RP Gress, RE Chan, AC Hesdorffer, C Biragyn, A AF Bodogai, Monica Chang, Catalina Lee Wejksza, Katarzyna Lai, Jinping Merino, Maria Wersto, Robert P. Gress, Ronald E. Chan, Andrew C. Hesdorffer, Charles Biragyn, Arya TI Anti-CD20 Antibody Promotes Cancer Escape via Enrichment of Tumor-Evoked Regulatory B Cells Expressing Low Levels of CD20 and CD137L SO CANCER RESEARCH LA English DT Article ID CD4(+) T-CELLS; ANTITUMOR IMMUNITY; OVARIAN-CARCINOMA; SUPPRESSOR-CELLS; LYMPH-NODES; MICE; INDUCTION; RITUXIMAB; DEPLETION; RESPONSES AB The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo-targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20(Low) tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. Cancer Res; 73(7); 2127-38. (C)2013 AACR. C1 [Bodogai, Monica; Chang, Catalina Lee; Wejksza, Katarzyna; Biragyn, Arya] NIA, Immunotherapeut Sect, Baltimore, MD 21224 USA. [Hesdorffer, Charles] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Wersto, Robert P.] NIA, Flow Cytometry Unit, Baltimore, MD 21224 USA. [Lai, Jinping; Merino, Maria] NCI, Bethesda, MD 20892 USA. [Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Chan, Andrew C.] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA. RP Biragyn, A (reprint author), NIA, 251 Bayview Blvd,Suite 100, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov RI Lee-Chang, Catalina/A-5580-2015 OI Lee-Chang, Catalina/0000-0002-7675-2124 FU Intramural Research Program of the National Institute on Aging, NIH FX This research was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 51 TC 28 Z9 29 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2013 VL 73 IS 7 BP 2127 EP 2138 DI 10.1158/0008-5472.CAN-12-4184 PG 12 WC Oncology SC Oncology GA 118AU UT WOS:000316995600011 PM 23365136 ER PT J AU Garcia-Closas, M Rothman, N Figueroa, JD Prokunina-Olsson, L Han, SS Baris, D Jacobs, EJ Malats, N De Vivo, I Albanes, D Purdue, MP Sharma, S Fu, YP Kogevinas, M Wang, Z Tang, W Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Johnson, A Schwenn, M Karagas, MR Schned, A Andriole, G Grubb, R Black, A Gapstur, SM Thun, M Diver, WR Weinstein, SJ Virtamo, J Hunter, DJ Caporaso, N Landi, MT Hutchinson, A Burdett, L Jacobs, KB Yeager, M Fraumeni, JF Chanock, SJ Silverman, DT Chatterjee, N AF Garcia-Closas, Montserrat Rothman, Nathaniel Figueroa, Jonine D. Prokunina-Olsson, Ludmila Han, Summer S. Baris, Dalsu Jacobs, Eric J. Malats, Nuria De Vivo, Immaculata Albanes, Demetrius Purdue, Mark P. Sharma, Sapna Fu, Yi-Ping Kogevinas, Manolis Wang, Zhaoming Tang, Wei Tardon, Adonina Serra, Consol Carrato, Alfredo Garcia-Closas, Reina Lloreta, Josep Johnson, Alison Schwenn, Molly Karagas, Margaret R. Schned, Alan Andriole, Gerald, Jr. Grubb, Robert, III Black, Amanda Gapstur, Susan M. Thun, Michael Diver, William Ryan Weinstein, Stephanie J. Virtamo, Jarmo Hunter, David J. Caporaso, Neil Landi, Maria Teresa Hutchinson, Amy Burdett, Laurie Jacobs, Kevin B. Yeager, Meredith Fraumeni, Joseph F., Jr. Chanock, Stephen J. Silverman, Debra T. Chatterjee, Nilanjan TI Common Genetic Polymorphisms Modify the Effect of Smoking on Absolute Risk of Bladder Cancer SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; NAT2 SLOW ACETYLATION; CONFERS SUSCEPTIBILITY; SEQUENCE VARIANT; GSTM1 NULL; GENOTYPE; LOCUS; INDEPENDENCE; METAANALYSIS; INTENSITY AB Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7 x 10(-4)) and UGT1A6 (P = 8 x 10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive = 1 x 10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211-20. (C)2012 AACR. C1 [Garcia-Closas, Montserrat; Rothman, Nathaniel; Figueroa, Jonine D.; Prokunina-Olsson, Ludmila; Han, Summer S.; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fu, Yi-Ping; Tang, Wei; Black, Amanda; Weinstein, Stephanie J.; Caporaso, Neil; Landi, Maria Teresa; Fraumeni, Joseph F., Jr.; Chanock, Stephen J.; Silverman, Debra T.; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Garcia-Closas, Montserrat; Sharma, Sapna] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England. [Jacobs, Eric J.; Gapstur, Susan M.; Thun, Michael; Diver, William Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Malats, Nuria] Spanish Natl Canc Res Ctr, Madrid, Spain. [Carrato, Alfredo] Ramon y Cajal Univ Hosp, Madrid, Spain. [De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Kogevinas, Manolis] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Tardon, Adonina; Serra, Consol] CIBER Epidemiol & Salud Publ CIBERESP, Barcelona, Spain. [Serra, Consol] Univ Pompeu Fabra, Barcelona, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp Mar Inst Municipal Invest Med IMIM, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Wang, Zhaoming; Hutchinson, Amy; Burdett, Laurie; Jacobs, Kevin B.; Yeager, Meredith] NCI, Core Genotype Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME USA. [Karagas, Margaret R.; Schned, Alan] Dartmouth Med Sch, Hanover, NH USA. [Andriole, Gerald, Jr.; Grubb, Robert, III] Washington Univ, Sch Med, Dept Urol, St Louis, MO USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Helsinki, Finland. [Virtamo, Jarmo] Dept Chron Dis Prevent, Helsinki, Finland. RP Garcia-Closas, M (reprint author), Inst Canc Res, Div Genet & Epidemiol, 15 Cotswold Rd, Sutton SM2 5NG, Surrey, England. EM Montse.GarciaClosas@icr.ac.uk RI Tang, Wei/H-7103-2013; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Purdue, Mark/C-9228-2016; Kogevinas, Manolis/C-3918-2017; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Albanes, Demetrius/B-9749-2015 OI Tang, Wei/0000-0002-7089-4391; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Purdue, Mark/0000-0003-1177-3108; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; FU intramural research program of the NIH, NCI; NCI, NIH [HHSN261200800001E]; Division of Cancer Epidemiology and Genetics; FIS/Spain [98/1274, 00/0745, PI061614, G03/ 174]; Fundacio Marato TV3; Red Tematica Investigacion Cooperativa en Cancer (RTICC); Consolider ONCOBIO [EU-FP7-201663]; Intramural research program of the NIH, NCI, Division of Cancer Epidemiology and Genetics [NCI N02-CP-01037]; NIH Genes, Environment, and Health Initiative (GEI); DNA extraction and statistical analyses [HG-06-033-NCI-01, RO1HL091172-01, HG06- 033-NCI-01]; genotyping at the Johns Hopkins University Center for Inherited Disease Research [U01HG004438, NIH HHSN268200782096C]; study coordination at the GENEVA; study coordination at the GENEVA Coordination Center [U01 HG004446]; Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, NCI, NIH; Intramural Research Program of the NIH; NCI; U.S. Public Health Service from the NCI, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC37004, HHSN261201000006C]; [NCI N02-CP-11015]; [RO1-CA089715]; [CA34627]; [CA055075]; [CA087969] FX The NCI bladder cancer GWAS was supported by the intramural research program of the NIH, NCI. This work was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. Support for individual studies that participated in the effort is as follows:; SBCS (D. T. Silverman): Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-11015. FIS/Spain 98/1274, FIS/Spain 00/0745, PI061614, and G03/ 174, Fundacio Marato TV3, Red Tematica Investigacion Cooperativa en Cancer (RTICC), Consolider ONCOBIO, EU-FP7-201663; and RO1-CA089715 and CA34627. NEBCS (D. T. Silverman): Intramural research program of the NIH, NCI, Division of Cancer Epidemiology and Genetics and intramural contract number NCI N02-CP-01037. PLCO (M. P. Purdue): The NIH Genes, Environment, and Health Initiative (GEI) partly funded DNA extraction and statistical analyses (HG-06-033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA (N. Caporaso): The NIH GEI partly funded DNA extraction and statistical analyses (HG06- 033-NCI-01 and RO1HL091172-01), genotyping at the Johns Hopkins University Center for Inherited Disease Research (U01HG004438 and NIH HHSN268200782096C), and study coordination at the GENEVA Coordination Center (U01 HG004446) for EAGLE and part of PLCO studies. Genotyping for the remaining part of PLCO and all ATBC and CPS-II samples were supported by the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics. The PLCO is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, NCI, NIH. ATBC (D. Albanes): This research was supported in part by the Intramural Research Program of the NIH and the NCI. In addition, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC37004, and HHSN261201000006C from the NCI, Department of Health and Human Services. NHS and HPFS (I. D. Vivo): CA055075 and CA087969. NR 32 TC 40 Z9 41 U1 2 U2 20 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2013 VL 73 IS 7 BP 2211 EP 2220 DI 10.1158/0008-5472.CAN-12-2388 PG 10 WC Oncology SC Oncology GA 118AU UT WOS:000316995600019 PM 23536561 ER PT J AU Liu, XF FitzGerald, DJ Pastan, I AF Liu, Xiu Fen FitzGerald, David J. Pastan, Ira TI The Insulin Receptor Negatively Regulates the Action of Pseudomonas Toxin-Based Immunotoxins and Native Pseudomonas Toxin SO CANCER RESEARCH LA English DT Article ID I RECEPTORS; CANCER; MESOTHELIN; THERAPY; IMMUNOTHERAPY; APOPTOSIS; EXOTOXIN; GLUCOSE AB SS1P is a recombinant immunotoxin composed of an antimesothelin Fv fragment fused to a truncated portion of Pseudomonas exotoxin A. SS1P targets and kills mesothelin-expressing tumors, which include mesothlioma as well as ovarian, lung, and pancreatic cancers. SS1P is currently in clinical trials in mesothelioma. Because insulin acting through the insulin receptor is a survival factor for many cancer cell lines, we explored how lowering insulin receptor level would affect the cytotoxic action of SS1P. We show here that siRNA knockdown of the insulin receptor enhanced the cytotoxic action of native Pseudomonas exotoxin and enhanced SS1P toxicity on several human cell lines, but did not affect the response to other cytotoxic agents such as TRAIL, etoposide, and cycloheximide. To determine how insulin receptor knockdown enhances SS1P action, we analyzed various steps involved in cell killing. We found that insulin receptor knockdown increases the cleavage of SS1P by furin, which allows more toxin to reach the cytosol and inactivate elongation factor 2. These findings indicate that the insulin receptor negatively regulates immunotoxin action. Cancer Res; 73(7); 2281-8. (C)2013 AACR. C1 [Liu, Xiu Fen; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 23 TC 14 Z9 14 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2013 VL 73 IS 7 BP 2281 EP 2288 DI 10.1158/0008-5472.CAN-12-3436 PG 8 WC Oncology SC Oncology GA 118AU UT WOS:000316995600025 PM 23348423 ER PT J AU Omolo, B Carson, C Chu, HT Zhou, YC Simpson, DA Hesse, JE Paules, RS Nyhan, KC Ibrahim, JG Kaufmann, WK AF Omolo, Bernard Carson, Craig Chu, Haitao Zhou, Yingchun Simpson, Dennis A. Hesse, Jill E. Paules, Richard S. Nyhan, Kristine C. Ibrahim, Joseph G. Kaufmann, William K. TI A prognostic signature of G(2) checkpoint function in melanoma cell lines SO CELL CYCLE LA English DT Article DE G(2) checkpoint; melanoma; microarray; ionizing radiation; oncogene ID DNA-DAMAGE RESPONSE; ONCOGENE-INDUCED SENESCENCE; SISTER-CHROMATID COHESION; GENOMIC INSTABILITY; MALIGNANT-MELANOMA; CYCLE CHECKPOINTS; GENE-EXPRESSION; BRAF MUTATIONS; CANCER; COMPLEX AB As DNA damage checkpoints are barriers to carcinogenesis, G(2) checkpoint function was quantified to test for override of this checkpoint during melanomagenesis. Primary melanocytes displayed an effective G(2) checkpoint response to ionizing radiation (IR)-induced DNA damage. Thirty-seven percent of melanoma cell lines displayed a significant defect in G(2) checkpoint function. Checkpoint function was melanoma subtype-specific with "epithelial-like" melanoma lines, with wild type NRAS and BRAF displaying an effective checkpoint, while lines with mutant NRAS and BRAF displayed defective checkpoint function. Expression of oncogenic B-Raf in a checkpoint-effective melanoma attenuated G(2) checkpoint function significantly but modestly. Other alterations must be needed to produce the severe attenuation of G(2) checkpoint function seen in some BRAF-mutant melanoma lines. Quantitative trait analysis tools identified mRNA species whose expression was correlated with G(2) checkpoint function in the melanoma lines. A 165 gene signature was identified with a high correlation with checkpoint function (p < 0.004) and low false discovery rate (<= 0.077). The G(2) checkpoint gene signature predicted G(2) checkpoint function with 77-94% accuracy. The signature was enriched in lysosomal genes and contained numerous genes that are associated with regulation of chromatin structure and cell cycle progression. The core machinery of the cell cycle was not altered in checkpoint-defective lines but rather numerous mediators of core machinery function were. When applied to an independent series of primary melanomas, the predictive G(2) checkpoint signature was prognostic of distant metastasis-free survival. These results emphasize the value of expression profiling of primary melanomas for understanding melanoma biology and disease prognosis. C1 [Omolo, Bernard] Univ South Carolina Upstate, Div Math & Comp Sci, Spartanburg, SC USA. [Carson, Craig] Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. [Chu, Haitao] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Zhou, Yingchun; Simpson, Dennis A.; Kaufmann, William K.] Univ N Carolina, Chapel Hill, NC 27515 USA. [Hesse, Jill E.; Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, Res Triangle Pk, NC 27709 USA. [Nyhan, Kristine C.] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA USA. [Ibrahim, Joseph G.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Ibrahim, Joseph G.; Kaufmann, William K.] Univ N Carolina, Ctr Environm Hlth & Susceptibil, Chapel Hill, NC USA. [Ibrahim, Joseph G.; Kaufmann, William K.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Kaufmann, WK (reprint author), Univ N Carolina, Chapel Hill, NC 27515 USA. EM Bill_Kaufmann@med.unc.edu OI Chu, Haitao/0000-0003-0932-598X FU PHS [ES10126, CA16086, ES014635]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences FX We are grateful to Drs. Jayne Boyer and Leena Nylander-French for providing primary melanocyte cultures. Supported in part by PHS grants ES10126, CA16086 and ES014635. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 86 TC 8 Z9 8 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD APR 1 PY 2013 VL 12 IS 7 BP 1071 EP 1082 DI 10.4161/cc.24067 PG 12 WC Cell Biology SC Cell Biology GA 117HJ UT WOS:000316943900013 PM 23454897 ER PT J AU Palii, SS Cui, YX Innes, CL Paules, RS AF Palii, Stela S. Cui, Yuxia Innes, Cynthia L. Paules, Richard S. TI Dissecting cellular responses to irradiation via targeted disruptions of the ATM-CHK1-PP2A circuit SO CELL CYCLE LA English DT Article DE DNA damage; ataxia telangiectasia mutated; checkpoint kinase-1; phosphatase; feedback regulation ID MAMMARY EPITHELIAL-CELLS; PROTEIN PHOSPHATASE 2A; CHECKPOINT KINASE CHK1; DNA-DAMAGE; G(2) CHECKPOINT; TYROSINE PHOSPHORYLATION; P53; CANCER; INHIBITION; REPAIR AB Exposure of proliferating cells to genotoxic stresses activates a cascade of signaling events termed the DNA damage response (DDR). The DDR preserves genetic stability by detecting DNA lesions, activating cell cycle checkpoints and promoting DNA damage repair. The phosphoinositide 3-kinase-related kinases (PIKKs) ataxia telangiectasia-mutated (ATM), ATM and Rad 3-related kinase (ATR) and DNA-dependent protein kinase (DNA-PK) are crucial for sensing lesions and signal transduction. The checkpoint kinase 1 (CHK1) is a traditional ATR target involved in DDR and normal cell cycle progression and represents a pharmacological target for anticancer regimens. This study employed cell lines stably depleted for CHK1, ATM or both for dissecting cross-talk and compensatory effects on G(2)/M checkpoint in response to ionizing radiation (IR). We show that a 90% depletion of CHK1 renders cells radiosensitive without abrogating their IR-mediated G(2)/M checkpoint arrest. ATM phosphorylation is enhanced in CHK1-deficient cells compared with their wildtype counterparts. This correlates with lower nuclear abundance of the PP2A catalytic subunit in CHK1-depleted cells. Stable depletion of CHK1 in an ATM-deficient background showed only a 50% reduction from wild-type CHK1 protein expression levels and resulted in an additive attenuation of the G(2)/M checkpoint response compared with the individual knockdowns. ATM inhibition and 90% CHK1 depletion abrogated the early G(2)/M checkpoint and precluded the cells from mounting an efficient compensatory response to IR at later time points. Our data indicates that dual targeting of ATM and CHK1 functionalities disrupts the compensatory response to DNA damage and could be exploited for developing efficient anti-neoplastic treatments. C1 [Palii, Stela S.; Cui, Yuxia; Innes, Cynthia L.; Paules, Richard S.] NIEHS, Environm Stress & Canc Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), NIEHS, Environm Stress & Canc Grp, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01ES021157] FX The authors thank Drs. Janine Santos and Carl Anderson for their critical reading of the manuscript and helpful comments and the NIEHS Flow Cytometry Core for their assistance with data collection. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES021157). NR 50 TC 5 Z9 5 U1 1 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD APR 1 PY 2013 VL 12 IS 7 BP 1105 EP 1118 DI 10.4161/cc.24127 PG 14 WC Cell Biology SC Cell Biology GA 117HJ UT WOS:000316943900016 PM 23462183 ER PT J AU Carol, H Szymanska, B Evans, K Boehm, I Houghton, PJ Smith, MA Lock, RB AF Carol, Hernan Szymanska, Barbara Evans, Kathryn Boehm, Ingrid Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI The Anti-CD19 Antibody-Drug Conjugate SAR3419 Prevents Hematolymphoid Relapse Postinduction Therapy in Preclinical Models of Pediatric Acute Lymphoblastic Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL PRECURSOR LEUKEMIA; NON-HODGKINS-LYMPHOMA; PHASE-I TRIAL; ANTI-B4-BLOCKED RICIN; CHEMOTHERAPEUTIC DRUGS; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; XENOGRAFT MODELS; CANCER; IMMUNOCONJUGATE AB Purpose: Relapsed or refractory pediatric acute lymphoblastic leukemia (ALL) remains a major cause of death from cancer in children. In this study, we evaluated the efficacy of SAR3419, an antibody-drug conjugate of the maytansinoid DM4 and a humanized anti-CD19 antibody, against B-cell precursor (BCP)ALL and infant mixed lineage leukemia (MLL) xenografts. Experimental Design: ALL xenografts were established as systemic disease in immunodeficient (NOD/SCID) mice from direct patient explants. SAR3419 was administered as a single agent and in combination with an induction-type regimen of vincristine/dexamethasone/L-asparaginase (VXL). Leukemia progression and response to treatment were assessed in real-time, and responses were evaluated using strict criteria modeled after the clinical setting. Results: SAR3419 significantly delayed the progression of 4 of 4 CD19(+) BCP-ALL and 3 of 3 MLL-ALL xenografts, induced objective responses in all but one xenograft but was ineffective against T-lineage ALL xenografts. Relative surface CD19 expression across the xenograft panel significantly correlated with leukemia progression delay and objective response measure scores. SAR3419 also exerted significant efficacy against chemoresistant BCP-ALL xenografts over a large (10-fold) dose range and significantly enhanced VXL-induced leukemia progression delay in two highly chemoresistant xenografts by up to 82 days. When administered as protracted therapy following remission induction with VXL, SAR3419 prevented disease recurrence into hematolymphoid and other major organs with the notable exception of central nervous system involvement. Conclusion: These results suggest that incorporation of SAR3419 into remission induction protocols may improve the outcome for high-risk pediatric and adult CD19(+) ALL. Clin Cancer Res; 19(7); 1795-805. (C)2013 AACR. C1 [Carol, Hernan; Szymanska, Barbara; Evans, Kathryn; Boehm, Ingrid; Lock, Richard B.] Univ New S Wales, Childrens Canc Inst Australia Med Res, Sydney, NSW 2052, Australia. [Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Univ New S Wales, Childrens Canc Inst Australia, Lowy Canc Res Ctr, Sydney, NSW 2052, Australia. EM rlock@ccia.unsw.edu.au RI Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013 OI Carol, Hernan/0000-0002-9443-8032; FU National Cancer Institute [NOI-CM-42216, NOI-CM-91001-03] FX This study was supported by National Cancer Institute grant numbers: NOI-CM-42216 and NOI-CM-91001-03. NR 44 TC 31 Z9 32 U1 0 U2 17 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2013 VL 19 IS 7 BP 1795 EP 1805 DI 10.1158/1078-0432.CCR-12-3613 PG 11 WC Oncology SC Oncology GA 118BH UT WOS:000316996900018 PM 23426279 ER PT J AU Gojo, I Tan, M Fang, HB Sadowska, M Lapidus, R Baer, MR Carrier, F Beumer, JH Anyang, BN Srivastava, RK Espinoza-Delgado, I Ross, DD AF Gojo, Ivana Tan, Ming Fang, Hong-Bin Sadowska, Mariola Lapidus, Rena Baer, Maria R. Carrier, France Beumer, Jan H. Anyang, Bean N. Srivastava, Rakesh K. Espinoza-Delgado, Igor Ross, Douglas D. TI Translational Phase I Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) Combined with Cytarabine and Etoposide in Patients with Relapsed, Refractory, or High-Risk Acute Myeloid Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; MULTIDRUG-RESISTANCE; CANCER-CELLS; MEDIATED MULTIDRUG; CYCLOSPORINE-A; ONCOLOGY-GROUP; TRANSPORTER; EXPRESSION; APOPTOSIS; CYTOTOXICITY AB Purpose: To determine the maximum-tolerated dose (MTD) of the histone deacetylase inhibitor vorinostat combined with fixed doses of cytarabine (ara-C or cytosine arabinoside) and etoposide in patients with poor-risk or advanced acute leukemia, to obtain preliminary efficacy data, describe pharmacokinetics, and in vivo pharmacodynamic effects of vorinostat in leukemia blasts. Experimental Design: In this open-label phase I study, vorinostat was given orally on days one to seven at three escalating dose levels: 200 mg twice a day, 200 mg three times a day, and 300 mg twice a day. On days 11 to 14, etoposide (100 mg/m(2)) and cytarabine (1 or 2 g/m(2) twice a day if >= 65 or <65 years old, respectively) were given. The study used a stan dard 3+3 dose escalation design. Results: Eighteen of 21 patients with acute myelogenous leukemia (AML) treated on study completed planned therapy. Dose-limiting toxicities [hyperbilirubinemia/septic death (1) and anorexia/fatigue (1)] were encountered at the 200 mg three times a day level; thus, the MTD was established to be vorinostat 200 mg twice a day. Of 21 patients enrolled, seven attained a complete remission (CR) or CR with incomplete platelet recovery, including six of 13 patients treated at the MTD. The median remission duration was seven months. No differences in percentage S-phase cells or multidrug resistance transporter (MDR1 or BCRP) expression or function were observed in vivo in leukemia blasts upon vorinostat treatment. Conclusions: Vorinostat 200 mg twice a day can be given safely for seven days before treatment with cytarabine and etoposide. The relatively high CR rate seen at the MTD in this poor-risk group of patients with AML warrants further studies to confirm these findings. Clin Cancer Res; 19(7); 1838-51. (C)2013 AACR. C1 [Gojo, Ivana; Baer, Maria R.; Carrier, France; Ross, Douglas D.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr UMGCC, Baltimore, MD 21201 USA. [Tan, Ming; Fang, Hong-Bin] Univ Maryland, Sch Med, Dept Med, Div Biostat, Baltimore, MD 21201 USA. [Sadowska, Mariola; Lapidus, Rena] UMGCC, Translat Lab Shared Serv, Taipei, Taiwan. [Gojo, Ivana; Baer, Maria R.; Ross, Douglas D.] Univ Maryland, Sch Med, Dept Med, Div Hematol & Oncol, Baltimore, MD 21201 USA. [Tan, Ming; Fang, Hong-Bin] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Carrier, France] Univ Maryland, Sch Med, Dept Radiat Oncol, Baltimore, MD 21201 USA. [Ross, Douglas D.] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Espinoza-Delgado, Igor] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Beumer, Jan H.; Anyang, Bean N.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Srivastava, Rakesh K.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Ross, DD (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Room 9-031 Bressler Res Bldg,655 West Baltimore S, Baltimore, MD 21201 USA. EM dross@som.umaryland.edu OI Srivastava, Rakesh/0000-0002-0065-4069 FU Merck Inc.; UMGCC [P30-CA134274]; VA Merit Review grant; Translational Research Initiative grant program of the Cancer Therapy Evaluation Program (CTEP) of the NCI; Merck Corporation; CTEP; [P30CA047904]; [U01-CA099168] FX M. Sadowska, I. Espinoza-Delgado, and D. D. Ross have commercial research grant from Merck Inc. No potential conflicts of interest were disclosed by the other authors.; This study was supported by P30-CA134274 (UMGCC). D. D. Ross's research was supported in part by a VA Merit Review grant. The translational studies in this work were supported by the Translational Research Initiative grant program of the Cancer Therapy Evaluation Program (CTEP) of the NCI, and by a grant from the Merck Corporation. The clinical trial was sponsored by CTEP. This project also used the UPCI Clinical Pharmacology Analytical Facility (CPAF), which was supported in part by award P30CA047904 and by U01-CA099168 (to J.H. Beumer). NR 31 TC 19 Z9 21 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 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2013 VL 19 IS 7 BP 1838 EP 1851 DI 10.1158/1078-0432.CCR-12-3165 PG 14 WC Oncology SC Oncology GA 118BH UT WOS:000316996900022 PM 23403629 ER PT J AU Kummar, S Anderson, L Hill, K Majerova, E Allen, D Horneffer, Y Ivy, SP Rubinstein, L Harris, P Doroshow, JH Collins, JM AF Kummar, Shivaani Anderson, Larry Hill, Kimberly Majerova, Eva Allen, Deborah Horneffer, Yvonne Ivy, S. Percy Rubinstein, Larry Harris, Pamela Doroshow, James H. Collins, Jerry M. TI First-in-Human Phase 0 Trial of Oral 5-Iodo-2-Pyrimidinone-2 '-Deoxyribose in Patients with Advanced Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN GLIOBLASTOMA XENOGRAFTS; ANAPLASTIC ASTROCYTOMA; I TRIAL; IODODEOXYURIDINE; RADIOSENSITIZATION; RADIATION; 5-IODO-2'-DEOXYURIDINE; PHARMACOLOGY; MULTIFORME; TOXICITY AB Purpose: Iododeoxyuridine (IdUrd), a halogenated nucleoside analog, produced clinical responses when administered as a radiosensitizer via continuous intravenous (c.i.v.) infusion over the course of radiotherapy. We conducted a phase 0 trial of 5-iodo-2-pyrimidinone-20-deoxyribose (IPdR), an oral prodrug of IdUrd, in patients with advanced malignancies to assess whether the oral route was a feasible alternative to c.i.v. infusion before embarking on large-scale clinical trials. Plasma concentrations of IPdR, IdUrd, and other metabolites were measured after a single oral dose of IPdR. Experimental Design: Eligible patients had advanced refractory malignancies. A single oral dose of IPdR was administered per patient and patients were followed for 14 days for safety assessments; dose escalations were planned (150, 300, 600, 1,200, and 2,400 mg) with one patient per dose level and 6 patients at the highest dose level. Blood sampling was conducted over a 24-hour period for pharmacokinetic analysis. Results: There were no drug-related adverse events. Plasma concentrations of IdUrd generally increased as the dose of IPdR escalated from 150 to 2,400 mg. All patients at the 2,400 mg dose achieved peak IdUrd levels of (mean +/- SD) 4.0 mu mol/L +/- 1.02 mu mol/L at 1.67 +/- 1. 21 hours after IPdR administration. Conclusions: Adequate plasma levels of IdUrd were obtained to justify proceeding with a phase I trial of IPdR in combination with radiation. This trial shows the ability of a small, phase 0 study to provide critical information for decision-making regarding future development of a drug. Clin Cancer Res; 19(7); 1852-7. (C)2013 AACR. C1 [Kummar, Shivaani; Anderson, Larry; Ivy, S. Percy; Rubinstein, Larry; Harris, Pamela; Doroshow, James H.; Collins, Jerry M.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Kummar, Shivaani; Allen, Deborah; Horneffer, Yvonne; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Hill, Kimberly; Majerova, Eva] SAIC Frederick Inc, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Collins, JM (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM collinsje@mail.nih.gov FU National Cancer Institute, NIH [HHSN261200800001E] FX This work has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. NR 23 TC 9 Z9 10 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2013 VL 19 IS 7 BP 1852 EP 1857 DI 10.1158/1078-0432.CCR-12-3118 PG 6 WC Oncology SC Oncology GA 118BH UT WOS:000316996900023 PM 23403637 ER PT J AU Holkova, B Supko, JG Ames, MM Reid, JM Shapiro, GI Perkins, EB Ramakrishnan, V Tombes, MB Honeycutt, C McGovern, RM Kmieciak, M Shrader, E Wellons, MD Sankala, H Doyle, A Wright, J Roberts, JD Grant, S AF Holkova, Beata Supko, Jeffrey G. Ames, Matthew M. Reid, Joel M. Shapiro, Geoffrey I. Perkins, Edward Brent Ramakrishnan, Viswanathan Tombes, Mary Beth Honeycutt, Connie McGovern, Renee M. Kmieciak, Maciej Shrader, Ellen Wellons, Martha D. Sankala, Heidi Doyle, Austin Wright, John Roberts, John D. Grant, Steven TI A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory, or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2 SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; DEPENDENT KINASE INHIBITOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; FLAVOPIRIDOL INDUCES APOPTOSIS; BREAST-CARCINOMA CELLS; ACUTE MYELOID-LEUKEMIA; HYDROXAMIC ACID SAHA; DOWN-REGULATION; TRANSCRIPTIONAL REPRESSION; MYELODYSPLASTIC SYNDROMES AB Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200mgorally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily x 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873-83. (C)2013 AACR. C1 [Holkova, Beata; Perkins, Edward Brent; Ramakrishnan, Viswanathan; Tombes, Mary Beth; Honeycutt, Connie; Kmieciak, Maciej; Shrader, Ellen; Wellons, Martha D.; Sankala, Heidi; Roberts, John D.; Grant, Steven] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Holkova, Beata; Perkins, Edward Brent; Roberts, John D.; Grant, Steven] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA. [Ramakrishnan, Viswanathan] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Grant, Steven] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Grant, Steven] Virginia Commonwealth Univ, Inst Mol Med, Richmond, VA 23298 USA. [Supko, Jeffrey G.; Shapiro, Geoffrey I.] Dana Farber Harvard Canc Ctr, Boston, MA USA. [Ames, Matthew M.; Reid, Joel M.; McGovern, Renee M.] Mayo Clin, Ctr Comprehens Canc, Rochester, MN USA. [Doyle, Austin; Wright, John] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Grant, S (reprint author), Virginia Commonwealth Univ, POB 980035,401 Coll St, Richmond, VA 23298 USA. EM bholkova@mcvh-vcu.edu; stgrant@vcu.edu FU NIH [R21 CA115260, R01 CA93738, P30 CA016059, M01RR00065, U01 CA69912, 23XS026, P30 CA15083, P30 CA60516] FX This study was supported by NIH grants R21 CA115260, R01 CA93738, P30 CA016059, M01RR00065, U01 CA69912, 23XS026, P30 CA15083, and P30 CA60516. NR 50 TC 12 Z9 13 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2013 VL 19 IS 7 BP 1873 EP 1883 DI 10.1158/1078-0432.CCR-12-2926 PG 11 WC Oncology SC Oncology GA 118BH UT WOS:000316996900025 PM 23515411 ER PT J AU Nesterova, G Malicdan, MC Yasuda, K Sakaki, T Vilboux, T Ciccone, C Horst, R Huang, Y Golas, G Introne, W Huizing, M Adams, D Boerkoel, CF Collins, MT Gahl, WA AF Nesterova, Galina Malicdan, May Christine Yasuda, Kaori Sakaki, Toshiyuki Vilboux, Thierry Ciccone, Carla Horst, Ronald Huang, Yan Golas, Gretchen Introne, Wendy Huizing, Marjan Adams, David Boerkoel, Cornelius F. Collins, Michael T. Gahl, William A. TI 1,25-(OH)(2)D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID IDIOPATHIC INFANTILE HYPERCALCEMIA; VITAMIN-D; STONE DISEASE; UNDIAGNOSED DISEASES; SUBSTRATE-BINDING; KIDNEY-STONES; HUMAN CYP27A1; METABOLISM; NEPHROCALCINOSIS; INSIGHTS AB Background and objectives Elevated serum vitamin D with hypercalciuria can result in nephrocalcinosis and nephrolithiasis. This study evaluated the cause of excess 1,25-dihydroxycholecalciferol (1 alpha,25(OH)(2)D-3) in the development of those disorders in two individuals. Design, setting, participants, & measurements Two patients with elevated vitamin D levels and nephrocalcinosis or nephrolithiasis were investigated at the National Institutes of Health (NIH) Clinical Center and the NIH Undiagnosed Diseases Program, by measuring calcium, phosphate, and vitamin D metabolites, and by performing CYP24A1 mutation analysis. Results Both patients exhibited hypercalciuria, hypercalcemia, low parathyroid hormone, elevated vitamin D (1 alpha,25(OH)(2)D-3), normal 25-OHD3, decreased 24,25(OH)(2)D, and undetectable activity of 1,25(OH)(2)D-24-hydroxylase (CYP24A1), the enzyme that inactivates 1 alpha,25(OH)(2)D-3. Both patients had bi-allelic mutations in CYP24A1 leading to loss of function of this enzyme. On the basis of dbSNP data, the frequency of predicted deleterious bi-allelic CYP24A1 variants in the general population is estimated to be as high as 4%-20%. Conclusions The results of this study show that 1,25(OH)2D-24-hydroxylase deficiency due to bi-allelic mutations in CYP24A1 causes elevated serum vitamin D, hypercalciuria, nephrocalcinosis, and renal stones. Clin J Am Soc Nephrol 8: 649-657, 2013. doi: 10.2215/CJN.05360512 C1 [Nesterova, Galina; Malicdan, May Christine; Vilboux, Thierry; Ciccone, Carla; Huizing, Marjan; Gahl, William A.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yasuda, Kaori; Sakaki, Toshiyuki] Toyama Prefectural Univ, Fac Engn, Dept Biotechnol, Toyama, Japan. [Horst, Ronald] Heartland Assays, Ames, IA USA. [Huang, Yan; Adams, David; Boerkoel, Cornelius F.; Gahl, William A.] NHGRI, Undiagnosed Dis Program, Off Rare Dis Res, NIH, Bethesda, MD 20892 USA. [Golas, Gretchen; Introne, Wendy; Adams, David; Gahl, William A.] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Nesterova, G (reprint author), NHGRI, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Room 10C 107, Bethesda, MD 20892 USA. EM nesterovag@mail.nih.gov RI Malicdan, May Christine/F-2806-2013 FU Intramural Research Program; National Human Genome Research Institute; National Institute of Dental and Craniofacial Diseases; Undiagnosed Diseases Program; Office of Rare Disorders Research, National Institutes of Health, Bethesda, Maryland FX This work was supported by the Intramural Research Program, National Human Genome Research Institute, National Institute of Dental and Craniofacial Diseases, and Undiagnosed Diseases Program, and Office of Rare Disorders Research, National Institutes of Health, Bethesda, Maryland. NR 53 TC 27 Z9 28 U1 1 U2 42 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2013 VL 8 IS 4 BP 649 EP 657 DI 10.2215/CJN.05360512 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 118KB UT WOS:000317023300020 PM 23293122 ER PT J AU Ackerman, H AF Ackerman, Hans TI Management of Severe Malaria: Enthusiasm for Fluid Resuscitation Dampened by Lung Water SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE acute kidney injury; endothelial dysfunction; metabolic acidosis; Plasmodium falciparum; resuscitation ID SEVERE FALCIPARUM-MALARIA; INFECTED ERYTHROCYTES; SEQUESTRATION; DYSFUNCTION; CHILDREN; CELLS C1 NIAID, Lab Malaria & Vector Res, Rockville, MD USA. RP Ackerman, H (reprint author), NIAID, Lab Malaria & Vector Res, Rockville, MD USA. FU Intramural NIH HHS [ZIA AI001150-02] NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2013 VL 41 IS 4 BP 1139 EP 1140 DI 10.1097/CCM.0b013e318283cab1 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 114HN UT WOS:000316731800035 PM 23528760 ER PT J AU Memoli, MJ AF Memoli, Matthew James TI Pandemic Research in the ICU: Always Be Prepared SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE clinical research; H1N1; influenza; pandemic ID 2009 INFLUENZA A(H1N1); H1N1 INFLUENZA; A H1N1; SURVEILLANCE; IMPACT C1 NIAID, Viral Pathogenesis & Evolut Sect, NIH, Bethesda, MD 20892 USA. RP Memoli, MJ (reprint author), NIAID, Viral Pathogenesis & Evolut Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 16 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2013 VL 41 IS 4 BP 1147 EP 1148 DI 10.1097/CCM.0b013e31827c0605 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 114HN UT WOS:000316731800039 PM 23528764 ER PT J AU Mousa, SA Shaqura, M Khalefa, BI Zollner, C Schaad, L Schneider, J Shippenberg, TS Richter, JF Hellweg, R Shakibaei, M Schafer, M AF Mousa, Shaaban A. Shaqura, Mohammed Khalefa, Baled I. Zoellner, Christian Schaad, Laura Schneider, Jonas Shippenberg, Toni S. Richter, Jan F. Hellweg, Rainer Shakibaei, Mehdi Schaefer, Michael TI Rab7 Silencing Prevents mu-Opioid Receptor Lysosomal Targeting and Rescues Opioid Responsiveness to Strengthen Diabetic Neuropathic Pain Therapy SO DIABETES LA English DT Article ID NERVE GROWTH-FACTOR; INFLAMMATORY PAIN; SPINAL-CORD; SENSORY NEURONS; ENDOCYTIC TRAFFICKING; DOWN-REGULATION; RATS; BIOGENESIS; ACTIVATION; MORPHINE AB Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron mu-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis. Diabetes 62:1308-1319, 2013 C1 [Mousa, Shaaban A.; Shaqura, Mohammed; Khalefa, Baled I.; Schaad, Laura; Schneider, Jonas; Schaefer, Michael] Charite, Dept Anaesthesiol & Intens Care Med, D-13353 Berlin, Germany. [Zoellner, Christian] Univ Klinikum Hamburg Eppendorf, Dept Anaesthesiol, Hamburg, Germany. [Shippenberg, Toni S.] NIDA, Integrat Neurosci Sect, NIH, Baltimore, MD USA. [Richter, Jan F.] Charite, Dept Clin Physiol, D-13353 Berlin, Germany. [Hellweg, Rainer] Charite, Dept Psychiat & Psychotherapy, D-13353 Berlin, Germany. [Shakibaei, Mehdi] Univ Munich, Dept Anat, Munich, Germany. RP Schafer, M (reprint author), Charite, Dept Anaesthesiol & Intens Care Med, Campus Virchow Klinikum & Campus Charite Mitre, D-13353 Berlin, Germany. EM micha.schaefer@charite.de FU Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany) [KFO100, MO 1006/1-4, SCHA 820/3-2]; European Society of Anesthesiology FX This work was supported by the Deutsche Forschungsgemeinschaft (DFG, Bonn, Germany) grants KFO100, MO 1006/1-4, and SCHA 820/3-2 and by a grant of the European Society of Anesthesiology (C.Z.). NR 46 TC 18 Z9 18 U1 1 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2013 VL 62 IS 4 BP 1308 EP 1319 DI 10.2337/db12-0590 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 111MS UT WOS:000316526000041 PM 23230081 ER PT J AU Kerridge, BT Saha, TD Gmel, G Rehm, J AF Kerridge, Bradley T. Saha, Tulshi D. Gmel, Gerhard Rehm, Juergen TI Taxometric analysis of DSM-IV and DSM-5 alcohol use disorders SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcohol use disorder; Taxometric analysis; Latent structure; Taxon-dimensional hybrid structure; Structural analysis ID DIMENSIONAL LATENT STRUCTURE; GENERAL-POPULATION SAMPLE; 2 QUANTITATIVE INDICATORS; ITEM RESPONSE THEORY; ALL-CAUSE MORTALITY; DETECTING TAXONICITY; BULIMIA-NERVOSA; PRISON-INMATES; DRUG MODULES; AUDADIS-ADR AB Background: With preparations currently being made for the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5), one prominent issue to resolve is whether alcohol use disorders are better represented as discrete categorical entities or as a dimensional construct. The purpose of this study was to investigate the latent structure of DSM-4th edition (DSM-IV) and proposed DSM-5 alcohol use disorders. Methods: The study used the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to conduct taxometric analyses of DSM-IV and DSM-5 alcohol use disorders defined by different thresholds to determine the taxonic or dimensional structure underlying the disorders. Results: DSM-IV and DSM-5 alcohol abuse and dependence criteria with 3+ thresholds demonstrated a dimensional structure. Corresponding thresholds with 4+ criteria were clearly taxonic, as were thresholds defined by cut-offs of 5+ and 6+ criteria. Conclusions: DSM-IV and DSM-5 alcohol use disorders demonstrated a hybrid taxonic-dimensional structure. That is, DSM-IV and DSM-5 alcohol use disorders may be taxonically distinct compared to no disorder if defined by a threshold of 4 or more criteria. However, there may be dimensional variation remaining among non-problematic to subclinical cases. A careful and systematic program of structural research using taxometric and psychometric procedures is warranted. Published by Elsevier Ireland Ltd. C1 [Kerridge, Bradley T.] Univ Maryland, Sch Publ Hlth, Dept Epidemiol & Biostat, College Pk, MD 20740 USA. [Saha, Tulshi D.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Rockville, MD 20852 USA. [Gmel, Gerhard] Lavsanne Univ Hosp, Alcohol Treatment Ctr, CH-1011 Lausanne, Switzerland. [Rehm, Juergen] Ctr Addict & Mental Hlth, Toronto, ON M5S 2S1, Canada. [Rehm, Juergen] Tech Univ Dresden, D-01187 Dresden, Germany. RP Saha, TD (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, 5635 Fishers Lane, Rockville, MD 20852 USA. EM sahatd@mail.nih.gov OI Kerridge, Bradley/0000-0003-0459-9439 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA); NIH/NIDA [5F31DA025377]; European Community [266813] FX The National Institute on Alcohol Abuse and Alcoholism (NIAAA) funded the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) with supplemental funding from the National Institute on Drug Abuse (NIDA). Support acknowledged for Mr. Kerridge, NIH/NIDA Fellowship 5F31DA025377. The research leading to these results or outcomes has also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013), under Grant Agreement no 266813 Addictions and Lifestyle in Contemporary Europe - Reframing Addictions Project (ALICE RAP) with support acknowledges for Drs. Gmel and Rehm and Mr. Kerridge. NR 71 TC 11 Z9 11 U1 1 U2 11 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 APR 1 PY 2013 VL 129 IS 1-2 BP 60 EP 69 DI 10.1016/j.drugalcdep.2012.09.010 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 115QS UT WOS:000316827600009 PM 23122488 ER PT J AU Edskes, HK Wickner, RB AF Edskes, Herman K. Wickner, Reed B. TI The [URE3] Prion in Candida SO EUKARYOTIC CELL LA English DT Article ID NITROGEN CATABOLITE REPRESSION; BETA-SHEET STRUCTURE; AMINO-ACID PERMEASE; SACCHAROMYCES-CEREVISIAE; TRANSPORTER GENE; SPECIES BARRIER; SHUTTLE VECTORS; SUP35 PROTEIN; DOMAINS FORM; MATING TYPES AB Ure2p, normally a regulator of nitrogen catabolism in Saccharomyces cerevisiae, can be a prion (infectious protein) by forming a folded in-register parallel amyloid called [URE3]. Using S. cerevisiae as a test bed, we previously showed that Ure2p of Candida albicans (CaUre2p) can also form a prion, but that Ure2p of C. glabrata (CgUre2p) cannot. Here, we constructed C. glabrata strains to test whether CgUre2p can form a prion in its native environment. We find that while CaUre2p can form a [URE3] in C. glabrata, CgUre2p cannot, although the latter has a prion domain sequence more similar to that of ScUre2p than that of CaUre2p. This supports the notion that prion formation is not a conserved property of Ure2p but is a pathology arising sporadically. We find that some [URE3albicans] variants are restricted in their transmissibility to certain recipient strains. In addition, we show that the C. glabrata HO can induce switching of the C. glabrata mating type locus. C1 [Edskes, Herman K.; Wickner, Reed B.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 56 TC 12 Z9 15 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD APR PY 2013 VL 12 IS 4 BP 551 EP 558 DI 10.1128/EC.00015-13 PG 8 WC Microbiology; Mycology SC Microbiology; Mycology GA 115IF UT WOS:000316805100009 PM 23397567 ER PT J AU Djousse, L Bartz, TM Ix, JH Kochar, J Kizer, JR Gottdiener, JS Tracy, RP Mozaffarian, D Siscovick, DS Mukamal, KJ Zieman, SJ AF Djousse, Luc Bartz, Traci M. Ix, Joachim H. Kochar, Jinesh Kizer, Jorge R. Gottdiener, John S. Tracy, Russell P. Mozaffarian, Dariush Siscovick, David S. Mukamal, Kenneth J. Zieman, Susan J. TI Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Epidemiology; Adiposity; Heart failure; Fatty acid-binding protein 4 ID CORONARY-ARTERY-DISEASE; TYPE-2 DIABETES-MELLITUS; METABOLIC SYNDROME; ADIPOSE-TISSUE; OBESITY; RISK; ASSOCIATION; POPULATION; BIOMARKER; SURVIVAL AB To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure. In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95 confidence interval (CI) 1.251.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95 CI 1.011.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion. An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors. C1 [Djousse, Luc] Brigham & Womens Hosp, Div Aging, Dept Med, Boston, MA 02120 USA. [Djousse, Luc; Mozaffarian, Dariush; Mukamal, Kenneth J.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Kochar, Jinesh] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Gottdiener, John S.] Univ Maryland, Med Ctr, Div Cardiol, Baltimore, MD 21201 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Dept Med, Boston, MA 02120 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Mukamal, Kenneth J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Zieman, Susan J.] NIA, NIH, Bethesda, MD 20892 USA. RP Djousse, L (reprint author), Brigham & Womens Hosp, Div Aging, 1620 Tremont St,3rd Floor, Boston, MA 02120 USA. EM ldjousse@rics.bwh.harvard.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL-094555, HHSN268201200036C, N01-HC-85239, N01-HC-85079-N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295]; National Institute of Neurological Disorders and Stroke (NINDS); National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058] FX The National Heart, Lung, and Blood Institute (NHLBI) [grant R01 HL-094555; contracts HHSN268201200036C, N01-HC-85239, N01-HC-85079-N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295 to C. H. S., with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS)]; the National Institute on Aging (NIA) [additional support through AG-023629, AG-15928, AG-20098, and AG-027058). Funding agencies did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data. NR 39 TC 8 Z9 8 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD APR PY 2013 VL 15 IS 4 BP 394 EP 399 DI 10.1093/eurjhf/hfs196 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 117LR UT WOS:000316955400006 PM 23223158 ER PT J AU Hafed, ZM Lovejoy, LP Krauzlis, RJ AF Hafed, Ziad M. Lovejoy, Lee P. Krauzlis, Richard J. TI Superior colliculus inactivation alters the relationship between covert visual attention and microsaccades SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE attention; fixational eye movements; muscimol; perceptual processing; rhesus macaque ID SACCADIC EYE MOVEMENTS; FIXATION; SHIFTS; SUPPRESSION; GENERATION; BEHAVIOR; TRACKING; MONKEYS; BURSTS; CORTEX AB Microsaccades are tiny saccades that occur during gaze fixation. Whereas these movements have traditionally been viewed as random, it was recently discovered that microsaccade directions can be significantly biased by covertly attended visual stimuli. The detailed mechanisms mediating such a bias are neither known nor immediately obvious, especially because the amplitudes of the movements influenced by attentional cueing could be up to two orders of magnitude smaller than the eccentricity of the attended location. Here, we tested whether activity in the peripheral superior colliculus (SC) is necessary for this correlation between attentional cueing and microsaccades. We reversibly and focally inactivated SC neurons representing peripheral regions of visual space while rhesus monkeys performed a demanding covert visual attention task. The normal bias of microsaccade directions observed in each monkey before SC inactivation was eliminated when a cue was placed in the visual region affected by the inactivation; microsaccades were, instead, biased away from the affected visual space. When the cue was placed at another location unaffected by SC inactivation, the baseline cue-induced bias of microsaccade directions remained mostly intact, because the cue was in unaffected visual space, and any remaining changes were again explained by a repulsion of microsaccades away from the inactivated region. Our results indicate that peripheral SC activity is required for the link between microsaccades and the cueing of covert visual attention, and that it could do so by altering the probability of triggering microsaccades without necessarily affecting the motor generation of these movements. C1 [Hafed, Ziad M.] Werner Reichardt Ctr Integrat Neurosci, D-72076 Tubingen, Germany. [Hafed, Ziad M.] Univ Tubingen, Inst Neurobiol, Tubingen, Germany. [Lovejoy, Lee P.] Columbia Univ, Dept Psychiat, New York, NY USA. [Lovejoy, Lee P.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Krauzlis, Richard J.] Salk Inst Biol Studies, Syst Neurobiol Lab, La Jolla, CA 92037 USA. [Krauzlis, Richard J.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Hafed, ZM (reprint author), Werner Reichardt Ctr Integrat Neurosci, Otfried Muller Str 25, D-72076 Tubingen, Germany. EM ziad.m.hafed@cin.uni-tuebingen.de OI Lovejoy, Lee/0000-0002-5732-9224 FU Werner Reichardt Center for Integrative Neuroscience; Institute for Neural Computation; Aginsky Scholars Award Program; National Institutes of Health [EY12212]; National Eye Institute Intramural Research Program at the National Institutes of Health FX Z. M. Hafed was funded by the Werner Reichardt Center for Integrative Neuroscience. L. P. Lovejoy was funded by the Institute for Neural Computation and the Aginsky Scholars Award Program. R. J. Krauzlis was funded by the National Institutes of Health (Grant EY12212) and the National Eye Institute Intramural Research Program at the National Institutes of Health. NR 33 TC 16 Z9 16 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2013 VL 37 IS 7 BP 1169 EP 1181 DI 10.1111/ejn.12127 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 117OR UT WOS:000316963400014 PM 23331638 ER PT J AU Coelho, SG Zmudzka, BZ Yin, LL Miller, SA Yamaguchi, Y Tadokoro, T Hearing, VJ Beer, JZ AF Coelho, Sergio G. Zmudzka, Barbara Z. Yin, Lanlan Miller, Sharon A. Yamaguchi, Yuji Tadokoro, Taketsugu Hearing, Vincent J. Beer, Janusz Z. TI Non-invasive diffuse reflectance measurements of cutaneous melanin content can predict human sensitivity to ultraviolet radiation SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE DNA damage; erythema; melanin; race/ethnicity ultraviolet radiation ID MAST-CELLS; ANGIOGENIC FACTORS; TUMOR ENVIRONMENT; SCHWANN-CELLS; NEUROFIBROMATOSIS; EXPRESSION; NF1; MICROENVIRONMENT; NF1(+/-); GAP AB The diversity of human skin phenotypes and the ubiquitous exposure to ultraviolet radiation (UVR) underscore the need for a non-invasive tool to predict an individual's UVR sensitivity. We analysed correlations between UVR sensitivity, melanin content, diffuse reflectance spectroscopy (DR) and UVR-induced DNA damage in the skin of subjects from three racial/ethnic groups: Asian, Black or African American and White. UVR sensitivity was determined by evaluating each subject's response to one minimal erythemal dose (MED) of UVR one day after the exposure. Melanin content was measured using DR and by densitometric analysis of Fontana-Masson staining (FM) in skin biopsies taken from unexposed areas. An individual's UVR sensitivity based on MED was highly correlated with melanin content measured by DR and by FM. Therefore, a predictive model for the non-invasive determination of UVR sensitivity using DR was developed. The MED precision was further improved when we took race/ethnicity into consideration. The use of DR serves as a tool for predicting UVR sensitivity in humans that should be invaluable for determining appropriate UVR doses for therapeutic, diagnostic and/or cosmetic devices. C1 [Coelho, Sergio G.; Yin, Lanlan; Yamaguchi, Yuji; Tadokoro, Taketsugu; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Zmudzka, Barbara Z.; Miller, Sharon A.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Coelho, SG (reprint author), NIH, Pigment Cell Biol Sect, Cell Biol Lab, Bldg 37 Rm 2132, Bethesda, MD 20892 USA. EM coelhos@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We also thank Dr. Nikiforos Kollias for valuable comments and suggestions for improving the manuscript. The mention of commercial products, their sources or their use in connection with material reported herein is not to be construed as either an actual or an implied endorsement of such products by the Department of Health and Human Services. NR 21 TC 7 Z9 8 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD APR PY 2013 VL 22 IS 4 BP 266 EP 271 DI 10.1111/exd.12116 PG 6 WC Dermatology SC Dermatology GA 115PS UT WOS:000316825000006 PM 23528212 ER PT J AU Liu, CY Dupuis, J Larson, MG Levy, D AF Liu, Chunyu Dupuis, Josee Larson, Martin G. Levy, Daniel TI Association Testing of the Mitochondrial Genome Using Pedigree Data SO GENETIC EPIDEMIOLOGY LA English DT Article DE mitochondrial DNA; association test; polygenic effect; maternal lineage; permutation test ID HAN CHINESE FAMILY; BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; GENETIC-VARIATION; FASTING GLUCOSE; EUROPEAN MTDNAS; DNA MUTATIONS; DISEASE; HAPLOGROUPS; FRAMINGHAM AB In humans, mitochondria contain their own DNA (mtDNA) that is inherited exclusively from the mother. The mitochondrial genome encodes 13 polypeptides that are components of oxidative phosphorylation to produce energy. Any disruption in these genes might interfere with energy production and thus contribute to metabolic derangement. Mitochondria also regulate several important cellular activities including cell death and calcium homeostasis. Aided by sharply declining costs of high-density genotyping, hundreds of mitochondrial variants will soon be available in several cohorts with pedigree structures. Association testing of mitochondrial variants with disease traits using pedigree data raises unique challenges because of the difficulty in separating the effects of nuclear and mitochondrial genomes, which display different modes of inheritance. Failing to correctly account for these effects might decrease power or inflate type I error in association tests. In this report, we sought to identify the best strategy for association testing of mitochondrial variants when genotype and phenotype data are available in pedigrees. We proposed several strategies to account for polygenic effects of the nuclear and mitochondrial genomes and we performed extensive simulation studies to evaluate type I error and power of these strategies. In addition, we proposed two permutation tests to obtain empirical P values for these strategies. Furthermore, we applied two of the analytical strategies to association analysis of 196 mitochondrial variants with blood pressure and fasting blood glucose in the pedigree rich, Framingham Heart Study. Finally, we discussed strategies for study design, genotyping, and data cleaning in association testing of mtDNA in pedigrees. C1 [Liu, Chunyu; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA USA. [Liu, Chunyu; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Liu, CY (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM chunyu.liu@nih.gov OI Larson, Martin/0000-0002-9631-1254; Dupuis, Josee/0000-0003-2871-3603 FU NIH [NO1-HC-25195]; Division of Intramural Research of the National Heart, Lung, and Blood Institute FX This work is supported by NIH contract NO1-HC-25195 (to the Framingham Heart Study). The Center for Population Studies is supported by the Division of Intramural Research of the National Heart, Lung, and Blood Institute (D.L.). We thank Dr. Kathy Lunetta of Biostatistics, School of Public Health at Boston University for discussions and providing R codes for implanting the BO strategy. We acknowledge Illumina, Inc., for free genotyping of 2,455 FHS individuals with the HumanOmni5- Quad BeadChip. Illumina did not participate or had any influence on the analysis, interpretation, or reporting of the results. The authors declare that there is no conflict of interest. NR 45 TC 2 Z9 2 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD APR PY 2013 VL 37 IS 3 BP 239 EP 247 DI 10.1002/gepi.21706 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 115KI UT WOS:000316810600002 PM 23319385 ER PT J AU Manolio, TA Chisholm, RL Ozenberger, B Roden, DM Williams, MS Wilson, R Bick, D Bottinger, EP Brilliant, MH Eng, C Frazer, KA Korf, B Ledbetter, DH Lupski, JR Marsh, C Mrazek, D Murray, MF O'Donnell, PH Rader, DJ Relling, MV Shuldiner, AR Valle, D Weinshilboum, R Green, ED Ginsburg, GS AF Manolio, Teri A. Chisholm, Rex L. Ozenberger, Brad Roden, Dan M. Williams, Marc S. Wilson, Richard Bick, David Bottinger, Erwin P. Brilliant, Murray H. Eng, Charis Frazer, Kelly A. Korf, Bruce Ledbetter, David H. Lupski, James R. Marsh, Clay Mrazek, David Murray, Michael F. O'Donnell, Peter H. Rader, Daniel J. Relling, Mary V. Shuldiner, Alan R. Valle, David Weinshilboum, Richard Green, Eric D. Ginsburg, Geoffrey S. TI Implementing genomic medicine in the clinic: the future is here SO GENETICS IN MEDICINE LA English DT Review DE medical genomics; practice standards ID EGAPP-WORKING-GROUP; PERSONALIZED MEDICINE; CYP2C19 GENOTYPE; RISK-ASSESSMENT; FAMILY-HISTORY; LYNCH SYNDROME; PRIMARY-CARE; DISEASE; HEALTH; PHARMACOGENETICS AB Although the potential for genomics to contribute to clinical care has long been anticipated, the pace of defining the risks and benefits of incorporating genomic findings into medical practice has been relatively slow. Several institutions have recently begun genomic medicine programs, encountering many of the same obstacles and developing the same solutions, often independently. Recognizing that successful early experiences can inform subsequent efforts, the National Human Genome Research Institute brought together a number of these groups to describe their ongoing projects and challenges, identify common infrastructure and research needs, and outline an implementation framework for investigating and introducing similar programs elsewhere. Chief among the challenges were limited evidence and consensus on which genomic variants were medically relevant; lack of reimbursement for genomically driven interventions; and burden to patients and clinicians of assaying, reporting, intervening, and following up genomic findings. Key infrastructure needs included an openly accessible knowledge base capturing sequence variants and their phenotypic associations and a framework for defining and cataloging clinically actionable variants. Multiple institutions are actively engaged in using genomic information in clinical care. Much of this work is being done in isolation and would benefit from more structured collaboration and sharing of best practices. Genet Med 2013:15(4):258-267 C1 [Manolio, Teri A.; Ozenberger, Brad; Green, Eric D.] NHGRI, NIH, Bethesda, MD 20892 USA. [Chisholm, Rex L.] Northwestern Univ, Ctr Genet Med, Chicago, IL 60611 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. [Williams, Marc S.] Intermt Healthcare, Clin Genet Inst, Salt Lake City, UT USA. [Williams, Marc S.; Ledbetter, David H.] Geisinger Hlth Syst, Genom Med Inst, Danville, PA USA. [Wilson, Richard] Washington Univ, Sch Med, Genome Inst, St Louis, MO USA. [Bick, David] Med Coll Wisconsin, Dept Pediat, Div Genet, Milwaukee, WI 53226 USA. [Bottinger, Erwin P.] Mt Sinai Sch Med, Charles Bronfman Inst Personalized Med, New York, NY USA. [Brilliant, Murray H.] Marshfield Clin Fdn Med Res & Educ, Ctr Human Genet, Marshfield, WI USA. [Eng, Charis] Cleveland Clin, Lerner Res Inst, Genom Med Inst, Cleveland, OH 44106 USA. [Frazer, Kelly A.] Univ Calif San Diego, Dept Pediat, Div Genome Informat Sci, La Jolla, CA 92093 USA. [Korf, Bruce] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Lupski, James R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Marsh, Clay] Ohio State Univ, Med Ctr, Ctr Personalized Hlth Care, Columbus, OH 43210 USA. [Mrazek, David] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. [Murray, Michael F.] Brigham & Womens Hosp, Genet Div, Boston, MA 02115 USA. [O'Donnell, Peter H.] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Rader, Daniel J.] Univ Penn, Dept Med, Div Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Relling, Mary V.] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Valle, David] Johns Hopkins Univ, Sch Med, Inst Genet Med, Baltimore, MD USA. [Weinshilboum, Richard] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN USA. [Ginsburg, Geoffrey S.] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA. [Ginsburg, Geoffrey S.] Duke Univ, Ctr Personalized Med, Durham, NC USA. RP Manolio, TA (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM manolio@nih.gov OI Williams, Marc/0000-0001-6165-8701; Eng, Charis/0000-0002-3693-5145 FU NHGRI NIH HHS [U01 HG006380]; NHLBI NIH HHS [R01 HL109481] NR 54 TC 144 Z9 147 U1 1 U2 76 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD APR PY 2013 VL 15 IS 4 BP 258 EP 267 DI 10.1038/gim.2012.157 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 118OR UT WOS:000317035400002 PM 23306799 ER PT J AU Kullo, IJ Jarvik, GP Manolio, TA Williams, MS Roden, DM AF Kullo, Iftikhar J. Jarvik, Gail P. Manolio, Teri A. Williams, Marc S. Roden, Dan M. TI Leveraging the electronic health record to implement genomic medicine SO GENETICS IN MEDICINE LA English DT Editorial Material C1 [Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Jarvik, Gail P.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Jarvik, Gail P.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Manolio, Teri A.] NHGRI, Bethesda, MD 20892 USA. [Williams, Marc S.] Geisinger Med Ctr, Danville, PA 17822 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. RP Kullo, IJ (reprint author), Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. EM kullo.iftikhar@mayo.edu RI Jarvik, Gail/N-6476-2014; OI Jarvik, Gail/0000-0002-6710-8708; Williams, Marc/0000-0001-6165-8701 FU NHGRI NIH HHS [U01 HG006375, U01 HG006379, U01 HG006378] NR 4 TC 14 Z9 14 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD APR PY 2013 VL 15 IS 4 BP 270 EP 271 DI 10.1038/gim.2012.131 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 118OR UT WOS:000317035400004 PM 23018749 ER PT J AU Varshney, GK Lu, J Gildea, DE Huang, HG Pei, WH Yang, ZA Huang, SC Schoenfeld, D Pho, NH Casero, D Hirase, T Mosbrook-Davis, D Zhang, SY Jao, LE Zhang, B Woods, IG Zimmerman, S Schier, AF Wolfsberg, TG Pellegrini, M Burgess, SM Lin, S AF Varshney, Gaurav K. Lu, Jing Gildea, Derek E. Huang, Haigen Pei, Wuhong Yang, Zhongan Huang, Sunny C. Schoenfeld, David Pho, Nam H. Casero, David Hirase, Takashi Mosbrook-Davis, Deborah Zhang, Suiyuan Jao, Li-En Zhang, Bo Woods, Ian G. Zimmerman, Steven Schier, Alexander F. Wolfsberg, Tyra G. Pellegrini, Matteo Burgess, Shawn M. Lin, Shuo TI A large-scale zebrafish gene knockout resource for the genome-wide study of gene function SO GENOME RESEARCH LA English DT Article ID INSERTIONAL MUTAGENESIS; POSITIONAL CLONING; INTEGRATION; RETROVIRUS; REGIONS; EFFICIENCY; MUTATIONS; TARGETS AB With the completion of the zebrafish genome sequencing project, it becomes possible to analyze the function of zebrafish genes in a systematic way. The first step in such an analysis is to inactivate each protein-coding gene by targeted or random mutation. Here we describe a streamlined pipeline using proviral insertions coupled with high-throughput sequencing and mapping technologies to widely mutagenize genes in the zebrafish genome. We also report the first 6144 mutagenized and archived Firs predicted to carry up to 3776 mutations in annotated genes. Using in vitro fertilization, we have rescued and characterized similar to 0.5% of the predicted mutations, showing mutation efficacy and a variety of phenotypes relevant to both developmental processes and human genetic diseases. Mutagenized fish lines are being made freely available to the public through the Zebrafish International Resource Center. These fish lines establish an important milestone for zebrafish genetics research and should greatly facilitate systematic functional studies of the vertebrate genome. C1 [Varshney, Gaurav K.; Pei, Wuhong; Huang, Sunny C.; Pho, Nam H.; Mosbrook-Davis, Deborah; Burgess, Shawn M.] NHGRI, Dev Genom Sect, NIH, Bethesda, MD 20892 USA. [Lu, Jing; Lin, Shuo] Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Sch Chem Biol & Biotechnol, Shenzhen 100083, Peoples R China. [Lu, Jing; Huang, Haigen; Yang, Zhongan; Schoenfeld, David; Casero, David; Hirase, Takashi; Pellegrini, Matteo; Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Gildea, Derek E.; Zhang, Suiyuan; Wolfsberg, Tyra G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Jao, Li-En] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37235 USA. [Zhang, Bo] Peking Univ, Key Lab Cell Proliferat & Differentiat, Minist Educ, Ctr Dev Biol & Genet,Coll Life Sci, Beijing 100083, Peoples R China. [Woods, Ian G.; Zimmerman, Steven; Schier, Alexander F.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Burgess, SM (reprint author), NHGRI, Dev Genom Sect, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov; shuolin@ucla.edu RI Casero, David/E-7365-2010; Varshney, Gaurav/L-5261-2014; OI Casero, David/0000-0002-7347-3330; Burgess, Shawn/0000-0003-1147-0596; Varshney, Gaurav K./0000-0002-0429-1904 FU Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health [R01 GM085357, R01 HL109525, R01 DK084349]; NSFC [31110103904] FX We would like to thank Colin Huck for superior animal care, Darryl Leja for illustrations and graphics work, and Robert Blakesley, Alice Young, and the National Intramural Sequencing Center (NISC) for providing sequence data. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (S.M.B. and T.G.W.), R01 GM085357 and R01 HL109525 (A.F.S.), and R01 DK084349 (S.L.) and NSFC 31110103904 (B.Z., S.L.). NR 25 TC 42 Z9 43 U1 3 U2 26 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 APR PY 2013 VL 23 IS 4 BP 727 EP 735 DI 10.1101/gr.151464.112 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 116YY UT WOS:000316920500014 PM 23382537 ER PT J AU Beydoun, H Kancherla, V Stadtmauer, L Beydoun, M AF Beydoun, Hind Kancherla, Vijaya Stadtmauer, Laurel Beydoun, May TI Patterns of use of insulin-sensitizing agents among diabetic, borderline diabetic and non-diabetic women in the National Health and Nutrition Examination Surveys SO GYNECOLOGICAL ENDOCRINOLOGY LA English DT Article DE Diabetes; insulin resistance; metformin; obesity; survey ID POLYCYSTIC-OVARY-SYNDROME; PROSTATE-SPECIFIC ANTIGEN; METFORMIN; TROGLITAZONE; PIOGLITAZONE; PREVENTION; RESISTANCE; DISCOVERY; BIGUANIDE; MELLITUS AB The purpose of this cross-sectional study based on the 2001-2006 National Health and Nutrition Examination Survey is to examine demographic, socioeconomic, lifestyle and reproductive characteristics that may distinguish users and non-users of insulin sensitizing agents among the US diabetic, borderline diabetic and non-diabetic women. Use of insulin-sensitizing agents was evaluated among 19 579 (3882 diabetic, 387 borderline diabetic and 15 310 non-diabetic) women. Overall, 2% of women in the study sample were users of insulin-sensitizers, including metformin, rosiglitazone and pioglitazone. Multivariate logistic regression models were constructed for predictors of insulin-sensitizer use according to diabetic status. In the overall sample, being younger or diabetic were the only factors associated with an increased odds of using insulin-sensitizing agents, after adjustment of confounders. Among diabetics, use of insulin-sensitizing agents was inversely related to age, but not other factors in the multivariable model. Among borderline and non-diabetics, body mass index (BMI) was the only predictor that remained significantly associated with the use of insulin-sensitizing agents after controlling for confounders. In conclusion, the main predictors of insulin-sensitizer use are young age and diabetic status in all women, young age in diabetic women and high BMI in borderline and non-diabetic women. C1 [Beydoun, Hind] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Kancherla, Vijaya] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Stadtmauer, Laurel] Eastern Virginia Med Sch, Jones Inst Reprod Med, Norfolk, VA 23501 USA. [Beydoun, May] NIA, NIH, IRP, Baltimore, MD 21224 USA. RP Beydoun, H (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, POB 1980, Norfolk, VA 23501 USA. EM baydouha@evms.edu FU Intramural Research Program of the National Institute on Aging; Centers for Disease Control and Prevention FX This research was partly supported by the Intramural Research Program of the National Institute on Aging and the Centers for Disease Control and Prevention. NR 25 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0951-3590 J9 GYNECOL ENDOCRINOL JI Gynecol. Endocrinol. PD APR PY 2013 VL 29 IS 4 BP 350 EP 356 DI 10.3109/09513590.2012.752457 PG 7 WC Endocrinology & Metabolism; Obstetrics & Gynecology SC Endocrinology & Metabolism; Obstetrics & Gynecology GA 117AV UT WOS:000316925400018 PM 23323803 ER PT J AU Gonzaludo, N Zheng, HX Wang, JC Chanock, SJ Jin, L Scherer, S Wijmenga, C Kwok, PY Brookes, AJ AF Gonzaludo, Nina Zheng, Hong-Xiang Wang, Jiucun Chanock, Stephen J. Jin, Li Scherer, Stephen Wijmenga, Cisca Kwok, Pui-Yan Brookes, Anthony J. TI HGV2012: Leveraging Next-Generation Technology and Large Datasets to Advance Disease Research SO HUMAN MUTATION LA English DT Editorial Material DE variation; SNP; GWAS; next-generation sequencing; NGS; inherited disease AB The 13th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2012: Shanghai, China, 6th8th September 2012) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included advancements in next-generation sequencing (NGS) technology, investigation of common and rare diseases, employing NGS in the clinic, utilizing large datasets that leverage biobanks and population-specific cohorts, and exploration of genomic features. C1 [Gonzaludo, Nina; Kwok, Pui-Yan] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA. [Gonzaludo, Nina; Brookes, Anthony J.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA. [Zheng, Hong-Xiang; Wang, Jiucun; Jin, Li] Fudan Univ, Minist Educ, Key Lab Contemporary Anthropol, Sch Life Sci, Shanghai 200433, Peoples R China. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Scherer, Stephen] Hosp Sick Children, McLaughlin Ctr, Toronto, ON M5G 1X8, Canada. [Scherer, Stephen] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Brookes, Anthony J.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. RP Gonzaludo, N (reprint author), Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, Cardiovasc Res Inst, 555 Mission Bay Blvd South,MC 3118,Room 282, San Francisco, CA 94158 USA. EM Nina.Gonzaludo@ucsf.edu RI Scherer, Stephen /B-3785-2013; Wijmenga, Cisca/D-2173-2009; Kwok, Pui-Yan/F-7725-2014; Jin, Li/C-1468-2009; OI Scherer, Stephen /0000-0002-8326-1999; Kwok, Pui-Yan/0000-0002-5087-3059; Jin, Li/0000-0002-4546-2415; Wijmenga, Cisca/0000-0002-5635-1614 FU NIH [T32 GM007175]; Fudan University; National Natural Science Foundation of China [C060501]; National Genome Research Institute [R13 HG003953]; EU Project GEN2PHEN; University of Leicester; McLaughlin Centre at the University of Toronto; Affymetrix; Illumina; Macrogen; Agilent Technologies; BGI Tech Solutions; Wuxi Genome Center (WuXi AppTec); Genesky Biotechnologies; Complete Genomics; Life Technologies; eBiotrade FX Contract grant sponsors: NIH Training Grant (T32 GM007175); Fudan University; the National Natural Science Foundation of China (C060501); National Genome Research Institute (R13 HG003953); EU Project GEN2PHEN; University of Leicester; McLaughlin Centre at the University of Toronto; Affymetrix; Illumina; Macrogen; Agilent Technologies; BGI Tech Solutions; Wuxi Genome Center (WuXi AppTec); Genesky Biotechnologies; Complete Genomics; Life Technologies; eBiotrade. NR 2 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD APR PY 2013 VL 34 IS 4 BP 657 EP 660 DI 10.1002/humu.22270 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 112XS UT WOS:000316629000018 PM 23315969 ER PT J AU Oetting, WS Robinson, PN Greenblatt, MS Cotton, RG Beck, T Carey, JC Doelken, SC Girdea, M Groza, T Hamilton, CM Hamosh, A Kerner, B MacArthur, JAL Maglott, DR Mons, B Rehm, HL Schofield, PN Searle, BA Smedley, D Smith, CL Bernstein, IT Zankl, A Zhao, EY AF Oetting, William S. Robinson, Peter N. Greenblatt, Marc S. Cotton, Richard G. Beck, Tim Carey, John C. Doelken, Sandra C. Girdea, Marta Groza, Tudor Hamilton, Carol M. Hamosh, Ada Kerner, Berit MacArthur, Jacqueline A. L. Maglott, Donna R. Mons, Barend Rehm, Heidi L. Schofield, Paul N. Searle, Beverly A. Smedley, Damian Smith, Cynthia L. Bernstein, Inge Thomsen Zankl, Andreas Zhao, Eric Y. TI Getting Ready for the Human Phenome Project: The 2012 Forum of the Human Variome Project SO HUMAN MUTATION LA English DT Editorial Material DE meeting report; databases; phenotype; database interoperability ID INFORMATION; ONTOLOGY; CARE AB A forum of the Human Variome Project (HVP) was held as a satellite to the 2012 Annual Meeting of the American Society of Human Genetics in San Francisco, California. The theme of this meeting was Getting Ready for the Human Phenome Project. Understanding the genetic contribution to both rare single-gene Mendelian disorders and more complex common diseases will require integration of research efforts among many fields and better defined phenotypes. The HVP is dedicated to bringing together researchers and research populations throughout the world to provide the resources to investigate the impact of genetic variation on disease. To this end, there needs to be a greater sharing of phenotype and genotype data. For this to occur, many databases that currently exist will need to become interoperable to allow for the combining of cohorts with similar phenotypes to increase statistical power for studies attempting to identify novel disease genes or causative genetic variants. Improved systems and tools that enhance the collection of phenotype data from clinicians are urgently needed. This meeting begins the HVP's effort toward this important goal. C1 [Oetting, William S.] Univ Minnesota, Dept Expt & Clin Pharmacol, Coll Pharm, Minneapolis, MN 55455 USA. [Robinson, Peter N.; Doelken, Sandra C.] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany. [Greenblatt, Marc S.] Univ Vermont, Dept Med, Burlington, VT USA. [Greenblatt, Marc S.] Univ Vermont, Vermont Canc Ctr, Burlington, VT USA. [Cotton, Richard G.] Univ Melbourne, Human Variome Project Coordinating Off, Melbourne, Vic, Australia. [Beck, Tim] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Carey, John C.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA. [Girdea, Marta] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Groza, Tudor] Univ Queensland, Sch Informat Technol & Elect Engn, St Lucia, Qld, Australia. [Hamilton, Carol M.] RTI Int, Res Comp Div, Durham, NC USA. [Hamosh, Ada] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Kerner, Berit] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [MacArthur, Jacqueline A. L.] European Bioinformat Inst EMBL EBI, Cambridge, England. [Maglott, Donna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Mons, Barend] Leiden Univ, Med Ctr, Netherlands Bioinformat Ctr, NL-2300 RA Leiden, Netherlands. [Rehm, Heidi L.] Partners Healthcare Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA USA. [Rehm, Heidi L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Schofield, Paul N.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England. [Searle, Beverly A.] Unique, Caterham, Surrey, England. [Smith, Cynthia L.] Jackson Lab, Bar Harbor, ME 04609 USA. [Bernstein, Inge Thomsen] Copenhagen Univ Hosp, Dept Gastroenterol, HNPCC Register, Hvidovre, Denmark. [Bernstein, Inge Thomsen] Copenhagen Univ Hosp, Clin Res Ctr, Hvidovre, Denmark. [Zankl, Andreas] Univ Queensland, Clin Res Ctr, Brisbane, Qld, Australia. [Zhao, Eric Y.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. RP Oetting, WS (reprint author), Univ Minnesota, MMC 485,420 Delaware St SE, Minneapolis, MN 55455 USA. EM oetti001@umn.edu RI Smith, Cynthia/A-5646-2009; OI Smith, Cynthia/0000-0003-3691-0324; Mons, Barend/0000-0003-3934-0072; Zankl, Andreas/0000-0001-8612-1062; Robinson, Peter/0000-0002-0736-9199; Zhao, Eric/0000-0003-1277-6335 FU NHGRI NIH HHS [U41 HG000330]; NIMH NIH HHS [R01 MH085744, K08 MH074057] NR 8 TC 9 Z9 9 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 EI 1098-1004 J9 HUM MUTAT JI Hum. Mutat. PD APR PY 2013 VL 34 IS 4 BP 661 EP 666 DI 10.1002/humu.22293 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 112XS UT WOS:000316629000019 PM 23401191 ER PT J AU Delahanty, RJ Beeghly-Fadiel, A Long, JR Gao, YT Lu, W Xiang, YB Zheng, Y Ji, BT Wen, WQ Cai, QY Zheng, W Shu, XO AF Delahanty, R. J. Beeghly-Fadiel, A. Long, J. R. Gao, Y. T. Lu, W. Xiang, Y. B. Zheng, Y. Ji, B. T. Wen, W. Q. Cai, Q. Y. Zheng, W. Shu, X. O. TI Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women SO HUMAN REPRODUCTION LA English DT Article DE menarche; genome-wide association study; genetics; reproductive endocrinology ID GENOME-WIDE ASSOCIATION; ENDOMETRIAL CANCER; SUSCEPTIBILITY LOCUS; ADOLESCENT GIRLS; SECULAR TRENDS; BREAST-CANCER; RISK; OBESITY; METAANALYSIS; DEPRESSION AB Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P 3.71 10(6), binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche 5 months later than those in the lowest quintile. Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare. C1 [Delahanty, R. J.; Beeghly-Fadiel, A.; Long, J. R.; Wen, W. Q.; Cai, Q. Y.; Zheng, W.; Shu, X. O.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Gao, Y. T.; Xiang, Y. B.] Shanghai Canc Inst, Dept Epidemiol, Shanghai 200032, Peoples R China. [Lu, W.; Zheng, Y.] Shanghai Municipal Ctr Dis Prevent & Control, Shanghai Inst Prevent Med, Shanghai 200336, Peoples R China. [Ji, B. T.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, 2525 West End Ave,Suite 600 IMPH, Nashville, TN 37203 USA. EM xiao-ou.shu@vanderbilt.edu FU US National Institutes of Health [R01CA124558, R01CA090899, R01CA070867, R01CA064277, R01CA092585, UL1 RR024975]; ngram professorship funds; Allen Foundation funds FX This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. NR 34 TC 5 Z9 6 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD APR PY 2013 VL 28 IS 4 BP 1135 EP 1143 DI 10.1093/humrep/det011 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 113VZ UT WOS:000316698800034 PM 23406970 ER PT J AU Ryan, JF Pang, K Schnitzler, CE Koch, BJ Nguyen, AD Moreland, RT Mullikin, JC Wolfsberg, TG Martindale, MQ Baxevanis, AD AF Ryan, J. F. Pang, K. Schnitzler, C. E. Koch, B. J. Nguyen, A-D Moreland, R. T. Mullikin, J. C. Wolfsberg, T. G. Martindale, M. Q. Baxevanis, A. D. TI The Genome of the Ctenophore, Mnemiopsis leidyi: Insights into the Genetics of Innovation and the Evolution of Multicellularity SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology (SICB) CY JAN 03-07, 2013 CL San Francisco, CA SP Soc Integrat & Comparat Biol (SICB) C1 NHGRI, NIH, Bethesda, MD USA. Univ Hawaii, Sars Intl Ctr Marine Mol Biol, Kewalo Marine Lab, Honolulu, HI 96822 USA. EM andy@mail.nih.gov RI Schnitzler, Christine/G-8733-2013 NR 0 TC 0 Z9 0 U1 1 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD APR PY 2013 VL 53 SU 1 BP E187 EP E187 PG 1 WC Zoology SC Zoology GA 117ZG UT WOS:000316991401281 ER PT J AU Schnitzler, CE Pang, K Powers, ML Reitzel, AM Ryan, JF Simmons, D Tada, T Yokoyama, S Haddock, SHD Martindale, MQ Baxevanis, AD AF Schnitzler, C. E. Pang, K. Powers, M. L. Reitzel, A. M. Ryan, J. F. Simmons, D. Tada, T. Yokoyama, S. Haddock, S. H. D. Martindale, M. Q. Baxevanis, A. D. TI Ctenophore photocytes express a light-sensing opsin as well as bioluminescent photoproteins during development SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology (SICB) CY JAN 03-07, 2013 CL San Francisco, CA SP Soc Integrat & Comparat Biol (SICB) C1 NHGRI, NIH, Bethesda, MD USA. Woods Hole Oceanog Inst, Woods Hole, MA USA. Univ Hawaii, Kewalo Marine Lab, Honolulu, HI 96822 USA. Emory Univ, Atlanta, GA 30322 USA. EM christine.schnitzler@nih.gov RI Schnitzler, Christine/G-8733-2013 NR 0 TC 0 Z9 0 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD APR PY 2013 VL 53 SU 1 BP E190 EP E190 PG 1 WC Zoology SC Zoology GA 117ZG UT WOS:000316991401296 ER PT J AU Cizza, G Rother, KI AF Cizza, Giovanni Rother, Kristina I. TI An Ounce of Prevention: Securing Bone Health in Adolescence SO JOURNAL OF ADOLESCENT HEALTH LA English DT Editorial Material ID FRACTURE; DENSITY; MASS C1 [Cizza, Giovanni] NIDDKD, Sect Neuroendocrinol Obes, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Rother, Kristina I.] NIDDKD, Sect Pediat Diabet & Metab, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDKD, Sect Neuroendocrinol Obes, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA DK047049-07, ZIA DK047049-06, ZIA DK047049-04] NR 14 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD APR PY 2013 VL 52 IS 4 BP 379 EP 381 DI 10.1016/j.jadohealth.2013.01.016 PG 3 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 114HE UT WOS:000316730900001 PM 23521896 ER PT J AU Uhrigshardt, H Rouault, TA Missirlis, F AF Uhrigshardt, Helge Rouault, Tracey A. Missirlis, Fanis TI Insertion mutants in Drosophila melanogaster Hsc20 halt larval growth and lead to reduced iron-sulfur cluster enzyme activities and impaired iron homeostasis SO JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY LA English DT Article DE Mitochondria; Iron-sulfur clusters; DnaJ protein; Iron regulatory protein; Iron regulatory element ID FRIEDREICHS-ATAXIA; DROSOPHILA-MELANOGASTER; CIRCADIAN CLOCK; SACCHAROMYCES-CEREVISIAE; SUPEROXIDE-DISMUTASE; DNA METABOLISM; HUMAN-DISEASE; BIOGENESIS; PROTEINS; FRATAXIN AB Despite the prominence of iron-sulfur cluster (ISC) proteins in bioenergetics, intermediary metabolism, and redox regulation of cellular, mitochondrial, and nuclear processes, these proteins have been given scarce attention in Drosophila. Moreover, biosynthesis and delivery of ISCs to target proteins requires a highly regulated molecular network that spans different cellular compartments. The only Drosophila ISC biosynthetic protein studied to date is frataxin, in attempts to model Friedreich's ataxia, a disease arising from reduced expression of the human frataxin homologue. One of several proteins involved in ISC biogenesis is heat shock protein cognate 20 (Hsc20). Here we characterize two piggyBac insertion mutants in Drosophila Hsc20 that display larval growth arrest and deficiencies in aconitase and succinate dehydrogenase activities, but not in isocitrate dehydrogenase activity; phenotypes also observed with ubiquitous frataxin RNA interference. Furthermore, a disruption of iron homeostasis in the mutant flies was evidenced by an apparent reduction in induction of intestinal ferritin with ferric iron accumulating in a subcellular pattern reminiscent of mitochondria. These phenotypes were specific to intestinal cell types that regulate ferritin expression, but were notably absent in the iron cells where ferritin is constitutively expressed and apparently translated independently of iron regulatory protein 1A. Hsc20 mutant flies represent an independent tool to disrupt ISC biogenesis in vivo without using the RNA interference machinery. C1 [Uhrigshardt, Helge; Rouault, Tracey A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Mol Med, NIH, Bethesda, MD 20892 USA. [Missirlis, Fanis] Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Mexico City 07360, DF, Mexico. RP Missirlis, F (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Mexico City 07360, DF, Mexico. EM fanis@fisio.cinvestav.mx RI Missirlis, Fanis/C-1137-2011 OI Missirlis, Fanis/0000-0003-0467-8444 FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in the USA; CONACYT in Mexico [179835] FX The authors acknowledge the invaluable support of Mary Lilly, who provided her laboratory fly facility that allowed this project to be conducted. This work was supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in the USA and CONACYT project 179835 in Mexico. NR 67 TC 13 Z9 13 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-8257 J9 J BIOL INORG CHEM JI J. Biol. Inorg. Chem. PD APR PY 2013 VL 18 IS 4 BP 441 EP 449 DI 10.1007/s00775-013-0988-2 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 115NP UT WOS:000316819300004 PM 23444034 ER PT J AU Qin, M Schmidt, KC Zametkin, AJ Bishu, S Horowitz, LM Burlin, TV Xia, ZY Huang, TJ Quezado, ZM Smith, CB AF Qin, Mei Schmidt, Kathleen C. Zametkin, Alan J. Bishu, Shrinivas Horowitz, Lisa M. Burlin, Thomas V. Xia, Zengyan Huang, Tianjiang Quezado, Zenaide M. Smith, Carolyn Beebe TI Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE brain; Fmr1 knockout mouse; leucine; positron emission tomography; propofol anesthesia; protein synthesis ID MENTAL-RETARDATION PROTEIN; TISSUE AMINO-ACIDS; REGIONAL RATES; MOUSE MODEL; PROPOFOL ANESTHESIA; RHESUS-MONKEYS; NITROUS-OXIDE; MESSENGER-RNA; IN-VIVO; PET AB Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model (Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-C-11] leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 499-507; doi:10.1038/jcbfm.2012.205; published online 9 January 2013 C1 [Qin, Mei; Schmidt, Kathleen C.; Zametkin, Alan J.; Bishu, Shrinivas; Burlin, Thomas V.; Xia, Zengyan; Huang, Tianjiang; Smith, Carolyn Beebe] NIMH, Sect Neuroadaptat & Prot Metab, NIH, Bethesda, MD 20892 USA. [Horowitz, Lisa M.] NIMH, Off Clin Director, NIH, Bethesda, MD 20892 USA. [Quezado, Zenaide M.] NIH, Dept Perioperat Med, Ctr Clin, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Rm 2D56,10 Ctr Dr, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU Intramural Research Program, National Institute of Mental Health; Clinical Center, National Institutes of Health; Fragile X Research Foundation FX This research was supported by the Intramural Research Program, National Institute of Mental Health; Clinical Center, National Institutes of Health; the Fragile X Research Foundation. NR 39 TC 9 Z9 9 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD APR PY 2013 VL 33 IS 4 BP 499 EP 507 DI 10.1038/jcbfm.2012.205 PG 9 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 117CR UT WOS:000316930200005 PM 23299245 ER PT J AU Onnis, B Fer, N Rapisarda, A Perez, VS Melillo, G AF Onnis, Barbara Fer, Nicole Rapisarda, Annamaria Perez, Victor S. Melillo, Giovanni TI Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID INTERLEUKIN-11 RECEPTOR-ALPHA; INDUCIBLE FACTOR 1-ALPHA; HUMAN COLORECTAL ADENOCARCINOMA; PROSTATE-CANCER; CARCINOMA CELLS; BREAST-CANCER; HEMATOPOIETIC CYTOKINE; STAT3 ACTIVATION; BONE METASTASIS; GROWTH-FACTOR AB IL-11 and its receptor, IL-11R alpha, are expressed in human cancers; however, the functional role of IL-11 in tumor progression is not known. We found that IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells and that expression of IL11 mRNA was dependent, at least in part, on HIF-1. A cooperative interaction between HIF-1 and AP-1 mediated transcriptional activation of the IL11 promoter. Additionally, we found that human cancer cells expressed a functional IL-11R alpha subunit, which triggered signal transduction either by exogenous recombinant human IL-11 or by autocrine production of IL-11 in cells cultured under hypoxic conditions. Silencing of IL11 dramatically abrogated the ability of hypoxia to increase anchorage-independent growth and significantly reduced tumor growth in xenograft models. Notably, these results were phenocopied by partial knockdown of STAT1 in a human prostate cancer cell line (PC3), suggesting that this pathway may play an important role in mediating the effects of IL-11 under hypoxic conditions. In conclusion, these results identify IL11 as an oxygen- and VHL-regulated gene and provide evidence of a pathway "hijacked" by hypoxic cancer cells that may contribute to tumor progression. C1 [Onnis, Barbara; Perez, Victor S.] Frederick Natl Lab Canc Res, Dev Therapeut Program, Frederick, MD USA. [Fer, Nicole; Rapisarda, Annamaria; Melillo, Giovanni] Frederick Natl Lab Canc Res, SAIC Frederick Inc, Frederick, MD USA. RP Melillo, G (reprint author), Bristol Myers Squibb Co, Discovery Med Oncol, Route 206 & Prov Line Rd, Princeton, NJ 08540 USA. EM rapisardaa@mail.nih.gov; giovanni.melillo@bms.com FU National Cancer Institute (NIH) [HHSN261200800001E]; Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX The authors thank Miriam Anver for analysis of immunohistochemistry slides, Beverly Teicher for critical review, and Badarch Uranchimeg for technical support. This project was funded by federal funds from the National Cancer Institute (NIH contract HHSN261200800001E) and by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 65 TC 26 Z9 27 U1 1 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2013 VL 123 IS 4 BP 1615 EP 1629 DI 10.1172/JCI59623 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 118JM UT WOS:000317021800023 PM 23549086 ER PT J AU Chen, KD Liu, MY Liu, Y Yoshimura, T Shen, W Le, YY Durum, S Gong, WH Wang, CY Gao, JL Murphy, PM Wang, JM AF Chen, Kediang Liu, Mingyong Liu, Ying Yoshimura, Teizo Shen, Wei Le, Yingying Durum, Scott Gong, Wanghua Wang, Chunyan Gao, Ji-Liang Murphy, Philip M. Wang, Ji Ming TI Formylpeptide receptor-2 contributes to colonic epithelial homeostasis, inflammation, and tumorigenesis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FORMYL-PEPTIDE RECEPTORS; METHIONYL-LEUCYL-PHENYLALANINE; TOLL-LIKE RECEPTOR-4; BOWEL-DISEASE; ULCERATIVE-COLITIS; CHEMOTACTIC PEPTIDES; INTESTINAL INFLAMMATION; CHEMOKINE EXPRESSION; CELLS; MICE AB Commensal bacteria and their products provide beneficial effects to the mammalian gut by stimulating epithelial cell turnover and enhancing wound healing, without activating overt inflammation. We hypothesized that N-formylpeptide receptors, which bind bacterial N-formylpeptides and are expressed by intestinal epithelial cells, may contribute to these processes. Here we report that formylpeptide receptor-2 (FPR2), which we show is expressed on the apical and lateral membranes of colonic crypt epithelial cells, mediates N-formylpeptide-dependent epithelial cell proliferation and renewal. Colonic epithelial cells in FPR2-deficient mice displayed defects in commensal bacterium-dependent homeostasis as shown by the absence of responses to N-formylpeptide stimulation, shortened colonic crypts, reduced acute inflammatory responses to dextran sulfate sodium (DSS) challenge, delayed mucosal restoration after injury, and increased azoxymethane-induced tumorigenesis. These results indicate that FPR2 is critical in mediating homeostasis, inflammation, and epithelial repair processes in the colon. C1 [Chen, Kediang; Liu, Mingyong; Liu, Ying; Yoshimura, Teizo; Shen, Wei; Durum, Scott; Wang, Chunyan; Wang, Ji Ming] Ctr Canc Res, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Liu, Mingyong] Third Mil Med Univ, Dept Spine Surg, Daping Hosp, Chongqing, Peoples R China. [Liu, Ying] Tsinghua Univ, Dept Basic Med Sci, Sch Med, Beijing 100084, Peoples R China. [Le, Yingying] Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai, Peoples R China. [Gong, Wanghua] SAIC Frederick, Frederick, MD USA. [Gao, Ji-Liang; Murphy, Philip M.] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Wang, JM (reprint author), Ctr Canc Res, Lab Mol Immunoregulat, Canc & Inflammat Program, Frederick Natl Lab Canc Res, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM wangji@mail.nih.gov FU National Cancer Institute (NCI), NIH [HHSN261200800001E] FX The authors thank J.J. Oppenheim and A. Mantovani for critically reviewing the manuscript, and C. Lamb and S. Sheriff for secretarial assistance. This project was funded in part with federal funds from the National Cancer Institute (NCI), NIH, under contract no. HHSN261200800001E. The research was also supported in part by the Intramural Research Program of the NCI, NIH. NR 55 TC 25 Z9 27 U1 1 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2013 VL 123 IS 4 BP 1694 EP 1704 DI 10.1172/JCI65569 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 118JM UT WOS:000317021800029 PM 23454745 ER PT J AU Jain, S de Azua, IR Lu, HY White, MF Guettier, JM Wess, J AF Jain, Shalini de Azua, Inigo Ruiz Lu, Huiyan White, Morris F. Guettier, Jean-Marc Wess, Juergen TI Chronic activation of a designer G(q)-coupled receptor improves beta cell function SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TRANSCRIPTION FACTORS; INSULIN-RESISTANCE; SIGNALING PATHWAYS; IN-VIVO; MECHANISMS; IRS2; SUBSTRATE-2; REGULATOR; MICE AB Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic beta cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of beta cell G(q) signaling greatly improve beta cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for beta cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel beta cell pathway through which receptor-activated G(q) leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve beta cell function. Importantly, we found that chronic stimulation of a designer G(q)-coupled receptor selectively expressed in beta cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since beta cells are endowed with numerous receptors that mediate their cellular effects via activation of G(q)-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors. C1 [Jain, Shalini; de Azua, Inigo Ruiz; Guettier, Jean-Marc; Wess, Juergen] NIDDKD, Lab Bioorgan Chem, Mol Signaling Sect, Bethesda, MD 20892 USA. [Lu, Huiyan] NIDDKD, Mouse Transgen Core Facil, Bethesda, MD 20892 USA. [White, Morris F.] Harvard Univ, Sch Med, Howard Hughes Med Inst,Karp Family Res Labs, Div Endocrinol,Childrens Hosp Boston, Boston, MA 02115 USA. RP Wess, J (reprint author), NIDDKD, Lab Bioorgan Chem, Mol Signaling Sect, Bldg 8A,Room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH FX This research was funded by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH. We thank Sushil G. Rane, So-Yoon Kim, Hariom Yadav, Oksana Gavrilova, Yinghong Cui, and Yoskaly Lazo Fernandez (all from NIDDK) for advice and experimental support. NR 41 TC 37 Z9 37 U1 0 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD APR PY 2013 VL 123 IS 4 BP 1750 EP 1762 DI 10.1172/JCI66432 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 118JM UT WOS:000317021800034 PM 23478411 ER PT J AU Berg, AK Mandrekar, SJ Ziegler, KLA Carlson, EC Szabo, E Ames, MM Boring, D Limburg, PJ Reid, JM AF Berg, Alexander K. Mandrekar, Sumithra J. Ziegler, Katie L. Allen Carlson, Elsa C. Szabo, Eva Ames, Mathew M. Boring, Daniel Limburg, Paul J. Reid, Joel M. CA Canc Prevention Network TI Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE chemoprevention; exisulind; NONMEM; population pharmacokinetics; sulindac ID ENTEROHEPATIC RECIRCULATION; DRUG; ABSORPTION; EXISULIND; ENZYMES; NONMEM AB Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent. C1 [Berg, Alexander K.; Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Carlson, Elsa C.; Ames, Mathew M.; Limburg, Paul J.; Reid, Joel M.] Mayo Clin, Rochester, MN 55905 USA. [Szabo, Eva; Boring, Daniel] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Reid, JM (reprint author), Mayo Clin, Gonda 19-365,200 1st St SW, Rochester, MN 55905 USA. EM reid.joel@mayo.edu FU NIH [T32 GM08685, N01-CN-35000, M01-RR00585, P30CA015083] FX This work was supported by a NIH Training Grant in Clinical Pharmacology (T32 GM08685), NIH contract N01-CN-35000 as well as NIH grants M01-RR00585 and P30CA015083. A. K. B. would like to acknowledge Dr. Richard Brundage and colleagues at the University of Minnesota for discussions regarding model development and validation. At the time of model development, A. K. B. was a research fellow at Mayo Clinic, and is currently employed as a clinical research scientist by Upsher-Smith Laboratories, Inc. NR 37 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4604 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD APR PY 2013 VL 53 IS 4 BP 403 EP 412 DI 10.1002/jcph.26 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 116WZ UT WOS:000316915300006 PM 23436338 ER PT J AU Peterson, JC Czajkowski, S Charlson, ME Link, AR Wells, MT Isen, AM Mancuso, CA Allegrante, JP Boutin-Foster, C Ogedegbe, G Jobe, JB AF Peterson, Janey C. Czajkowski, Susan Charlson, Mary E. Link, Alissa R. Wells, Martin T. Isen, Alice M. Mancuso, Carol A. Allegrante, John P. Boutin-Foster, Carla Ogedegbe, Gbenga Jobe, Jared B. TI Translating Basic Behavioral and Social Science Research to Clinical Application: The EVOLVE Mixed Methods Approach SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE behavioral intervention; behavioral risk reduction; health behavior; mixed methods; translational research ID RANDOMIZED CONTROLLED-TRIAL; POSITIVE-AFFECT; PHYSICAL-ACTIVITY; AFRICAN-AMERICANS; SELF-AFFIRMATION; MEDICATION ADHERENCE; HEALTH-PROMOTION; UNITED-STATES; SHORT-FORM; ASTHMA AB Objective: To describe a mixed-methods approach to develop and test a basic behavioral science-informed intervention to motivate behavior change in 3 high-risk clinical populations. Our theoretically derived intervention comprised a combination of positive affect and self-affirmation (PA/SA), which we applied to 3 clinical chronic disease populations. Method: We employed a sequential mixed methods model (EVOLVE) to design and test the PA/SA intervention in order to increase physical activity in people with coronary artery disease (post-percutaneous coronary intervention [PCI]) or asthma (ASM) and to improve medication adherence in African Americans with hypertension (HTN). In an initial qualitative phase, we explored participant values and beliefs. We next pilot tested and refined the intervention and then conducted 3 randomized controlled trials with parallel study design. Participants were randomized to combined PA/SA versus an informational control and were followed bimonthly for 12 months, assessing for health behaviors and interval medical events. Results: Over 4.5 years, we enrolled 1,056 participants. Changes were sequentially made to the intervention during the qualitative and pilot phases. The 3 randomized controlled trials enrolled 242 participants who had undergone PCI, 258 with ASM, and 256 with HTN (n = 756). Overall, 45.1% of PA/SA participants versus 33.6% of informational control participants achieved successful behavior change (p = .001). In multivariate analysis, PA/SA intervention remained a significant predictor of achieving behavior change (p < .002, odds ratio = 1.66), 95% CI [1.22, 2.27], controlling for baseline negative affect, comorbidity, gender, race/ethnicity, medical events, smoking, and age. Conclusions: The EVOLVE method is a means by which basic behavioral science research can be translated into efficacious interventions for chronic disease populations. C1 [Peterson, Janey C.; Charlson, Mary E.; Link, Alissa R.; Boutin-Foster, Carla] Weill Cornell Med Coll, Div Clin Epidemiol & Evaluat Sci Res, Dept Med, New York, NY 10065 USA. [Peterson, Janey C.; Charlson, Mary E.; Link, Alissa R.; Boutin-Foster, Carla] Weill Cornell Med Coll, Ctr Integrat Med, New York, NY 10065 USA. [Czajkowski, Susan; Jobe, Jared B.] NHLBI, Behav Med Sci Res Grp, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Wells, Martin T.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [Wells, Martin T.] Cornell Univ, Dept Stat Sci, Ithaca, NY 14853 USA. [Isen, Alice M.] Cornell Univ, Div Mkt, Johnson Grad Sch Management, Ithaca, NY 14853 USA. [Mancuso, Carol A.] Hosp Special Surg, Dept Med, New York, NY 10021 USA. [Allegrante, John P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Hlth & Behav Studies, Teachers Coll, New York, NY 10027 USA. [Allegrante, John P.] Columbia Univ, Mailman Sch Publ Hlth, Dept Sociomed Sci, New York, NY 10027 USA. [Ogedegbe, Gbenga] NYU, Sch Med, Dept Med, New York, NY 10003 USA. [Ogedegbe, Gbenga] NYU, Sch Med, Ctr Healthful Behav Change, New York, NY 10003 USA. RP Peterson, JC (reprint author), Weill Cornell Med Coll, Div Clin Epidemiol & Evaluat Sci Res, Dept Med, 1300 York Ave,Box 46, New York, NY 10065 USA. EM jcpeters@med.cornell.edu FU NHLBI NIH HHS [N01 HC025196, 1N01-HC-25096]; NIA NIH HHS [K23 AG042869]; NIMHD NIH HHS [P60 MD003421] NR 71 TC 12 Z9 12 U1 2 U2 22 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD APR PY 2013 VL 81 IS 2 SI SI BP 217 EP 230 DI 10.1037/a0029909 PG 14 WC Psychology, Clinical SC Psychology GA 116UM UT WOS:000316908500004 PM 22963594 ER PT J AU Senay, I Hensley-Alford, S Kaphingst, KA AF Senay, Ibrahim Hensley-Alford, Sharon Kaphingst, Kimberly A. TI Judging risk for multiple diseases: The role of disease worry SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE Disease risk; disease worry; affect heuristic; genetic testing ID RANDOMIZED CONTROLLED-TRIAL; HEALTH BEHAVIOR; PERCEPTION; FEELINGS; SMOKING; MODEL AB Risk perceptions and disease worry of 1,959 healthy adults were measured in a telephone-based survey. In the model for each of eight health conditions, people's perceived risk was related to their worry for that condition (p < .0001) and their worry for the other seven conditions (p < .001). There was also an interaction indicating that the less people were worried about a certain condition, the more their worry about the other seven conditions increased their risk perception for that condition (p < .0001). The results are important for preventing biased risk perceptions in multiple-disease contexts. C1 [Senay, Ibrahim; Kaphingst, Kimberly A.] NIH, Bethesda, MD 20892 USA. [Hensley-Alford, Sharon] Josephine Ford Canc Ctr, Brownstown Twp, MI USA. RP Senay, I (reprint author), Zirve Univ, Kizilhisar Kampusu, TR-27260 Sahinbey, Gaziantep, Turkey. EM ibrahim.senay@zirve.edu.tr FU Intramural NIH HHS [Z01 HG200321-04] NR 23 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD APR PY 2013 VL 18 IS 4 BP 554 EP 560 DI 10.1177/1359105312437263 PG 7 WC Psychology, Clinical SC Psychology GA 114MV UT WOS:000316746400011 PM 22843634 ER PT J AU Martinu, T Kelly, FL Sun, J Zhang, HL Beasley, RF Potts-Kant, EN Flake, GP Morgan, DL Foster, WM Palmer, SM AF Martinu, T. Kelly, F. L. Sun, J. Zhang, H. L. Beasley, R. F. Potts-Kant, E. N. Flake, G. P. Morgan, D. L. Foster, W. M. Palmer, S. M. TI T Cell-Deficiency Exacerbates Diacetyl-Induced Obliterative Bronchiolitis SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 33rd Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation CY APR 24-27, 2013 CL Montreal, CANADA SP Int Soc Heart & Lung Transplantat C1 [Martinu, T.; Kelly, F. L.; Sun, J.; Zhang, H. L.; Beasley, R. F.; Potts-Kant, E. N.; Foster, W. M.; Palmer, S. M.] Duke Univ, Durham, NC USA. [Flake, G. P.; Morgan, D. L.] NIEHS, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2013 VL 32 IS 4 SU S MA 203 BP S81 EP S81 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 114AM UT WOS:000316712100203 ER PT J AU Shah, MR Naftel, DC Miller, MA Baldwin, JT Feller, ED Desai, SS John, R Kormos, RL Holman, WL AF Shah, M. R. Naftel, D. C. Miller, M. A. Baldwin, J. T. Feller, E. D. Desai, S. S. John, R. Kormos, R. L. Holman, W. L. TI Thrombotic Complications Increase after Percutaneous Site/Pocket Infection in Patients with Left Ventricular Assist Devices: An INTERMACS Analysis SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract CT 33rd Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation CY APR 24-27, 2013 CL Montreal, CANADA SP Int Soc Heart & Lung Transplantat C1 [Shah, M. R.; Miller, M. A.; Baldwin, J. T.] NHLBI, Bethesda, MD 20892 USA. [Naftel, D. C.; Holman, W. L.] Univ Alabama Birmingham, Birmingham, AL USA. [Feller, E. D.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [Desai, S. S.] Inova Fairfax Hosp, Falls Church, VA USA. [John, R.] Univ Minnesota, Minneapolis, MN USA. [Kormos, R. L.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NR 0 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD APR PY 2013 VL 32 IS 4 SU S MA 212 BP S84 EP S85 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 114AM UT WOS:000316712100212 ER PT J AU Portugal, S Pierce, SK Crompton, PD AF Portugal, Silvia Pierce, Susan K. Crompton, Peter D. TI Young Lives Lost as B Cells Falter: What We Are Learning About Antibody Responses in Malaria SO JOURNAL OF IMMUNOLOGY LA English DT Review ID FALCIPARUM-INFECTED ERYTHROCYTES; MEROZOITE SURFACE PROTEIN-1; BLOOD-STAGE ANTIGENS; PLASMODIUM-FALCIPARUM; CLINICAL MALARIA; VACCINE DEVELOPMENT; TANZANIAN CHILDREN; ACQUIRED-IMMUNITY; HUMORAL IMMUNITY; VARIANT ANTIGENS AB Plasmodium falciparum malaria remains a major public health threat for which there is no licensed vaccine. Abs play a key role in malaria immunity, but Ab-mediated protection is only acquired after years of repeated infections, leaving children in endemic areas vulnerable to severe malaria and death. Many P. falciparum Ags are extraordinarily diverse and clonally variant, which likely contribute to the inefficient acquisition of protective Abs. However, mounting evidence suggests that there is more to the story and that infection-induced dysregulation of B cell function also plays a role. We herein review progress toward understanding the B cell biology of P. falciparum infection, focusing on what has been learned from population-based studies in malariaendemic areas. We suggest ways in which advances in immunology and genomics-based technology can further improve our understanding of the B cell response in malaria and perhaps illuminate new pathways to the development of effective vaccines. The Journal of Immunology, 2013, 190: 3039-3046. C1 [Portugal, Silvia; Pierce, Susan K.; Crompton, Peter D.] NIAID, Immunogenet Lab, Div Intramural Res, NIH, Rockville, MD 20852 USA. RP Crompton, PD (reprint author), NIAID, 12441 Parklawn Dr,Twinbrook 2, Rockville, MD 20852 USA. EM pcrompton@niaid.nih.gov RI Crompton, Peter/N-1130-2016 FU Intramural NIH HHS [Z99 AI999999, ZIA AI001155-02, ZIA AI001155-01] NR 112 TC 33 Z9 33 U1 0 U2 18 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2013 VL 190 IS 7 BP 3039 EP 3046 DI 10.4049/jimmunol.1203067 PG 8 WC Immunology SC Immunology GA 112RO UT WOS:000316610700004 PM 23526829 ER PT J AU Schreiner, J Kretschmer, D Klenk, J Otto, M Buhring, HJ Stevanovic, S Wang, JM Beer-Hammer, S Peschel, A Autenrieth, SE AF Schreiner, Jens Kretschmer, Dorothee Klenk, Juliane Otto, Michael Buehring, Hans-Joerg Stevanovic, Stefan Wang, Ji Ming Beer-Hammer, Sandra Peschel, Andreas Autenrieth, Stella E. TI Staphylococcus aureus Phenol-Soluble Modulin Peptides Modulate Dendritic Cell Functions and Increase In Vitro Priming of Regulatory T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; IMMUNE-RESPONSES; INTERFERON-GAMMA; ANTIGEN UPTAKE; INFECTION; RECEPTOR; MICE; ACTIVATION; ARTHRITIS; ALPHA AB The major human pathogen Staphylococcus aureus has very efficient strategies to subvert the human immune system. Virulence of the emerging community-associated methicillin-resistant S. aureus depends on phenol-soluble modulin (PSM) peptide toxins, which are known to attract and lyse neutrophils. However, their influences on other immune cells remain elusive. In this study, we analyzed the impact of PSMs on dendritic cells (DCs) playing an essential role in linking innate and adaptive immunity. In human neutrophils, PSMs exert their function by binding to the formyl peptide receptor (FPR) 2. We show that mouse DCs express the FPR2 homolog mFPR2 as well as its paralog mFPR1 and that PSMs are chemoattractants for DCs at noncytotoxic concentrations. PSMs reduced clathrin-mediated endocytosis and inhibited TLR2 ligand-induced secretion of the proinflammatory cytokines TNF, IL-12, and IL-6, while inducing IL-10 secretion by DCs. As a consequence, treatment with PSMs impaired the capacity of DCs to induce activation and proliferation of CD4(+) T cells, characterized by reduced Th1 but increased frequency of FOXP3(+) regulatory T cells. These regulatory T cells secreted high amounts of IL-10, and their suppression capacity was dependent on IL-10 and TGF-beta. Interestingly, the induction of tolerogenic DCs by PSMs appeared to be independent of mFPRs, as shown by experiments with mice lacking mFPR2 (mFPR2(-/-)) and the cognate G protein (p110 gamma(-/-)). Thus, PSMs from highly virulent pathogens affect DC functions, thereby modulating the adaptive immune response and probably increasing the tolerance toward the pathogen. The Journal of Immunology, 2013, 190: 3417-3426. C1 [Schreiner, Jens; Klenk, Juliane; Autenrieth, Stella E.] Univ Tubingen, Interfac Inst Cell Biol, D-72076 Tubingen, Germany. [Kretschmer, Dorothee; Peschel, Andreas; Autenrieth, Stella E.] Univ Tubingen, Interfac Inst Microbiol & Infect Dis, D-72076 Tubingen, Germany. [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Buehring, Hans-Joerg] Univ Tubingen, Div Hematol Oncol & Immunol, Dept Internal Med 2, D-72076 Tubingen, Germany. [Stevanovic, Stefan] Univ Tubingen, Dept Immunol, Interfac Inst Cell Biol, D-72076 Tubingen, Germany. [Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,Frederick Natl Labs Canc Res, Frederick, MD 21702 USA. [Beer-Hammer, Sandra] Univ Tubingen, Dept Pharmacol & Expt Therapy, Inst Expt & Clin Pharmacol & Toxicol, D-72074 Tubingen, Germany. RP Autenrieth, SE (reprint author), Univ Tubingen, Morgenstelle 15, D-72076 Tubingen, Germany. EM Stella.Autenrieth@medizin.uni-tuebingen.de RI Beer-Hammer, Sandra/C-7442-2014; OI Otto, Michael/0000-0002-2222-4115 FU German Research Foundation [SFB685, TRR34]; Fortune Program of the University of Tubingen Medical Faculty; Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by German Research Foundation Grants SFB685 (to S.E.A., A.P., H.-J.B., and S.S.) and TRR34 (to A.P.), the Fortune Program of the University of Tubingen Medical Faculty (to D.K.), and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (to M.O.). NR 54 TC 28 Z9 29 U1 2 U2 18 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2013 VL 190 IS 7 BP 3417 EP 3426 DI 10.4049/jimmunol.1202563 PG 10 WC Immunology SC Immunology GA 112RO UT WOS:000316610700044 PM 23460735 ER PT J AU London, A Benhar, I Mattapallil, MJ Mack, M Caspi, RR Schwartz, M AF London, Anat Benhar, Inbal Mattapallil, Mary J. Mack, Matthias Caspi, Rachel R. Schwartz, Michal TI Functional Macrophage Heterogeneity in a Mouse Model of Autoimmune Central Nervous System Pathology SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; SUPPRESSOR-CELLS; BONE-MARROW; INFLAMMATORY PHENOTYPE; LEUKOCYTE INFILTRATION; RESIDENT MICROGLIA; BLOOD MONOCYTES; MYELOID CELLS; IN-VIVO; UVEORETINITIS AB Functional macrophage heterogeneity is well appreciated outside the CNS in wound healing and cancer, and was recently also demonstrated in several CNS compartments after "sterile" insults. Yet, such heterogeneity was largely overlooked in the context of inflammatory autoimmune pathology, in which macrophages were mainly associated with disease induction and propagation. In this article, we show the diversity of monocyte-derived macrophages along the course of experimental autoimmune uveitis, an inflammatory condition affecting the ocular system, serving as a model for CNS autoimmune pathology. Disease induction resulted in the appearance of a distinct myeloid population in the retina, and in the infiltration of monocyte-derived macrophages that were absent from control eyes. During the disease course, the frequency of CX(3)CR1(high) infiltrating macrophages that express markers associated with inflammation-resolving activity was increased, along with a decrease in the frequency of inflammation-associated Ly6C(+) macrophages. Inhibition of monocyte infiltration at the induction phase of experimental autoimmune uveitis prevented disease onset, whereas monocyte depletion at the resolution phase resulted in a decrease in Foxp3(+) regulatory T cells and in exacerbated disease. Thus, monocyte-derived macrophages display distinct phenotypes throughout the disease course, even in an immune-induced pathology, reflecting their differential roles in disease induction and resolution. The Journal of Immunology, 2013, 190: 3570-3578. C1 [London, Anat; Benhar, Inbal; Schwartz, Michal] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Mattapallil, Mary J.; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Mack, Matthias] Univ Regensburg, Dept Internal Med, D-93042 Regensburg, Germany. RP Schwartz, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM michal.schwartz@weizmann.ac.il OI Caspi, Rachel/0000-0002-7140-7671 FU Glaucoma Research Foundation; European Research Council [232835]; National Institutes of Health/National Eye Institute [EY000184-29] FX This work was supported by the Glaucoma Research Foundation and by a European Research Council Advanced Grant (Agreement No. 232835). R.R.C. was supported by National Institutes of Health/National Eye Institute intramural funding (Project EY000184-29). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. NR 59 TC 21 Z9 21 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2013 VL 190 IS 7 BP 3570 EP 3578 DI 10.4049/jimmunol.1202076 PG 9 WC Immunology SC Immunology GA 112RO UT WOS:000316610700060 PM 23447691 ER PT J AU Srinivasalu, H Srinivasalu, H Sanchez, GAM Brundidge, AD Ward, MM Colbert, RA Hill, SC AF Srinivasalu, H. Srinivasalu, H. Sanchez, G. A. Montealegre Brundidge, A. D. Ward, M. M. Colbert, R. A. Hill, S. C. TI WHOLE BODY MAGNETIC RESONANCE IMAGING IN EVALUATION OF ENTHESITIS IN SPONDYLOARTHROPATHY SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Combined Annual Meeting of the Central-Society-for-Clinical-and-Translational-Research (CSCTR) and Midwestern-Section-American-Federation-for-Medical-Research (MWAFMR) CY APR 25-26, 2013 CL Chicago, IL SP Cent Soc Clinl & Translat Res (CSCTR), Midwestern Sect Amer Federat Med Res (MWAFMR) C1 [Srinivasalu, H.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Srinivasalu, H.; Sanchez, G. A. Montealegre; Brundidge, A. D.; Ward, M. M.; Colbert, R. A.] NIAMS, NIH, Bethesda, MD USA. [Hill, S. C.] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD APR PY 2013 VL 61 IS 4 BP 799 EP 799 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 114FB UT WOS:000316725300118 ER PT J AU Gage, JC Duggan, MA Nation, JG Gao, S Castle, PE AF Gage, Julia C. Duggan, Maire A. Nation, Jill G. Gao, Song Castle, Philip E. TI Comparative Risk of High-Grade Histopathology Diagnosis After a CIN 1 Finding in Endocervical Curettage Versus Cervical Biopsy SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE cervical intraepithelial neoplasia; colposcopy; curettage; diagnosis; endocervical sampling AB Objective. No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia grade 1(CIN 1) result when the concurrent cervical biopsy is not high-grade. For women with these pathologic findings, we assessed their short-term risk of high-grade histopathologic diagnosis in the Calgary Health Region where ECC was routinely performed. Materials and Methods. We analyzed pathology and colposcopy reports from 1,902 referral colposcopies where both ECC and biopsies were normal or CIN 1. We calculated the short-term risk of CIN 2 or more severe (CIN 2+) detected 12 to 24 months after colposcopy. Pearson W 2 tests or Fisher exact tests were used to compare risks of a CIN 2+ diagnosis between combinations of test results and strata of risk factors. Results. The short-term risk of CIN 2+ was the same after a CIN 1 biopsy and CIN 1 ECC (4.9% of 1,389 vs 5.0% of 359, respectively, p = .37). Compared with low-grade referral cytology, the risk of CIN 2+ after high-grade cytology was elevated significantly for CIN 1 ECC (13.3% vs 3.3%, p < .01) and nonsignificantly for CIN 1 biopsy (7.1% vs 4.6%, p = .12). Conclusions. After low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN 1 ECC or biopsy is equivalent, suggesting similar management. A CIN 1 ECC may warrant different management in the context of high-grade referral cytology. C1 [Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Duggan, Maire A.] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB T2N 1N4, Canada. [Nation, Jill G.] Univ Calgary, Dept Obstet & Gynecol, Calgary, AB T2N 1N4, Canada. [Gao, Song] Alberta Canc Board, Alberta Cerv Canc Screening Program, Calgary, AB, Canada. [Castle, Philip E.] Amer Soc Clin Pathologists, Washington, DC USA. RP Gage, JC (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7013,MSC 7234, Rockville, MD 20892 USA. EM gagej@mail.nih.gov FU National Institutes of Health, National Cancer Institute FX Dr Gage was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 7 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 IS 2 BP 137 EP 141 DI 10.1097/LGT.0b013e3182630c41 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112PU UT WOS:000316605400006 PM 23343702 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risk of Recurrence After Treatment of CIN 2, CIN 3, or AIS: Performance of HPV and Pap Cotesting in Posttreatment Management SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cancer prevention; pap; cervical intraepithelial neoplasia (CIN); posttreatment; test of cure ID CERVICAL INTRAEPITHELIAL NEOPLASIA; ELECTROSURGICAL EXCISION PROCEDURE; HUMAN-PAPILLOMAVIRUS; FOLLOW-UP; RESIDUAL/RECURRENT DISEASE; WOMEN; CYTOLOGY; LESIONS; CANCER; TERMINOLOGY AB Objective. After excisional treatment, cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) can recur. It is not clear how many negative posttreatment Pap or cotest results are needed to ensure adequate safety against CIN 2+ before returning to extended retesting intervals. Methods. We observed 5-year risks of CIN 2+ for 3 follow-up management strategies after treatment (Pap-alone, human papillomavirus [HPV]-alone, and HPV/Pap cotesting) for 3,273 women aged 25 years and older who were treated for CIN 2, CIN 3, or adenocarcinoma in situ (AIS) between 2003 and 2010 at Kaiser Permanente Northern California. Results. Five-year risks of recurrent CIN 2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN 2 preceded by HPV-positive/atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion to 16% for CIN 3/AIS preceded by atypical glandular cells (AGC)/atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (ASC-H)/high-grade squamous intraepithelial lesion or worse (HSIL+) (p < .0001). However, after posttreatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN 2+ risk after a negative posttreatment cotest (2.4%) was lower than that following a negative HPV test (3.7%, p = .3) or negative Pap result (4.2%, p = .1). Two negative posttreatment tests of each kind conferred slightly lower 5-year CIN 2+ risk than one (2 negative Pap tests vs. 1, 2.7% vs 4.2%, p = .2; 2 negative HPV tests vs. 1, 2.7% vs 3.7%, p = .7; 2 negative cotests vs. 1, 1.5% vs 2.4%, p = .8). The 5-year CIN 2+ risk after 2 negative cotests of 1.5% (95% confidence interval = 0.3%-7.2%) approached the 0.68% risk after a negative Pap test during routine screening. Conclusions. Women with antecedent AGC/A5C-H/HSIL+ Pap results or those treated for CIN 3/AIS had a substantial risk of developing CIN 2+ posttreatment. On the basis of the principle of "equal management of equal risks," after negative test results posttreatment, no subgroup of women achieved risk sufficiently low to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN 2+ than either negative Pap tests or HPV tests alone. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-03] NR 26 TC 21 Z9 24 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S78 EP S84 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800009 PM 23519309 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risks of CIN 3+and Cervical Cancer Among Women With HPV-Positive and HPV-Negative High-Grade Pap Results SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cervical intraepithelial neoplasia (CIN); AGC; ASC-H ID HUMAN-PAPILLOMAVIRUS; CYTOLOGY AB Objective. High-grade Pap results (e.g., atypical glandular cells [AGC], atypical squamous cells cannot rule out HSIL [ASC-H], and high-grade squamous intraepithelial lesion [HSIL]) predict high cancer risks, resulting in referral for colposcopy without HPV triage. However, new guidelines recommending cotesting for women 30 years and older imply that clinicians will often receive the HPV test result concurrently for high-grade Pap results. We examined whether HPV testing provides useful risk stratification in this context. Methods. From a cohort of 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California, we estimated 5-year risks for cervical cancer and CIN 3+ after AGC (2,074 women), ASC-H (1,647 women), and HSIL (2,019 women) according to HPV test results. Results. HPV positivity of AGC Pap results was 25% and decreased with age (30 to 34 vs 60 to 64 years, 44% vs 17%, p < .0001), whereas HPV positivity of ASC-H and HSIL was much higher (71% and 94%) and decreased less with age. Even for these high-grade Pap results, 5-year CIN 3+ risks differed substantially between HPV-positive and HPV-negative women (AGC, 33% vs 0.93%, p < .0001; ASC-H, 25% vs 3.5%, p < .0001; HSIL, 49% vs 30%, p = .006). However, except for AGC, cervical cancer risks differed less between HPV-positive and HPV-negative women (AGC, 9.0% vs 0.37%, p < .0001; ASC-H, 2.5% vs 2.1%, p = .8; HSIL, 6.6% vs 6.8%, p = .7). Conclusions. The risks of CIN 3+ among women with HPV-negative high-grade Pap results were lower than those among women with HPV-positive high-grade Pap results, especially after AGC. However, by the principle of "equal management of equal risks," all HPV-negative high-grade Pap results had cancer risks high enough to warrant colposcopy, confirming that there is no current role for HPV triage of high-grade Pap results. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-03] NR 10 TC 18 Z9 20 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S50 EP S55 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800005 PM 23519305 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Benchmarking CIN 3+Risk as the Basis for Incorporating HPV and Pap Cotesting into Cervical Screening and Management Guidelines SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN) ID HUMAN-PAPILLOMAVIRUS; AMERICAN SOCIETY; CANCER; PATHOLOGY; RISK; TERMINOLOGY; PREVENTION; COLPOSCOPY; REGRESSION; CYTOLOGY AB Objective, In 2012, the US Preventive Services Task Force (USPSTF) and a consensus of 25 organizations endorsed concurrent cytology and human papillomavirus (HPV) testing ("cotesting") for cervical cancer screening. Past screening and management guidelines were implicitly based on risks defined by Pap-alone, without consideration of HPV test results. To promote management that is consistent with accepted practice, new guidelines incorporating cotesting should aim to achieve equal management of women at equal risk of cervical intraepithelial neoplasia grade 3 and cancer (CIN 3+). Methods. We estimated cumulative 5-year risks of CIN 3+ for 965,360 women aged 30 to 64 years undergoing cotesting at Kaiser Permanente Northern California over 2003 to 2010. We calculated the implicit risk thresholds for Pap-alone and applied them for new management guidance on HPV and Pap cotesting, citing 2 examples: HPV-positive/atypical squamous cells of undetermined significance (ASC-US) and HPV-negative/Pap-negative. We call this guidance process "benchmarking." Results. A low-grade squamous intraepithelial lesion result, for which immediate colposcopy is prescribed, carries a 5-year CIN 3+ risk of 5.2%, suggesting that test results with similar risks should be managed with colposcopy. Similarly, ASC-US (2.6% risk) is managed with a 6- to 12-month follow-up visit and Pap-negative (0.26% risk) is managed with a 3-year follow-up visit. The 5-year CIN 3+ risk among women with HPV-positive/ASC-US was 6.8% (95% confidence interval = 6.2%-7.6%). This is greater than the 5.2% risk implicitly leading to referral for colposcopy, consistent with current management recommendations that women with HPV-positive/ASC-US be referred for immediate colposcopy. The 5-year CIN 3+ risk among women with HPV-negative/Pap-negative results was 0.08% (95% confidence interval = 0.07%-0.09%), far below the 0.26% implicitly required for a 3-year return and justifying a longer (e.g., 5-year) return. Conclusions. Using the principle of "equal management of equal risks," benchnnarking to implicit risk thresholds based on Pap-alone can be used to achieve safe and consistent incorporation of cotesting. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010206-03, ZIA CP010181-12] NR 16 TC 58 Z9 62 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S28 EP S35 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800002 PM 23519302 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risks of CIN 3+and Cervical Cancer Among Women With HPV Testing of ASC-US Pap Results SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); Pap; cervical intraepithelial neoplasia (CIN); ASC-US ID PATHOLOGY SCREENING GUIDELINES; RANDOMIZED CONTROLLED-TRIAL; ATYPICAL SQUAMOUS-CELLS; HUMAN-PAPILLOMAVIRUS; UNDETERMINED SIGNIFICANCE; CONVENTIONAL CYTOLOGY; AMERICAN SOCIETY; PREVENTION; COLPOSCOPY; MANAGEMENT AB Objective. New screening guidelines recommend that human papillomavirus (HPV) negative/atypical squamous cells of undetermined significance (ASC-US) results be considered as equivalent to HPV-negative/Pap-negative results, leading to rescreening in 5 years. However, despite ample data, the routine clinical performance of HPV testing of women with ASC-US has not been adequately documented. Methods. We estimated 5-year risks of cervical intraepithelial neoplasia (CIN) 3+ and of cancer among 2 groups of women between 2003 and 2010 at Kaiser Pernnanente Northern California: 27,050 aged 30 to 64 years who underwent HPV and Pap cotesting and had an ASC-US Pap result and 12,209 aged 25 to 29 years who underwent HPV triage of ASC-US. Results. Five-year risks of CIN 3+ and of cancer among women aged 30 to 64 years testing HPV-negative/ASC-US and among 923,152 women testing Pap-negative alone were similar although statistically distinguishable (CIN 3+, 0.43% vs 0:26%, p = .001; cancer, 0.050% vs 0.025%, p = .1). The increased risk of cancer after HPV-negative/ASC-US versus Pap-negative alone was confined to women aged 60 to 64 years (0.26% vs 0.035%, p = .3). Five-year risks of CIN 3+ and cancer among women with HPV-negative/ASC-US results were substantially higher than those among women testing HPV-negative/Pap-negative (CIN 3+, 0.43% vs 0.08%, p < .0001; cancer, 0.050% vs 0.011%, p = .003). For women aged 30 to 64 years testing HPV-positive/ASC-US, 5-year risks of CIN 3+ and cancer were slightly higher than those among 9,374 women with low-grade squamous intraepithelial lesion (LSIL) (CIN 3+, 6.8% vs 5.2%, p = .0007; cancer, 0.41% vs 0.16%, p = .04). Similar patterns were seen for women aged 25 to 29 years. Conclusions. Women with HPV-negative/ASC-US had a similar risk as women testing Pap-negative alone but had a higher risk than women testing HPV-negative/Pap-negative. Based upon the principle of "equal management of equal risks," our findings support the equal management of women with HPV-negative/ASC-US and those with Pap-negative alone, except for exiting women from screening because cancer risks at ages 60 to 64 years may be higher for women testing HPV-negative/ASC-US. Our findings also support managing HPV-positive/ASC-US and LSIL similarly. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-03] NR 19 TC 28 Z9 30 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S36 EP S42 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800003 PM 23519303 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risks of CIN 3+and Cervical Cancer Among Women Who Test Pap-Negative But Are HPV-Positive SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); prospective cohort ID HUMAN-PAPILLOMAVIRUS DNA; YOUNG-WOMEN; CYTOLOGY; NEOPLASIA; INFECTIONS; CLEARANCE; PATHOLOGY; TRIAGE; COHORT AB Objective. Current US guidelines for cotesting recommend that the large numbers of women who test Pap-negative, but human papillomavirus (HPV) positive, return in 1 year, and those who remain HPV-positive or have lowgrade squamous intraepithelial lesion (LSIL) or worse Pap results be referred for colposcopy. However, the performance of these guidelines in routine clinical practice has not been evaluated. Methods. We estimated cumulative 5-year risks of cervical intraepithelial neoplasia grade 3 or worse (CIN 3+) among 32,374 women aged 30 to 64 years with HPV-positive/Pap-negative cotest results at Kaiser Permanente Northern California during 2003 to 2010. Results. The 5-year CIN 3+ risk after an HPV-positive/Pap-negative cotest result, which was found in 3.6% of women, was 4.5% (95% confidence interval [Cl] = 4.2%-4.8%). The 5-year cancer risk was 0.34% (95% Cl 0.26%-0.45%), and half of the cases were adenocarcinoma. Overall, 48% of the women remained HPV-positive on return (median = 418 days after baseline), a percentage that varied little over ages 30 to 64 years. At the return after a baseline HPV-positive/Pap-negative result, almost every repeat cotest result predicted greater subsequent 5-year CIN 3+ risk than the same cotest result had at baseline (HPV-positive/LSIL, 9.2% vs 6.1%, p = .01; HPV-positive/atypical squamous cells of undetermined significance [ASC-US], 7.9% vs 6.8%, p =. 2; HPV-positive/Pap-negative, 7.4% vs 4.5%, p < .0001; HPV-negative/LSIL, 1.7% vs 2.0%, p = .8; HPV-negative/ASC-US, 2.9% vs 0.43%, p = .0005; HPV-negative/Pap-negative, 0.93% vs 0.08%, p < .0001). Conclusions. Using the principle of "equal management of equal risks," women testing HPV-positive/Pap-negative had a subsequent CIN 3+ risk consistent with risk thresholds for a 1-year return. However, on returning in approximately 1 year, about one-half of women will be referred for colposcopy because of continued HPV positivity or Pap abnormality. Clinicians should keep in mind that cotest results at the return after a baseline HPV-positive/Pap-negative finding are riskier than the same baseline cotest results in the general population, supporting intensified clinical management at return testing. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-03] NR 24 TC 28 Z9 30 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S56 EP S63 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800006 PM 23519306 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risk of CIN 3+to Guide the Management of Women Aged 21 to 24 Years SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelial neoplasia (CIN); young adult ID CERVICAL CYTOLOGY; CANCER AB Objective. Current US national guidelines recommend beginning screening at age 21 using Pap tests only, with cotesting starting at age 30. To inform the management of Pap test abnormalities among women aged 21 to 24 years, who have extremely low cancer risks, we compared risks of CIN 3+ among women aged 21 to 24 versus 25 to 29 years or 30 to 64 years. Methods. We estimated 5-year risks of CIN 3+ given different Pap test results, with human papillomavirus (HPV) triage of atypical squamous cells of undetermined significance (ASC-US), among 133,947 women aged 21 to 24 years, compared with 135,382 women aged 25 to 29 years and 965,360 women aged 30 to 64 years, between 2003 and 2010 at Kaiser Permanente Northern California. Results. There were 3 cancers diagnosed during follow-up in women aged 21 to 24 years. After high-grade Pap results (0.6% of Pap results), the 5-year CIN 3+ risks among women aged 21 to 24 years were comparable to those aged 25 to 29 and 30 to 64 years (atypical glandular cells, 6.9% vs 14% vs 8.5%, p = .8; atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion, 16% vs 24% vs 18%, p = .8; high-grade squannous intraepithelial lesion, 28% vs 28% vs 47%, p = .4). After low-grade squamous intraepithelial lesion, the 5-year CIN 3+ risk was lower among women aged 21 to 24 years (3.0%) than that among women aged 25 to 29 years (5.0%, p = .01) or aged 30 to 64 years (5.2%, p = .0002). Although the 5-year CIN 3+ risk after HPV-negative/ASC-US was similar across all 3 groups (0.57% vs 0.59% vs 0.43%, p = 1), risk after HPV-positive/ASC-US was lower among women aged 21 to 24 years (4.4%) than that among women aged 25 to 29 years (7.1%, p < .0001) or 30 to 64 years (6.8%, p < .0001). Conclusions. Women aged 21 to 24 years had almost zero cancer risk, and positive Pap test results predicted low CIN 3+ risk except for the 0.6% of women with high-grade Pap results. The generally low risk supports conservative management of women aged 21 to 24 years. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Womens Hlth Res Inst, Div Res, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-02] NR 11 TC 15 Z9 16 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S64 EP S68 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800007 PM 23519307 ER PT J AU Katki, HA Gage, JC Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Kinney, WK AF Katki, Hormuzd A. Gage, Julia C. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Kinney, Walter K. TI Follow-up Testing After Colposcopy: Five-Year Risk of CIN 2+After a Colposcopic Diagnosis of CIN 1 or Less SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE Human papillomavirus (HPV); Pap; cervical intraepithelial neoplasia (CIN); colposcopy ID CERVICAL INTRAEPITHELIAL NEOPLASIA; NATURAL-HISTORY; CANCER AB Objective. Most women referred for colposcopy are not diagnosed with cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) but, nonetheless, are typically asked to return much sooner than their next routine screening interval in 3 to 5 years. An important question is how many subsequent negative Pap results, or negative Pap and human papillomavirus (HPV) cotest results, are needed before returning to an extended retesting interval. Methods. We estimated 5-year risks of CIN 2+ for 3 follow-up management strategies after colposcopy (Pap-alone, HPV-alone, and cotesting) for 20,319 women aged 25 years and older screened from 2003 to 2010 at Kaiser Permanente Northern California who were referred for colposcopy but for whom CIN 2+ was not initially diagnosed (i.e., "women with CIN 1/negative colposcopy"). Results. Screening results immediately antecedent to CIN 1/negative colposcopy influenced subsequent 5-year CIN 2+ risk: women with an antecedent HPV-positive/atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap had a lower risk (10%) than those with antecedent atypical squamous cells cannot rule out HSIL (ASC-H; 16%, p < .0001) or high-grade squamous intraepithelial lesion or worse (HSIL+; 24%, p < .0001). For women with an antecedent HPV-positive/ASC-US or LSIL, a single negative cotest approximately 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (1.1%) than 2 sequential negative HPV tests (1.8%, p = .3) or 2 sequential negative Pap results (4.0%, p < .0001). For those with an antecedent ASC-H or HSIL+ Pap, 1 negative cotest 1 year after colposcopy predicted lower subsequent 5-year risk of CIN 2+ (2.2%) than 1 negative HPV test (4.4%, p = .4) or 1 negative Pap (7.0%, p = .06); insufficient data existed to calculate the risk after sequential negative cotests for women with high-grade antecedent cytology. Conclusions. Women with a CIN 1/negative colposcopy followed by negative postcolposcopy tests did not achieve sufficiently low CIN 2+ risk to return to 5-year routine screening. For women with antecedent HPV-positive/ASC-US or LSIL, a single negative postcolposcopy cotest reduced their risk to a level consistent with a 3-year return. For women with antecedent ASC-H or HSIL+, no single negative test result sufficed to reduce their risk to a level consistent with a 3-year return. C1 [Katki, Hormuzd A.; Gage, Julia C.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-02] NR 11 TC 14 Z9 18 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S69 EP S77 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800008 PM 23519308 ER PT J AU Katki, HA Schiffman, M Castle, PE Fetterman, B Poitras, NE Lorey, T Cheung, LC Raine-Bennett, T Gage, JC Kinney, WK AF Katki, Hormuzd A. Schiffman, Mark Castle, Philip E. Fetterman, Barbara Poitras, Nancy E. Lorey, Thomas Cheung, Li C. Raine-Bennett, Tina Gage, Julia C. Kinney, Walter K. TI Five-Year Risks of CIN 2+and CIN 3+Among Women With HPV-Positive and HPV-Negative LSIL Pap Results SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE human papillomavirus (HPV); cytology; cervical intraepithelial neoplasia (CIN); LSIL ID RANDOMIZED CONTROLLED-TRIAL; LIQUID-BASED CYTOLOGY; HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; INTRAEPITHELIAL NEOPLASIA; CONVENTIONAL CYTOLOGY; ABNORMALITIES; METAANALYSIS; ACCURACY AB Objective. Low-grade squamous intraepithelial lesion (LSIL) Pap results do not typically lead to human papillomavirus (HPV) testing. HPV triage is not cost-effective because most cases are HPV-positive. However, under new national guidelines recommending cotesting for women aged 30 to 64 years, clinicians will increasingly receive the HPV test result with LSIL Pap results. Some authors have suggested that HPV triage might be effective at older ages, when the percentage of HPV positivity among women with LSIL declines. Methods. We estimated 5-year risks of CIN 2+ and CIN 3+ among 9,033 women aged 30 to 64 years who had both an HPV test and an LSIL Pap result. Results. HPV positivity among women with LSIL decreased only slightly with age (30 to 34 vs 60 to 64 years, 88% vs 72%, p < .0001). The 5-year risks of CIN 2+ and CIN 3+ of women aged 30 to 64 years testing HPV-positive/LSIL were larger than those among women testing HPV-negative/LSIL (CIN 2+, 19% vs 5.1%, p < .0001; CIN 3+, 6.1% vs 2.0%, p < .0001). The 5-year risk of CIN 3+ in HPV-negative/LSIL women was similar to that for women with atypical squamous cells of undetermined significance (ASC-US) Pap test result without knowledge of HPV test results (2.0% vs 2.6%, p = .4). Conclusions. HPV-negative/LSIL posed lower risk than other Pap results that guidelines currently recommend for referral to immediate colposcopy. By the principle of "equal management of equal risks," women with HPV-negative/LSIL might reasonably be managed similarly to those with ASC-US Pap results without knowledge of HPV testing, that is, retesting at 6 to 12 months, rather than immediate colposcopy. Although the HPV test result for LSIL Pap results provides actionable information to clinicians who screen with cotesting, the high HPV positivity of LSIL at even the oldest ages suggests the lack of cost-effectiveness of HPV triage of LSIL for clinicians who do not use routine cotesting. C1 [Katki, Hormuzd A.; Schiffman, Mark; Gage, Julia C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20882 USA. [Castle, Philip E.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Fetterman, Barbara; Poitras, Nancy E.; Lorey, Thomas] Kaiser Permanente Northern Calif, Reg Lab, Berkeley, CA USA. [Cheung, Li C.] Informat Management Serv Inc, Calverton, MD USA. [Raine-Bennett, Tina] Kaiser Permanente Northern Calif, Div Res, Womens Hlth Res Inst, Oakland, CA USA. [Kinney, Walter K.] Kaiser Permanente Med Care Program, Div Gynecol Oncol, Oakland, CA USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 8014,EPS MSC 7244, Bethesda, MD 20882 USA. EM katkih@mail.nih.gov; walter.kinney@kp.org RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS [ZIA CP010181-12, ZIA CP010206-03] NR 25 TC 12 Z9 13 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S43 EP S49 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800004 PM 23519304 ER PT J AU Massad, LS Einstein, MH Huh, WK Katki, HA Kinney, WK Schiffman, M Solomon, D Wentzensen, N Lawson, HW AF Massad, L. Stewart Einstein, Mark H. Huh, Warner K. Katki, Hormuzd A. Kinney, Walter K. Schiffman, Mark Solomon, Diane Wentzensen, Nicolas Lawson, Herschel W. CA 2012 ASCCP Consensus Guidelines TI 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article ID ADENOCARCINOMA IN-SITU; SQUAMOUS INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS INFECTION; ATYPICAL GLANDULAR CELLS; OF-AMERICAN-PATHOLOGISTS; UNDETERMINED SIGNIFICANCE; ENDOCERVICAL CURETTAGE; RANDOMIZED-TRIAL; UTERINE CERVIX; YOUNG-WOMEN AB A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillonnavirus negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up. C1 Washington Univ, Sch Med, St Louis, MO 63110 USA. Albert Einstein Coll Med, New York, NY USA. Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Permanente Med Grp Inc, Sacramento, CA USA. Emory Univ, Sch Med, Atlanta, GA USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu RI Katki, Hormuzd/B-4003-2015 NR 93 TC 166 Z9 186 U1 1 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD APR PY 2013 VL 17 SU S BP S1 EP S27 PG 27 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 113EH UT WOS:000316648800001 PM 23519301 ER PT J AU Qian, CQ Zabow, G Koretsky, A AF Qian, Chunqi Zabow, Gary Koretsky, Alan TI Engineering novel detectors and sensors for MRI SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Microresonator; Inductive coupling; Microfabrication; Contrast agents ID MAGNETIC-RESONANCE MICROSCOPY; RESOLUTION INTRAVASCULAR MRI; RAT SPINAL-CORD; CONTRAST AGENTS; TRANSMISSION-LINE; PARACEST AGENTS; IMPLANTED COIL; SURFACE COILS; INVIVO NMR; RF COIL AB Increasing detection sensitivity and image contrast have always been major topics of research in MRI. In this perspective, we summarize two engineering approaches to make detectors and sensors that have potential to extend the capability of MRI. The first approach is to integrate miniaturized detectors with a wireless powered parametric amplifier to enhance the detection sensitivity of remotely coupled detectors. The second approach is to microfabricate contrast agents with encoded multispectral frequency shifts, whose properties can be specified and fine-tuned by geometry. These two complementary approaches will benefit from the rapid development in nanotechnology and microfabrication which should enable new opportunities for MRI. Published by Elsevier Inc. C1 [Qian, Chunqi; Zabow, Gary; Koretsky, Alan] NINDS, NIH, Bethesda, MD 20892 USA. [Zabow, Gary] NIST, Electromagnet Div, Boulder, CO 80305 USA. RP Koretsky, A (reprint author), 10 Ctr Dr,Room 1D728,MSC 1065, Bethesda, MD 20892 USA. EM koretskya@ninds.nih.gov RI Qian, Chunqi/A-7481-2012; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural Research Program of the NIH, NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. NR 58 TC 5 Z9 5 U1 1 U2 27 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2013 VL 229 BP 67 EP 74 DI 10.1016/j.jmr.2012.11.012 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 115VT UT WOS:000316840700008 PM 23245489 ER PT J AU Duyn, J AF Duyn, Jeff TI MR susceptibility imaging SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Susceptibility contrast; Myelin; Fiber bundle; Microstructure; Brain; Anisotropy ID HIGH-FIELD MRI; MYELIN WATER FRACTION; ENABLED DIPOLE INVERSION; HUMAN BRAIN; MAGNETIC-SUSCEPTIBILITY; WHITE-MATTER; IN-VIVO; MULTIPLE-SCLEROSIS; DIAMAGNETIC ANISOTROPY; FIBER ORIENTATION AB This work reviews recent developments in the use of magnetic susceptibility contrast for human MRI, with a focus on the study of brain anatomy. The increase in susceptibility contrast with modern high field scanners has led to novel applications and insights into the sources and mechanism contributing to this contrast in brain tissues. Dedicated experiments have demonstrated that in most of healthy brain, iron and myelin dominate tissue susceptibility variations, although their relative contribution varies substantially. Local variations in these compounds can affect both amplitude and frequency of the MRI signal. In white matter, the myelin sheath introduces an anisotropic susceptibility that has distinct effects on the water compartments inside the axons, between the myelin sheath, and the axonal space, and renders their signals dependent on the angle between the axon and the magnetic field. This offers opportunities to derive tissue properties specific to these cellular compartments. (C) 2012 Elsevier Inc. All rights reserved. C1 NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Duyn, J (reprint author), NINDS, Adv MRI Sect, Lab Funct & Mol Imaging, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov FU Intramural NIH HHS [ZIA NS002990-13] NR 109 TC 22 Z9 22 U1 1 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD APR PY 2013 VL 229 BP 198 EP 207 DI 10.1016/j.jmr.2012.11.013 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 115VT UT WOS:000316840700018 PM 23273840 ER PT J AU Fodi, E McAreavey, D Abd-Elmoniem, KZ Ohayon, J Saba, M Elagha, A Pettigrew, RI Gharib, AM AF Fodi, Eszter McAreavey, Dorothea Abd-Elmoniem, Khaled Z. Ohayon, Jacques Saba, Magdi Elagha, Abdalla Pettigrew, Roderic I. Gharib, Ahmed M. TI Pulmonary vein morphology by free-breathing whole heart magnetic resonance imaging at 3 tesla versus breathhold multi-detector computed tomography SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance imaging; multidetector computed tomography; atrium; pulmonary vein; vessels ID RADIOFREQUENCY CATHETER ABLATION; CORONARY MR-ANGIOGRAPHY; CROSS-SECTIONAL AREA; ATRIAL-FIBRILLATION; CLINICAL-OUTCOMES; ARTERY STENOSIS; CONTRAST; ACCURACY; DIAMETER; ANATOMY AB Purpose: To compare pulmonary vein and left atrial anatomy using three-dimensional free-breathing whole-heart magnetic resonance imaging (MR) at 3 Tesla (T) and multi-detector computed tomography (MDCT). Materials and Methods: Thirty-three subjects (19 male, age 49 +/- 12 years) underwent free-breathing 3T MR and contrast-enhanced MDCT during inspiratory breath hold. Pulmonary vein parameters (ostial areas, diameters, angles) were measured. Results: All pulmonary veins and anomalies were identified by 3T MR and by MDCT. The right-sided pulmonary veins were directed more posteriorly, the right superior pulmonary vein more inferiorly, and the right inferior pulmonary vein more superiorly by 3T MR when compared with MDCT. The cross-sectional area, perimeters and minimum diameters of right-sided pulmonary vein ostia were significantly larger by MR, as were the maximum diameters of right and left inferior pulmonary veins. There were no significant differences between techniques in distance to first pulmonary vein branch. Conclusion: Pulmonary vein measurements demonstrated significant differences in angulations and dimensions when 3T MR is compared with MDCT. These differences likely represent hemodynamic and respiratory variation during free-breathing with MR versus breath-holding with MDCT. MR imaging at 3T during free-breathing offers an alternate method to define pulmonary vein and left atrial anatomy without exposure to radiation. J. Magn. Reson. Imaging 2013;37:846852. (c) 2012 Wiley Periodicals, Inc. C1 [Fodi, Eszter; Abd-Elmoniem, Khaled Z.; Ohayon, Jacques; Elagha, Abdalla; Pettigrew, Roderic I.; Gharib, Ahmed M.] NIDDK, NIH, Bethesda, MD USA. [McAreavey, Dorothea] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Saba, Magdi] Univ London, Dept Cardiovasc Med, London WC1E 7HU, England. RP Gharib, AM (reprint author), 10 Ctr Dr,CRC Room 3-5340, Bethesda, MD 20892 USA. EM agharib@niddk.nih.gov RI Ohayon, Jacques/M-6576-2014; Gharib, Ahmed/O-2629-2016; Abd-Elmoniem, Khaled/B-9289-2008; OI Gharib, Ahmed/0000-0002-2476-481X; Abd-Elmoniem, Khaled/0000-0002-1001-1702; Elagha, Abdalla/0000-0003-3136-2293 FU NIH FX Contract grant sponsor: NIH. NR 33 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD APR PY 2013 VL 37 IS 4 BP 846 EP 852 DI 10.1002/jmri.23865 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 113TH UT WOS:000316690800010 PM 23172711 ER PT J AU Lorenzo, FR Yang, CZ Fui, MNT Vankayalapati, H Zhuang, ZP Huynh, T Grossmann, M Pacak, K Prchal, JT AF Lorenzo, Felipe R. Yang, Chunzhang Fui, Mark Ng Tang Vankayalapati, Hariprasad Zhuang, Zhengping Thanh Huynh Grossmann, Mathis Pacak, Karel Prchal, Josef T. TI A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Article DE HIF2A; Paraganglioma; Familial erythrocytosis ID HYPOXIA-INDUCIBLE FACTOR; TRANSCRIPTION FACTOR; OXYGEN HOMEOSTASIS; PHD2 MUTATION; FACTOR-I; ERYTHROCYTOSIS; GENE; HIF-1 AB Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development. C1 [Lorenzo, Felipe R.; Prchal, Josef T.] Univ Utah, Div Hematol, Sch Med, Salt Lake City, UT 84132 USA. [Lorenzo, Felipe R.; Prchal, Josef T.] VAH, Salt Lake City, UT 84132 USA. [Yang, Chunzhang; Zhuang, Zhengping] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Fui, Mark Ng Tang; Grossmann, Mathis] Univ Melbourne, Austin Hlth, Dept Endocrinol, Melbourne, Vic 3084, Australia. [Fui, Mark Ng Tang; Grossmann, Mathis] Univ Melbourne, Austin Hlth, Dept Med Austin Hlth, Melbourne, Vic 3084, Australia. [Vankayalapati, Hariprasad] Univ Utah, Ctr Invest Therapeut, Salt Lake City, UT 84112 USA. [Vankayalapati, Hariprasad] Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Thanh Huynh; Pacak, Karel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Prchal, JT (reprint author), Univ Utah, Div Hematol, Sch Med, 30N 1900E,5C402, Salt Lake City, UT 84132 USA. EM josef.prchal@hsc.utah.edu OI Ng Tang Fui, Mark/0000-0002-5101-8572 FU VA Merit Review Award; University of Utah; National Health and Medical Research Council of Australia [1006407]; NIH, NICHD; NIH, NINDS; [NIH-P01CA108671] FX JTP is supported by NIH-P01CA108671, VA Merit Review Award and University of Utah Seed Grant Program for studies of hypoxic adaptation. MG is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia (#1006407). KP, ZZ, CY, and TH are supported, in part, by the Intramural Research Program of the NIH, NICHD, and NINDS. NR 26 TC 53 Z9 54 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED JI J. Mol. Med. PD APR PY 2013 VL 91 IS 4 BP 507 EP 512 DI 10.1007/s00109-012-0967-z PG 6 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 119DI UT WOS:000317077200010 PM 23090011 ER PT J AU Keleshian, VL Modi, HR Rapoport, SI Rao, JS AF Keleshian, Vasken L. Modi, Hiren R. Rapoport, Stanley I. Rao, Jagadeesh S. TI Aging is associated with altered inflammatory, arachidonic acid cascade, and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE aging; arachidonic acid; BDNF; CREB; DNA methylation; synaptophysin ID NF-KAPPA-B; MILD COGNITIVE IMPAIRMENT; CYTOSOLIC PHOSPHOLIPASE A(2); ALZHEIMERS-DISEASE BRAIN; BLOOD-CELL CHOLINE; DNA METHYLATION; GENE-EXPRESSION; RAT-BRAIN; COX-2 TRANSCRIPTION; OXIDATIVE STRESS AB Aging is a risk factor for Alzheimer's disease (AD) and is associated with cognitive decline. However, underlying molecular mechanisms of brain aging are not clear. Recent studies suggest epigenetic influences on gene expression in AD, as DNA methylation levels influence protein and mRNA expression in postmortem AD brain. We hypothesized that some of these changes occur with normal aging. To test this hypothesis, we measured markers of the arachidonic acid (AA) cascade, neuroinflammation, pro- and anti-apoptosis factors, and gene specific epigenetic modifications in postmortem frontal cortex from nine middle-aged [41 +/- 1 (SEM) years] and 10 aged subjects (70 +/- 3years). The aged compared with middle-aged brain showed elevated levels of neuroinflammatory and AA cascade markers, altered pro and anti-apoptosis factors and loss of synaptophysin. Some of these changes correlated with promoter hypermethylation of brain derived neurotrophic factor (BDNF), cyclic AMP responsive element binding protein (CREB), and synaptophysin and hypomethylation of BCL-2 associated X protein (BAX). These molecular alterations in aging are different from or more subtle than changes associated with AD pathology. The degree to which they are related to changes in cognition or behavior during normal aging remains to be evaluated. C1 [Keleshian, Vasken L.; Modi, Hiren R.; Rapoport, Stanley I.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect IS 126, Lab Neurosci, NIH, 9000 Rockville Pike,Bldg 9, Bethesda, MD 20892 USA. EM jrao@grc.nia.nih.gov FU Harvard Brain Bank, Boston, MA [R24MH068855]; Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD USA FX We thank the NIH Fellows Editorial Board for editorial assistance. We thank the Harvard Brain Bank, Boston, MA for providing the postmortem brain samples under PHS grant number R24MH068855. This research was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Bethesda, MD USA. NR 78 TC 22 Z9 22 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD APR PY 2013 VL 125 IS 1 BP 63 EP 73 DI 10.1111/jnc.12153 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 112YR UT WOS:000316631900008 PM 23336521 ER PT J AU Branum, AM Bailey, R Singer, BJ AF Branum, Amy M. Bailey, Regan Singer, Barbara J. TI Dietary Supplement Use and Folate Status during Pregnancy in the United States SO JOURNAL OF NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEY; CHILDBEARING AGE; NATIONAL-HEALTH; FOLIC-ACID; WOMEN; NHANES; ADULTS; IRON; PRECONCEPTION; REQUIREMENTS AB Adequate folate and iron intake during pregnancy is critical for maternal and fetal health. No previous studies to our knowledge have reported dietary supplement use and folate status among pregnant women sampled in NHANES, a nationally representative, cross-sectional survey. We analyzed data on 1296 pregnant women who participated in NHANES from 1999 to 2006 to characterize overall supplement use, iron and folic acid use, and R BC folate status. The majority of pregnant women (77%) reported use of a supplement in the previous 30 d, most frequently a multivitamin/-mineral containing folic acid (mean 817 mu g/d) and iron 148 mg/d). Approximately 55-60% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 76-78% in their second trimester and 89% in their third trimester. ABC folate was lowest in the first trimester and differed by supplement use across all trimesters. Median RBC folate was 1628 nmol/L among users and 1041 nmol/L among nonusers. Among all pregnant women, median RBC folate increased with trimester (1256 nmol/L in the first, 1527 nmol/L in the second, and 1773 nmol/L in the third). Given the role of folic acid in the prevention of neural tube defects, it is notable that supplement use and median ABC folate was lowest in the first trimester of pregnancy, with 55% of women taking a supplement containing folic acid. Future research is needed to determine the reasons for low compliance with supplement recommendations, particularly folic acid, in early pregnancy. J. Nutr. 143: 486-492, 2013. C1 [Branum, Amy M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Bailey, Regan] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Singer, Barbara J.] Univ Maryland, Sch Publ Hlth, Dept Family Sci, College Pk, MD 20742 USA. RP Branum, AM (reprint author), Natl Ctr Hlth Stat, Off Anal & Epidemiol, 3311 Toledo Rd,Room 6113, Hyattsville, MD 20782 USA. EM ambranum@cdc.gov FU Intramural CDC HHS [CC999999] NR 46 TC 36 Z9 36 U1 2 U2 38 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD APR PY 2013 VL 143 IS 4 BP 486 EP 492 DI 10.3945/jn.112.169987 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 110JB UT WOS:000316437300013 PM 23365107 ER PT J AU Chattopadhyay, A Patton, LL AF Chattopadhyay, Amit Patton, Lauren L. TI Smoking as a risk factor for oral candidiasis in HIV-infected adults SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE Candida; HIV; interaction; regression models; smoking ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE INHIBITOR; HAIRY LEUKOPLAKIA; TOBACCO SMOKING; LESIONS; SMOKERS; HAART; ALBICANS; MANIFESTATIONS; CANDIDOSIS AB Objective We aimed to examine if smoking is an independent predictor of oral candidiasis (OC) among HIV-1 infected persons. Methods The cross-sectional part of this study evaluated 631 adult dentate HIV-1 seropositive persons examined for OC from 19952000 at the University of North Carolina Hospitals in Chapel Hill, NC. In the second part, from the above sample, a total of 283 individuals who were free of HIV-associated oral diseases at baseline were followed up for 2years to assess incident OC events. Data collected from medical record review, interview questionnaires, and clinical examinations were analyzed using chi-squared tests and t-tests. Logistic regression models were developed for prevalent OC employing the likelihood ratio test, whereas Poisson regression models were developed for assessing cumulative incidence of OC. These models included a variety of independent variables to adjust for confounding. Results Thirteen percent of participants had OC only; 4.6% had OC with Oral Hairy Leukoplakia; and 69.7% had neither. Smoking was associated with OC in all models [prevalent OC current smokers: logistic regression Odd ratio (95% CI)=2.5 (1.3, 4.8); Incident OC current smokers: Poisson regression (main effects model) Incidence rate ratio (95% CI)=1.9 (1.1, 3.8)]. Other Poisson regression models suggested evidence for effect modification between CD4 cell count and incident OC by smoking. Conclusion Smoking is an independent risk factor for the development of OC in HIV-1 infected persons, and the risk of OC is modified by CD4 cell count which measures strength of the immune system. C1 [Chattopadhyay, Amit] NIH NIDCR, Off Sci Policy & Anal, Bethesda, MD USA. [Patton, Lauren L.] Univ N Carolina, Sch Dent, Dept Dent Ecol, Chapel Hill, NC 27599 USA. RP Chattopadhyay, A (reprint author), Ste 5B55,Bldg 31,31 Ctr Dr,MSC 2190, Bethesda, MD 20892 USA. EM Amit.Chattopadhyay@nih.gov RI Chattopadhyay, Amit/L-1919-2013; OI Chattopadhyay, Amit/0000-0003-3278-7525; Patton, Lauren/0000-0002-8253-4588 FU USPHS Grant from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [5T32DE07191, P30-HD27360, R29DE11369] FX The views expressed in this article are that of the authors and do not necessarily represent the views of the National Institutes of Health or the US Government. This investigation was supported by USPHS Grant 5T32DE07191, P30-HD27360, and R29DE11369 from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. NR 37 TC 6 Z9 6 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD APR PY 2013 VL 42 IS 4 BP 302 EP 308 DI 10.1111/jop.12019 PG 7 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 118EW UT WOS:000317007200004 PM 23206208 ER PT J AU Estrada-Veras, J Groninger, H AF Estrada-Veras, Juvianee Groninger, Hunter TI Palliative Care for Patients with Cystic Fibrosis #265 SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID LIFE CARE; PAIN; END C1 [Groninger, Hunter] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Groninger, H (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM hunter.groninger@nih.gov NR 9 TC 0 Z9 0 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD APR PY 2013 VL 16 IS 4 BP 446 EP 447 DI 10.1089/jpm.2013.9515 PG 2 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 116BJ UT WOS:000316857000022 PM 23442038 ER PT J AU Cochran, EK AF Cochran, Elaine K. TI Severe Insulin Resistance in a Pediatric Patient: Key Areas to Address in the Screening SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Meeting Abstract C1 [Cochran, Elaine K.] NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD APR PY 2013 VL 28 IS 2 BP 204 EP 204 DI 10.1016/j.pedn.2013.02.007 PG 1 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 115WN UT WOS:000316842700022 ER PT J AU Van Ryzin, C AF Van Ryzin, Carol TI Adrenal Insufficiency: Causes of Adrenal Insufficiency and Prevention of Adrenal Crisis SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Meeting Abstract C1 [Van Ryzin, Carol] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD APR PY 2013 VL 28 IS 2 BP 206 EP 207 DI 10.1016/j.pedn.2013.02.013 PG 2 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 115WN UT WOS:000316842700028 ER PT J AU Cochran, EK AF Cochran, Elaine K. TI Defining the Unique Roles and Responsibilities of the Pediatric Endocrine Nurse in the Clinical Research Setting SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Meeting Abstract C1 [Cochran, Elaine K.] NIH, NIDDKD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD APR PY 2013 VL 28 IS 2 BP 207 EP 207 DI 10.1016/j.pedn.2013.02.014 PG 1 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 115WN UT WOS:000316842700029 ER PT J AU Carlo, WA Goudar, SS Pasha, O Chomba, E Wallander, JL Biasini, FJ McClure, EM Thorsten, V Chakraborty, H Wallace, D Shearer, DL Wright, LL AF Carlo, Waldemar A. Goudar, Shivaprasad S. Pasha, Omrana Chomba, Elwyn Wallander, Jan L. Biasini, Fred J. McClure, Elizabeth M. Thorsten, Vanessa Chakraborty, Hrishikesh Wallace, Dennis Shearer, Darlene L. Wright, Linda L. CA Brain Res Ameliorate Impaired Natl Inst Child Hlth Human Dev TI Randomized Trial of Early Developmental Intervention on Outcomes in Children after Birth Asphyxia in Developing Countries SO JOURNAL OF PEDIATRICS LA English DT Article ID PERINATAL-MORTALITY; DEVELOPMENT PROGRAM; PREMATURE-INFANTS; AGE; ENCEPHALOPATHY; RESUSCITATION; POPULATION; WEIGHT; DISABILITY; HEALTH AB Objective To determine if early developmental intervention (EDI) improves developmental abilities in resuscitated children. Study design This was a parallel group, randomized controlled trial of infants unresponsive to stimulation who received bag and mask ventilation as part of their resuscitation at birth and infants who did not require any resuscitation born in rural communities in India, Pakistan, and Zambia. Intervention infants received a parent-implemented EDI delivered with home visits by parent trainers every other week for 3 years starting the first month after birth. Parents in both intervention and control groups received health and safety counseling during home visits on the same schedule. The main outcome measure was the Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd edition, assessed at 36 months by evaluators unaware of treatment group and resuscitation history. Results MDI was higher in the EDI (102.6 +/- 9.8) compared with the control resuscitated children (98.0 +/- 14.6, 1-sided P = .0202), but there was no difference between groups in the nonresuscitated children (100.1 +/- 10.7 vs 97.7 +/- 10.4, P = .1392). The Psychomotor Development Index was higher in the EDI group for both the resuscitated (P = .0430) and nonresuscitated children (P = .0164). Conclusions This trial of home-based, parent provided EDI in children resuscitated at birth provides evidence of treatment benefits on cognitive and psychomotor outcomes. MDI and Psychomotor Development Index scores of both nonresuscitated and resuscitated infants were within normal range, independent of early intervention. (J Pediatr 2013;162:705-12). C1 [Carlo, Waldemar A.; Biasini, Fred J.] Univ Alabama Birmingham, Birmingham, AL 35233 USA. [Carlo, Waldemar A.; Chomba, Elwyn] Ctr Infect Dis Res Zambia, Lusaka, Zambia. [Goudar, Shivaprasad S.] KLE Univ, Jawaharlal Nehru Med Coll, Belgaum, India. [Pasha, Omrana] Aga Kahn Univ, Coll Med, Karachi, Pakistan. [Chomba, Elwyn] Univ Zambia, Lusaka, Zambia. [Wallander, Jan L.] Univ Calif, Merced, CA USA. [McClure, Elizabeth M.; Thorsten, Vanessa; Chakraborty, Hrishikesh; Wallace, Dennis] RTI Int, Durham, NC USA. [Chakraborty, Hrishikesh] Univ S Carolina, Columbia, SC 29208 USA. [Shearer, Darlene L.] Western Kentucky Univ, Bowling Green, KY 42101 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Carlo, WA (reprint author), Univ Alabama Birmingham, 1700 6th Ave South,176F Suite 9380, Birmingham, AL 35233 USA. EM wcarlo@peds.uab.edu OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Eunice Kennedy Shriver National Institute of Child Health; Human Development Global Network for Women's and Children's Health Research; National Institute of Neurological Disorders and Stroke [HD43464, HD42372, HD40607, HD40636]; Fogarty International Center [TW006703]; Perinatal Health and Human Development Research Program; Children's of Alabama Centennial Scholar Fund of the University of Alabama at Birmingham FX Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research and the National Institute of Neurological Disorders and Stroke (HD43464, HD42372, HD40607, and HD40636), the Fogarty International Center (TW006703), the Perinatal Health and Human Development Research Program, and the Children's of Alabama Centennial Scholar Fund of the University of Alabama at Birmingham. W.C. is on the Mednax Board of Directors. The other authors declare no conflicts of interest. NR 39 TC 13 Z9 13 U1 1 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2013 VL 162 IS 4 BP 705 EP + DI 10.1016/j.jpeds.2012.09.052 PG 11 WC Pediatrics SC Pediatrics GA 114GK UT WOS:000316728900015 PM 23164311 ER PT J AU Nachman, RM Fox, SD Golden, WC Sibinga, E Veenstra, TD Groopman, JD Lees, PSJ AF Nachman, Rebecca M. Fox, Stephen D. Golden, W. Christopher Sibinga, Erica Veenstra, Timothy D. Groopman, John D. Lees, Peter S. J. TI Urinary Free Bisphenol A and Bisphenol A-Glucuronide Concentrations in Newborns SO JOURNAL OF PEDIATRICS LA English DT Article ID EXPOSURE AB Infants are exposed to the endocrine disruptor bisphenol A (BPA) through breast milk and baby formula. Detoxication by conjugation of BPA may be limited in infants. We demonstrate BPA exposure in 11 neonates and 1 young infant, but find no evidence of a low capacity for BPA conjugation. (J Pediatr 2013;162:870-2). C1 [Nachman, Rebecca M.; Groopman, John D.; Lees, Peter S. J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Fox, Stephen D.; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Prote, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Golden, W. Christopher; Sibinga, Erica] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. RP Nachman, RM (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, 615 N Wolfe St,Rm E7402, Baltimore, MD 21205 USA. EM rnachman@jhsph.edu FU Johns Hopkins Center for a Livable Future; National Institutes of Health [P01 ES006052, P30 ES003819, N01-CO-12400, T32 ES007141] FX Supported by the Johns Hopkins Center for a Livable Future and the National Institutes of Health (P01 ES006052, P30 ES003819, Contract N01-CO-12400, and training grant T32 ES007141). Neither sponsor had a role in the study design, collection, analysis, or interpretation of data, the writing of the report, or the decision to submit the paper for publication. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. The authors declare no conflicts of interest. NR 12 TC 10 Z9 10 U1 0 U2 19 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR-US JI J. Pediatr. PD APR PY 2013 VL 162 IS 4 BP 870 EP 872 DI 10.1016/j.jpeds.2012.11.083 PG 3 WC Pediatrics SC Pediatrics GA 114GK UT WOS:000316728900048 PM 23312693 ER PT J AU Ince, WL Gueye-Mbaye, A Bennink, JR Yewdell, JW AF Ince, William L. Gueye-Mbaye, Aissatou Bennink, Jack R. Yewdell, Jonathan W. TI Reassortment Complements Spontaneous Mutation in Influenza A Virus NP and M1 Genes To Accelerate Adaptation to a New Host SO JOURNAL OF VIROLOGY LA English DT Article ID GUINEA-PIG MODEL; EVOLUTIONARY DYNAMICS; ANIMAL-MODELS; TRANSMISSION; NUCLEOPROTEIN; PATHOGENESIS; VARIANTS; SEGMENT; MICE AB Influenza A virus (IAV) infects a remarkably wide variety of avian and mammalian hosts. Evolution finely hones IAV genes to optimally infect and be transmitted in a particular host species. Sporadically, IAV manages to jump between species, introducing novel antigenic strains into the new host population that wreak havoc until herd immunity develops. IAV adaptation to new hosts typically involves reassortment of IAV gene segments from coinfecting virus strains adapted to different hosts in conjunction with multiple adaptive mutations in the various IAV genes. To better understand host adaptation between mammalian species in real time, we passaged mouse-adapted A/PR8/34 (PR8) in guinea pigs. Guinea pigs, unlike mice, support spontaneous and robust IAV transmission. For some IAV strains, including PR8, adaptation is required for a virus to attain transmissibility, providing an opportunity to understand the evolution of transmissibility in guinea pigs. Multiple guinea pig-adapted PR8 mutants generated by serial nasal wash passaging in independent lines replicated more efficiently and were transmitted by cocaging. All transmissible variants possessed one of two nonsynonymous mutations in M1, either alone or in combination with mutations in PB2, HA, NP, or NA. Rapid reassortment between independently selected variants combined beneficial mutations in NP and M1 to form the fittest virus capable of being transmitted. These findings provide further insight into genetic determinants in NP and M1 involved in PR8 IAV adaptation to be transmitted in a new host and clearly show the benefit of a segmented genome in rapidly generating optimal combinations of mutations in IAV evolution. C1 [Ince, William L.; Gueye-Mbaye, Aissatou; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov FU Division of Intramural Research, NIAID; American Recovery and Reinvestment Act FX This work was supported by the Division of Intramural Research, NIAID, and funds provided by the American Recovery and Reinvestment Act. NR 40 TC 22 Z9 25 U1 2 U2 21 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4330 EP 4338 DI 10.1128/JVI.02749-12 PG 9 WC Virology SC Virology GA 113MC UT WOS:000316671000019 PM 23365443 ER PT J AU Del Prete, GQ Scarlotta, M Newman, L Reid, C Parodi, LM Roser, JD Oswald, K Marx, PA Miller, CJ Desrosiers, RC Barouch, DH Pal, R Piatak, M Chertova, E Giavedoni, LD O'Connor, DH Lifson, JD Keele, BF AF Del Prete, Gregory Q. Scarlotta, Matthew Newman, Laura Reid, Carolyn Parodi, Laura M. Roser, James D. Oswald, Kelli Marx, Preston A. Miller, Christopher J. Desrosiers, Ronald C. Barouch, Dan H. Pal, Ranajit Piatak, Michael, Jr. Chertova, Elena Giavedoni, Luis D. O'Connor, David H. Lifson, Jeffrey D. Keele, Brandon F. TI Comparative Characterization of Transfection- and Infection-Derived Simian Immunodeficiency Virus Challenge Stocks for In Vivo Nonhuman Primate Studies SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN TRIMERS; FUSION INHIBITOR T-20; RHESUS MACAQUES; MOLECULAR CLONES; VIRAL LOADS; SIVMAC251; TYPE-1; HIV-1; SIV; ANTIBODY AB Simian immunodeficiency virus (SIV) stocks for in vivo nonhuman primate models of AIDS are typically generated by transfection of 293T cells with molecularly cloned viral genomes or by expansion in productively infected T cells. Although titers of stocks are determined for infectivity in vitro prior to in vivo inoculation, virus production methods may differentially affect stock features that are not routinely analyzed but may impact in vivo infectivity, mucosal transmissibility, and early infection events. We performed a detailed analysis of nine SIV stocks, comprising five infection-derived SIVmac251 viral swarm stocks and paired infection- and transfected-293T-cell-derived stocks of both SIVmac239 and SIVmac766. Representative stocks were evaluated for (i) virus content, (ii) infectious titer, (iii) sequence diversity and polymorphism frequency by single-genome amplification and 454 pyrosequencing, (iv) virion-associated Env content, and (v) cytokine and chemokine content by 36-plex Luminex analysis. Regardless of production method, all stocks had comparable particle/infectivity ratios, with the transfected-293T stocks possessing the highest overall virus content and infectivity titers despite containing markedly lower levels of virion-associated Env than infection-derived viruses. Transfected-293T stocks also contained fewer and lower levels of cytokines and chemokines than infection-derived stocks, which had elevated levels of multiple analytes, with substantial variability among stocks. Sequencing of the infection-derived SIVmac251 stocks revealed variable levels of viral diversity between stocks, with evidence of stock-specific selection and expansion of unique viral lineages. These analyses suggest that there may be underappreciated features of SIV in vivo challenge stocks with the potential to impact early infection events, which may merit consideration when selecting virus stocks for in vivo studies. C1 [Del Prete, Gregory Q.; Newman, Laura; Reid, Carolyn; Roser, James D.; Oswald, Kelli; Piatak, Michael, Jr.; Chertova, Elena; Lifson, Jeffrey D.; Keele, Brandon F.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. [Scarlotta, Matthew; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [O'Connor, David H.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI USA. [Parodi, Laura M.; Giavedoni, Luis D.] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX USA. [Giavedoni, Luis D.] Texas Biomed Res Inst, Southwest Natl Primate Res Ctr, San Antonio, TX USA. [Marx, Preston A.] Tulane Univ, Div Microbiol, Tulane Natl Primate Res Ctr, Covington, LA USA. [Miller, Christopher J.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Desrosiers, Ronald C.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA. [Barouch, Dan H.] MIT & Harvard, Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA USA. [Barouch, Dan H.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Pal, Ranajit] Adv Biosci Labs Inc, Kensington, MD USA. RP Keele, BF (reprint author), SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. EM keelebf@mail.nih.gov RI Del Prete, Gregory/C-2030-2012; OI o'connor, david/0000-0003-2139-470X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH [OD013096, AI077376, AI08747, AI096040, AI095985, AI078526]; National Center for Research Resources; Office of Research Infrastructure Programs (ORIP) of the NIH [P51 RR00164-50, P51 RR000167, P51 OD011133]; Research Facilities Improvement Program [RR15459-01, RR020141-01] FX This work was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E, and in part by NIH grants OD013096 to L.D.G., AI077376 and AI08747 to D.H.O., and AI096040, AI095985, and AI078526 to D.H.B. The National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) of the NIH supported this study through grants P51 RR00164-50, P51 RR000167, and P51 OD011133. Additionally, some of this work was conducted in a facility constructed with support from Research Facilities Improvement Program grant no. RR15459-01 and RR020141-01. NR 47 TC 28 Z9 28 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4584 EP 4595 DI 10.1128/JVI.03507-12 PG 12 WC Virology SC Virology GA 113MC UT WOS:000316671000041 PM 23408608 ER PT J AU Grover, JR Llewellyn, GN Soheilian, F Nagashima, K Veatch, SL Ono, A AF Grover, Jonathan R. Llewellyn, G. Nicholas Soheilian, Ferri Nagashima, Kunio Veatch, Sarah L. Ono, Akira TI Roles Played by Capsid-Dependent Induction of Membrane Curvature and Gag-ESCRT Interactions in Tetherin Recruitment to HIV-1 Assembly Sites SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS TYPE-1 GAG; PLASMA-MEMBRANE; PARTICLE RELEASE; LIPID RAFTS; CELL-SURFACE; VPU PROTEIN; LATE DOMAIN; BINDING; ASSOCIATION; MICROSCOPY AB Tetherin/BST-2 (here called tetherin) is an antiviral protein that restricts release of diverse enveloped viruses from infected cells through physically tethering virus envelope and host plasma membrane. For HIV-1, specific recruitment of tetherin to assembly sites has been observed as its colocalization with the viral structural protein Gag or its accumulation in virus particles. Because of its broad range of targets, we hypothesized that tetherin is recruited through conserved features shared among various enveloped viruses, such as lipid raft association, membrane curvature, or ESCRT dependence. We observed that reduction of cellular cholesterol does not block tetherin anti-HIV-1 function, excluding an essential role for lipid rafts. In contrast, mutations in the capsid domain of Gag, which inhibit induction of membrane curvature, prevented tetherin-Gag colocalization detectable by confocal microscopy. Disruption of Gag-ESCRT interactions also inhibited tetherin-Gag colocalization when disruption was accomplished via amino acid substitutions in late domain motifs, expression of a dominant-negative Tsg101 derivative, or small interfering RNA (siRNA)-mediated depletion of Tsg101 or Alix. However, further analyses of these conditions by quantitative superresolution localization microscopy revealed that Gag-tetherin coclustering is significantly reduced but persists at intermediate levels. Notably, this residual tetherin recruitment was still sufficient for the full restriction of HIV-1 release. Unlike the late domain mutants, the capsid mutants defective in inducing membrane curvature showed little or no coclustering with tetherin in superresolution analyses. These results support a model in which both Gag-induced membrane curvature and Gag-ESCRT interactions promote tetherin recruitment, but the recruitment level achieved by the former is sufficient for full restriction. C1 [Grover, Jonathan R.; Ono, Akira] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Llewellyn, G. Nicholas; Ono, Akira] Univ Michigan, Sch Med, Cellular & Mol Biol Program, Ann Arbor, MI 48109 USA. [Soheilian, Ferri; Nagashima, Kunio] NCI, Electron Microscopy Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. [Veatch, Sarah L.] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA. RP Veatch, SL (reprint author), Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA. EM sveatch@umich.edu; akiraono@umich.edu RI Veatch, Sarah/G-9512-2016; OI Veatch, Sarah/0000-0002-9317-2308; Ono, Akira/0000-0001-7841-851X FU NIH [R00 GM087810, R56 AI089282, R21 AI095022, T32 AI007527-13] FX This work was supported by NIH grants, R00 GM087810 (to S. L. V.), R56 AI089282 (to A.O.), and R21 AI095022 (to A.O.). J.R.G. is supported by NIH training grant T32 AI007527-13. NR 90 TC 16 Z9 16 U1 1 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4650 EP 4664 DI 10.1128/JVI.03526-12 PG 15 WC Virology SC Virology GA 113MC UT WOS:000316671000046 PM 23408603 ER PT J AU Murcia, PR Baillie, GJ Stack, JC Jervis, C Elton, D Mumford, JA Daly, J Kellam, P Grenfell, BT Holmes, EC Wood, JLN AF Murcia, Pablo R. Baillie, Gregory J. Stack, J. Conrad Jervis, Carley Elton, Debra Mumford, Jennifer A. Daly, Janet Kellam, Paul Grenfell, Bryan T. Holmes, Edward C. Wood, James L. N. TI Evolution of Equine Influenza Virus in Vaccinated Horses SO JOURNAL OF VIROLOGY LA English DT Article ID H3N8; DYNAMICS; DOGS AB Influenza A viruses are characterized by their ability to evade host immunity, even in vaccinated individuals. To determine how prior immunity shapes viral diversity in vivo, we studied the intra- and interhost evolution of equine influenza virus in vaccinated horses. Although the level and structure of genetic diversity were similar to those in naive horses, intrahost bottlenecks may be more stringent in vaccinated animals, and mutations shared among horses often fall close to putative antigenic sites. C1 [Murcia, Pablo R.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Infect Inflammat & Immun, MRC,Univ Glasgow Ctr Virus Res, Glasgow, Lanark, Scotland. [Baillie, Gregory J.; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge, England. [Stack, J. Conrad] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Mumford, Jennifer A.; Wood, James L. N.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge, England. [Kellam, Paul] UCL, Dept Infect, Div Infect & Immun, London, England. [Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. [Grenfell, Bryan T.; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Holmes, Edward C.] Univ Sydney, Sch Biol Sci, Sydney Emerging Infect & Biosecur Inst, Sydney, NSW 2006, Australia. [Holmes, Edward C.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. RP Wood, JLN (reprint author), Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge, England. EM jlnw2@cam.ac.uk RI Wood, James/A-1626-2008; Baillie, Gregory/F-9478-2013; OI Wood, James/0000-0002-0258-3188; Baillie, Gregory/0000-0002-6130-250X; Daly, Janet/0000-0002-1912-4500; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust; Medical Research Council of the United Kingdom; National Institutes of Health [R01 GM080533-06]; National Health and Medical Research Council Australia; Alborada Trust; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; DEFRA [VT0105]; HEFCE under the Veterinary Training and Research Initiative FX P.R.M. was funded by the Wellcome Trust and the Medical Research Council of the United Kingdom. E. C. H. was funded by grant R01 GM080533-06 from the National Institutes of Health and a National Health and Medical Research Council Australia Fellowship. J.L.N.W. was funded by Alborada Trust. B. T. G. and J.L.N.W. were supported by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. The work was supported by grant VT0105 from DEFRA and HEFCE under the Veterinary Training and Research Initiative to the Cambridge Infectious Disease Consortium. NR 15 TC 12 Z9 12 U1 0 U2 31 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4768 EP 4771 DI 10.1128/JVI.03379-12 PG 4 WC Virology SC Virology GA 113MC UT WOS:000316671000058 PM 23388708 ER PT J AU Shin, EC Park, SH Nascimbeni, M Major, M Caggiari, L de Re, V Feinstone, SM Rice, CM Rehermann, B AF Shin, Eui-Cheol Park, Su-Hyung Nascimbeni, Michelina Major, Marian Caggiari, Laura de Re, Valli Feinstone, Stephen M. Rice, Charles M. Rehermann, Barbara TI The Frequency of CD127(+) Hepatitis C Virus (HCV)-Specific T Cells but Not the Expression of Exhaustion Markers Predicts the Outcome of Acute HCV Infection SO JOURNAL OF VIROLOGY LA English DT Article ID PD-1 EXPRESSION; VIRAL PERSISTENCE; FUNCTIONAL RESTORATION; PROGRAMMED DEATH-1; CD8 RESPONSES; PHENOTYPE; BLOCKADE; LYMPHOCYTES; DYSFUNCTION; CHIMPANZEES AB T cells are exhausted and overexpress inhibitory molecules in chronic hepatitis C virus (HCV) infection. It is unclear whether this is the cause or consequence of HCV persistence. By studying serial blood and liver samples of chimpanzees during acute infection, we demonstrate that the early expression of the memory precursor marker CD127 on HCV-specific T cells, but not the expression of inhibitory molecules on those T cells or their ligands in the liver, predicts the outcome of acute infection. C1 [Shin, Eui-Cheol; Park, Su-Hyung; Nascimbeni, Michelina; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD USA. [Shin, Eui-Cheol] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Lab Immunol & Infect Dis, Taejon 305701, South Korea. [Major, Marian; Feinstone, Stephen M.] US FDA, Ctr Biol Evaluat & Res, Lab Hepatitis Viruses, Bethesda, MD USA. [Caggiari, Laura; de Re, Valli] IRCCS, Natl Canc Inst, CRO Ctr Riferimento Oncol, Expt & Clin Pharmacol Unit, Aviano, PN, Italy. [Rice, Charles M.] Rockefeller Univ, Ctr Study Hepatitis C, New York, NY 10021 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD USA. EM Rehermann@nih.gov RI Shin, Eui-Cheol/C-1690-2011; Park, Su-Hyung/N-3514-2014 FU NIDDK, NIH; [AIRC-10266]; Associazione Italiana per la Ricerca sul Cancro FX This work was supported by grant AIRC-10266 to V. D. R. and by the NIDDK, NIH, intramural research program. NR 35 TC 17 Z9 21 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4772 EP 4777 DI 10.1128/JVI.03122-12 PG 6 WC Virology SC Virology GA 113MC UT WOS:000316671000059 PM 23388706 ER PT J AU Safronetz, D Prescott, J Haddock, E Scott, DP Feldmann, H Ebiharaa, H AF Safronetz, David Prescott, Joseph Haddock, Elaine Scott, Dana P. Feldmann, Heinz Ebiharaa, Hideki TI Hamster-Adapted Sin Nombre Virus Causes Disseminated Infection and Efficiently Replicates in Pulmonary Endothelial Cells without Signs of Disease SO JOURNAL OF VIROLOGY LA English DT Article ID SYRIAN GOLDEN-HAMSTER; ANDES VIRUS; HANTAVIRUS; MODEL AB To date, a laboratory animal model for the study of Sin Nombre virus (SNV) infection or associated disease has not been described. Unlike infection with Andes virus, which causes lethal hantavirus pulmonary syndrome (HPS)-like disease in hamsters, SNV infection is short-lived, with no viremia and little dissemination. Here we investigated the effect of passaging SNV in hamsters. We found that a host-adapted SNV achieves prolonged and disseminated infection in hamsters, including efficient replication in pulmonary endothelial cells, albeit without signs of disease. C1 [Safronetz, David; Prescott, Joseph; Haddock, Elaine; Feldmann, Heinz; Ebiharaa, Hideki] NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Scott, Dana P.] NIAID, Rocky Mt Vet Branch, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol & Infect Dis, Winnipeg, MB, Canada. RP Safronetz, D (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH,Rocky Mt Labs, Hamilton, MT USA. EM safronetzd@niaid.nih.gov 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 14 TC 15 Z9 15 U1 1 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4778 EP 4782 DI 10.1128/JVI.03291-12 PG 5 WC Virology SC Virology GA 113MC UT WOS:000316671000060 PM 23388711 ER PT J AU Gadegbeku, CA Gipson, DS Holzman, LB Ojo, AO Song, PXK Barisoni, L Sampson, MG Kopp, JB Lemley, KV Nelson, PJ Lienczewski, CC Adler, SG Appel, GB Cattran, DC Choi, MJ Contreras, G Dell, KM Fervenza, FC Gibson, KL Greenbaum, LA Hernandez, JD Hewitt, SM Hingorani, SR Hladunewich, M Hogan, MC Hogan, SL Kaskel, FJ Lieske, JC Meyers, KEC Nachman, PH Nast, CC Neu, AM Reich, HN Sedor, JR Sethna, CB Trachtman, H Tuttle, KR Zhdanova, O Zilleruelo, GE Kretzler, M AF Gadegbeku, Crystal A. Gipson, Debbie S. Holzman, Lawrence B. Ojo, Akinlolu O. Song, Peter X. K. Barisoni, Laura Sampson, Matthew G. Kopp, Jeffrey B. Lemley, Kevin V. Nelson, Peter J. Lienczewski, Chrysta C. Adler, Sharon G. Appel, Gerald B. Cattran, Daniel C. Choi, Michael J. Contreras, Gabriel Dell, Katherine M. Fervenza, Fernando C. Gibson, Keisha L. Greenbaum, Larry A. Hernandez, Joel D. Hewitt, Stephen M. Hingorani, Sangeeta R. Hladunewich, Michelle Hogan, Marie C. Hogan, Susan L. Kaskel, Frederick J. Lieske, John C. Meyers, Kevin E. C. Nachman, Patrick H. Nast, Cynthia C. Neu, Alicia M. Reich, Heather N. Sedor, John R. Sethna, Christine B. Trachtman, Howard Tuttle, Katherine R. Zhdanova, Olga Zilleruelo, Gaston E. Kretzler, Matthias TI Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach SO KIDNEY INTERNATIONAL LA English DT Article DE clinical trial; focal segmental glomerulosclerosis; membranous nephropathy; nephrotic syndrome ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; IDIOPATHIC MEMBRANOUS NEPHROPATHY; GENETIC-HETEROGENEITY; CLINICAL SPECTRUM; MICROARRAY DATA; KIDNEY-DISEASE; RENAL-DISEASE; CLASSIFICATION; CHILDHOOD; FAILURE AB The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies. Kidney International (2013) 83, 749-756; doi:10.1038/ki.2012.428; published online 16 January 2013 C1 [Gadegbeku, Crystal A.] Temple Univ, Dept Med, Philadelphia, PA 19122 USA. [Gipson, Debbie S.; Ojo, Akinlolu O.; Song, Peter X. K.; Sampson, Matthew G.; Lienczewski, Chrysta C.; Kretzler, Matthias] Univ Michigan, Dept Nephrol Internal Med, Ann Arbor, MI 48109 USA. [Gipson, Debbie S.; Ojo, Akinlolu O.; Song, Peter X. K.; Sampson, Matthew G.; Lienczewski, Chrysta C.; Kretzler, Matthias] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Gipson, Debbie S.; Ojo, Akinlolu O.; Song, Peter X. K.; Sampson, Matthew G.; Lienczewski, Chrysta C.; Kretzler, Matthias] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Gipson, Debbie S.; Ojo, Akinlolu O.; Song, Peter X. K.; Sampson, Matthew G.; Lienczewski, Chrysta C.; Kretzler, Matthias] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Holzman, Lawrence B.; Meyers, Kevin E. C.] Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. [Holzman, Lawrence B.; Meyers, Kevin E. C.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Barisoni, Laura; Contreras, Gabriel; Zilleruelo, Gaston E.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA. [Barisoni, Laura; Contreras, Gabriel; Zilleruelo, Gaston E.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Barisoni, Laura; Contreras, Gabriel; Zilleruelo, Gaston E.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Kopp, Jeffrey B.] NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. [Lemley, Kevin V.] Univ So Calif, Dept Pediat, Div Nephrol, Childrens Hosp Los Angeles, Los Angeles, CA 90089 USA. [Nelson, Peter J.] Univ Washington, Dept Med, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA. [Adler, Sharon G.] Univ Calif Los Angeles, Med Ctr, Dept Med, Los Angeles Biomed Res Inst Harbor, Los Angeles, CA 90024 USA. [Nast, Cynthia C.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Appel, Gerald B.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. [Cattran, Daniel C.; Hladunewich, Michelle; Reich, Heather N.] Univ Toronto, Dept Med, Univ Hlth Network, Toronto, ON, Canada. [Choi, Michael J.; Neu, Alicia M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Choi, Michael J.; Neu, Alicia M.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Dell, Katherine M.; Sedor, John R.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Dell, Katherine M.; Sedor, John R.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Dell, Katherine M.; Sedor, John R.] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Fervenza, Fernando C.; Hogan, Marie C.; Lieske, John C.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Lieske, John C.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Gibson, Keisha L.; Hogan, Susan L.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Gibson, Keisha L.; Hogan, Susan L.] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. [Greenbaum, Larry A.] Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. [Greenbaum, Larry A.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Hernandez, Joel D.; Tuttle, Katherine R.] Sacred Heart Med Ctr, Dept Med, Providence Med Res Ctr, Spokane, WA USA. [Hernandez, Joel D.; Tuttle, Katherine R.] Sacred Heart Med Ctr, Dept Pediat, Providence Med Res Ctr, Spokane, WA USA. [Hewitt, Stephen M.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Hingorani, Sangeeta R.] Univ Washington, Dept Pediat, Div Nephrol, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Kaskel, Frederick J.] Montefiore Med Ctr, Dept Pediat, Bronx, NY 10467 USA. [Sethna, Christine B.] Cohen Childrens Med Ctr New York, Dept Pediat, New Hyde Pk, NY USA. [Trachtman, Howard; Zhdanova, Olga] NYU, Dept Pediat, Sch Med, New York, NY 10016 USA. [Trachtman, Howard; Zhdanova, Olga] NYU, Sch Med, Dept Med, New York, NY 10016 USA. RP Kretzler, M (reprint author), Univ Michigan, Dept Nephrol Internal Med, Ctr Computat Med & Bioinformat, 1560 MSRB 2,1150 W Med Ctr Dr SPC5676, Ann Arbor, MI 48109 USA. EM kretzler@umich.edu OI Hewitt, Stephen/0000-0001-8283-1788; Kopp, Jeffrey/0000-0001-9052-186X; Trachtman, Howard/0000-0001-7447-9489 FU Office of Rare Diseases Research (ORDR)/NCATS, NIDDK [U54 DK083912]; NephCure Foundation; University of Michigan FX NEPTUNE is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by U54 DK083912 from the Office of Rare Diseases Research (ORDR)/NCATS, NIDDK, the NephCure Foundation, and the University of Michigan. The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services, nor does the mention by trade names, commercial practices, or organizations imply endorsement by the US Government. We thank D. Taylor-Moon for assistance in manuscript preparation. NR 41 TC 45 Z9 45 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD APR PY 2013 VL 83 IS 4 BP 749 EP 756 DI 10.1038/ki.2012.428 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 117HY UT WOS:000316945400027 PM 23325076 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and APHIS SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD APR PY 2013 VL 42 IS 4 BP 121 EP 121 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 115XW UT WOS:000316846200017 PM 23511079 ER PT J AU Cardiff, RD Hubbard, NE Engelberg, JA Munn, RJ Miller, CH Walls, JE Chen, JQ Velasquez-Garcia, HA Galvez, JJ Bell, KJ Beckett, LA Li, YJ Borowsky, AD AF Cardiff, Robert D. Hubbard, Neil E. Engelberg, Jesse A. Munn, Robert J. Miller, Claramae H. Walls, Judith E. Chen, Jane Q. Velasquez-Garcia, Hector A. Galvez, Jose J. Bell, Katie J. Beckett, Laurel A. Li, Yue-Ju Borowsky, Alexander D. TI Quantitation of fixative-induced morphologic and antigenic variation in mouse and human breast cancers SO LABORATORY INVESTIGATION LA English DT Article DE estrogen receptor; Her2; IHC4 biomarker panel; immunohistochemistry; MIB1 (Ki67); progesterone receptor; quantitative image analysis ID PARAFFIN-EMBEDDED TISSUE; ESTROGEN-RECEPTOR; NUCLEIC-ACIDS; FORMALIN; RNA; PROTEIN; IMMUNOHISTOCHEMISTRY; INTEGRITY; DNA; HISTOPATHOLOGY AB Quantitative Image Analysis (QIA) of digitized whole slide images for morphometric parameters and immunohistochemistry of breast cancer antigens was used to evaluate the technical reproducibility, biological variability, and intratumoral heterogeneity in three transplantable mouse mammary tumor models of human breast cancer. The relative preservation of structure and immunogenicity of the three mouse models and three human breast cancers was also compared when fixed with representatives of four distinct classes of fixatives. The three mouse mammary tumor cell models were an ER + /PR + model (SSM2), a Her2 + model (NDL), and a triple negative model (MET1). The four breast cancer antigens were ER, PR, Her2, and Ki67. The fixatives included examples of (1) strong cross-linkers, (2) weak cross-linkers, (3) coagulants, and (4) combination fixatives. Each parameter was quantitatively analyzed using modified Aperio Technologies ImageScope algorithms. Careful pre-analytical adjustments to the algorithms were required to provide accurate results. The QIA permitted rigorous statistical analysis of results and grading by rank order. The analyses suggested excellent technical reproducibility and confirmed biological heterogeneity within each tumor. The strong cross-linker fixatives, such as formalin, consistently ranked higher than weak cross-linker, coagulant and combination fixatives in both the morphometric and immunohistochemical parameters. Laboratory Investigation (2013) 93, 480-497; doi:10.1038/labinvest.2013.10; published online 11 February 2013 C1 [Cardiff, Robert D.; Hubbard, Neil E.; Engelberg, Jesse A.; Munn, Robert J.; Miller, Claramae H.; Walls, Judith E.; Chen, Jane Q.; Velasquez-Garcia, Hector A.; Bell, Katie J.; Borowsky, Alexander D.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Cardiff, Robert D.; Munn, Robert J.; Miller, Claramae H.; Borowsky, Alexander D.] Univ Calif Davis, Dept Pathol & Lab Med, Sch Med, Davis, CA 95616 USA. [Galvez, Jose J.] NCI, Ctr Biomed Informat & Informat Technol, NIH, Washington, DC USA. [Beckett, Laurel A.; Li, Yue-Ju] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Div Biostat, Davis, CA 95616 USA. RP Borowsky, AD (reprint author), Univ Calif Davis, Ctr Comparat Med, Cty Rd 98,Hutchison Dr, Davis, CA 95616 USA. EM adborowsky@ucdavis.edu OI Beckett, Laurel/0000-0002-2418-9843 FU Athena Breast Health Network, through the support of the Safeway Foundation; University of California Office of the President; National Cancer Institute's Mouse Models of Human Cancers Consortium [U01 CA141582, U01 CA141541, U01 CA105490-01] FX We acknowledge the genesis of these studies as arising from our participation in two cooperative organizations. First, the Athena Breast Health Network (a University of California-wide collaboration aiming to integrate clinical care and research and drive innovation in patient-centered prevention, screening, and treatment of breast cancer) and, second, the National Cancer Institute's Mouse Models of Human Cancers Consortium. Athena program needs include the preservation of structural, antigenic, and molecular analysis quality maximizing the utility of increasingly small specimens for research and standard of care diagnosis. We wish to acknowledge the support of Dr Laura Esserman, Athena Breast Health Network and University of California, San Francisco, who inspired and encouraged this project. The SSM2 cells were a gift from Drs RD Schreiber and S Chan, Washington University, Department of Pathology, St Louis, MO. We thank Dr Sarah Elson, Athena, for critical review of the manuscript and Dr Josh Miller for thoughtful commentary during the development of the project. The research described here was supported by the Athena Breast Health Network, through the support of the Safeway Foundation and the University of California Office of the President (RC, JE, AB, NH, and JW); National Cancer Institute's Mouse Models of Human Cancers Consortium (U01 CA141582, U01 CA141541, U01 CA105490-01) (RC, AB, QC, JG, HV). Statistical support was made possible by the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research (UL1 RR024146) (LB, YJL); its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 43 TC 16 Z9 16 U1 0 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD APR PY 2013 VL 93 IS 4 BP 480 EP 497 DI 10.1038/labinvest.2013.10 PG 18 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 115HZ UT WOS:000316804500010 PM 23399853 ER PT J AU DeKlotz, TR Kim, HJ Kelly, M Collins, MT AF DeKlotz, Timothy R. Kim, Hung Jeffrey Kelly, Marilyn Collins, Michael T. TI Sinonasal Disease in Polyostotic Fibrous Dysplasia and McCune-Albright Syndrome SO LARYNGOSCOPE LA English DT Article DE Fibrous dysplasia; McCune-Albright Syndrome; sinonasal; Level of Evidence: 4 ID SURGICAL-TREATMENT; PARANASAL SINUSES; BONE; SURGERY; DYSFUNCTION; MUTATIONS; HORMONE AB Objectives/Hypothesis: To characterize the spectrum, symptoms, progression, and effects of endocrine dysfunction on sinonasal disease in polyostotic fibrous dysplasia (PFD) and McCuneAlbright Syndrome (MAS). Study Design: Retrospective review. Methods: A prospectively followed cohort of subjects with PFD/MAS underwent a comprehensive evaluation that included otolaryngologic and endocrine evaluation, and imaging studies. Head and facial computed tomography scans were analyzed, and the degree of fibrous dysplasia (FD) was graded using a modified LundMacKay scale. Those followed for >4 years were analyzed for progression. Results: A total of 106 patients meeting inclusion criteria were identified with craniofacial FD. A majority (92%) demonstrated sinonasal involvement. There were significant positive correlations between the sinonasal FD scale score and chronic congestion, hyposmia, growth hormone excess, and hyperthyroidism (P < .05 for all). Significant correlations were not found for headache/facial pain or recurrent/chronic sinusitis. Thirty-one subjects met the criteria for longitudinal analysis (follow-up mean, 6.3 years; range, 4.49 years). Those who demonstrated disease progression were significantly younger than those who did not (mean age, 11 vs. 25 years). Progression after age of 13 years was uncommon (n = 3) and minimal. Concomitant endocrinopathy or bisphosphonate use did not have any significant effect on progression of disease. Conclusions: Sinonasal involvement of fibrous dysplasia in PFD/MAS is common. Symptoms are usually few and mild, and disease progression occurs primarily in young subjects. Concomitant endocrinopathy is associated with disease severity, but not progression. C1 [DeKlotz, Timothy R.; Kim, Hung Jeffrey] Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, Washington, DC 20007 USA. [Kim, Hung Jeffrey] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Kelly, Marilyn; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Kim, HJ (reprint author), Georgetown Univ Hosp, Dept Otolaryngol Head & Neck Surg, Gorman Bldg,1st Floor,3800 Reservoir Rd NW, Washington, DC 20007 USA. EM HK7@gunet.georgetown.edu FU Division of Intramural Research, National Institute of Dental and Craniofacial Research; National Institute on Deafness and Other Communication Disorders; National Institutes of Health, Department of Health and Human Services FX Financial support was received from the Division of Intramural Research, National Institute of Dental and Craniofacial Research and National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Department of Health and Human Services. NR 30 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2013 VL 123 IS 4 BP 823 EP 828 DI 10.1002/lary.23758 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 115KZ UT WOS:000316812400005 PM 23444264 ER PT J AU Moriguchi, T Harauma, A Salem, N AF Moriguchi, Toru Harauma, Akiko Salem, Norman, Jr. TI Plasticity of Mouse Brain Docosahexaenoic Acid: Modulation by Diet and Age SO LIPIDS LA English DT Article DE Docosahexaenoic acid; Docosapentaenoic acid; Arachidonic acid; Nervous system; n-3 Fatty acid deficiency; Diet; Essential fatty acids ID POLYUNSATURATED FATTY-ACIDS; ALPHA-LINOLENIC-ACID; RHESUS-MONKEYS; RAT-BRAIN; DEFICIENT RATS; GUINEA-PIG; LIVER; RETINA; MATURATION; REVERSIBILITY AB Decreases in brain docosahexaenoic acid (DHA) have been associated with losses in brain function leading to an interest in the conditions which lead to such brain decreases, and such variables as age. Also of relevance would be the rate of repletion of DHA when the n-3 dietary deficiency is reversed. This experiment describes dietary deficiency in n-3 fatty acids induced in weanling (3 week) and young adult (7 week) mice. There was an immediate and continuous loss of brain DHA with similar rates in the two age groups. Serum DHA declined more rapidly in younger animals with respect to similarly treated adults. Brain and serum docosapentaenoic acid (DPAn-6) increased more rapidly and to higher levels in the younger animals. A second experiment determined the rates of normalization of brain fatty acid profiles when alpha-linolenic acid was added to the diets of n-3 deficient mice. Brain DHA recovery occurred at a faster rate (half-time, T (1/2) = 1.4 weeks) when begun at weaning relative to young adult mice (T (1/2) = 3.5 weeks). Correspondingly, brain DPAn-6 recovered faster in the younger animals; the adult group had a half-time of more than twice that of the 3-week old group. This study therefore demonstrates that the young adult mouse brain DHA is somewhat plastic and can be partially depleted via a low n-3 fatty acid diet and subsequently restored when dietary n-3 fatty acids are repleted. Relevance of these findings for human nutrition is discussed. C1 [Moriguchi, Toru; Harauma, Akiko] Wakunaga Pharmaceut Co Ltd, Inst Healthcare Res, Hiroshima, Japan. [Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. [Salem, Norman, Jr.] DSM Nutr Prod Inc, Nutr Lipids, Columbia, MD 21045 USA. RP Salem, N (reprint author), DSM Nutr Prod Inc, Nutr Lipids, 6480 Dobbin Rd, Columbia, MD 21045 USA. EM moriguchi@azabu-u.ac.jp; harauma@azabu-u.ac.jp; nsalem@martek.com FU National Institutes of Health, NIAAA FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIAAA. NR 44 TC 7 Z9 7 U1 1 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0024-4201 J9 LIPIDS JI Lipids PD APR PY 2013 VL 48 IS 4 BP 343 EP 355 DI 10.1007/s11745-013-3775-5 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 114NQ UT WOS:000316748800003 PM 23460301 ER PT J AU Allen, JP Wurst, FM Thon, N Litten, RZ AF Allen, John P. Wurst, Friedrich M. Thon, Natasha Litten, Raye Z. TI Assessing the drinking status of liver transplant patients with alcoholic liver disease SO LIVER TRANSPLANTATION LA English DT Review ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; URINARY ETHYL GLUCURONIDE; GAMMA-GLUTAMYL-TRANSPEPTIDASE; HEAVY DRINKERS; CONSUMPTION; PHOSPHATIDYLETHANOL; ETHANOL; SULFATE; HAIR; BIOMARKERS AB The accurate assessment of drinking by patients with alcoholic liver disease is important both before and after liver transplantation. Unfortunately, self-reports by these individuals often underestimate their actual alcohol consumption. Several recently developed biochemical measures can provide additional information on a patient's use of alcohol. This article describes ethyl glucuronide, ethyl sulfate, phosphatidyl ethanol, and carbohydrate-deficient transferrin as biomarkers of drinking and summarizes research dealing with their application in patients with alcohol use disorders who are candidates for or recipients of liver transplantation. The article also offers suggestions for enhancing the reliability of self-report measures of drinking status. Liver Transpl 19:369376, 2013. (c) 2013 AASLD. C1 [Allen, John P.] Durham Vet Adm Med Ctr, Vet Integrated Serv Network 6, Midatlantic Mental Illness Res Educ & Clin Ctr, Durham, NC USA. [Allen, John P.] Duke Univ, Dept Psychiat & Behav Sci, Div Addict Res & Treatment, Durham, NC USA. [Wurst, Friedrich M.; Thon, Natasha] Paracelsus Med Univ, Christian Doppler Hosp, Dept Psychiat & Psychotherapy 2, Salzburg, Austria. [Litten, Raye Z.] NIAAA, Bethesda, MD USA. RP Allen, JP (reprint author), Vet Hlth Affairs, 2009 Carriage Court, Vienna, VA 22181 USA. EM john.paul.allen@us.army.mil NR 63 TC 16 Z9 16 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD APR PY 2013 VL 19 IS 4 BP 369 EP 376 DI 10.1002/lt.23596 PG 8 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 117OG UT WOS:000316962200006 PM 23281299 ER PT J AU Bagnato, F Hametner, S Welch, EB AF Bagnato, Francesca Hametner, Simon Welch, Edward Brian TI Visualizing iron in multiple sclerosis SO MAGNETIC RESONANCE IMAGING LA English DT Review DE Multiple sclerosis; Iron; MRI ID DEEP-GRAY-MATTER; BRAIN IRON; T2 HYPOINTENSITY; QUANTITATIVE ASSESSMENT; MR-IMAGES; BLACK T2; PHASE; ATROPHY; LESIONS; STORES AB Magnetic resonance imaging (MRI) protocols that are designed to be sensitive to iron typically take advantage of (I) iron effects on the relaxation of water protons and/or (2) iron-induced local magnetic field susceptibility changes. Increasing evidence sustains the notion that imaging iron in brain of patients with multiple sclerosis (MS) may add some specificity toward the identification of the disease pathology. The present review summarizes currently reported in vivo and post morterm MRI evidence of (1) iron detection in white matter and gray matter of MS brains, (2) pathological and physiological correlates of iron as disclosed by imaging and (3) relations between iron accumulation and disease progression as measured by clinical metrics. Published by Elsevier Inc. C1 [Bagnato, Francesca; Welch, Edward Brian] Vanderbilt Univ, Inst Imaging Sci, Dept Radiol, Nashville, TN 37232 USA. [Bagnato, Francesca] Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. [Bagnato, Francesca] NINDS, NIH, Bethesda, MD 20852 USA. [Hametner, Simon] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria. RP Bagnato, F (reprint author), Vanderbilt Univ, Inst Imaging Sci, Dept Radiol, 1161 21st Ave S,AA1105 MCN, Nashville, TN 37232 USA. EM francesca.r.bagnato@vanderbilt.edu RI Welch, E. Brian/F-3095-2013 OI Welch, E. Brian/0000-0003-4184-9361 FU Intramural Research Program of the NINDS, NIH FX Dr. Bagnato's contribution to this research was supported by the Intramural Research Program of the NINDS, NIH. We thank Drs. S. Pawate and R. Zivadinov for permitting the authors to use images of their work. NR 59 TC 15 Z9 15 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD APR PY 2013 VL 31 IS 3 BP 376 EP 384 DI 10.1016/j.mri.2012.11.011 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 115QQ UT WOS:000316827400007 PM 23347601 ER PT J AU Zhang, Y Shen, J AF Zhang, Yan Shen, Jun TI Soft Constraints in Nonlinear Spectral Fitting with Regularized Lineshape Deconvolution SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE lineshape; deconvolution; regularization; soft constraints; spectral fitting ID TE-AVERAGED PRESS; MAGNETIC-RESONANCE-SPECTROSCOPY; ACETYL-ASPARTYL-GLUTAMATE; H-1 MR SPECTRA; HUMAN BRAIN; IN-VIVO; METABOLITE CONCENTRATIONS; MULTIPLE-SCLEROSIS; PRIOR KNOWLEDGE; T-2 RELAXATION AB This article presents a novel method for incorporating a priori knowledge into regularized nonlinear spectral fitting as soft constraints. Regularization was recently introduced to lineshape deconvolution as a method for correcting spectral distortions. Here, the deconvoluted lineshape was described by a new type of lineshape model and applied to spectral fitting. The nonlinear spectral fitting was carried out in two steps that were subject to hard constraints and soft constraints, respectively. The hard constraints step provided a starting point and, therefore, only the changes of the relevant variables were constrained in the soft constraints step and incorporated into the linear substeps of the Levenberg-Marquardt algorithm. The method was demonstrated using localized averaged echo time point resolved spectroscopy proton spectroscopy of human brains. Magn Reson Med 69:912-919, 2013. (C) 2012 Wiley Periodicals, Inc. C1 [Zhang, Yan; Shen, Jun] NIMH, MR Spect Core Facil, NIH, Bethesda, MD 20892 USA. [Shen, Jun] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, Y (reprint author), NIMH, MR Spect Core Facil, Bldg 10,Rm 2D50,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhangya@mail.nih.gov FU IRP-NIMH-NIH FX Intramural Research Program of the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH). NR 38 TC 4 Z9 4 U1 0 U2 8 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 APR PY 2013 VL 69 IS 4 BP 912 EP 919 DI 10.1002/mrm.24337 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112XU UT WOS:000316629300002 PM 22618964 ER PT J AU Xu, S Ji, YD Chen, X Yang, YH Gullapalli, RP Masri, R AF Xu, Su Ji, Yadong Chen, Xi Yang, Yihong Gullapalli, Rao P. Masri, Radi TI In Vivo High-Resolution Localized H-1 MR Spectroscopy in the Awake Rat Brain at 7 T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE awake; H-1 localized MR spectroscopy; brain; high resolution ID MAGNETIC-RESONANCE-SPECTROSCOPY; CEREBRAL-BLOOD-FLOW; NEUROCHEMICAL PROFILE; H-1-NMR SPECTROSCOPY; ANESTHETIZED RATS; ALPHA-CHLORALOSE; FUNCTIONAL MRI; SOMATOSENSORY CORTEX; 14.1 TESLA; ANESTHESIA AB In vivo localized high-resolution H-1 MR spectroscopy was performed in multiple brain regions without the use of anesthetic or paralytic agents in awake head-restrained rats that were previously trained in a simulated MRI environment using a 7T MR system. Spectra were obtained using a short echo time single-voxel point-resolved spectroscopy technique with voxel size ranging from 27 to 32.4 mm(3) in the regions of anterior cingulate cortex, somatosensory cortex, hippocampus, and thalamus. Quantifiable spectra, without the need for any additional postprocessing to correct for possible motion, were reliably detected including the metabolites of interest such as gamma-aminobutyric acid, glutamine, glutamate, myo-inositol, N-acetylaspartate, taurine, glycerophosphorylcholine/phosphorylcholine, creatine/phosphocreatine, and N-acetylaspartate/N-acetylaspartylglutamate. The spectral quality was comparable to spectra from anesthetized animals with sufficient spectral dispersion to separate metabolites such as glutamine and glutamate. Results from this study suggest that reliable information on major metabolites can be obtained without the confounding effects of anesthesia or paralytic agents in rodents. Magn Reson Med 69:937-943, 2013. (C) 2012 Wiley Periodicals, Inc. C1 [Xu, Su; Gullapalli, Rao P.] Univ Maryland, Dept Diagnost Radiol & Nucl Med, Sch Med, Baltimore, MD 21201 USA. [Xu, Su; Gullapalli, Rao P.] Univ Maryland, Core Translat Res Imaging Maryland, Sch Med, Baltimore, MD 21201 USA. [Ji, Yadong; Masri, Radi] Univ Maryland, Dept Endodont Prosthodont & Operat Dent, Sch Dent, Baltimore, MD 21201 USA. [Chen, Xi; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD USA. RP Masri, R (reprint author), Univ Maryland, Dept Endodont Prosthodont & Operat Dent, Sch Dent, 650 W Baltimore St Off 6253, Baltimore, MD 21201 USA. EM radi.masri@gmail.com RI Chen, Xi/E-7514-2011 FU National Institute of Neurological Disorders and Stroke [R01-NS069568]; Department of Defense [SC090126] FX National Institute of Neurological Disorders and Stroke; Grant number: R01-NS069568 (to R.M.); Grant sponsor: Department of Defense; Grant number: SC090126 (to R.M.). NR 50 TC 7 Z9 7 U1 1 U2 12 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 APR PY 2013 VL 69 IS 4 BP 937 EP 943 DI 10.1002/mrm.24321 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112XU UT WOS:000316629300005 PM 22570299 ER PT J AU Tosh, DK Jacobson, KA AF Tosh, Dilip K. Jacobson, Kenneth A. TI Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches SO MEDCHEMCOMM LA English DT Review ID TRUNCATED (N)-METHANOCARBA NUCLEOSIDES; L-CYCLOPENTENONE DERIVATIVES; CARBOCYCLIC NUCLEOSIDES; NEPLANOCIN-C; (NORTH)-METHANOCARBA NUCLEOSIDES; ENANTIOSELECTIVE SYNTHESIS; STEREOSELECTIVE-SYNTHESIS; BIOLOGICAL-ACTIVITY; ADENOSINE; AGONISTS AB Adenosine receptors (ARs) and P2Y receptors for purine and pyrimidine nucleotides have widespread distribution and regulate countless physiological processes. Various synthetic ligands are in clinical trials for treatment of inflammatory diseases, pain, cancer, thrombosis, ischemia, and other conditions. The methanocarba (bicyclo[3.1.0]hexane) ring system as a rigid substitution for ribose, which maintains either a North (N) or South (S) conformation, tends to preserve or enhance the potency and/or selectivity for certain receptor subtypes. This review summarizes recent developments in the synthetic approaches to these biologically important nucleoside and nucleotide analogues. C1 [Tosh, Dilip K.; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kennethj@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK Intramural Research Program FX Support from the NIDDK Intramural Research Program is acknowledged. NR 48 TC 3 Z9 3 U1 0 U2 10 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2040-2503 J9 MEDCHEMCOMM JI MedChemComm PD APR PY 2013 VL 4 IS 4 BP 619 EP 630 DI 10.1039/c2md20348k PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 116FT UT WOS:000316868900001 ER PT J AU Pillai, AD Addo, R Sharma, P Nguitragool, W Srinivasan, P Desai, SA AF Pillai, Ajay D. Addo, Rachel Sharma, Paresh Nguitragool, Wang Srinivasan, Prakash Desai, Sanjay A. TI Malaria parasites tolerate a broad range of ionic environments and do not require host cation remodelling SO MOLECULAR MICROBIOLOGY LA English DT Article ID RED-BLOOD-CELLS; SURFACE ANION CHANNEL; FALCIPARUM-INFECTED ERYTHROCYTES; X-RAY-MICROANALYSIS; PLASMODIUM-FALCIPARUM; NA+/H+ EXCHANGER; TOXOPLASMA-GONDII; NUTRIENT-UPTAKE; MEMBRANE; POTASSIUM AB Malaria parasites grow within erythrocytes, but are also free in host plasma between cycles of asexual replication. As a result, the parasite is exposed to fluctuating levels of Na+ and K+, ions assumed to serve important roles for the human pathogen, Plasmodium falciparum. We examined these assumptions and the parasite's ionic requirements by establishing continuous culture in novel sucrose-based media. With sucrose as the primary osmoticant and K+ and Cl as the main extracellular ions, we obtained parasite growth and propagation at rates indistinguishable from those in physiological media. These conditions abolish long-known increases in intracellular Na+ via parasite-induced channels, excluding a requirement for erythrocyte cation remodelling. We also dissected Na+, K+ and Cl requirements and found that unexpectedly low concentrations of each ion meet the parasite's demands. Surprisingly, growth was not adversely affected by up to 148mM K+, suggesting that low extracellular K+ is not an essential trigger for erythrocyte invasion. At the same time, merozoite egress and invasion required a threshold ionic strength, suggesting critical electrostatic interactions between macromolecules at these stages. These findings provide insights into transmembrane signalling in malaria and reveal fundamental differences between host and parasite ionic requirements. C1 [Pillai, Ajay D.; Addo, Rachel; Sharma, Paresh; Nguitragool, Wang; Srinivasan, Prakash; Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov FU National Institutes of Health, NIAID; Medicines for Malaria Venture (MMV) FX We thank Wandy Beatty for assistance with electron microscopy. This work was supported by the Intramural Research Programs of the National Institutes of Health, NIAID and the Medicines for Malaria Venture (MMV). NR 64 TC 21 Z9 21 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2013 VL 88 IS 1 BP 20 EP 34 DI 10.1111/mmi.12159 PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 115KW UT WOS:000316812100003 PM 23347042 ER PT J AU Boulanger, A Chen, Q Hinton, DM Stibitz, S AF Boulanger, Alice Chen, Qing Hinton, Deborah M. Stibitz, Scott TI In vivo phosphorylation dynamics of the Bordetella pertussis virulence-controlling response regulator BvgA SO MOLECULAR MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI; RNA-POLYMERASE; DNA-BINDING; BACILLUS-SUBTILIS; FHAB GENE; ACTIVATION; TRANSCRIPTION; MUTATIONS; EXPRESSION; PROMOTER AB We have used protein electrophoresis through polyacrylamide gels derivatized with the proprietary ligand Phos-tag to separate the response regulator BvgA from its phosphorylated counterpart BvgA approximate to P. This approach has allowed us to readily ascertain the degree of phosphorylation of BvgA in in vitro reactions, or in crude lysates of Bordetella pertussis grown under varying laboratory conditions. We have used this technique to examine the kinetics of BvgA phosphorylation after shift of B.pertussis cultures from non-permissive to permissive conditions, or of its dephosphorylation following a shift from permissive to non-permissive conditions. Our results provide the first direct evidence that levels of BvgA approximate to Pin vivo correspond temporally to the expression of early and late BvgA-regulated virulence genes. We have also examined a number of other aspects of BvgA function predicted from previous studies and by analogy with other two-component response regulators. These include the site of BvgA phosphorylation, the exclusive role of the cognate BvgS sensor kinase in its phosphorylation in Bordetella pertussis, and the effect of the T194M mutation on phosphorylation. We also detected the phosphorylation of a small but consistent fraction of BvgA purified after expression in Escherichia coli. C1 [Boulanger, Alice; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Chen, Qing; Stibitz, Scott] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Stibitz, S (reprint author), US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM stibitz@helix.nih.gov FU Intramural Research Program of the NIH, NIDDK FX The authors thank A. Battesti, L. Knipling, T. James, S. Jha, L. Abell and J. Kassis for helpful discussions, Ilana Cohen for technical assistance and J. P. Castaing for the construction of pET21a+ D54N. This research was supported in part by the Intramural Research Program of the NIH, NIDDK. NR 49 TC 19 Z9 20 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD APR PY 2013 VL 88 IS 1 BP 156 EP 172 DI 10.1111/mmi.12177 PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 115KW UT WOS:000316812100012 PM 23489959 ER PT J AU Kokel, D Cheung, CYJ Mills, R Coutinho-Budd, J Huang, LY Setola, V Sprague, J Jin, S Jin, YN Huang, XP Bruni, G Woolf, CJ Roth, BL Hamblin, MR Zylka, MJ Milan, DJ Peterson, RT AF Kokel, David Cheung, Chung Yan J. Mills, Robert Coutinho-Budd, Jaeda Huang, Liyi Setola, Vincent Sprague, Jared Jin, Shan Jin, Youngnam N. Huang, Xi-Ping Bruni, Giancarlo Woolf, Clifford J. Roth, Bryan L. Hamblin, Michael R. Zylka, Mark J. Milan, David J. Peterson, Randall T. TI Photochemical activation of TRPA1 channels in neurons and animals SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ION CHANNELS; GLUTAMATE-RECEPTOR; REMOTE-CONTROL; COVALENT MODIFICATION; CAGED GLUTAMATE; OPTICAL CONTROL; ZEBRAFISH; LIGHT; PHOTOSTIMULATION AB Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans. C1 [Kokel, David; Cheung, Chung Yan J.; Mills, Robert; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Milan, David J.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiovasc Res Ctr, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Mills, Robert; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Milan, David J.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [Coutinho-Budd, Jaeda; Zylka, Mark J.] Univ N Carolina, Ctr Neurosci, Chapel Hill, NC USA. [Zylka, Mark J.] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC USA. [Huang, Liyi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Liyi; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Huang, Liyi] Guangxi Med Univ, Affiliated Coll & Hosp 1, Dept Infect Dis, Nanning, Peoples R China. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Sprague, Jared; Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Childrens Hosp Boston, Boston, MA 02115 USA. [Sprague, Jared] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Massachusetts Inst Technol Div Hlth Sci &, Cambridge, MA USA. RP Kokel, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiovasc Res Ctr, Charlestown, MA USA. EM dkokel@cvrc.mgh.harvard.edu; peterson@cvrc.mgh.harvard.edu RI Roth, Bryan/F-3928-2010; OI Bruni, Giancarlo/0000-0003-2850-4633; kokel, david/0000-0002-1981-1511; Hamblin, Michael/0000-0001-6431-4605 FU US National Institutes of Health (NIH) [K01MH091449, MH086867, MH085205, P01 NS072040, R01 AI050875]; Charles and Ann Sanders Massachusetts General Hospital; Michael Hooker Chair; NIMH PDSP; National Institute of Neurological Disorders and Stroke (NINDS) [R01NS060725, R01NS067688]; NINDS [F31NS068038]; NIH [HL109004, DA026982] FX We thank K. Kwan and D. Corey (Harvard Medical School), T. Miyamoto and A. Patapoutian (Scripps Research Institute), and T. Numata and Y. Mori (Kyoto University) for human TrpA1 constructs. A. Schier, D. Prober and D. Robson (Harvard University) generously provided TrpA1 mutant zebrafish. We thank R. Gaudet, A. Vakkasglu, B. Shoichet, T. Dunn, M. Ahrens, F. Engert, R. Mazitschek and members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449 (D.K.), MH086867 and MH085205 (R.T.P.), P01 NS072040 (C.J.W.), R01 AI050875 (L.H. and M.R.H.); the Charles and Ann Sanders Massachusetts General Hospital Research Scholar award (R.T.P.); and the Michael Hooker Chair and the NIMH PDSP (B.L.R.). M.J.Z. was supported by grants from National Institute of Neurological Disorders and Stroke (NINDS; R01NS060725, R01NS067688), J.C.-B. was supported by a National Research Service Award training grant from NINDS (F31NS068038) and D.J.M. was supported by NIH grants HL109004 and DA026982. NR 45 TC 22 Z9 23 U1 1 U2 40 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2013 VL 9 IS 4 BP 257 EP 263 DI 10.1038/NCHEMBIO.1183 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 118LA UT WOS:000317025800016 PM 23396078 ER PT J AU Jaremko, M Jaremko, L Kim, HY Cho, MK Schwieters, CD Giller, K Becker, S Zweckstetter, M AF Jaremko, Mariusz Jaremko, Lukasz Kim, Hai-Young Cho, Min-Kyu Schwieters, Charles D. Giller, Karin Becker, Stefan Zweckstetter, Markus TI Cold denaturation of a protein dimer monitored at atomic resolution SO NATURE CHEMICAL BIOLOGY LA English DT Article ID NMR RELAXATION DISPERSION; FOLDING INTERMEDIATE; MOLTEN GLOBULE; ALPHA-LACTALBUMIN; PATHWAY; STATE; SPECTROSCOPY; MECHANISM; LYSOZYME; RESIDUES AB Protein folding and unfolding are crucial for a range of biological phenomena and human diseases. Defining the structural properties of the involved transient species is therefore of prime interest. Using a combination of cold denaturation with NMR spectroscopy, we reveal detailed insight into the unfolding of the homodimeric repressor protein CylR2. Seven three-dimensional structures of CylR2 at temperatures from 25 degrees C to 16 degrees C reveal a progressive dissociation of the dimeric protein into a native-like monomeric intermediate followed by transition into a highly dynamic, partially folded state. The core of the partially folded state seems critical for biological function and misfolding. C1 [Jaremko, Mariusz; Jaremko, Lukasz; Kim, Hai-Young; Cho, Min-Kyu; Giller, Karin; Becker, Stefan; Zweckstetter, Markus] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. [Jaremko, Mariusz] Polish Acad Sci, Inst Biochem & Biophys, Warsaw, Poland. [Jaremko, Lukasz] Warsaw Univ, Fac Chem, Warsaw, Poland. [Schwieters, Charles D.] US Natl Inst Hlth, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD USA. [Zweckstetter, Markus] German Ctr Neurodegenerat Dis DZNE, Gottingen, Germany. RP Zweckstetter, M (reprint author), Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, D-37077 Gottingen, Germany. EM Markus.Zweckstetter@dzne.de RI Cho, Min-Kyu/H-1303-2011; b, a/A-3101-2009 OI Cho, Min-Kyu/0000-0003-0537-2340; FU START; Ventures Programmes of Foundation for Polish Science (Fundacja narzecz Nauki Polskiej); Polish Ministry of Sciences and Higher Education; Cluster of Excellence and Deutsche Forschungsgemeinschaft Research Center; Center for Information Technology at the US National Institutes of Health FX We thank N. Rezaei-Ghaleh for useful discussions. This work was supported by the START and Ventures Programmes of Foundation for Polish Science (Fundacja narzecz Nauki Polskiej; http://www.frip.org.pl/)operated within the Innovative Economy Operational Programme (IE OP) 2007-2013 within European Regional Development Fund (L.J. and M.J.), the Iuventus Plus project no. IP2011 019471 from Polish Ministry of Sciences and Higher Education (M.J.) and the Cluster of Excellence and Deutsche Forschungsgemeinschaft Research Center "Nanoscale Microscopy and Molecular Physiology of the Brain" (to M.Z.). C.D.S. was supported by the Intramural Research Program of the Center for Information Technology at the US National Institutes of Health. NR 47 TC 14 Z9 14 U1 2 U2 48 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2013 VL 9 IS 4 BP 264 EP 270 DI 10.1038/NCHEMBIO.1181 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 118LA UT WOS:000317025800017 PM 23396077 ER PT J AU Michailidou, K Hall, P Gonzalez-Neira, A Ghoussaini, M Dennis, J Milne, RL Schmidt, MK Chang-Claude, J Bojesen, SE Bolla, MK Wang, Q Dicks, E Lee, A Turnbull, C Rahman, N Fletcher, O Peto, J Gibson, L Silva, ID Nevanlinna, H Muranen, TA Aittomaki, K Blomqvist, C Czene, K Irwanto, A Liu, JJ Waisfisz, Q Meijers-Heijboer, H Adank, M van der Luijt, RB Hein, R Dahmen, N Beckman, L Meindl, A Schmutzler, RK Muller-Myhsok, B Lichtner, P Hopper, JL Southey, MC Makalic, E Schmidt, DF Uitterlinden, AG Hofman, A Hunter, DJ Chanock, SJ Vincent, D Bacot, F Tessier, DC Canisius, S Wessels, LFA Haiman, CA Shah, M Luben, R Brown, J Luccarini, C Schoof, N Humphreys, K Li, JM Nordestgaard, BG Nielsen, SF Flyger, H Couch, FJ Wang, XS Vachon, C Stevens, KN Lambrechts, D Moisse, M Paridaens, R Christiaens, MR Rudolph, A Nickels, S Flesch-Janys, D Johnson, N Aitken, Z Aaltonen, K Heikkinen, T Broeks, A Van't Veer, LJ van der Schoot, CE Guenel, P Truong, T Laurent-Puig, P Menegaux, F Marme, F Schneeweiss, A Sohn, C Burwinke, B Zamora, MP Perez, JIA Pita, G Alonso, MR Cox, A Brock, IW Cross, SS Reed, MWR Sawyer, EJ Tomlinson, I Kerin, MJ Miller, N Henderson, BE Schumacher, F Le Marchand, L Andrulis, IL Knight, JA Glendon, G Mulligan, AM Lindblom, A Margolin, S Hooning, MJ Hollestelle, A van den Ouweland, AMW Jager, A Bui, QM Stone, J Dite, GS Apicella, C Tsimiklis, H Giles, GG Severi, G Baglietto, L Fasching, PA Haeberle, L Ekici, AB Beckmann, MW Brenner, H Muller, H Arndt, V Stegmaier, C Swerdlown, A Ashworth, A Orr, N Jones, M Figueroa, J Lissowska, J Brinton, L Goldberg, MS Labreche, F Dumont, M Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Brauch, H Hamann, U Bruning, T Radice, P Peterlongo, P Manouldan, S Bonanni, B Devilee, P Tollenaar, RAEM Seynaeve, C van Asperen, CJ Jakubowska, A Lubinski, J Jaworska, K Durda, K Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Bogdanova, NV Antonenkova, NN Dork, T Kristensen, VN Anton-Culver, H Slager, S Toland, AE Edge, S Fostira, F Kang, D Yoo, KY Noh, DY Matsuo, K Ito, H Iwata, H Sueta, A Wu, AH Tseng, CC Van den Berg, D Stram, DO Shu, XO Lu, W Gao, YT Cai, H Teo, SH Yip, CH Phuah, SY Cornes, BK Hartman, M Miao, H Lim, WY Sng, JH Muir, K Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Shen, CY Hsiung, CN Wu, PE Ding, SL Sangrajrang, S Gaborieau, V Brennan, P Mckay, J Blot, WJ Signorello, LB Cai, QY Zheng, W Deming-Halverson, S Shrubsole, M Long, JR Simard, J Garcia-Closas, M Pharoah, PDP Chenevix-Trench, G Dunning, AM Benitez, J Easton, DF AF Michailidou, Kyriaki Hall, Per Gonzalez-Neira, Anna Ghoussaini, Maya Dennis, Joe Milne, Roger L. Schmidt, Marjanka K. Chang-Claude, Jenny Bojesen, Stig E. Bolla, Manjeet K. Wang, Qin Dicks, Ed Lee, Andrew Turnbull, Clare Rahman, Nazneen Fletcher, Olivia Peto, Julian Gibson, Lorna Silva, Isabel dos Santos Nevanlinna, Heli Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Czene, Kamila Irwanto, Astrid Liu, Jianjun Waisfisz, Quinten Meijers-Heijboer, Hanne Adank, Muriel van der Luijt, Rob B. Hein, Rebecca Dahmen, Norbert Beckman, Lars Meindl, Alfons Schmutzler, Rita K. Mueller-Myhsok, Bertram Lichtner, Peter Hopper, John L. Southey, Melissa C. Makalic, Enes Schmidt, Daniel F. Uitterlinden, Andre G. Hofman, Albert Hunter, David J. Chanock, Stephen J. Vincent, Daniel Bacot, Francois Tessier, Daniel C. Canisius, Sander Wessels, Lodewyk F. A. Haiman, Christopher A. Shah, Mitul Luben, Robert Brown, Judith Luccarini, Craig Schoof, Nils Humphreys, Keith Li, Jingmei Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Couch, Fergus J. Wang, Xianshu Vachon, Celine Stevens, Kristen N. Lambrechts, Diether Moisse, Matthieu Paridaens, Robert Christiaens, Marie-Rose Rudolph, Anja Nickels, Stefan Flesch-Janys, Dieter Johnson, Nichola Aitken, Zoe Aaltonen, Kirsimari Heikkinen, Tuomas Broeks, Annegien Van't Veer, Laura J. van der Schoot, C. Ellen Guenel, Pascal Truong, Therese Laurent-Puig, Pierre Menegaux, Florence Marme, Frederik Schneeweiss, Andreas Sohn, Christof Burwinke, Barbara Pilar Zamora, M. Arias Perez, Jose Ignacio Pita, Guillermo Rosario Alonso, M. Cox, Angela Brock, Ian W. Cross, Simon S. Reed, Malcolm W. R. Sawyer, Elinor J. Tomlinson, Ian Kerin, Michael J. Miller, Nicola Henderson, Brian E. Schumacher, Fredrick Le Marchand, Loic Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Lindblom, Annika Margolin, Sara Hooning, Maartje J. Hollestelle, Antoinette van den Ouweland, Ans M. W. Jager, Agnes Bui, Quang M. Stone, Jennifer Dite, Gillian S. Apicella, Carmel Tsimiklis, Helen Giles, Graham G. Severi, Gianluca Baglietto, Laura Fasching, Peter A. Haeberle, Lothar Ekici, Arif B. Beckmann, Matthias W. Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Swerdlown, Anthony Ashworth, Alan Orr, Nick Jones, Michael Figueroa, Jonine Lissowska, Jolanta Brinton, Louise Goldberg, Mark S. Labreche, France Dumont, Martine Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Brauch, Hiltrud Hamann, Ute Bruening, Thomas Radice, Paolo Peterlongo, Paolo Manouldan, Siranoush Bonanni, Bernardo Devilee, Peter Tollenaar, Rob A. E. M. Seynaeve, Caroline van Asperen, Christi J. Jakubowska, Anna Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Bogdanova, Natalia V. Antonenkova, Natalia N. Doerk, Thilo Kristensen, Vessela N. Anton-Culver, Hoda Slager, Susan Toland, Amanda E. Edge, Stephen Fostira, Florentia Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Matsuo, Keitaro Ito, Hidemi Iwata, Hiroji Sueta, Aiko Wu, Anna H. Tseng, Chiu-Chen Van den Berg, David Stram, Daniel O. Shu, Xiao-Ou Lu, Wei Gao, Yu-Tang Cai, Hui Teo, Soo Hwang Yip, Cheng Har Phuah, Sze Yee Cornes, Belinda K. Hartman, Mikael Miao, Hui Lim, Wei Yen Sng, Jen-Hwei Muir, Kenneth Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Shen, Chen-Yang Hsiung, Chia-Ni Wu, Pei-Ei Ding, Shian-Ling Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Blot, William J. Signorello, Lisa B. Cai, Qiuyin Zheng, Wei Deming-Halverson, Sandra Shrubsole, Martha Long, Jirong Simard, Jacques Garcia-Closas, Montse Pharoah, Paul D. P. Chenevix-Trench, Georgia Dunning, Alison M. Benitez, Javier Easton, Douglas F. CA Breast Ovarian Canc Susceptibility Hereditary Breast Ovarian Canc Res kConFab Investigators Australian Ovarian Can Study Grp GENICA Gene Environm Interaction B TI Large-scale genotyping identifies 41 new loci associated with breast cancer risk SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; HORMONE-RELATED PROTEIN; SUSCEPTIBILITY LOCI; COMMON VARIANTS; CONFER SUSCEPTIBILITY; SIGNALING PATHWAY; 14Q24.1 RAD51L1; GENE; CONSORTIUM; EXPRESSION AB Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for similar to 9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 x 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. C1 [Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Lee, Andrew; Luben, Robert; Brown, Judith; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Czene, Kamila; Hofman, Albert; Schoof, Nils; Humphreys, Keith] Karolinska Inst, Stockholm, Sweden. [Gonzalez-Neira, Anna; Hofman, Albert; Pita, Guillermo; Rosario Alonso, M.; Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Human Genotyping Unit, Ctr Nacl Genotipado CEGEN, Madrid, Spain. [Ghoussaini, Maya; Dicks, Ed; Shah, Mitul; Luccarini, Craig; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Milne, Roger L.] CNIO, Human Canc Genet Programme, Genet & Mol Epidemiol Grp, Madrid, Spain. [Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Chang-Claude, Jenny; Hein, Rebecca; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter] Deutsch Krebsforschungszentrum, Div Canc Epidemiol, Heidelberg, Germany. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Nordestgaard, Borge G.; Nielsen, Sune F.; kConFab Investigators] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Turnbull, Clare; Rahman, Nazneen; Swerdlown, Anthony; Jones, Michael; Garcia-Closas, Montse] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Fletcher, Olivia; Johnson, Nichola; Ashworth, Alan; Orr, Nick; Garcia-Closas, Montse] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Peto, Julian; Gibson, Lorna; Silva, Isabel dos Santos; Aitken, Zoe] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Nevanlinna, Heli; Muranen, Taru A.; Aaltonen, Kirsimari; Heikkinen, Tuomas] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.; Aittomaki, Kristiina; Blomqvist, Carl; Aaltonen, Kirsimari; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina; Aaltonen, Kirsimari] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl; Aaltonen, Kirsimari] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Irwanto, Astrid; Liu, Jianjun; Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Oncogenet, Amsterdam, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Hein, Rebecca] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, PMV Primar Med Versorgung Res Grp, D-50931 Cologne, Germany. [Dahmen, Norbert] Johannes Gutenberg Univ Mainz, Dept Psychiat, D-55122 Mainz, Germany. [Beckman, Lars] Inst Qual & Efficiency Hlth Care IQWiG, Cologne, Germany. [Meindl, Alfons] Tech Univ Munich, Clin Gynaecol & Obstet, Div Gynaecol Tumor Genet, D-80290 Munich, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Familial Breast & Ovarian Canc, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Mol Med CMMC, D-50931 Cologne, Germany. [Mueller-Myhsok, Bertram] Univ Cologne, Max Planck Inst Psychiat, D-50931 Cologne, Germany. [Lichtner, Peter] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Human Genet, Neuherberg, Germany. [Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.; Bui, Quang M.; Stone, Jennifer; Dite, Gillian S.; Apicella, Carmel; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa C.; Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Hofman, Albert] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Chanock, Stephen J.; Figueroa, Jonine; Brinton, Louise] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] McGill Univ, Montreal, PQ, Canada. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Canisius, Sander; Wessels, Lodewyk F. A.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands. [Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Wu, Anna H.; Tseng, Chiu-Chen; Van den Berg, David; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Vachon, Celine; Stevens, Kristen N.; Slager, Susan] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lambrechts, Diether; Moisse, Matthieu] VIB, Vesalius Res Ctr, Louvain, Belgium. [Lambrechts, Diether; Moisse, Matthieu] Univ Louvain, Dept Oncol, Lab Translat Genet, Louvain, Belgium. [Paridaens, Robert; Christiaens, Marie-Rose] Univ Louvain, Dept Oncol, Univ Hosp Gasthuisberg, Louvain, Belgium. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [van der Schoot, C. Ellen] Sanquin Res, Amsterdam, Netherlands. [Guenel, Pascal; Truong, Therese; Menegaux, Florence] INSERM Natl Inst Hlth & Med Res, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Guenel, Pascal; Truong, Therese; Menegaux, Florence] Univ Paris 11, Unite Mixte Rech Sci UMRS 1018, Villejuif, France. [Laurent-Puig, Pierre] Univ Paris 04, INSERM, UMRS 775, Paris, France. [Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinke, Barbara] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Burwinke, Barbara] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany. [Pilar Zamora, M.] Hosp Univ La Paz, Med Oncol Serv, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirurgia Gen & Especialidades, Oviedo, Spain. [Cox, Angela; Brock, Ian W.; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Canc Res UK Yorkshire Canc Res Sheffield Canc Res, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England. [Sawyer, Elinor J.] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust Par, Div Canc Studies, NIHR, Comprehens Biomed Res Ctr, London, England. [Tomlinson, Ian] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Kerin, Michael J.; Miller, Nicola] Univ Hosp Galway, Inst Clin Sci, Galway, Ireland. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Andrulis, Irene L.; Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Hooning, Maartje J.; Hollestelle, Antoinette; Jager, Agnes] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands. [van den Ouweland, Ans M. W.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Fasching, Peter A.; Haeberle, Lothar; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr Franconia, D-91054 Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Miller, Nicola; Brenner, Hermann; Arndt, Volker] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Ashworth, Alan; Orr, Nick; Garcia-Closas, Montse] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [Labreche, France] Univ Montreal, Dept Sante Environm & Sante Travail, Dept Med Sociale & Prevent, Montreal, PQ, Canada. [Dumont, Martine] CHU Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr, Oulu Univ Hosp, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Grip, Mervi] Univ Oulu, Dept Surg, Oulu Univ Hosp, Oulu, Finland. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Tubingen, Germany. [Hamann, Ute] DKFZ, Heidelberg, Germany. [Bruening, Thomas] Inst Ruhr Univ Bochum IPA, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Radice, Paolo; Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Radice, Paolo; Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, Ist FIRC Oncol Mol IFOM, Milan, Italy. [Manouldan, Siranoush] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Tollenaar, Rob A. E. M.] Leiden Univ, Dept Surg Oncol, Med Ctr, Leiden, Netherlands. [Seynaeve, Caroline] Erasmus Med Ctr Daniel den Hoed Canc Ctr, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [van Asperen, Christi J.] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Kristensen, Vessela N.] Warsaw Med Univ, Postgrad Sch Mol Med, Warsaw, Poland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med & Oncol, Sch Med, Kuopio, Finland. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Bogdanova, Natalia V.; Doerk, Thilo] Hannover Med Schbol, Dept Obstet & Gynaecol, Hannover, Germany. [Bogdanova, Natalia V.] Hannover Med Schbol, Dept Radiat Oncol, Hannover, Germany. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Kristensen, Vessela N.] Univ Oslo, Fac Med, Inst Clin Epidemiol & Mol Biol EpiGen, Oslo, Norway. [Kristensen, Vessela N.] Rikshosp Radiumhosp, Inst Canc Res, Dept Genet, Grp Canc Genome Variat, Oslo, Norway. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Toland, Amanda E.] Univ Calif Irvine, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Irvine, CA USA. [Edge, Stephen] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Fostira, Florentia] Natl Ctr Sci Res Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Matsuo, Keitaro; Ito, Hidemi; Sueta, Aiko] Aichi Canc Ctr, Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 464, Japan. [Shu, Xiao-Ou; Cai, Hui; Cai, Qiuyin; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Div Epidemiol,Dept Med, Nashville, TN 37212 USA. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Malaysia. [Teo, Soo Hwang; Phuah, Sze Yee] Canc Res Initiat Fdn, Sims Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har] Univ Malaya, Med Ctr, Univ Malaya Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Cornes, Belinda K.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Hartman, Mikael; Miao, Hui; Lim, Wei Yen] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Hartman, Mikael; Sng, Jen-Hwei] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Bangkok, Thailand. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] China Med Univ, Taichong, Taiwan. [Wu, Pei-Ei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Ding, Shian-Ling] Kang Ning Jr Coll Med Care & Management, Dept Nursing, Taipei, Taiwan. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Gaborieau, Valerie; Brennan, Paul; McKay, James] Int Agcy Res Canc, Lyon, France. [Blot, William J.; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Madrid, Spain. RP Easton, DF (reprint author), Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. EM per.hall@ki.se; dfe20@medschl.cam.ac.uk RI Yip, Cheng-Har/B-1909-2010; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; laurent-puig, pierre/B-2226-2013; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Rahman, Nazneen/D-2802-2013; Verdrengh, Evelien/H-4571-2012; Andrulis, Irene/E-7267-2013; Ekici, Arif/C-3971-2013; Li, Jingmei/I-2904-2012; Toland, Amanda/E-4202-2011; Kerin, Michael/D-6748-2013; Radice, Paolo/O-3119-2013; Knight, Julia/A-6843-2012; Dork, Thilo/J-8620-2012; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Noh, Dong-Young/G-5531-2011; Jakubowska, Anna/O-8050-2014; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Shrubsole, Martha/0000-0002-5591-7575; laurent-puig, pierre/0000-0001-8475-5459; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Hollestelle, Antoinette/0000-0003-1166-1966; Dite, Gillian/0000-0002-2448-2548; Devilee, Peter/0000-0002-8023-2009; Cross, Simon/0000-0003-2044-1754; Rahman, Nazneen/0000-0003-4376-0440; Rudolph, Anja/0000-0001-7520-2035; Czene, Kamila/0000-0002-3233-5695; Lissowska, Jolanta/0000-0003-2695-5799; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Dennis, Joe/0000-0003-4591-1214; Luben, Robert/0000-0002-5088-6343; Aitken, Zoe/0000-0002-5413-2450; Dunning, Alison Margaret/0000-0001-6651-7166; Li, Jingmei/0000-0001-8587-7511; Muranen, Taru/0000-0002-5895-1808; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Moisse, Matthieu/0000-0001-8880-9311; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684 FU Cancer Research UK [C1287/A10118, C1287/Al2014, C1287/A10710]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Union European Cooperation in Science and Technology (COST) [BM0606]; European Union [HEALTH-F2-2009-223175]; Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program; Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; US National Institutes of Health (NIH) Cancer Post-Cancer GWAS [1 U19 CA 148065-01] FX The authors wish to thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/Al2014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative grant 1 U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative). A full description of funding and acknowledgments is provided in the Supplementary Note. NR 61 TC 391 Z9 394 U1 9 U2 160 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 APR PY 2013 VL 45 IS 4 BP 353 EP 361 DI 10.1038/ng.2563 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600005 PM 23535729 ER PT J AU Pharoah, PDP Tsai, YY Ramus, SJ Phelan, CM Goode, EL Lawrenson, K Buckley, M Fridley, BL Tyrer, JP Shen, H Weber, R Karevan, R Larson, MC Song, HL Tessier, DC Bacot, F Vincent, D Cunningham, JM Dennis, J Dicks, E Katja, KA Anton-Culver, H Antonenkova, N Armasu, SM Baglietto, L Bandera, EV Beckmann, MW Birrer, MJ Bloom, G Bogdanova, N Brenton, JD Brinton, LA Brooks-Wilson, A Brown, R Butzow, R Campbell, I Carney, ME Carvalho, RS Chang-Claude, J Chen, YA Chen, ZH Chow, WH Cicek, MS Coetzee, G Cook, LS Cramer, DW Cybulski, C Dansonka-Mieszkowska, A Despierre, E Doherty, JA Doerk, T du Bois, A Duerst, M Eccles, D Edwards, R Ekici, AB Fasching, PA Fenstermacher, D Flanagan, J Gao, YT Garcia-Closas, M Gentry-Maharaj, A Giles, G Gjyshi, A Gore, M Gronwald, J Guo, Q Halle, MK Harter, P Hein, A Heitz, F Hillemanns, P Hoatlin, M Hogdall, E Hogdall, CK Hosono, S Jakubowska, A Jensen, A Kalli, KR Karlan, BY Kelemen, LE Kiemeney, LA Kjaer, SK Konecny, GE Krakstad, C Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, N Lee, J Leminen, A Lim, BK Lissowska, J Lubinski, J Lundvall, L Lurie, G Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR Menon, U Modugno, F Moysich, KB Nakanishi, T Narod, SA Ness, RB Nevanlinna, H Nickels, S Noushmehr, H Odunsi, K Olson, S Orlow, I Paul, J Pejovic, T Pelttari, LM Permuth-Wey, J Pike, MC Poole, EM Qu, XT Risch, HA Rodriguez-Rodriguez, L Rossing, MA Rudolph, A Runnebaum, I Rzepecka, IK Salvesen, HB Schwaab, I Severi, G Shen, H Shridhar, V Shu, XO Sieh, W Southey, MC Spellman, P Tajima, K Teo, SH Terry, KL Thompson, PJ Timorek, A Tworoger, SS van Altena, AM van den Berg, D Vergote, I Vierkant, RA Vitonis, AF Wang-Gohrke, S Wentzensen, N Whittemore, AS Wik, E Winterhoff, B Woo, YL Wu, AH Yang, HP Zheng, W Ziogas, A Zulkifli, F Goodman, MT Hall, P Easton, DF Pearce, CL Berchuck, A Chenevix-Trench, G Iversen, E Monteiro, ANA Gayther, SA Schildkraut, JM Sellers, TA AF Pharoah, Paul D. P. Tsai, Ya-Yu Ramus, Susan J. Phelan, Catherine M. Goode, Ellen L. Lawrenson, Kate Buckley, Melissa Fridley, Brooke L. Tyrer, Jonathan P. Shen, Howard Weber, Rachel Karevan, Rod Larson, Melissa C. Song, Honglin Tessier, Daniel C. Bacot, Francois Vincent, Daniel Cunningham, Julie M. Dennis, Joe Dicks, Ed Aben, Katja K. Anton-Culver, Hoda Antonenkova, Natalia Armasu, Sebastian M. Baglietto, Laura Bandera, Elisa V. Beckmann, Matthias W. Birrer, Michael J. Bloom, Greg Bogdanova, Natalia Brenton, James D. Brinton, Louise A. Brooks-Wilson, Angela Brown, Robert Butzow, Ralf Campbell, Ian Carney, Michael E. Carvalho, Renato S. Chang-Claude, Jenny Chen, Y. Anne Chen, Zhihua Chow, Wong-Ho Cicek, Mine S. Coetzee, Gerhard Cook, Linda S. Cramer, Daniel W. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka Despierre, Evelyn Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Duerst, Matthias Eccles, Diana Edwards, Robert Ekici, Arif B. Fasching, Peter A. Fenstermacher, David Flanagan, James Gao, Yu-Tang Garcia-Closas, Montserrat Gentry-Maharaj, Aleksandra Giles, Graham Gjyshi, Anxhela Gore, Martin Gronwald, Jacek Guo, Qi Halle, Mari K. Harter, Philipp Hein, Alexander Heitz, Florian Hillemanns, Peter Hoatlin, Maureen Hogdall, Estrid Hogdall, Claus K. Hosono, Satoyo Jakubowska, Anna Jensen, Allan Kalli, Kimberly R. Karlan, Beth Y. Kelemen, Linda E. Kiemeney, Lambertus A. Kjaer, Susanne Kruger Konecny, Gottfried E. Krakstad, Camilla Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Nathan Lee, Janet Leminen, Arto Lim, Boon Kiong Lissowska, Jolanta Lubinski, Jan Lundvall, Lene Lurie, Galina Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. Menon, Usha Modugno, Francesmary Moysich, Kirsten B. Nakanishi, Toru Narod, Steven A. Ness, Roberta B. Nevanlinna, Heli Nickels, Stefan Noushmehr, Houtan Odunsi, Kunle Olson, Sara Orlow, Irene Paul, James Pejovic, Tanja Pelttari, Liisa M. Permuth-Wey, Jenny Pike, Malcolm C. Poole, Elizabeth M. Qu, Xiaotao Risch, Harvey A. Rodriguez-Rodriguez, Lorna Rossing, Mary Anne Rudolph, Anja Runnebaum, Ingo Rzepecka, Iwona K. Salvesen, Helga B. Schwaab, Ira Severi, Gianluca Shen, Hui Shridhar, Vijayalakshmi Shu, Xiao-Ou Sieh, Weiva Southey, Melissa C. Spellman, Paul Tajima, Kazuo Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Timorek, Agnieszka Tworoger, Shelley S. van Altena, Anne M. van den Berg, David Vergote, Ignace Vierkant, Robert A. Vitonis, Allison F. Wang-Gohrke, Shan Wentzensen, Nicolas Whittemore, Alice S. Wik, Elisabeth Winterhoff, Boris Woo, Yin Ling Wu, Anna H. Yang, Hannah P. Zheng, Wei Ziogas, Argyrios Zulkifli, Famida Goodman, Marc T. Hall, Per Easton, Douglas F. Pearce, Celeste L. Berchuck, Andrew Chenevix-Trench, Georgia Iversen, Edwin Monteiro, Alvaro N. A. Gayther, Simon A. Schildkraut, Joellen M. Sellers, Thomas A. CA Australian Canc Study Australian Ovarian Canc Study Grp TI GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RISK; GENE; EXPRESSION; CARCINOMA; NEBULETTE; LEUKEMIA; CELLS; 19P13; MYC AB Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 x 10(-9)) and 10p12 (rs1243180, P = 1.8 x 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 x 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer. C1 [Pharoah, Paul D. P.; Tyrer, Jonathan P.; Song, Honglin; Dicks, Ed; Guo, Qi; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Pharoah, Paul D. P.; Dennis, Joe; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Tsai, Ya-Yu; Phelan, Catherine M.; Buckley, Melissa; Bloom, Greg; Chen, Y. Anne; Chen, Zhihua; Fenstermacher, David; Gjyshi, Anxhela; Permuth-Wey, Jenny; Qu, Xiaotao; Monteiro, Alvaro N. A.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33682 USA. [Ramus, Susan J.; Lawrenson, Kate; Shen, Howard; Karevan, Rod; Lee, Nathan; Lee, Janet; Pike, Malcolm C.; van den Berg, David; Wu, Anna H.; Pearce, Celeste L.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Goode, Ellen L.; Fridley, Brooke L.; Cicek, Mine S.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Weber, Rachel; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Larson, Melissa C.; Armasu, Sebastian M.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] McGill Univ, Ctr Technol, Montreal, PQ, Canada. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Cunningham, Julie M.; Shridhar, Vijayalakshmi] Mayo Clin, Dept Lab Med & Pathol, Div Anat Pathol, Rochester, MN USA. [Aben, Katja K.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K.; Kiemeney, Lambertus A.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Antonenkova, Natalia] NN Aleksandrov Byelorussian Inst Oncol & Med Radi, Minsk, Byelarus. [Baglietto, Laura; Giles, Graham; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Baglietto, Laura; Giles, Graham; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Bandera, Elisa V.; Rodriguez-Rodriguez, Lorna] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Beckmann, Matthias W.; Fasching, Peter A.; Hein, Alexander] Univ Erlangen Nurnberg, Dept Gynecol & Obstet, Univ Hosp Erlangen, Ctr Comprehens Canc, D-91054 Erlangen, Germany. [Birrer, Michael J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Bogdanova, Natalia; Doerk, Thilo] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany. [Brenton, James D.] Li Ka Shing Ctr, Cambridge Res Inst, Cambridge, England. [Brinton, Louise A.; Wentzensen, Nicolas; Yang, Hannah P.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brown, Robert; Flanagan, James] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Butzow, Ralf] Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. [Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Campbell, Ian] Peter MacCallum Canc Ctr, Div Res, Canc Genet Lab, Melbourne, Vic, Australia. [Campbell, Ian] Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. [Carney, Michael E.; Lurie, Galina; Thompson, Pamela J.; Goodman, Marc T.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Chang-Claude, Jenny; Nickels, Stefan; Rudolph, Anja] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Chow, Wong-Ho] NCI, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. [Coetzee, Gerhard; Noushmehr, Houtan] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Microbiol & Prevent Med, Los Angeles, CA 90033 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel W.; Poole, Elizabeth M.; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Mol Pathol, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Inst Oncol, Warsaw, Poland. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Leuven Canc Inst, Dept Obstet & Gynaecol, Div Gynecol Oncol, Louvain, Belgium. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Lebanon, NH USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Duerst, Matthias; Runnebaum, Ingo] Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Edwards, Robert; Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert] Magee Womens Res Inst, Womens Canc Program, Pittsburgh, PA USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Fasching, Peter A.; Konecny, Gottfried E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Elizabeth Garrett Anderson Inst Womens Hlth, Gynaecol Canc Res Ctr, London, England. [Giles, Graham] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Halle, Mari K.; Krakstad, Camilla; Salvesen, Helga B.; Wik, Elisabeth] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Halle, Mari K.; Krakstad, Camilla; Salvesen, Helga B.; Wik, Elisabeth] Univ Bergen, Dept Clin Med, Bergen, Norway. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Hoatlin, Maureen] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. [Hogdall, Estrid; Jensen, Allan; Kjaer, Susanne Kruger] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Hogdall, Claus K.; Kjaer, Susanne Kruger; Lundvall, Lene] Rigshosp, Dept Obstet & Gynecol, Juliane Marie Ctr, DK-2100 Copenhagen, Denmark. [Hosono, Satoyo; Matsuo, Keitaro; Tajima, Kazuo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [Karlan, Beth Y.] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Lambrechts, Diether] Katholieke Univ Leuven, Vesalius Res Ctr, Louvain, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Lim, Boon Kiong; Woo, Yin Ling] Univ Malaya, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands. [McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Modugno, Francesmary] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Moysich, Kirsten B.; Odunsi, Kunle] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Nakanishi, Toru] Aichi Canc Ctr Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi, Japan. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Noushmehr, Houtan; Shen, Hui] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Epigenome Ctr, Los Angeles, CA 90033 USA. [Olson, Sara; Orlow, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Risch, Harvey A.] Yale Univ, Dept Epidemiol & Publ Hlth, Sch Publ Hlth, New Haven, CT 06520 USA. [Risch, Harvey A.] Yale Univ, Sch Med, New Haven, CT USA. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Schwaab, Ira] Inst Human Genet & Anthropol, Wiesbaden, Germany. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA. [Shu, Xiao-Ou; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Spellman, Paul] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Teo, Soo-Hwang; Zulkifli, Famida] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Zulkifli, Famida] Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia. [Timorek, Agnieszka] Warsaw Med Univ, Fac Med 2, Dept Obstet Gynecol & Oncol, Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, Dept Obstet & Gynaecol, Warsaw, Poland. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynaecol, D-89069 Ulm, Germany. [Winterhoff, Boris] Mayo Clin, Dept Obstet & Gynaecol, Rochester, MN USA. [Hall, Per] Karolinska Istitutet, Dept Epidemiol & Biostat, Stockholm, Sweden. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynaecol, Durham, NC USA. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Canc Div, Herston, Qld 4006, Australia. [Iversen, Edwin] Duke Univ, Dept Stat, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. RP Pharoah, PDP (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. EM paul.pharoah@medschl.cam.ac.uk RI Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; campbell, Ian/F-6006-2011; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Woo, Yin Ling/B-5198-2010; van Altena, Anne/B-9824-2016; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017; salvesen, Helga/C-1187-2017; McLaughlin, John/E-4577-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Dork, Thilo/J-8620-2012; Whittemore, Alice/F-9925-2014; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Bandera, Elisa/M-4169-2014; Hein, Alexander/F-6999-2010; Noushmehr, Houtan/C-9692-2013; Verdrengh, Evelien/H-4571-2012; Ekici, Arif/C-3971-2013 OI Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Rudolph, Anja/0000-0001-7520-2035; Brenton, James/0000-0002-5738-6683; Tworoger, Shelley/0000-0002-6986-7046; Kjaer, Susanne/0000-0002-8347-1398; Monteiro, Alvaro/0000-0002-8448-4801; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Dennis, Joe/0000-0003-4591-1214; Nevanlinna, Heli/0000-0002-0916-2976; Halle, Mari/0000-0002-2660-8271; Orlow, Irene/0000-0001-6234-6961; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Woo, Yin Ling/0000-0003-1742-1066; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871; salvesen, Helga/0000-0002-4438-8831; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; Bandera, Elisa/0000-0002-8789-2755; Hein, Alexander/0000-0003-2601-3398; Noushmehr, Houtan/0000-0003-4051-8114; FU European Commission's Seventh Framework Programme [223175, HEALTH-F22009-223175]; Ovarian Cancer Research Fund; Genetic Associations and Mechanisms in Oncology (GAME-ON); National Cancer Institute Cancer Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113] FX We thank all the individuals who took part in this study and all the researchers, clinicians and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F22009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by the Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found on the website (see URLs). NR 31 TC 144 Z9 146 U1 3 U2 48 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 362 EP 370 DI 10.1038/ng.2564 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600006 PM 23535730 ER PT J AU Bojesen, SE Pooley, KA Johnatty, SE Beesley, J Michailidou, K Tyrer, JP Edwards, SL Pickett, HA Shen, HC Smart, CE Hillman, KM Mai, PL Lawrenson, K Stutz, MD Lu, Y Karevan, R Woods, N Johnstonw, RL French, JD Chen, XQ Weischer, M Nielsen, SF Maranian, MJ Ghoussaini, M Ahmed, S Baynes, C Bolla, MK Wang, Q Dennis, J McGuffog, L Barrowdale, D Lee, A Healey, S Lush, M Tessier, DC Vincent, D Bacot, F Vergote, I Lambrechts, S Despierre, E Risch, HA Gonzaalez-Neira, A Rossing, MA Pita, G Doherty, JA Alvarez, N Larson, MC Fridley, BL Schoof, N Chang-Claude, J Cicek, MS Peto, J Kalli, KR Broeks, A Armasu, SM Schmidt, MK Braaf, LM Winterhoff, B Nevanlinna, H Konecny, GE Lambrechts, D Rogmann, L Guenel, P Teoman, A Milne, RL Garcia, JJ Cox, A Shridhar, V Burwinkel, B Marme, F Hein, R Sawyer, EJ Haiman, CA Wang-Gohrke, S Andrulis, IL Moysich, KB Hopper, JL Odunsi, K Lindblom, A Giles, GG Brenner, H Simard, J Lurie, G Fasching, PA Carney, ME Radice, P Wilkens, LR Swerdlow, A Goodman, MT Brauch, H Garcia-Closas, M Hillemanns, P Winqvist, R Durst, M Devilee, P Runnebaum, I Jakubowska, A Lubinski, J Mannermaa, A Butzow, R Bogdanova, NV Dork, T Pelttari, LM Zheng, W Leminen, A Anton-Culver, H Bunker, CH Kristensen, V Ness, RB Muir, K Edwards, R Meind, A Heitz, F Matsuo, K du Bois, A Wu, AH Harter, P Teo, SH Schwaab, I Shu, XO Blot, W Hosono, S Kang, D Nakanishi, T Hartman, M Yatabe, Y Hamann, U Karlan, BY Sangrajrang, S Kjaer, SK Gaborieau, V Jensen, A Eccles, D Hogdall, E Shen, CY Brown, J Woo, YL Shah, M Azmi, MAN Luben, R Omar, SZ Czene, K Vierkant, RA Nordestgaard, BG Flyger, H Vachon, C Olson, JE Wang, XS Levine, DA Rudolph, A Weber, RP Flesch-Janys, D Iversen, E Nickels, S Schildkraut, JM Silva, ID Cramer, DW Gibson, L Terry, KL Fletcher, O Vitonis, AF van der Schoot, CE Poole, EM Hogervorst, FBL Tworoger, SS Liu, JJ Bandera, EV Li, JM Olson, SH Humphreys, K Row, I Blomqvist, C Rodriguez-Rodriguez, L Aittomaki, K Salvesen, HB Muranen, TA Wik, E Brouwers, B Krakstad, C Wauters, E Halle, MK Wildiers, H Kiemeney, LA Mulot, C Aben, KK Laurent-Puig, P Altena, AM Truong, T Massuger, LFAG Benitez, J Pejovic, T Perez, JIA Hoatlin, M Zamora, MP Cook, LS Balasubramanian, SP Kelemen, LE Schneeweiss, A Le, ND Sohn, C Brooks-Wilson, A Tomlinson, I Kerin, MJ Miller, N Cybulski, C Henderson, BE Menkiszak, J Schumacher, F Wentzensen, N Le Marchand, L Yang, HP Mulligan, AM Glendon, G Engelholm, SA Knight, JA Hogdall, CK Apicella, C Gore, M Tsimiklis, H Song, HL Southey, MC Jager, A den Ouweland, AMW Brown, R Martens, JWM Flanagan, JM Kriege, M Paul, J Margolin, S Siddiqui, N Severi, G Whittemore, AS Baglietto, L McGuire, V Stegmaier, C Sieh, W Muller, H Arndt, V Labreche, F Gao, YT Goldberg, MS Yang, G Dumont, M McLaughlin, JR Hartmann, A Ekici, AB Beckmann, MW Phelan, CM Lux, MP Permuth-Wey, J Peissel, B Sellers, TA Ficarazzi, F Barile, M Ziogas, A Ashworth, A Gentry-Maharaj, A Jones, M Ramus, SJ Orr, N Menon, U Pearce, CL Bruning, T Pike, MC Ko, YD Lissowska, J Figueroa, J Kupryjanczyk, J Chanock, SJ Dansonka-Mieszkowska, A Jukkola-Vuorinen, A Rzepecka, IK Pylkas, K Bidzinski, M Kauppila, S Hollestelle, A Seynaeve, C Tollenaar, RAEM Durda, K Jaworska, K Hartikainen, JM Kosma, VM Kataja, V Antonenkova, NN Long, JR Shrubsole, M Deming-Halverson, S Lophatananon, A Siriwanarangsan, P Stewart-Brown, S Ditsch, N Lichtner, P Schmutzler, RK Ito, H Iwata, H Tajima, K Tseng, CC Stram, DO van den Berg, D Yip, CH Ikrarn, MK Teh, YC Cai, H Lu, W Signorello, LB Cai, QY Noh, DY Yoo, KY Miao, H Iau, PTC Teo, YY McKay, J Shapiro, C Ademuyiwa, F Fountzilas, G Hsiung, CN Yu, JC Hou, MF Healey, CS Luccarini, C Peock, S Stoppa-Lyonnet, D Peterlongo, P Rebbeck, TR Piedmonte, M Singer, CF Friedman, E Thomassen, M Offit, K Hansen, TVO Neuhausen, SL Szabo, CI Blanco, I Garber, J Narod, SA Weitzel, JN Montagna, M Olah, E Godwin, AK Yannoukakos, D Goldgar, DE Caldes, T Imyanitov, EN Tihomirova, L Arun, BK Campbell, I Mensenkamp, AR van Asperen, CJ van Roozendaa, KEP Meijers-Heijboer, H Collee, JM Oosterwijk, JC Hooning, MJ Rookus, MA van der Luijt, RB Os, TAM Evans, DG Frost, D Fineberg, E Barwell, J Walker, L Kennedy, MJ Platte, R Davidson, R Ellis, SD Cole, T Bressac-de Paillerets, B Buecher, B Damiola, F Faivre, L Frenay, M Sinilnikova, OM Caron, O Giraud, S Mazoyer, S Bonadona, V Caux-Moncoutier, V Toloczko-Grabarek, A Gronwald, J Byrski, T Spurdle, AB Bonanni, B Zaffaroni, D Giannini, G Bernard, L Dolcetti, R Manoukian, S Arnold, N Engel, C Deissler, H Rhiem, K Niederacher, D Pendl, H Sutter, C Wappenschmidt, B Borg, A Mein, B Rantala, J Soller, M Nathanson, KL Domchek, SM Rodriguez, GC Salani, R Kaulich, DG Tea, MK Paluch, SS Laitman, Y Skytte, AB Kruse, TA Jensen, UB Robson, M Gerdes, AM Ejlertsen, B Foretova, L Savage, SA Lesterm, J Soucy, P Kuchenbaecker, KB Olswold, C Cunningham, JM Slager, S Pankratz, VS Dicks, E Lakhani, SR Couch, FJ Hall, P Monteiro, ANA Gayther, SA Pharoah, PDP Reddel, RR Goode, EL Greene, MH Easton, DF Berchuck, A Antoniou, AC Chenevix-Trench, G Dunning, AM AF Bojesen, Stig E. Pooley, Karen A. Johnatty, Sharon E. Beesley, Jonathan Michailidou, Kyriaki Tyrer, Jonathan P. Edwards, Stacey L. Pickett, Hilda A. Shen, Howard C. Smart, Chanel E. Hillman, Kristine M. Mai, Phuong L. Lawrenson, Kate Stutz, Michael D. Lu, Yi Karevan, Rod Woods, Nicholas Johnstonw, Rebecca L. French, Juliet D. Chen, Xiaoqing Weischer, Maren Nielsen, Sune F. Maranian, Melanie J. Ghoussaini, Maya Ahmed, Shahana Baynes, Caroline Bolla, Manjeet K. Wang, Qin Dennis, Joe McGuffog, Lesley Barrowdale, Daniel Lee, Andrew Healey, Sue Lush, Michael Tessier, Daniel C. Vincent, Daniel Bacot, Francis Vergote, Ignace Lambrechts, Sandrina Despierre, Evelyn Risch, Harvey A. Gonzalez-Neira, Anna Rossing, Mary Anne Pita, Guillermo Doherty, Jennifer A. Alvarez, Nuria Larson, Melissa C. Fridley, Brooke L. Schoof, Nils Chang-Claude, Jenny Cicek, Mine S. Peto, Julian Kalli, Kimberly R. Broeks, Annegien Armasu, Sebastian M. Schmidt, Marjanka K. Braaf, Linde M. Winterhoff, Boris Nevanlinna, Heli Konecny, Gottfried E. Lambrechts, Diether Rogmann, Lisa Guenel, Pascal Teoman, Attila Milne, Roger L. Garcia, Joaquin J. Cox, Angela Shridhar, Vijayalakshmi Burwinkel, Barbara Marme, Frederik Hein, Rebecca Sawyer, Elinor J. Haiman, Christopher A. Wang-Gohrke, Shan Andrulis, Irene L. Moysich, Kirsten B. Hopper, John L. Odunsi, Kunle Lindblom, Annika Giles, Graham G. Brenner, Hermann Simard, Jacques Lurie, Galina Fasching, Peter A. Carney, Michael E. Radice, Paolo Wilkens, Lynne R. Swerdlow, Anthony Goodman, Marc T. Brauch, Hiltrud Garcia-Closas, Montserrat Hillemanns, Peter Winqvist, Robert Durst, Matthias Devilee, Peter Runnebaum, Ingo Jakubowska, Anna Lubinski, Jan Mannermaa, Arto Butzow, Ralf Bogdanova, Natalia V. Doerk, Thilo Pelttari, Liisa M. Zheng, Wei Leminen, Arto Anton-Culver, Hoda Bunker, Clareann H. Kristensen, Vessela Ness, Roberta B. Muir, Kenneth Edwards, Robert Meindl, Alfons Heitz, Florian Matsuo, Keitaro du Bois, Andreas Wu, Anna H. Harter, Philipp Teo, Soo-Hwang Schwaab, Ira Shu, Xiao-Ou Blot, William Hosono, Satoyo Kang, Daehee Nakanishi, Toru Hartman, Mikael Yatabe, Yasushi Hamann, Ute Karlan, Beth Y. Sangrajrang, Suleeporn Kjaer, Susanne Kruger Gaborieau, Valerie Jensen, Allan Eccles, Diana Hogdall, Estrid Shen, Chen-Yang Brown, Judith Woo, Yin Ling Shah, Mitul Azmi, Mat Adenan Noor Luben, Robert Omar, Siti Zawiah Czene, Kamila Vierkant, Robert A. Nordestgaard, Borge G. Flyger, Henrik Vachon, Celine Olson, Janet E. Wang, Xianshu Levine, Douglas A. Rudolph, Anja Weber, Rachel Palmieri Flesch-Janys, Dieter Iversen, Edwin Nickels, Stefan Schildkraut, Joellen M. Silva, Isabel Dos Santos Cramer, Daniel W. Gibson, Lorna Terry, Kathryn L. Fletcher, Olivia Vitonis, Allison F. van der Schoot, C. Ellen Poole, Elizabeth M. Hogervorst, Frans B. L. Tworoger, Shelley S. Liu, Jianjun Bandera, Elisa V. Li, Jingmei Olson, Sara H. Humphreys, Keith Row, Irene Blomqvist, Carl Rodriguez-Rodriguez, Lorna Aittomaki, Kristiina Salvesen, Helga B. Muranen, Taru A. Wik, Elisabeth Brouwers, Barbara Krakstad, Camilla Wauters, Els Halle, Mari K. Wildiers, Hans Kiemeney, Lambertus A. Mulot, Claire Aben, Katja K. Laurent-Puig, Pierre Altena, Anne Mvan Therese Truong Massuger, Leon F. A. G. Benitez, Javier Pejovic, Tanja Arias Perez, Jose Ignacio Hoatlin, Maureen Zamora, M. Pilar Cook, Linda S. Balasubramanian, Sabapathy P. Kelemen, Linda E. Schneeweiss, Andreas Le, Nhu D. Sohn, Christof Brooks-Wilson, Angela Tomlinson, Ian Kerin, Michael J. Miller, Nicola Cybulski, Cezary Henderson, Brian E. Menkiszak, Janusz Schumacher, Fredrick Wentzensen, Nicolas Marchand, Loic Le Yang, Hannah P. Mulligan, Anna Marie Glendon, Gord Engelholm, Svend Aage Knight, Julia A. Hogdall, Claus K. Apicella, Carmel Gore, Martin Tsimiklis, Helen Song, Honglin Southey, Melissa C. Jager, Agnes den Ouweland, Ans M. Wvan Brown, Robert Martens, John W. M. Flanagan, James M. Kriege, Mieke Paul, James Margolin, Sara Siddiqui, Nadeem Severi, Gianluca Whittemore, Alice S. Baglietto, Laura McGuire, Valerie Stegmaier, Christa Sieh, Weiva Mueller, Heiko Arndt, Volker Labreche, France Gao, Yu-Tang Goldberg, Mark S. Yang, Gong Dumont, Martine McLaughlin, John R. Hartmann, Arndt Ekici, Arif B. Beckmann, Matthias W. Phelan, Catherine M. Lux, Michael P. Permuth-Wey, Jenny Peissel, Bernard Sellers, Thomas A. Ficarazzi, Filomena Barile, Monica Ziogas, Argyrios Ashworth, Alan Gentry-Maharaj, Aleksandra Jones, Michael Ramus, Susan J. Orr, Nick Menon, Usha Pearce, Celeste L. Bruening, Thomas Pike, Malcolm C. Ko, Yon-Dschun Lissowska, Jolanta Figueroa, Jonine Kupryjanczyk, Jolanta Chanock, Stephen J. Dansonka-Mieszkowska, Agnieszka Jukkola-Vuorinen, Arja Rzepecka, Iwona K. Pylkas, Katri Bidzinski, Mariusz Kauppila, Saila Hollestelle, Antoinette Seynaeve, Caroline Tollenaar, Rob A. E. M. Durda, Katarzyna Jaworska, Katarzyna Hartikainen, Jaana M. Kosma, Veli-Matti Kataja, Vesa Antonenkova, Natalia N. Long, Jirong Shrubsole, Martha Deming-Halverson, Sandra Lophatananon, Artitaya Siriwanarangsan, Pornthep Stewart-Brown, Sarah Ditsch, Nina Lichtner, Peter Schmutzler, Rita K. Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Tseng, Chiu-Chen Stram, Daniel O. van den Berg, David Yip, Cheng Har Ikrarn, M. Kamran Teh, Yew-Ching Cai, Hui Lu, Wei Signorello, Lisa B. Cai, Qiuyin Noh, Dong-Young Yoo, Keun-Young Miao, Hui Iau, Philip Tsau-Choong Teo, Yik Ying McKay, James Shapiro, Charles Ademuyiwa, Foluso Fountzilas, George Hsiung, Chia-Ni Yu, Jyh-Cherng Hou, Ming-Feng Healey, Catherine S. Luccarini, Craig Peock, Susan Stoppa-Lyonnet, Dominique Peterlongo, Paolo Rebbeck, Timothy R. Piedmonte, Marion Singer, Christian F. Friedman, Eitan Thomassen, Mads Offit, Kenneth Hansen, Thomas V. O. Neuhausen, Susan L. Szabo, Csilla I. Blanco, Ignacio Garber, Judy Narod, Steven A. Weitzel, Jeffrey N. Montagna, Marco Olah, Edith Godwin, Andrew K. Yannoukakos, Drakoulis Goldgar, David E. Caldes, Trinidad Imyanitov, Evgeny N. Tihomirova, Laima Arun, Banu K. Campbell, Ian Mensenkamp, Arjen R. van Asperen, Christi J. van Roozendaa, Kees E. P. Meijers-Heijboer, Hanne Collee, J. Margriet Oosterwijk, Jan C. Hooning, Maartje J. Rookus, Matti A. van der Luijt, Rob B. Os, Theo A. Mvan Evans, D. Gareth Frost, Debra Fineberg, Elena Barwell, Julian Walker, Lisa Kennedy, M. John Platte, Radka Davidson, Rosemarie Ellis, Steve D. Cole, Trevor Bressac-de Paillerets, Brigitte Buecher, Bruno Damiola, Francesca Faivre, Laurence Frenay, Marc Sinilnikova, Olga M. Caron, Olivier Giraud, Sophie Mazoyer, Sylvie Bonadona, Valerie Caux-Moncoutier, Virginie Toloczko-Grabarek, Aleksandra Gronwald, Jacek Byrski, Tomasz Spurdle, Amanda B. Bonanni, Bernardo Zaffaroni, Daniela Giannini, Giuseppe Bernard, Loris Dolcetti, Riccardo Manoukian, Siranoush Arnold, Norbert Engel, Christoph Deissler, Helmut Rhiem, Kerstin Niederacher, Dieter Pendl, Hansjoerg Sutter, Christian Wappenschmidt, Barbara Borg, Ake Mein, Beatrice Rantala, Johanna Soller, Maria Nathanson, Katherine L. Domchek, Susan M. Rodriguez, Gustavo C. Salani, Ritu Kaulich, Daphne Gschwantler Tea, Muy-Kheng Paluch, Shani Shimon Laitman, Yael Skytte, Anne-Bine Kruse, Torben A. Jensen, Uffe Birk Robson, Mark Gerdes, Anne-Marie Ejlertsen, Bent Foretova, Lenka Savage, Sharon A. Lesterm, Jenny Soucy, Penny Kuchenbaecker, Karoline B. Olswold, Curtis Cunningham, Julie M. Slager, Susan Pankratz, Vernon S. Dicks, Ed Lakhani, Sunil R. Couch, Fergus J. Hall, Per Monteiro, Alvaro N. A. Gayther, Simon A. Pharoah, Paul D. P. Reddel, Roger R. Goode, Ellen L. Greene, Mark H. Easton, Douglas F. Berchuck, Andrew Antoniou, Antonis C. Chenevix-Trench, Georgia Dunning, Alison M. CA Australian Canc Study Australian Ovarian Canc Study Kathleen Cuningham Fdn Consortium Gene Environm Interactimi Breast Swedish Breast Canc Study SWE-BRCA Hereditary Breast Ovarian Canc Res Epidemiological Study BRCA1 Genetic Modifiers Canc Risk BRCA1 TI Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; REVERSE-TRANSCRIPTASE HTERT; SUSCEPTIBILITY LOCI; TERT-CLPTM1L LOCUS; GENETIC-VARIATION; COMMON VARIANTS; BUCCAL CELLS; FIBROBLASTS; CARCINOMA; METAANALYSIS AB TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. C1 [Bojesen, Stig E.; Weischer, Maren; Nielsen, Sune F.; Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Weischer, Maren; Nielsen, Sune F.; Nordestgaard, Borge G.] Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Pooley, Karen A.; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; McGuffog, Lesley; Barrowdale, Daniel; Lee, Andrew; Lush, Michael; Brown, Judith; Luben, Robert; Peock, Susan; Frost, Debra; Fineberg, Elena; Ellis, Steve D.; Kuchenbaecker, Karoline B.; Dicks, Ed; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Johnatty, Sharon E.; Beesley, Jonathan; Lu, Yi; Chen, Xiaoqing; Healey, Sue; Spurdle, Amanda B.; Chenevix-Trench, Georgia] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia. [Tyrer, Jonathan P.; Maranian, Melanie J.; Ghoussaini, Maya; Ahmed, Shahana; Baynes, Caroline; Shah, Mitul; Song, Honglin; Healey, Catherine S.; Luccarini, Craig; Pharoah, Paul D. P.; Easton, Douglas F.; Dunning, Alison M.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Edwards, Stacey L.; Hillman, Kristine M.; French, Juliet D.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia. [Pickett, Hilda A.; Stutz, Michael D.; Reddel, Roger R.] Childrens Med Res Inst, Canc Res Unit, Westmead, NSW, Australia. [Pickett, Hilda A.; Stutz, Michael D.; Reddel, Roger R.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [Shen, Howard C.; Lawrenson, Kate; Karevan, Rod; Haiman, Christopher A.; Wu, Anna H.; Henderson, Brian E.; Schumacher, Fredrick; Ramus, Susan J.; Pearce, Celeste L.; Pike, Malcolm C.; Tseng, Chiu-Chen; Stram, Daniel O.; van den Berg, David; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Smart, Chanel E.; Johnstonw, Rebecca L.; Lakhani, Sunil R.] Univ Queensland, UQ Ctr Clin Res UQCCR, Royal Brisbane & Womens Hosp, Herston, Qld, Australia. [Mai, Phuong L.; Savage, Sharon A.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US Natl Inst Hlth, Rockville, MD USA. [Woods, Nicholas; Phelan, Catherine M.; Permuth-Wey, Jenny; Sellers, Thomas A.; Monteiro, Alvaro N. A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francis] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francis] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn] Katholieke Univ Leuven Hosp, Dept Obstet & Gynaecol, Div Gynecol Oncol, Louvain, Belgium. [Vergote, Ignace; Lambrechts, Sandrina; Despierre, Evelyn] Katholieke Univ Leuven Hosp, Leuven Canc Inst, Louvain, Belgium. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Risch, Harvey A.] Yale Univ, Sch Med, New Haven, CT USA. [Gonzalez-Neira, Anna; Pita, Guillermo; Alvarez, Nuria; Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Ctr Nacl Genotipac, Madrid, Spain. [Rossing, Mary Anne] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rossing, Mary Anne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Lebanon, NH USA. [Larson, Melissa C.; Armasu, Sebastian M.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Fridley, Brooke L.] Univ Kansas, Ctr Canc, Kansas IDeA Network Biomed Res Excellence Bioinfo, Kansas City, KS USA. [Schoof, Nils; Hartman, Mikael; Czene, Kamila; Humphreys, Keith; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chang-Claude, Jenny; Hein, Rebecca; Rudolph, Anja; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Cicek, Mine S.; Goode, Ellen L.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Peto, Julian; Silva, Isabel Dos Santos; Gibson, Lorna] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Kalli, Kimberly R.] Mayo Clin, Dept Med Oncol, Rochester, MN USA. [Broeks, Annegien; Schmidt, Marjanka K.; Braaf, Linde M.; Rookus, Matti A.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [Schmidt, Marjanka K.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Winterhoff, Boris; Rogmann, Lisa; Teoman, Attila] Mayo Clin, Dept Obstet & Gynecol, Rochester, MN USA. [Nevanlinna, Heli; Butzow, Ralf; Pelttari, Liisa M.; Leminen, Arto; Muranen, Taru A.] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Konecny, Gottfried E.; Fasching, Peter A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Lambrechts, Diether; Wauters, Els] Katholieke Univ Leuven, Dept Oncol, Lab Translat Genet, Louvain, Belgium. [Lambrechts, Diether; Wauters, Els] VIB, VRC, Louvain, Belgium. [Guenel, Pascal; Therese Truong] CESP Ctr Res Epidemiol & Populat Hlth, U1018, INSERM, Villejuif, France. [Guenel, Pascal; Therese Truong] Univ Paris Sud, UMRS, Villejuif, France. [Milne, Roger L.] CNIO, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid, Spain. [Garcia, Joaquin J.; Shridhar, Vijayalakshmi; Wang, Xianshu; Cunningham, Julie M.; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Div Expt Pathol, Rochester, MN USA. [Cox, Angela; Balasubramanian, Sabapathy P.] Univ Sheffield, Dept Oncol, Canc Res UK Norkshire Canc Res Sheffield Canc Red, Sheffield, S Yorkshire, England. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] DKFZ, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, Primarmed Versorgung PMV Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Sawyer, Elinor J.] Kings Coll London, Div Canc Studies, Natl Inst Hlth Res NIHR, Comprehens Biomed Res Ctr,Guys & St Thomas Natl H, London WC2R 2LS, England. [Wang-Gohrke, Shan; Deissler, Helmut] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Moysich, Kirsten B.; Odunsi, Kunle] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Hopper, John L.; Giles, Graham G.; Apicella, Carmel; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Simard, Jacques; Dumont, Martine; Soucy, Penny] CHU Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Simard, Jacques; Dumont, Martine; Soucy, Penny] Univ Laval, Quebec City, PQ, Canada. [Lurie, Galina; Carney, Michael E.; Wilkens, Lynne R.; Marchand, Loic Le] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Fasching, Peter A.; Beckmann, Matthias W.; Lux, Michael P.] Univ Breast Ctr Franconia Erlangen Univ Hosp, Dept Gynecol & Obstet, Erlangen, Germany. [Radice, Paolo; Peterlongo, Paolo] Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, I-20133 Milan, Italy. [Radice, Paolo; Ficarazzi, Filomena; Peterlongo, Paolo] Ist Fdn Italiana Ric Cancro Oncol Mol, Milan, Italy. [Swerdlow, Anthony; Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton, Surrey, England. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Fac Med, Tubingen, Germany. [Garcia-Closas, Montserrat; Fletcher, Olivia; Ashworth, Alan; Orr, Nick] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Oulu Univ Hosp, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Durst, Matthias; Runnebaum, Ingo] Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Toloczko-Grabarek, Aleksandra; Gronwald, Jacek; Byrski, Tomasz] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Mannermaa, Arto; Hartikainen, Jaana M.; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Sch Med,Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Cent Hosp, Helsinki, Finland. [Bogdanova, Natalia V.; Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Bogdanova, Natalia V.; Cai, Qiuyin] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Zheng, Wei; Shu, Xiao-Ou; Blot, William; Yang, Gong; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Cai, Hui; Signorello, Lisa B.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bunker, Clareann H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Kristensen, Vessela] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Fac Div Ahus, Oslo, Norway. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Edwards, Robert] Magee Womens Hosp, Pittsburgh, PA USA. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Gynecol & Obstet, D-80290 Munich, Germany. [Heitz, Florian; du Bois, Andreas; Harter, Philipp] Dr Horst Schmidt Klin Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Heitz, Florian; du Bois, Andreas; Harter, Philipp] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Matsuo, Keitaro; Hosono, Satoyo; Ito, Hidemi; Tajima, Kazuo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Teo, Soo-Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Yip, Cheng Har; Teh, Yew-Ching] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Blot, William; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Kang, Daehee; Noh, Dong-Young; Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Nakanishi, Toru] Aichi Canc Ctr Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi, Japan. [Hartman, Mikael; Iau, Philip Tsau-Choong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Hartman, Mikael; Miao, Hui; Teo, Yik Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Yatabe, Yasushi] Aichi Canc Ctr Cent Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan. [Hamann, Ute] DKFZ, Heidelberg, Germany. [Karlan, Beth Y.; Lesterm, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Div Res, Bangkok, Thailand. [Kjaer, Susanne Kruger; Jensen, Allan; Hogdall, Estrid] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Kjaer, Susanne Kruger; Hogdall, Claus K.] Rigshosp, Dept Obstet & Gynecol, Juliane Marie Ctr, DK-2100 Copenhagen, Denmark. [Gaborieau, Valerie; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichong, Taiwan. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Woo, Yin Ling; Azmi, Mat Adenan Noor; Omar, Siti Zawiah] Univ Malaya, Fac Med, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Vachon, Celine; Olson, Janet E.; Olswold, Curtis; Slager, Susan; Pankratz, Vernon S.; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC USA. [Iversen, Edwin; Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [van der Schoot, C. Ellen] Sanquin Res, Amsterdam, Netherlands. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hogervorst, Frans B. L.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Liu, Jianjun; Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Bandera, Elisa V.; Rodriguez-Rodriguez, Lorna] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Olson, Sara H.; Row, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Salvesen, Helga B.; Wik, Elisabeth; Krakstad, Camilla; Halle, Mari K.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Salvesen, Helga B.; Wik, Elisabeth; Krakstad, Camilla; Halle, Mari K.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Brouwers, Barbara] Katholieke Univ Leuven, Dept Oncol, Expt Oncol Lab, Louvain, Belgium. [Brouwers, Barbara; Wildiers, Hans] Katholieke Univ Leuven Hosp, Dept Gen Med Oncol, Louvain, Belgium. [Kiemeney, Lambertus A.; Aben, Katja K.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Kiemeney, Lambertus A.; Aben, Katja K.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Mulot, Claire; Laurent-Puig, Pierre] Univ Paris Sorbonne Cite, UMR S775, INSERM, Paris, France. [Altena, Anne Mvan; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynecol, NL-6525 ED Nijmegen, Netherlands. [Benitez, Javier] CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Hoatlin, Maureen] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. [Zamora, M. Pilar] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Le, Nhu D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Tomlinson, Ian] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Kerin, Michael J.; Miller, Nicola] Natl Univ Ireland Univ Coll Galway, Sch Med, Galway, Ireland. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Surg Gynecol & Gynecol Oncol Adults & Adolsc, Szczecin, Poland. [Wentzensen, Nicolas; Yang, Hannah P.; Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Glendon, Gord; McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Engelholm, Svend Aage] Univ Copenhagen, Rigshosp, Dept Radiat Oncol, DK-2100 Copenhagen, Denmark. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Tsimiklis, Helen; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Jager, Agnes; Martens, John W. M.; Kriege, Mieke; Hollestelle, Antoinette; Seynaeve, Caroline; Hooning, Maartje J.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [den Ouweland, Ans M. Wvan; Collee, J. Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands. [Brown, Robert; Flanagan, James M.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Margolin, Sara] Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Labreche, France] Univ Montreal, Fac Med, Dept Environm & Occupat Hlth, Montreal, PQ H3C 3J7, Canada. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Hartmann, Arndt] Univ Erlangen Nurnberg, Inst Pathol, Univ Hosp Erlangen, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Peissel, Bernard; Zaffaroni, Daniela; Manoukian, Siranoush] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Ficarazzi, Filomena; Bernard, Loris] Cogentech Canc Genet Test Lab, Milan, Italy. [Barile, Monica; Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Gynaecol Canc Res Ctr, Elizabeth Garrett Anderson Inst Womens Hlth, London, England. [Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Ko, Yon-Dschun] Johanniter Krankenhaus, Evangel Kliniken Bonn, Dept Internal Med, Bonn, Germany. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Mol Pathol, Warsaw, Poland. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Bidzinski, Mariusz] Inst Oncol, Warsaw, Poland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Bidzinski, Mariusz] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, Warsaw, Poland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Jaworska, Katarzyna] Warsaw Med Univ, Postgrad Sch Mol Med, Warsaw, Poland. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Bangkok, Thailand. [Ditsch, Nina] Univ Munich, Dept Gynecol & Obstet, Munich, Germany. [Lichtner, Peter] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Gynaecol & Obstet, Cologne, Germany. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Mol Med Cologne CMMC, Cologne, Germany. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Ikrarn, M. Kamran] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Shapiro, Charles] Ohio State Univ, Div Oncol, Wexner Med Ctr, Columbus, OH 43210 USA. [Ademuyiwa, Foluso] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Fountzilas, George] Aristotle Univ Thessaloniki, Sch Med, Dept Med Oncol, Papageorgiou Hosp, GR-54006 Thessaloniki, Greece. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Stoppa-Lyonnet, Dominique; Buecher, Bruno; Caux-Moncoutier, Virginie] Inst Curie, Dept Tumor Biol, Paris, France. [Stoppa-Lyonnet, Dominique] INSERM, Inst Curie, U830, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Paris, France. [Rebbeck, Timothy R.; Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Res Ctr, Philadelphia, PA USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat, Buffalo, NY 14263 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Ctr Data, Buffalo, NY 14263 USA. [Singer, Christian F.; Kaulich, Daphne Gschwantler; Tea, Muy-Kheng] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Friedman, Eitan; Paluch, Shani Shimon; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan; Paluch, Shani Shimon; Laitman, Yael] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Israel. [Thomassen, Mads; Kruse, Torben A.] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Offit, Kenneth; Robson, Mark] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Hansen, Thomas V. O.] Rigshosp, Copenhagen Univ Hosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Szabo, Csilla I.] Univ Delaware, Dept Biol Sci, Ctr Translat Canc Res, Newark, DE USA. [Blanco, Ignacio] Inst Invest Biomed Bellvitge Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain. [Garber, Judy] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA. [Montagna, Marco] IRCCS, Ist Oncol Veneto IOV, Immunol & Mol Oncol Unit, Padua, Italy. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Yannoukakos, Drakoulis] Aghia Paraskevi Attikis, Mol Diagnost Lab, Inst Radioisotopes & Radiodiagnost Prod, Natl Ctr Sci Res Demokritos, Athens, Greece. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg, Russia. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Campbell, Ian] Peter MacCallum Canc Ctr, Victorian Breast Canc Res Consortium Canc Genet L, Melbourne, Vic, Australia. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [van Roozendaa, Kees E. P.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Meijers-Heijboer, Hanne] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Oosterwijk, Jan C.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Os, Theo A. Mvan] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Barwell, Julian] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Kennedy, M. John] Trinity Coll Dublin, Acad Unit Clin & Mol Oncol, Dublin, Ireland. [Kennedy, M. John] St James Hosp, Dublin 8, Ireland. [Davidson, Rosemarie] So Gen Hosp, Lab Med, Glasgow G51 4TF, Lanark, Scotland. [Cole, Trevor] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Bressac-de Paillerets, Brigitte] Fdn Jean Dausset, INSERM, U946, Paris, France. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Villejuif, France. [Damiola, Francesca; Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon 1, INSERM, U1052, CNRS,UMR 5286,Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Faivre, Laurence] Univ Bourgogne, CHU Dijon, Ctr Genet, Dijon, France. [Faivre, Laurence] Ctr Georges Francois Leclerc, Dijon, France. [Frenay, Marc] Ctr Antoine Lacassagne, Nice, France. [Sinilnikova, Olga M.; Giraud, Sophie] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Caron, Olivier] Inst Cancerol Gustave Roussy, Dept Med, Villejuif, France. [Bonadona, Valerie] Ctr Leon Berard, Unite Prevent & Epiderniol Genet, F-69373 Lyon, France. [Bonadona, Valerie] Univ Lyon 1, CNRS, UMR 5558, F-69365 Lyon, France. [Giannini, Giuseppe] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Dolcetti, Riccardo] IRCCS, Ctr Riferimento Oncol, Canc Bioimmunotherapy Unit, Aviano, Italy. [Arnold, Norbert] Univ Hosp Schleswig Holstein, Dept Gynecol & Obstet, Kiel, Germany. [Arnold, Norbert] Univ Kiel, Kiel, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Niederacher, Dieter] Univ Dusseldorf, Univ Med Ctr, Dept Obstet & Gynecol, D-40225 Dusseldorf, Germany. [Pendl, Hansjoerg] Univ Kiel, Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel, Germany. [Sutter, Christian] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Mein, Beatrice] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Rantala, Johanna] Karolinska Hosp, Dept Clin Genet, S-10401 Stockholm, Sweden. [Soller, Maria] Univ Lund Hosp, Univ & Reg Labs, Dept Clin Genet, S-22185 Lund, Sweden. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rodriguez, Gustavo C.] Univ Chicago, North Shore Univ Hlth Syst, Div Gynecol Oncol, Evanston, IL USA. [Salani, Ritu] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Skytte, Anne-Bine] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Gerdes, Anne-Marie] Rigshosp, Copenhagen Univ Hosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Ejlertsen, Bent] Rigshosp, Copenhagen Univ Hosp, Dept Oncol, DK-2100 Copenhagen, Denmark. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Pathol Queensland, Herston, Qld, Australia. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. RP Bojesen, SE (reprint author), Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. EM stig.egil.bojesen@regionh.dk; Georgia.Trench@qimr.edu.au; amd24@medschl.cam.ac.uk RI Kiemeney, Lambertus/D-3357-2009; Giannini, Giuseppe/B-5672-2013; Verdrengh, Evelien/H-4571-2012; Andrulis, Irene/E-7267-2013; Smart, Chanel/C-9583-2011; Ekici, Arif/C-3971-2013; French, Juliet/A-4982-2011; Li, Jingmei/I-2904-2012; McLaughlin, John/E-4577-2013; Kerin, Michael/D-6748-2013; Radice, Paolo/O-3119-2013; Reddel, Roger/A-6635-2014; Knight, Julia/A-6843-2012; Tang, Macy/B-9798-2014; Spurdle, Amanda/A-4978-2011; Peissel, Bernard/E-8187-2017; Mensenkamp, A.R./L-4520-2015; laurent-puig, pierre/B-2226-2013; Savage, Sharon/B-9747-2015; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Edwards, Stacey/A-4980-2011; Menkiszak, Janusz/I-4036-2014; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; salvesen, Helga/C-1187-2017; manoukian, siranoush/E-7132-2017; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; Yip, Cheng-Har/B-1909-2010; campbell, Ian/F-6006-2011; Gonzalez-Neira, Anna/C-5791-2015; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; montagna, marco/E-2225-2012; Woo, Yin Ling/B-5198-2010; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Dolcetti, Riccardo/O-3832-2015; Blanco, Ignacio/D-2565-2013; Salani, Ritu/E-4008-2011; Dork, Thilo/J-8620-2012; Ditsch, Nina/F-6267-2014; Whittemore, Alice/F-9925-2014; Oosterwijk, Jan C./G-5770-2011; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Noh, Dong-Young/G-5531-2011; Bernard, Loris/K-5953-2014; Arnold, Norbert/E-3012-2010; BYRSKI, Tomasz/I-2844-2014 OI Ikram, Mohammad Kamran/0000-0003-0173-9571; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808; Skytte, Anne-Bine/0000-0002-0067-9557; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Evans, Gareth/0000-0002-8482-5784; Kiemeney, Lambertus/0000-0002-2368-1326; Giannini, Giuseppe/0000-0003-0299-4056; Li, Jingmei/0000-0001-8587-7511; Reddel, Roger/0000-0002-6302-6107; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Dennis, Joe/0000-0003-4591-1214; Luben, Robert/0000-0002-5088-6343; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Halle, Mari/0000-0002-2660-8271; Yannoukakos, Drakoulis/0000-0001-7509-3510; Orlow, Irene/0000-0001-6234-6961; Dunning, Alison Margaret/0000-0001-6651-7166; Krakstad, Camilla/0000-0002-0174-8139; ADEMUYIWA, FOLUSO/0000-0002-6766-2258; Devilee, Peter/0000-0002-8023-2009; Kjaer, Susanne/0000-0002-8347-1398; Monteiro, Alvaro/0000-0002-8448-4801; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Lissowska, Jolanta/0000-0003-2695-5799; Peissel, Bernard/0000-0001-9233-3571; Hollestelle, Antoinette/0000-0003-1166-1966; Nathanson, Katherine/0000-0002-6740-0901; Rudolph, Anja/0000-0001-7520-2035; Lux, Michael Patrick/0000-0002-2781-2178; Robson, Mark/0000-0002-3109-1692; Czene, Kamila/0000-0002-3233-5695; Tworoger, Shelley/0000-0002-6986-7046; laurent-puig, pierre/0000-0001-8475-5459; Savage, Sharon/0000-0001-6006-0740; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; salvesen, Helga/0000-0002-4438-8831; manoukian, siranoush/0000-0002-6034-7562; Bandera, Elisa/0000-0002-8789-2755; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; montagna, marco/0000-0002-4929-2150; Woo, Yin Ling/0000-0003-1742-1066; Shrubsole, Martha/0000-0002-5591-7575; Dolcetti, Riccardo/0000-0003-1625-9853; Blanco, Ignacio/0000-0002-7414-7481; Brooks-Wilson, Angela/0000-0003-1009-6408; Arnold, Norbert/0000-0003-4523-8808; FU European Commission's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/Al2014]; European Union Cooperation in Science and Technology (COST) [BM0606]; Cancer Research UK; Canadian Institutes of Health Research (CIHR); Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; Genetic Associations and Mechanisms in Oncology [U19-CA148112]; US National Institutes of Health [CAl28978]; National Cancer Institute (NCI) [CA116201]; US Department of Defense Ovarian Cancer Idea [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Komen Foundation for the Cure; Wellcome Trust Case Control Consortium; Wellcome Trust [076113] FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. COGS is funded through a grant from the European Commission's Seventh Framework Programme (agreement 223175 HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/Al2014). BCAC meetings have been funded by the European Union Cooperation in Science and Technology (COST) programme (BM0606). Telomere length measurement and analysis were funded by Cancer Research UK project grant C1287/A9540 and Chief Physician Johan Boserup and Lise Boserup's Fund. CIMBA data management and analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program (J.S. and D.E.) and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701; J.S., D.E. and P. Hall). Scientific development and funding of the OCAC portion of this project were supported by Genetic Associations and Mechanisms in Oncology (GAME-ON; U19-CA148112). CIMBA genotyping was supported by US National Institutes of Health (NIH) grant CAl28978, a National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a US Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. This study made use of data generated by The Wellcome Trust Case Control Consortium (funding was provided by Wellcome Trust award 076113) and the TCGA Pilot Project established by NCI and the National Human Genome Research Institute. NR 70 TC 211 Z9 216 U1 15 U2 171 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 371 EP 384 DI 10.1038/ng.2566 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600007 PM 23535731 ER PT J AU Eeles, RA Al Olama, AA Benlloch, S Saunders, EJ Leongamornlert, DA Tymrakiewicz, M Ghoussaini, M Luccarini, C Dennis, J Jugurnauth-Little, S Dadaev, T Neal, DE Hamdy, FC Donovan, JL Muir, K Giles, GG Severi, G Wiklund, F Gronberg, H Haiman, CA Schumacher, F Henderson, BE Le Marchand, L Lindstrom, S Kraft, P Hunter, DJ Gapstur, S Chanock, SJ Berndt, SI Albanes, D Andriole, G Schleutker, J Weischer, M Canzian, F Riboli, E Key, TJ Travis, RC Campa, D Ingles, SA John, EM Hayes, RB Pharoah, PDP Pashayan, N Khaw, KT Stanford, JL Ostrander, EA Signorello, LB Thibodeau, SN Schaid, D Maier, C Vogel, W Kibel, AS Cybulski, C Lubhiski, J Cannon-Albright, L Brenner, H Park, JY Kaneva, R Batra, J Spurdle, AB Clements, JA Teixeira, MR Dicks, E Lee, A Dunning, AM Baynes, C Conroy, D Maranian, MJ Ahmed, S Govindasami, K Guy, M Wilkinson, RA Sawyer, EJ Morgan, A Dearnaley, DP Horwich, A Huddart, RA Khoo, VS Parker, CC Van As, NJ Woodhouse, CJ Thompson, A Dudderidge, T Ogden, C Cooper, CS Lophatananon, A Cox, A Southey, MC Hopper, JL English, DR Aly, M Adolfsson, J Xu, JF Zheng, SL Yeager, M Kaaks, R Diver, WR Gaudet, MM Stern, MC Corral, R Joshi, AD Shahabi, A Wahlfors, T Tammela, TLJ Auvinen, A Virtamo, J Klarskov, P Nordestgaard, BG Roder, MA Nielsen, SF Bojesen, SE Siddiq, A FitzGerald, LM Kolb, S Kwon, EM Karyadi, DM Blot, WJ Zheng, W Cai, QY McDonnell, SK Rinckleb, AE Drake, B Colditz, G Wokolorczyk, D Stephenson, RA Teerlink, C Muller, H Rothenbacher, D Sellers, TA Lin, HY Slavov, C Mitev, V Lose, F Srinivasan, S Maia, S Paulo, P Lange, E Cooney, KA Antoniou, AC Vincent, D Bacot, F Tessier, DC Kote-Jarai, Z Easton, DF AF Eeles, Rosalind A. Al Olama, Ali Amin Benlloch, Sara Saunders, Edward J. Leongamornlert, Daniel A. Tymrakiewicz, Malgorzata Ghoussaini, Maya Luccarini, Craig Dennis, Joe Jugurnauth-Little, Sarah Dadaev, Tokhir Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Ken Giles, Graham G. Severi, Gianluca Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Le Marchand, Loic Lindstrom, Sara Kraft, Peter Hunter, David J. Gapstur, Susan Chanock, Stephen J. Berndt, Sonja I. Albanes, Demetrius Andriole, Gerald Schleutker, Johanna Weischer, Maren Canzian, Federico Riboli, Elio Key, Tim J. Travis, Ruth C. Campa, Daniele Ingles, Sue A. John, Esther M. Hayes, Richard B. Pharoah, Paul D. P. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Ostrander, Elaine A. Signorello, Lisa B. Thibodeau, Stephen N. Schaid, Dan Maier, Christiane Vogel, Walther Kibel, Adam S. Cybulski, Cezary Lubhiski, Jan Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y. Kaneva, Radka Batra, Jyotsna Spurdle, Amanda B. Clements, Judith A. Teixeira, Manuel R. Dicks, Ed Lee, Andrew Dunning, Alison M. Baynes, Caroline Conroy, Don Maranian, Melanie J. Ahmed, Shahana Govindasami, Koveela Guy, Michelle Wilkinson, Rosemary A. Sawyer, Emma J. Morgan, Angela Dearnaley, David P. Horwich, Alan Huddart, Robert A. Khoo, Vincent S. Parker, Christopher C. Van As, Nicholas J. Woodhouse, Christopher J. Thompson, Alan Dudderidge, Tim Ogden, Chris Cooper, Colin S. Lophatananon, Artitaya Cox, Angela Southey, Melissa C. Hopper, John L. English, Dallas R. Aly, Markus Adolfsson, Jan Xu, Jiangfeng Zheng, Siqun L. Yeager, Meredith Kaaks, Rudolf Diver, W. Ryan Gaudet, Mia M. Stern, Mariana C. Corral, Roman Joshi, Amit D. Shahabi, Ahva Wahlfors, Tiina Tammela, Teuvo L. J. Auvinen, Anssi Virtamo, Jarmo Klarskov, Peter Nordestgaard, Borge G. Roder, M. Andreas Nielsen, Sune F. Bojesen, Stig E. Siddiq, Afshan FitzGerald, Liesel M. Kolb, Suzanne Kwon, Erika M. Karyadi, Danielle M. Blot, William J. Zheng, Wei Cai, Qiuyin McDonnell, Shannon K. Rinckleb, Antje E. Drake, Bettina Colditz, Graham Wokolorczyk, Dominika Stephenson, Robert A. Teerlink, Craig Muller, Heiko Rothenbacher, Dietrich Sellers, Thomas A. Lin, Hui-Yi Slavov, Chavdar Mitev, Vanio Lose, Felicity Srinivasan, Srilakshmi Maia, Sofia Paulo, Paula Lange, Ethan Cooney, Kathleen A. Antoniou, Antonis C. Vincent, Daniel Bacot, Francois Tessier, Daniel C. Kote-Jarai, Zsofia Easton, Douglas F. CA COGS-Canc Res UK GWAS-ELLIPSE Part Australian Prostate Canc UK Genetic Prostate Canc Study UK ProtecT Prostate Testing Canc PRACTICAL Prostate Canc Assoc Grp TI Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; VARIANTS; RISK; HOXB13; PREDISPOSITION; MUTATIONS; MEN AB Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom II lumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genomewide significance (P < 5 x 10(-8)). More than 70 prostate cancer susceptibility loci, explaining similar to 30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. C1 [Eeles, Rosalind A.; Saunders, Edward J.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Jugurnauth-Little, Sarah; Dadaev, Tokhir; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A.; Sawyer, Emma J.; Morgan, Angela; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Cooper, Colin S.; Kote-Jarai, Zsofia] Inst Canc Res, Sutton, Surrey, England. [Eeles, Rosalind A.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas J.; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv NHS Fdn, London, England. [Eeles, Rosalind A.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas J.; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv NHS Fdn, Sutton, Surrey, England. [Al Olama, Ali Amin; Benlloch, Sara; Ghoussaini, Maya; Luccarini, Craig; Dennis, Joe; Pharoah, Paul D. P.; Pashayan, Nora; Dicks, Ed; Lee, Andrew; Dunning, Alison M.; Baynes, Caroline; Conroy, Don; Maranian, Melanie J.; Ahmed, Shahana; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Neal, David E.] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX3 9DU, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Muir, Ken; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Ken] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Giles, Graham G.; Severi, Gianluca; English, Dallas R.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Giles, Graham G.; Severi, Gianluca; Hopper, John L.; English, Dallas R.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Wiklund, Fredrik; Gronberg, Henrik; Aly, Markus] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Ingles, Sue A.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lindstrom, Sara; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Gapstur, Susan; Diver, W. Ryan; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Chanock, Stephen J.; Berndt, Sonja I.; Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, US NIH, Bethesda, MD 20892 USA. [Andriole, Gerald; Drake, Bettina; Colditz, Graham] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Schleutker, Johanna; Wahlfors, Tiina] Univ Tampere, Inst Biomed Technol BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna; Wahlfors, Tiina] FimLab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.; Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Canzian, Federico; Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Key, Tim J.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Sch Med, Div Epidemiol, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Langone Med Ctr, Div Epidemiol, New York, NY 10016 USA. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Stanford, Janet L.; FitzGerald, Liesel M.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Ostrander, Elaine A.; Kwon, Erika M.; Karyadi, Danielle M.] NHGRI, US NIH, Bethesda, MD 20892 USA. [Signorello, Lisa B.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Signorello, Lisa B.; Blot, William J.; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Dept Med,Div Epidemiol, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Nashville, TN 37212 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Schaid, Dan] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Maier, Christiane; Rinckleb, Antje E.] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane; Vogel, Walther; Rinckleb, Antje E.] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Div Urol Surg, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cybulski, Cezary; Lubhiski, Jan; Wokolorczyk, Dominika] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Cannon-Albright, Lisa; Teerlink, Craig] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa; Stephenson, Robert A.] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. [Brenner, Hermann; Muller, Heiko; Rothenbacher, Dietrich] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi] Univ S Florida, H Lee Moffitt Canc Ctr, Div Canc Prevent & Control, Tampa, FL 33682 USA. [Kaneva, Radka; Mitev, Vanio] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Batra, Jyotsna; Clements, Judith A.; Srinivasan, Srilakshmi] Queensland Univ Technol, Australian Prostate Canc Res Ctr, Queensland Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Batra, Jyotsna; Clements, Judith A.; Srinivasan, Srilakshmi] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Spurdle, Amanda B.; Lose, Felicity] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [Teixeira, Manuel R.; Maia, Sofia; Paulo, Paula] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.; Maia, Sofia; Paulo, Paula] Univ Porto, Abel Salazar Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal. [Cooper, Colin S.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. [Cox, Angela] Univ Sheffield, Canc Res UK Yorkshire Canc Res Sheffield Canc Res, Sheffield, S Yorkshire, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Aly, Markus] Karolinska Inst, Danderyd Hosp, Div Urol, Dept Clin Sci, Stockholm, Sweden. [Adolfsson, Jan] Karolinska Inst, Reg Canc Ctr, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden. [Xu, Jiangfeng] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Zheng, Siqun L.] Wake Forest Univ Hlth Sci, Ctr Canc Genom, Genom Genotyping Lab, Winston Salem, NC USA. [Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick, US NIH, Gaithersburg, MD USA. [Kaaks, Rudolf] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Tammela, Teuvo L. J.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Univ Tampere, Dept Epidemiol, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Herlev, Denmark. [Roder, M. Andreas] Copenhagen Univ Hosp, Rigshosp, Dept Urol, Copenhagen, Denmark. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Stephenson, Robert A.] Huntsman Canc Inst, Salt Lake City, UT USA. [Slavov, Chavdar] Med Univ Sofia, Alexandrovska Univ Hosp, Dept Urol, Sofia, Bulgaria. [Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Ctr Comprehens Canc, Div Hematol Oncol, Ann Arbor, MI USA. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] McGill Univ, Montreal, PQ, Canada. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Eeles, RA (reprint author), Inst Canc Res, Sutton, Surrey, England. EM rosalind.eeles@icr.ac.uk RI Spurdle, Amanda/A-4978-2011; Batra, Jyotsna/B-4130-2011; Albanes, Demetrius/B-9749-2015; Paulo, Paula/F-1441-2016; Teixeira, Manuel/E-4885-2011; Campa, Daniele/K-1617-2016; Colditz, Graham/A-3963-2009; Brenner, Hermann/B-4627-2017; OI albright, lisa/0000-0003-2602-3668; Cox, Angela/0000-0002-5138-1099; Drake, Bettina/0000-0001-9340-5848; Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; English, Dallas/0000-0001-7828-8188; Ostrander, Elaine/0000-0001-6075-9738; Eeles, Rosalind/0000-0002-3698-6241; Lose, Felicity/0000-0001-8337-3547; Roder, Martin Andreas/0000-0002-0019-5333; Spurdle, Amanda/0000-0003-1337-7897; Adolfsson, Jan/0000-0003-2992-1869; Dennis, Joe/0000-0003-4591-1214; Teerlink, Craig/0000-0002-1992-2326; Neal, David/0000-0002-6033-5086; Leongamornlert, Daniel/0000-0002-3486-3168; Hayes, Richard/0000-0002-0918-661X; van As, Nicholas/0000-0001-6829-8788; Paulo, Paula/0000-0001-8387-2127; Teixeira, Manuel/0000-0002-4896-5982; Campa, Daniele/0000-0003-3220-9944; Colditz, Graham/0000-0002-7307-0291; Brenner, Hermann/0000-0002-6129-1572; Dadaev, Tokhir/0000-0002-8268-0438; Auvinen, Anssi/0000-0003-1125-4818; Saunders, Ed/0000-0003-4343-3570 FU Cancer Research UK [10118, 10124, 10588, 11174, 13065, 14136]; Intramural NIH HHS [Z99 CA999999, ZIA CP010195-06]; Medical Research Council [G0401527, G0900871, G1000143]; NCATS NIH HHS [TL1 TR000132]; NCI NIH HHS [R01 CA082664, P30 CA042014, P30 CA076292, R01 CA056678, R01 CA092447, R01 CA092579]; Prostate Cancer UK [G2011/36] NR 29 TC 228 Z9 229 U1 4 U2 61 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 APR PY 2013 VL 45 IS 4 BP 385 EP 391 DI 10.1038/ng.2560 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600008 PM 23535732 ER PT J AU Garcia-Closas, M Couch, FJ Lindstrom, S Michailidouo, K Schmidt, MK Brook, MN Orr, N Rhie, SK Riboli, E Feigelson, HS Le Marchand, L Buring, JE Eccles, D Miron, P Fasching, PA Brauch, H Chang-Claude, J Carpenter, J Godwin, AK Nevanlinna, H Giles, GG Cox, A Hopper, JL Bolla, MK Wang, Q Dennis, J Dicks, E Howat, WJ Schoof, N Bojesen, SE Lambrechts, D Broeks, A Andrulis, IL Guenel, P Burwinkel, B Sawyer, EJ Hollestelle, A Fletcher, O Winqvist, R Brenner, H Mannermaa, A Hamann, U Meindl, A Lindblom, A Zheng, W Devillee, P Goldberg, MS Lubinski, J Kristensen, V Swerdlow, A Anton-Culver, H Doerk, T Muir, K Matsuo, K Wu, AH Radice, P Teo, SH Shu, XO Blot, W Kang, D Hartman, M Sangrajrang, S Shen, CY Southey, MC Park, DJ Hammet, F Stone, J Van't Veer, LJ Rutgers, EJ Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Peto, J Schrauder, MG Ekici, AB Beckmann, MW Silva, ID Johnson, N Warren, H Tomlins, I Kerin, MJ Miller, N Marme, F Schneeweiss, A Sohn, C Truong, T Laurent-Puig, P Kerbrat, P Nordestgaard, BG Nielsen, SF Flyger, H Milne, RL Perez, JIA Menendez, P Muller, H Arndt, V Stegmaier, C Lichtner, P Lochmann, M Justenhoven, C Ko, YD Muranen, TA Aittomaki, K Blomqvist, C Greco, D Heikkinen, T Ito, H Iwata, H Yatabe, Y Antonenkova, NN Margolin, S Kataja, V Kosma, VM Hartikainen, JM Balleine, R Tseng, CC Van den Berg, D Stram, DO Neven, P Dieudonne, AS Leunen, K Rudolph, A Nickels, S Flesch-Janys, D Peterlongo, P Peissel, B Bernard, L Olson, JE Wang, XS Stevens, K Severi, G Baglietto, L McLean, C Coetzee, GA Feng, Y Henderson, BE Schumacher, F Bogdanova, NV Labreche, F Dumont, M Yip, CH Taib, NAM Cheng, CY Shrubsole, M Long, JR Pylkas, K Jukkola-Vuorinen, A Kauppila, S Knight, JA Glendon, G Mulligan, AM Tollenaar, RAEM Seynaeve, CM Kriege, M Hooning, MJ van den Ouweland, AMW van Deurzen, CHM Lu, W Gao, YT Cai, H Balasubramanian, SP Cross, SS Reed, MWR Signorello, L Cai, QY Shah, M Miao, H Chan, CW Chia, KS Jakubowska, A Jaworska, K Durda, K Hsiung, CN Wu, P Yu, JC Ashworth, A Jones, M Tessier, DC Gonzalez-Neira, A Pita, G Alonso, MR Vincent, D Bacot, F Ambrosone, CB Bandera, EV John, EM Chen, GK Hu, JJ Rodriguez-Gil, JL Bernstein, L Press, MF Ziegler, RG Millikan, RM Deming-Halverson, SL Nyante, S Ingles, SA Waisfisz, Q Tsimiklis, H Makalic, E Schmidt, D Bui, M Gibson, L Muller-Myhsok, B Schmutzler, RK Hein, R Dahmen, N Beckmann, L Aaltonen, K Czene, K Irwanto, A Liu, JJ Turnbull, C Rahman, N Meijers-Heijboer, H Uitterlinden, AG Rivadeneira, F Olswold, C Slager, S Pilarski, R Ademuyiwa, F Konstantopoulou, I Martin, NG Montgomery, GW Slamon, DJ Rauh, C Lux, MP Jud, SM Bruning, T Weaver, J Harma, P Pathak, H Tapper, W Gerty, S Durcan, L Trichopoulos, D Tumino, R Peeters, PH Kaaks, R Campa, D Canzian, F Weiderpass, E Johansson, M Khaw, KT Travis, R Clavel-Chapelon, F Kolonel, LN Chen, C Beck, A Hankinson, SE Berg, CD Hoover, RN Lissowska, J Figueroa, JD Chasman, DI Gaudet, MM Diver, WR Willett, WC Hunter, DJ Simard, J Benitez, J Dunning, AM Sherman, ME Chenevix-Trench, G Chanock, SJ Hall, P Pharoah, PDP Vachon, C Easton, DF Haiman, CA Kraft, P AF Garcia-Closas, Montserrat Couch, Fergus J. Lindstrom, Sara Michailidouo, Kyriaki Schmidt, Marjanka K. Brook, Mark N. Orr, Nick Rhie, Suhn Kyong Riboli, Elio Feigelson, Heather S. Le Marchand, Loic Buring, Julie E. Eccles, Diana Miron, Penelope Fasching, Peter A. Brauch, Hiltrud Chang-Claude, Jenny Carpenter, Jane Godwin, Andrew K. Nevanlinna, Heli Giles, Graham G. Cox, Angela Hopper, John L. Bolla, Manjeet K. Wang, Qin Dennis, Joe Dicks, Ed Howat, Will J. Schoof, Nils Bojesen, Stig E. Lambrechts, Diether Broeks, Annegien Andrulis, Irene L. Guenel, Pascal Burwinkel, Barbara Sawyer, Elinor J. Hollestelle, Antoinette Fletcher, Olivia Winqvist, Robert Brenner, Hermann Mannermaa, Arto Hamann, Ute Meindl, Alfons Lindblom, Annika Zheng, Wei Devillee, Peter Goldberg, Mark S. Lubinski, Jan Kristensen, Vessela Swerdlow, Anthony Anton-Culver, Hoda Doerk, Thilo Muir, Kenneth Matsuo, Keitaro Wu, Anna H. Radice, Paolo Teo, Soo Hwang Shu, Xiao-Ou Blot, William Kang, Daehee Hartman, Mikael Sangrajrang, Suleeporn Shen, Chen-Yang Southey, Melissa C. Park, Daniel J. Hammet, Fleur Stone, Jennifer Van't Veer, Laura J. Rutgers, Emiel J. Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Peto, Julian Schrauder, Michael G. Ekici, Arif B. Beckmann, Matthias W. Silva, Isabel dos Santos Johnson, Nichola Warren, Helen Tomlins, Ian Kerin, Michael J. Miller, Nicola Marme, Federick Schneeweiss, Andreas Sohn, Christof Therese Truong Laurent-Puig, Pierre Kerbrat, Pierre Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Milne, Roger L. Arias Perez, Jose Ignacio Menendez, Primitiva Mueller, Heiko Arndt, Volker Stegmaier, Christa Lichtner, Peter Lochmann, Magdalena Justenhoven, Christina Ko, Yon-Dschun Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Greco, Dario Heikkinen, Tuomas Ito, Hidemi Iwata, Hiroji Yatabe, Yasushi Antonenkova, Natalia N. Margolin, Sara Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Balleine, Rosemary Tseng, Chiu-Chen Van den Berg, David Stram, Daniel O. Neven, Patrick Dieudonne, Anne-Sophie Leunen, Karin Rudolph, Anja Nickels, Stefan Flesch-Janys, Dieter Peterlongo, Paolo Peissel, Bernard Bernard, Loris Olson, Janet E. Wang, Xianshu Stevens, Kristen Severi, Gianluca Baglietto, Laura McLean, Catriona Coetzee, Gerhard A. Feng, Ye Henderson, Brian E. Schumacher, Fredrick Bogdanova, Natalia V. Labreche, France Dumont, Martine Yip, Cheng Har Taib, Nur Aishah Mohd Cheng, Ching-Yu Shrubsole, Martha Long, Jirong Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Tollenaar, Robertus A. E. M. Seynaeve, Caroline M. Kriege, Mieke Hooning, Maartje J. van den Ouweland, Ans M. W. van Deurzen, Carolien H. M. Lu, Wei Gao, Yu-Tang Cai, Hui Balasubramanian, Sabapathy P. Cross, Simon S. Reed, Malcolm W. R. Signorello, Lisa Cai, Qiuyin Shah, Mitul Miao, Hui Chan, Ching Wan Chia, Kee Seng Jakubowska, Anna Jaworska, Katarzyna Durda, Katarzyna Hsiung, Chia-Ni Wu, Peiei Yu, Jyh-Cherng Ashworth, Alan Jones, Michael Tessier, Daniel C. Gonzalez-Neira, Anna Pita, Guillermo Alonso, M. Rosario Vincent, Daniel Bacot, Francois Ambrosone, Christine B. Bandera, Elisa V. John, Esther M. Chen, Gary K. Hu, Jennifer J. Rodriguez-Gil, Jorge L. Bernstein, Leslie Press, Michael F. Ziegler, Regina G. Millikan, Robert M. Deming-Halverson, Sandra L. Nyante, Sarah Ingles, Sue A. Waisfisz, Quinten Tsimiklis, Helen Makalic, Enes Schmidt, Daniel Bui, Minh Gibson, Lorna Mueller-Myhsok, Bertram Schmutzler, Rita K. Hein, Rebecca Dahmen, Norbert Beckmann, Lars Aaltonen, Kirsimari Czene, Kamila Irwanto, Astrid Liu, Jianjun Turnbull, Clare Rahman, Nazneen Meijers-Heijboer, Hanne Uitterlinden, Andre G. Rivadeneira, Fernando Olswold, Curtis Slager, Susan Pilarski, Robert Ademuyiwa, Foluso Konstantopoulou, Irene Martin, Nicholas G. Montgomery, Grant W. Slamon, Dennis J. Rauh, Claudia Lux, Michael P. Jud, Sebastian M. Bruning, Thomas Weaver, JoEllen Harma, Priyanka Pathak, Harsh Tapper, Will Gerty, Sue Durcan, Lorraine Trichopoulos, Dimitrios Tumino, Rosario Peeters, Petra H. Kaaks, Rudolf Campa, Daniele Canzian, Federico Weiderpass, Elisabete Johansson, Mattias Khaw, Kay-Tee Travis, Ruth Clavel-Chapelon, Francoise Kolonel, Laurence N. Chen, Constance Beck, Andy Hankinson, Susan E. Berg, Christine D. Hoover, Robert N. Lissowska, Jolanta Figueroa, Jonine D. Chasman, Daniel I. Gaudet, Mia M. Diver, W. Ryan Willett, Walter C. Hunter, David J. Simard, Jacques Benitez, Javier Dunning, Alison M. Sherman, Mark E. Chenevix-Trench, Georgia Chanock, Stephen J. Hall, Per Pharoah, Paul D. P. Vachon, Celine Easton, Douglas F. Haiman, Christopher A. Kraft, Peter CA Gene ENvironm Interaction Breast KConFab Investigators Familial Breast Canc Study FBCS Australian Breast Canc Tissue Bank TI Genome-wide association studies identify four ER negative-specific breast cancer risk loci SO NATURE GENETICS LA English DT Article ID BODY-MASS INDEX; COMMON VARIANT; SUSCEPTIBILITY; EXPRESSION; ESTROGEN; GENE AB Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. C1 [Garcia-Closas, Montserrat; Brook, Mark N.; Swerdlow, Anthony; Jones, Michael; Turnbull, Clare; Rahman, Nazneen] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat; Orr, Nick; Fletcher, Olivia; Johnson, Nichola; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Stevens, Kristen; Olswold, Curtis; Slager, Susan; Vachon, Celine] Mayo Clin, Coll Med, Rochester, MN USA. [Lindstrom, Sara; Trichopoulos, Dimitrios; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Michailidouo, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dicks, Ed; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Rutgers, Emiel J.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Rhie, Suhn Kyong; Wu, Anna H.; Tseng, Chiu-Chen; Van den Berg, David; Stram, Daniel O.; Coetzee, Gerhard A.; Feng, Ye; Henderson, Brian E.; Schumacher, Fredrick; Chen, Gary K.; Ingles, Sue A.; Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Feigelson, Heather S.] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Buring, Julie E.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Eccles, Diana; Tapper, Will; Gerty, Sue; Durcan, Lorraine] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Miron, Penelope] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fasching, Peter A.; Schrauder, Michael G.; Beckmann, Matthias W.; Rauh, Claudia; Lux, Michael P.; Jud, Sebastian M.] Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Univ Hosp Erlangen, Erlangen, Germany. [Fasching, Peter A.; Slamon, Dennis J.] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Brauch, Hiltrud; Justenhoven, Christina] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud; Justenhoven, Christina] Univ Tubingen, Tubingen, Germany. [Chang-Claude, Jenny; Rudolph, Anja; Nickels, Stefan; Hein, Rebecca; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Carpenter, Jane] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Westmead, NSW 2145, Australia. [Godwin, Andrew K.; Pathak, Harsh] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Nevanlinna, Heli; Muranen, Taru A.; Greco, Dario; Heikkinen, Tuomas; Aaltonen, Kirsimari] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.; Greco, Dario; Heikkinen, Tuomas; Aaltonen, Kirsimari] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.; Makalic, Enes; Schmidt, Daniel; Bui, Minh] Univ Melbourne, Sch Populat Hlth, Melbourne, Vic, Australia. [Cox, Angela; Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.] Univ Sheffield, Dept Oncol, Canc Res UK Yorkshire Canc Res Sheffield Canc Res, Sheffield, S Yorkshire, England. [Hopper, John L.; Stone, Jennifer; Severi, Gianluca; Baglietto, Laura; Makalic, Enes; Schmidt, Daniel; Bui, Minh] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Howat, Will J.] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Schoof, Nils; Czene, Kamila; Weiderpass, Elisabete; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Dept Clin Biochem, Herlev Hosp, Copenhagen Gen Populat Study,Copenhagen Univ Hosp, Copenhagen, Denmark. [Lambrechts, Diether] VIB, VRC, Louvain, Belgium. [Lambrechts, Diether] Katholieke Univ Leuven, Dept Oncol, Louvain, Belgium. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Guenel, Pascal; Therese Truong; Clavel-Chapelon, Francoise] Univ Paris Sud, UMRS 1018, Villejuif, France. [Guenel, Pascal; Therese Truong; Clavel-Chapelon, Francoise] Environm Epidemiol Canc, INSERM, Natl Inst Hlth & Med Res, CESP Ctr Res Epidemiol & Populat Hlth, Villejuif, France. [Burwinkel, Barbara; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] DKFZ, Mol Epidemiol Grp, Heidelberg, Germany. [Sawyer, Elinor J.] Kings Coll London, Div Canc Studies, Natl Inst Hlth Res NIHR Comprehens Biomed Res Ctr, Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, London WC2R 2LS, England. [Hollestelle, Antoinette; Seynaeve, Caroline M.; Kriege, Mieke; Hooning, Maartje J.] Erasmus Univ, Med Ctr, Dept Med Oncol, Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Bioctr Oulu,Oulu Univ Hosp, Oulu, Finland. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Bioctr Kuopio, Canc Ctr Eastern Finland, Kuopio, Finland. [Hamann, Ute] DKFZ, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol Tumor Genet, Clin Gynaecol & Obstet, D-80290 Munich, Germany. [Meindl, Alfons; Lochmann, Magdalena] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Zheng, Wei; Shu, Xiao-Ou; Blot, William; Shrubsole, Martha; Long, Jirong; Cai, Hui; Signorello, Lisa; Deming-Halverson, Sandra L.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Devillee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devillee, Peter; van Deurzen, Carolien H. M.] Erasmus Univ, Med Ctr, Dept Pathol, Rotterdam, Netherlands. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.; Cai, Qiuyin] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [Lubinski, Jan; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Kristensen, Vessela] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Fac Div Ahus, Oslo, Norway. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Doerk, Thilo; Bogdanova, Natalia V.] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Matsuo, Keitaro; Ito, Hidemi] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Radice, Paolo; Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Mol Bases Genet Risk & Genet Testing, Dept Prevent & Predict Med, Milan, Italy. [Radice, Paolo; Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Teo, Soo Hwang] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia. [Teo, Soo Hwang] Univ Malaya, Canc Res Inst, Kuala Lumpur, Malaysia. [Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd] Univ Malaya, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Blot, William] Int Epidemiol Inst, Rockville, MD USA. [Kang, Daehee] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Hartman, Mikael; Cheng, Ching-Yu] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Hartman, Mikael; Cheng, Ching-Yu; Miao, Hui; Chia, Kee Seng] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Sangrajrang, Suleeporn] Natl Canc Inst, Bangkok, Thailand. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichong, Taiwan. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Southey, Melissa C.; Park, Daniel J.; Hammet, Fleur] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Bangkok, Thailand. [Peto, Julian; Silva, Isabel dos Santos; Warren, Helen; Gibson, Lorna] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1, England. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Tomlins, Ian] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Tomlins, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Kerin, Michael J.; Miller, Nicola] Univ Hosp, Inst Clin Sci, Dept Surg, Galway, Ireland. [Kerin, Michael J.; Miller, Nicola] Natl Univ Ireland, Galway, Ireland. [Marme, Federick; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Laurent-Puig, Pierre] Univ Paris Sorbonne Cite, INSERM, UMRS 775, Paris, France. [Kerbrat, Pierre] Ctr Eugene Marquis, Dept Med Oncol, Rennes, France. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Menendez, Primitiva] Hosp Monte Naranco, Serv Anat Patol, Oviedo, Spain. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Lichtner, Peter] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Lichtner, Peter] Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Human Genet, Neuherberg, Germany. [Ko, Yon-Dschun] Johanniter Krankenhaus, Evangel Kliniken Bonn, Dept Internal Med, Bonn, Germany. [Aittomaki, Kristiina; Aaltonen, Kirsimari] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Blomqvist, Carl; Aaltonen, Kirsimari] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi 464, Japan. [Yatabe, Yasushi] Aichi Canc Ctr Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi 464, Japan. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Margolin, Sara] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Kataja, Vesa] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Balleine, Rosemary] Univ Sydney, Westmead Millennium Inst Med Res, Sydney, NSW 2006, Australia. [Neven, Patrick; Dieudonne, Anne-Sophie; Leunen, Karin] Katholieke Univ Leuven, Dept Oncol, Univ Hosp Gasthuisberg, Multidisciplinary Breast Ctr, Louvain, Belgium. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Dept Canc Epidemiol Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Peissel, Bernard] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Wang, Xianshu] Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Bernard, Loris] Cogentech Canc Genet Test Lab, Milan, Italy. [Wang, Xianshu] Mayo Clin, Div Expt Pathol, Dept Lab Med & Pathol, Rochester, MN USA. [McLean, Catriona] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [Coetzee, Gerhard A.] Univ So Calif, Keck Sch Med, Dept Urol, Los Angeles, CA 90033 USA. [Bogdanova, Natalia V.] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Labreche, France; Kolonel, Laurence N.] Univ Montreal, Dept Med Sociale & Prevent, Dept Sante Environm & Sante Travail, Montreal, PQ, Canada. [Dumont, Martine; Simard, Jacques] CHU Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Dumont, Martine; Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Cheng, Ching-Yu] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] St Michaels Hosp, Dept Lab Med, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Tollenaar, Robertus A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [van den Ouweland, Ans M. W.] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Shah, Mitul; Dunning, Alison M.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Chan, Ching Wan] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Wu, Peiei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Gonzalez-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Benitez, Javier] CNIO, Human Canc Genet Programme, Human Genotyping Unit CEGEN, Madrid, Spain. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol,Stanford Canc Inst, Stanford, CA 94305 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Press, Michael F.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Ziegler, Regina G.; Hoover, Robert N.; Figueroa, Jonine D.; Sherman, Mark E.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. [Millikan, Robert M.; Nyante, Sarah] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Waisfisz, Quinten; Meijers-Heijboer, Hanne] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Oncogenet, Amsterdam, Netherlands. [Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, Stat Genet Res Grp, D-80804 Munich, Germany. [Schmutzler, Rita K.] Univ Hosp, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany. [Hein, Rebecca] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, PMV Primarmed Versorgung Res Grp, D-50931 Cologne, Germany. [Dahmen, Norbert] Johannes Gutenberg Univ Mainz, Dept Psychiat, Mainz, Germany. [Beckmann, Lars] Inst Qual & Efficiency Hlth Care IQWiG, Cologne, Germany. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Human Genet Div, Singapore, Singapore. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands. [Pilarski, Robert] Ohio State Univ, Dept Internal Med, James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Ademuyiwa, Foluso] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, Inst Radioisotopes & Radiodiagnost Prod IRRP, Mol Diagnost Lab, Athens, Greece. [Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res, QIMR GWAS Collect, Brisbane, Qld 4006, Australia. [Slamon, Dennis J.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Bruning, Thomas] Inst Prevent & Occupat Med German Social Accident, Bochum, Germany. [Weaver, JoEllen] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Harma, Priyanka] Univ Kansas, Med Ctr, Dept Internal Med, Div Hematol & Oncol, Kansas City, KS USA. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Tumino, Rosario] Civile MPArezzo Hosp, Canc Registry, Histopathol Unit, Ragusa, Italy. [Peeters, Petra H.] Univ Med Ctr Utrecht, Julius Ctr, Utrecht, Netherlands. [Weiderpass, Elisabete] Univ Tromso, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Folkhalsan Res Canc Ctr, Helsinki, Finland. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Johansson, Mattias] World Hlth Org, Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Travis, Ruth] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Beck, Andy] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Beck, Andy] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hankinson, Susan E.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Berg, Christine D.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Gaudet, Mia M.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Benitez, Javier] CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Madrid, Spain. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia. RP Garcia-Closas, M (reprint author), Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. EM montse.garciaclosas@icr.ac.uk RI Brenner, Hermann/B-4627-2017; Peissel, Bernard/E-8187-2017; Bandera, Elisa/M-4169-2014; Jakubowska, Anna/O-8050-2014; Yip, Cheng-Har/B-1909-2010; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Pilarski, Robert/E-3871-2011; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Montgomery, Grant/B-7148-2008; laurent-puig, pierre/B-2226-2013; Bruning, Thomas/G-8120-2015; Campa, Daniele/K-1617-2016; Weiderpass, Elisabete/M-4029-2016; Cheng, Ching-Yu/K-7017-2013; Radice, Paolo/O-3119-2013; Knight, Julia/A-6843-2012; Dork, Thilo/J-8620-2012; Clavel-Chapelon, Francoise/G-6733-2014; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Berg , Christine/K-1047-2014; Bernard, Loris/K-5953-2014; Verdrengh, Evelien/H-4571-2012; Andrulis, Irene/E-7267-2013; Ekici, Arif/C-3971-2013; Kerin, Michael/D-6748-2013 OI Dennis, Joe/0000-0003-4591-1214; Dunning, Alison Margaret/0000-0001-6651-7166; Brook, Mark/0000-0002-8969-2378; Rivadeneira, Fernando/0000-0001-9435-9441; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Bui, Minh/0000-0002-9099-6870; Park, Daniel/0000-0002-6354-0931; ADEMUYIWA, FOLUSO/0000-0002-6766-2258; Giles, Graham/0000-0003-4946-9099; Brenner, Hermann/0000-0002-6129-1572; Peissel, Bernard/0000-0001-9233-3571; Hollestelle, Antoinette/0000-0003-1166-1966; Konstantopoulou, Irene/0000-0002-0470-0309; Rudolph, Anja/0000-0001-7520-2035; Greco, Dario/0000-0001-9195-9003; Lux, Michael Patrick/0000-0002-2781-2178; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Martin, Nicholas/0000-0003-4069-8020; Bandera, Elisa/0000-0002-8789-2755; Garcia-Closas, Montserrat /0000-0003-1033-2650; Shrubsole, Martha/0000-0002-5591-7575; Montgomery, Grant/0000-0002-4140-8139; laurent-puig, pierre/0000-0001-8475-5459; Bruning, Thomas/0000-0001-9560-5464; Campa, Daniele/0000-0003-3220-9944; Weiderpass, Elisabete/0000-0003-2237-0128; Cheng, Ching-Yu/0000-0003-0655-885X; FU Cancer Research UK [C1287/A10118, C1287/Al2014]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Union European Cooperation in Science and Technology (COST) [BM0606]; US National Cancer Institute [U01-CA98233, U01-CA98710, U01CA98216, U01-CA98758]; Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute, Division of Cancer Epidemiology and Genetics; Mayo Clinic Breast Cancer Study (MCBCS); US NIH [CA122340, CA116201]; Komen Foundation; European Union [HEALTH-F2-2009223175]; Breast Cancer Research Foundation; Canadian Institutes of Health Research (CIHR); Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI701]; US NIH Cancer Post-Cancer GWAS initiative [U19 CA 148065-01] FX The authors wish to thank all the individuals who took part in these studies and all the researchers, clinicians and administrative staff who have enabled this work to be carried out. We are very grateful to Illumina, in particular J. Stone, S. McBean, J. Hadlington, A. Mustafa and K. Cook, for their help with designing the array. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/Al2014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). BPC3 is funded by US National Cancer Institute cooperative agreements U01-CA98233, U01-CA98710, U01CA98216 and U01-CA98758 and the Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute, Division of Cancer Epidemiology and Genetics. TNBCC is supported by Mayo Clinic Breast Cancer Study (MCBCS) (US NIH grants CAl22340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)), grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation. Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009223175), Cancer Research UK (C1287/A10710), US NIH grant CAl22340, the Komen Foundation for the Cure, the Breast Cancer Research Foundation, the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program (J. Simiard and D.E.) and Ministry of Economic Development, Innovation and Export Trade of Quebec grant PSR-SIIRI701 (J. Simiard, D.E. and P.H.). J. Simiard holds the Canada Research Chair in Oncogenetics. Combination of the GWAS data was supported in part by US NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative) and Breakthrough Breast Cancer Research. NR 17 TC 174 Z9 177 U1 10 U2 99 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 392 EP 398 DI 10.1038/ng.2561 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600009 PM 23535733 ER PT J AU Chatterjee, N Wheeler, B Sampson, J Hartge, P Chanock, SJ Park, JH AF Chatterjee, Nilanjan Wheeler, Bill Sampson, Joshua Hartge, Patricia Chanock, Stephen J. Park, Ju-Hyun TI Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; SUSCEPTIBILITY LOCI; GENETIC RISK; BREAST-CANCER; COMMON SNPS; MISSING HERITABILITY; COMPLEX DISEASES; VARIANTS; IDENTIFICATION; PROPORTION AB We report a new method to estimate the predictive performance of polygenic models for risk prediction and assess predictive performance for ten complex traits or common diseases. Using estimates of effect-size distribution and heritability derived from current studies, we project that although 45% of the variance of height has been attributed to SNPs, a model trained on one million people may only explain 33.4% of variance of the trait. Models based on current studies allow for identification of 3.0%, 1.1% and 7.0% of the populations at twofold or higher than average risk for type 2 diabetes, coronary artery disease and prostate cancer, respectively. Tripling of sample sizes could elevate these percentages to 18.8%, 6.1% and 12.2%, respectively. The utility of polygenic models for risk prediction will depend on achievable sample sizes for the training data set, the underlying genetic architecture and the inclusion of information on other risk factors, including family history. C1 [Chatterjee, Nilanjan; Sampson, Joshua; Hartge, Patricia; Chanock, Stephen J.; Park, Ju-Hyun] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. [Wheeler, Bill] Informat Management Syst, Rockville, MD USA. [Park, Ju-Hyun] Dongguk Univ Seoul, Dept Stat, Seoul, South Korea. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD USA. EM chattern@mail.nih.gov FU US National Cancer Institute FX This research was supported by the intramural program of the US National Cancer Institute. NR 42 TC 91 Z9 94 U1 4 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 400 EP 405 DI 10.1038/ng.2579 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600010 PM 23455638 ER PT J AU Iles, MM Law, MH Stacey, SN Han, JL Fang, SY Pfeiffer, R Harland, M MacGregor, S Taylor, JC Aben, KK Akslen, LA Avril, MF Azizi, E Bakker, B Benediktsdottir, KR Bergman, W Scarra, GB Brown, KM Calista, D Chaudru, V Fargnoli, MC Cust, AE Demenais, F de Waal, AC Debniak, T Elder, DE Friedman, E Galan, P Ghiorzo, P Gillanders, EM Goldstein, AM Gruis, NA Hansson, J Helsing, P Hocevar, M Hoiom, V Hopper, JL Ingvar, C Janssen, M Jenkins, MA Kanetsky, PA Kiemeney, LA Lang, JL Lathrop, GM Leachman, S Lee, JE Lubinski, J Mackie, RM Mann, GJ Martin, NG Mayordomo, JI Molven, A Mulder, S Nagore, E Novakovic, S Okamoto, I Olafsson, JH Olsson, H Pehamberger, H Peris, K Grasa, MP Planelles, D Puig, S Puig-Butille, JA Randerson-Moor, J Requena, C Rivoltini, L Rodolfo, M Santinami, M Sigurgeirsson, B Snowden, H Song, FJ Sulem, P Thorisdottir, K Tuominen, R Van Belle, P van der Stoep, N van Rossum, MM Wei, QY Wendt, J Zelenika, D Zhang, MF Landi, MT Thorleifsson, G Bishop, DT Amos, CI Hayward, NK Stefansson, K Bishop, JAN Barrett, JH AF Iles, Mark M. Law, Matthew H. Stacey, Simon N. Han, Jiali Fang, Shenying Pfeiffer, Ruth Harland, Mark MacGregor, Stuart Taylor, John C. Aben, Katja K. Akslen, Lars A. Avril, Marie-Francoise Azizi, Esther Bakker, Bert Benediktsdottir, Kristrun R. Bergman, Wilma Scarra, Giovanna Bianchi Brown, Kevin M. Calista, Donato Chaudru, Valerie Fargnoli, Maria Concetta Cust, Anne E. Demenais, Florence Waal, Anne C. de Debniak, Tadeusz Elder, David E. Friedman, Eitan Galan, Pilar Ghiorzo, Paola Gillanders, Elizabeth M. Goldstein, Alisa M. Gruis, Nelleke A. Hansson, Johan Helsing, Per Hocevar, Marko Hoiom, Veronica Hopper, John L. Ingvar, Christian Janssen, Marjolein Jenkins, Mark A. Kanetsky, Peter A. Kiemeney, Lambertus A. Lang, Julie Lathrop, G. Mark Leachman, Sancy Lee, Jeffrey E. Lubinski, Jan Mackie, Rona M. Mann, Graham J. Martin, Nicholas G. Mayordomo, Jose I. Molven, Anders Mulder, Suzanne Nagore, Eduardo Novakovic, Srdjan Okamoto, Ichiro Olafsson, Jon H. Olsson, Haan Pehamberger, Hubert Peris, Ketty Grasa, Maria Pilar Planelles, Dolores Puig, Susana Puig-Butille, Joan Anton Randerson-Moor, Juliette Requena, Celia Rivoltini, Licia Rodolfo, Monica Santinami, Mario Sigurgeirsson, Bardur Snowden, Helen Song, Fengju Sulem, Patrick Thorisdottir, Kristin Tuominen, Rainer Van Belle, Patricia van der Stoep, Nienke van Rossum, Michelle M. Wei, Qingyi Wendt, Judith Zelenika, Diana Zhang, Mingfeng Landi, Maria Teresa Thorleifsson, Gudrnar Bishop, D. Timothy Amos, Christopher I. Hayward, Nicholas K. Stefansson, Kari Bishop, Julia A. Newton Barrett, Jennifer H. CA Q-MEGA AMFS Investigators GenoMEL Consortium TI A variant in FTO shows association with melanoma risk not due to BMI SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; SUSCEPTIBILITY LOCI; CUTANEOUS MELANOMA; PHENOTYPIC CHARACTERISTICS; ADULT OBESITY; IDENTIFIES 3; GENE; METAANALYSIS; PREDISPOSES AB We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity. C1 [Harland, Mark; Taylor, John C.; Randerson-Moor, Juliette; Snowden, Helen; Bishop, D. Timothy; Bishop, Julia A. Newton; Barrett, Jennifer H.] St James Univ Hosp, Leeds Canc Res UK Ctr, Leeds Inst Mol Med, Sect Epidemiol & Biostat, Leeds, W Yorkshire, England. [Law, Matthew H.; MacGregor, Stuart; Martin, Nicholas G.; Hayward, Nicholas K.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Stacey, Simon N.; Sulem, Patrick; Thorleifsson, Gudrnar; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Han, Jiali; Song, Fengju; Zhang, Mingfeng] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Han, Jiali] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Han, Jiali] Harvard Univ, Sch Med, Boston, MA USA. [Han, Jiali] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fang, Shenying; Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Pfeiffer, Ruth; Goldstein, Alisa M.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Aben, Katja K.; Kiemeney, Lambertus A.] Ctr Comprehens Canc, Nijmegen, Netherlands. [Aben, Katja K.; Waal, Anne C. de; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Akslen, Lars A.; Molven, Anders] Univ Bergen, Gade Inst, Ctr Canc Biomarkers, Bergen, Norway. [Iles, Mark M.; Akslen, Lars A.; Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Avril, Marie-Francoise] Univ Paris 05, Serv Dermatol, Hop Cochin, AP HP, Paris, France. [Azizi, Esther] Tel Aviv Univ, Sackler Fac Med, Sheba Med Ctr, Dept Dermatol & Oncogenet, IL-52621 Tel Hashomer, Israel. [Azizi, Esther; Friedman, Eitan] Tel Aviv Univ, Sackler Fac Med, Sheba Med Ctr, Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Bakker, Bert; van der Stoep, Nienke] Leiden Univ, Med Ctr, Dept Clin Genet, Ctr Human & Clin Genet, Leiden, Netherlands. [Benediktsdottir, Kristrun R.; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Benediktsdottir, Kristrun R.] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Bergman, Wilma; Gruis, Nelleke A.] Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands. [Scarra, Giovanna Bianchi; Ghiorzo, Paola] Univ Genoa, Dept Internal Med & Med Specialties, Genoa, Italy. [Scarra, Giovanna Bianchi; Ghiorzo, Paola] San Martino Ist Sci Tumori, Ist Ricovero & Cura Carattere Sci, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Brown, Kevin M.] NCI, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. [Calista, Donato] Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy. [Chaudru, Valerie] INSERM, UMR 946, Genet Variat & Human Dis Unit, Paris, France. [Chaudru, Valerie] Univ Evry Val dEssonne, Evry, France. [Chaudru, Valerie; Demenais, Florence; Lathrop, G. Mark] Fdn Jean Dausset, CEPH, Paris, France. [Fargnoli, Maria Concetta; Peris, Ketty] Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. [Cust, Anne E.] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia. [Demenais, Florence] Univ Paris Diderot, Inst Univ Hematol, Sorbonne Paris Cite, Paris, France. [Waal, Anne C. de; van Rossum, Michelle M.] Radboud Univ Nijmegen, Med Ctr, Dept Dermatol, NL-6525 ED Nijmegen, Netherlands. [Debniak, Tadeusz; Lubinski, Jan] Pomeranian Med Univ, Int Hereditary Canc Ctr, Szczecin, Poland. [Elder, David E.] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA. [Galan, Pilar] Univ Paris 13, Res Unit Nutr Epidemiol, INSERM, U557,Inst Sci Rech Agron,INRA U1125, Bobigny, France. [Gillanders, Elizabeth M.] NCI, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Hansson, Johan; Hoiom, Veronica; Tuominen, Rainer] Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden. [Helsing, Per] Univ Oslo, Rikshosp, Oslo Univ Hosp, Dept Dermatol, N-0027 Oslo, Norway. [Hocevar, Marko] Inst Oncol, Dept Surg Oncol, Ljubljana, Slovenia. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt MEGA Epidemiol, Melbourne, Vic, Australia. [Ingvar, Christian] Lund Univ, Dept Surg, Lund, Sweden. [Janssen, Marjolein; Mulder, Suzanne] ServiceXS BV, Leiden, Netherlands. [Kanetsky, Peter A.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kanetsky, Peter A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Lang, Julie] Univ Glasgow, Dept Med Genet, Glasgow, Lanark, Scotland. [Lathrop, G. Mark; Zelenika, Diana] Comis Nacl Energia Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Leachman, Sancy] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA. [Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Mackie, Rona M.] Univ Glasgow, Dept Publ Hlth, Glasgow G12 8QQ, Lanark, Scotland. [Mann, Graham J.] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. [Mann, Graham J.] Melanoma Inst Australia, Sydney, NSW, Australia. [Mayordomo, Jose I.; Grasa, Maria Pilar] Univ Zaragoza, Zaragoza, Spain. [Nagore, Eduardo; Requena, Celia] Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain. [Novakovic, Srdjan] Inst Oncol, Dept Mol Diagnost, Ljubljana, Slovenia. [Okamoto, Ichiro; Wendt, Judith] Med Univ Vienna, Dept Dermatol, Vienna, Austria. [Olafsson, Jon H.; Sigurgeirsson, Bardur; Thorisdottir, Kristin] Univ Iceland, Fac Med, Dept Dermatol, Reykjavik, Iceland. [Olsson, Haan] Lund Univ, Dept Oncol, Lund, Sweden. [Olsson, Haan] Lund Univ, Dept Canc Epidemiol, Lund, Sweden. [Pehamberger, Hubert; Planelles, Dolores] Ctr Blood Transfus, Lab Histocompatibil Mol Biol, Valencia, Spain. [Puig, Susana; Puig-Butille, Joan Anton] Univ Barcelona, Melanoma Unit, Dept Dermatol, Hosp Clin,Inst Invest Biorned August Pi Sune, Barcelona, Spain. [Puig, Susana; Puig-Butille, Joan Anton] Inst Salud Carlos III, Ctr Invest Biomed Red CIBER Enfermedades Raras, Barcelona, Spain. [Rivoltini, Licia; Rodolfo, Monica] Fdn Ist Ricovero & Cura Carattere Sci IRCCS Ist N, Immunotherapy Human Tumors Unit, Milan, Italy. [Santinami, Mario] Fdn IRCCS Ist Nazl Tumori, Melanoma & Sarcoma Surg Unit, Milan, Italy. [Song, Fengju] Tianjin Med Univ Canc Inst & Hosp, Dept Epidemiol, Tianjin, Peoples R China. [Van Belle, Patricia] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Amos, Christopher I.] Dartmouth Coll, Dept Community & Family Med, Geisel Coll Med, Hanover, NH 03755 USA. RP Iles, MM (reprint author), Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. EM m.m.iles@leeds.ac.uk RI Aben, Katja/G-9686-2016; Hoiom, Veronica/F-4153-2012; Akslen, Lars /C-1202-2017; Bakker, Egbert/D-3525-2009; Mayordomo, Jose/K-3453-2013; Kiemeney, Lambertus/D-3357-2009; Mann, Graham/G-4758-2014; Bianchi Scarra, Giovanna/G-8933-2014; de Waal, Anne/F-9379-2016; Demenais, Florence/G-3298-2013; Macgregor, Stuart/C-6442-2009; hayward, nicholas/C-1367-2015; PLANELLES, DOLORES/F-2689-2015; Mulder, S.F./L-4536-2015; Jenkins, Mark/P-7803-2015 OI Rodolfo, Monica/0000-0002-9196-0298; Newton Bishop, Julia/0000-0001-9147-6802; Puig, Susana/0000-0003-1337-9745; , Srdjan/0000-0002-8888-4810; Martin, Nicholas/0000-0003-4069-8020; Aben, Katja/0000-0002-0214-2147; Akslen, Lars /0000-0003-2710-9543; Sigurgeirsson, Bardur/0000-0002-9733-9742; Gruis, Nelleke/0000-0002-5210-9150; Barrett, Jenny/0000-0002-1720-7724; Rivoltini, Licia/0000-0002-2409-6225; Peris, Ketty/0000-0002-5237-0463; Fargnoli, Maria Concetta/0000-0002-7249-2556; Bishop, Tim/0000-0002-8752-8785; Bakker, Egbert/0000-0002-2843-7357; Kiemeney, Lambertus/0000-0002-2368-1326; Mann, Graham/0000-0003-1301-405X; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; Macgregor, Stuart/0000-0001-6731-8142; hayward, nicholas/0000-0003-4760-1033; PLANELLES, DOLORES/0000-0001-6433-4825; Jenkins, Mark/0000-0002-8964-6160 FU European Commission under the 6th Framework Programme [LSHC-CT-2006-018702]; Cancer Research UK Programme Awards [C588/A4994 and C588/A10589]; Cancer Research UK [C8216/A6129]; Leeds Cancer Research UK Centre [C37059/A11941]; US National Institutes of Health (NIH [CA83115]; intramural Research Program of the NIH; US National Cancer Institute (NCI); Division of Cancer Epidemiology and Genetics; Wellcome Trust [076113]; Swedish Cancer Society; Gunnar Nilsson Foundation; European Research Council [ERC-2011-AdG 294576]; Italian Ministry of Education, University and Research Progetti di Ricerca di Interesse Nazionale [2008W8JTPA_002]; Intergruppo Melanoma Italian; Mara Naum foundation; INCa [INCa-PL016]; Ligue Nationale Contre Le Cancer [PRE05/ FD, PRE 09/FD]; Programme Hospitaller de Recherche Clinique [AOM-07-195]; European Biobanking and Biomolecular Resources Research Infrastructure Netherlands hub [C018]; Fond de Investigaciones Sanitarias, Spain [P.I. 09/01393]; Centro de Investigaciones Biomedicas en Red (CIBER); Comprehensive Cancer Center, Oslo University Hospital [SE0728]; Norwegian Cancer Society [71512-PR-2006-0356]; Jubilaumsfonds of the Osterreichische Nationalbank [12161, 13036]; Hans und Blanca Moser Stiftung; NIH RO1 [CA65558-02]; Department of Health and Human Services; Intramural Research Program of NIH; NCI Division of Cancer Epidemiology and Genetics; NIH NCI [CA83115, P30CA023108, 2P50CA093459, CA88363, CAl22838, CA87969, CA055075, CA100264, CA133996, CA49449]; Marit Peterson Fund for Melanoma Research; Cancer Institute New South Wales; National Health and Medical Research Council; Dutch Cancer Society Koningin Wilhemina Fonds (KWF) Kankerbestrijding; Radboud University Medical Centre; Melanoma Research Alliance; National Health and Medical Research Council of Australia (NHMRC) [200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498]; Cancer Councils New South Wales; Victoria and Queensland; Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC); Cerylid Biosciences (Melbourne); Australian Cancer Research Foundation; The Wellcome Trust [WT084766/Z/08/Z]; NHMRC; Career Development award from the NHMRC [496674, 613705]; Cancer Australia [1011143] FX We thank M.I. McCarthy and C.M. Lindgren for assistance with the results of the GIANT study. The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract number LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project Grant (C8216/A6129), by the Leeds Cancer Research UK Centre (C37059/A11941) and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by the intramural Research Program of the NIH, US National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics. Genotyping of most of the samples collected in France that were included in GenoMEL was done at Centre National de Genotypage, Institut de Genomique-Commissariat a rEnergie Atomique and was supported by the Ministere de rEnseignement Superieur et de la Recherche and Institut National du Cancer (INCa). This study used data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from their website (see URLs); funding for the project was provided by the Wellcome Trust under award 076113. We thank the EGEA cooperative group for giving access to data of the EGEA study (see URLs). We acknowledge that the biological specimens of the French Familial Melanoma Study Group were obtained from the Institut Gustave Roussy and Fondation Jean Dausset-CEPH Biobanks. Work in Stockholm was funded by the Swedish Cancer Society and Karolinska Institutet research funds. Work in Lund was funded by the Swedish Cancer Society, the Gunnar Nilsson Foundation and the European Research Council (ERC-2011-AdG 294576-risk factors cancer). Work in Genoa was funded by the Italian Ministry of Education, University and Research Progetti di Ricerca di Interesse Nazionale (2008W8JTPA_002), Intergruppo Melanoma Italian and Mara Naum foundation. Work in Paris was funded by grants from INCa (INCa-PL016) and Ligue Nationale Contre Le Cancer (PRE05/ FD and PRE 09/FD) to F. Demenais, and Programme Hospitaller de Recherche Clinique (AOM-07-195) to M.-F. Avril and F. Demenais. Work in Leiden was funded by a grant provided by European Biobanking and Biomolecular Resources Research Infrastructure Netherlands hub (C018). Research at the Melanoma Unit in Barcelona is partially funded by grants from Fond de Investigaciones Sanitarias P.I. 09/01393, Spain and by the Centro de Investigaciones Biomedicas en Red (CIBER) de Enfermedades Raras of the Institut de Salud Carlos III, Spain; by the Agenda de Gestio d'Ajuts Universitaris i de Recerca 2009 SGR-1337 of the Catalan Government, Spain. Work in Norway was funded by grants from the Comprehensive Cancer Center, Oslo University Hospital (SE0728) and the Norwegian Cancer Society (71512-PR-2006-0356). Work in Vienna was supported by the Jubilaumsfonds of the Osterreichische Nationalbank (project numbers 12161 and 13036) and the Hans und Blanca Moser Stiftung. The Italian study was partially supported by a NIH RO1 grant CA65558-02 (to M.T. Landi), Department of Health and Human Services and by the Intramural Research Program of NIH, NCI Division of Cancer Epidemiology and Genetics. Work at the MD Anderson Cancer Center was supported by the NIH NCI (P30CA023108 and 2P50CA093459) and by the Marit Peterson Fund for Melanoma Research. A. Cust is supported by fellowships from the Cancer Institute New South Wales and the National Health and Medical Research Council.; Work in Nijmegen, The Netherlands, was funded by the Dutch Cancer Society Koningin Wilhemina Fonds (KWF) Kankerbestrijding and by the Radboud University Medical Centre. The Q-MEGA study was supported by the Melanoma Research Alliance, the NIH NCI (CA88363, CA83115, CAl22838, CA87969, CA055075, CA100264, CA133996 and CA49449), the National Health and Medical Research Council of Australia (NHMRC) (200071, 241944, 339462, 380385, 389927,389875, 389891, 389892,389938, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498), the Cancer Councils New South Wales, Victoria and Queensland, the Cancer Institute New South Wales, the Cooperative Research Centre for Discovery of Genes for Common Human Diseases (CRC), Cerylid Biosciences (Melbourne), the Australian Cancer Research Foundation, The Wellcome Trust (WT084766/Z/08/Z) and donations from Neville and Shirley Hawkins. N.K.H. was supported by the NHMRC Fellowships scheme. SM was supported by a Career Development award from the NHMRC (496674, 613705). M.H.L. is supported by Cancer Australia grant 1011143. NR 39 TC 29 Z9 30 U1 0 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 428 EP 432 DI 10.1038/ng.2571 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600014 PM 23455637 ER PT J AU Fritsche, LG Chen, W Schu, M Yaspan, BL Yu, Y Thorleifsson, G Zack, DJ Arakawa, S Cipriani, V Ripke, S Igo, RP Buitendijk, GHS Sim, XL Weeks, DE Guymer, RH Merriam, JE Francis, PJ Hannum, G Agarwal, A Armbrecht, AM Audo, I Aung, T Barile, GR Benchaboune, M Bird, AC Bishop, PN Branham, KE Brooks, M Brucker, AJ Cade, WH Cain, MS Campochiaroll, PA Chan, CC Cheng, CY Chew, EY Chin, KA Chowers, I Clayton, DG Cojocaru, R Conley, YP Cornes, BK Daly, MJ Dhillon, B Edwards, A Evangelou, E Fagemess, J Ferreyra, HA Friedman, JS Geirsdottir, A George, RJ Gieger, C Gupta, N Hagstrom, SA Harding, SP Haritoglou, C Heckenlively, JR Hoz, FG Hughes, G Ioannidis, JPA Ishibashi, T Joseph, P Jun, G Kamatani, Y Katsanis, N Keilhauer, CN Khan, JC Kim, IK Kiyohara, Y Klein, BEK Klein, R Kovach, JL Kozak, I Lee, CJ Lee, KE Lichtner, P Lotery, AJ Meitinger, T Mitchell, P Mohand-Said, S Moore, AT Morgan, DJ Margaux, AM Myers, CE Naj, AC Nakamura, Y Okada, Y Orlin, A Ortube, MC Othman, MI Pappas, C Park, KH Pauer, GJT Peachey, NS Poch, O Priya, RR Reynolds, R Richardson, AJ Ripp, R Rudolph, G Ryu, E Sahel, JA Schaumberg, DA Scholl, HPN Schwartz, SG Scott, WK Shahid, H Sigurdsson, H Silvestri, G Sivakumaran, TA Smith, RT Sobrin, L Souied, EH Stambolian, DE Stefansson, H Sturgill-Short, GM Takahashi, A Tosakulwong, N Truitt, BJ Tsironi, EE Uitterlinden, AG van Duijn, CM Vijaya, L Vingerling, JR Vithana, EN Webster, AR Wichmann, HE Winkler, TW Wong, TY Wright, AF Zelenika, D Zhang, M Zhao, L Zhang, K Klein, ML Hageman, GS Lathrop, GM Stefansson, K Allikmets, R Baird, PN Gorin, MB Wang, JJ Klaver, CCW Seddon, JM Pericak-Vance, MA Iyengar, SK Yates, JRW Swaroop, A Weber, BHF Kubo, M DeAngelis, MM Leveillard, T Thorsteinsdottir, U Haines, JL Farrer, LA Heid, IM Abecasis, GR AF Fritsche, Lars G. Chen, Wei Schu, Matthew Yaspan, Brian L. Yu, Yi Thorleifsson, Gudmar Zack, Donald J. Arakawa, Satoshi Cipriani, Valentina Ripke, Stephan Igo, Robert P., Jr. Buitendijk, Gabrielle H. S. Sim, Xueling Weeks, Daniel E. Guymer, Robyn H. Merriam, Joanna E. Francis, Peter J. Hannum, Gregory Agarwal, Anita Armbrecht, Ana Maria Audo, Isabelle Aung, Tin Barile, Gaetano R. Benchaboune, Mustapha Bird, Alan C. Bishop, Paul N. Branham, Kari E. Brooks, Matthew Brucker, Alexander J. Cade, William H. Cain, Melinda S. Campochiaroll, Peter A. Chan, Chi-Chao Cheng, Ching-Yu Chew, Emily Y. Chin, Kimberly A. Chowers, Itay Clayton, David G. Cojocaru, Radu Conley, Yvette P. Cornes, Belinda K. Daly, Mark J. Dhillon, Baljean Edwards, Albert Evangelou, Evangelos Fagemess, Jesen Ferreyra, Henry A. Friedman, James S. Geirsdottir, Asbjorg George, Ronnie J. Gieger, Christian Gupta, Neel Hagstrom, Stephanie A. Harding, Simon P. Haritoglou, Christos Heckenlively, John R. Hoz, Frank G. Hughes, Guy Ioannidis, John P. A. Ishibashi, Tatsuro Joseph, Peronne Jun, Gyungah Kamatani, Yoichiro Katsanis, Nicholas Keilhauer, Claudia N. Khan, Jane C. Kim, Ivana K. Kiyohara, Yutaka Klein, Barbara E. K. Klein, Ronald Kovach, Jaclyn L. Kozak, Igor Lee, Clara J. Lee, Kristine E. Lichtner, Peter Lotery, Andrew J. Meitinger, Thomas Mitchell, Paul Mohand-Saied, Saddek Moore, Anthony T. Morgan, Denise J. Morrison, Margaux A. Myers, Chelsea E. Naj, Adam C. Nakamura, Yusuke Okada, Yukinori Orlin, Anton Ortube, M. Carolina Othman, Mohammad I. Pappas, Chris Park, Kyu Hyung Pauer, Gayle J. T. Peachey, Neal S. Poch, Olivier Priya, Rinki Ratna Reynolds, Robyn Richardson, Andrea J. Ripp, Raymond Rudolph, Guenther Ryu, Euijung Sahel, Jose-Alain Schaumberg, Debra A. Scholl, Hendrik P. N. Schwartz, Stephen G. Scott, William K. Shahid, Humma Sigurdsson, Haraldur Silvestri, Giuliana Sivakumaran, Theru A. Smith, R. Theodore Sobrin, Lucia Souied, Eric H. Stambolian, Dwight E. Stefansson, Hreinn Sturgill-Short, Gwen M. Takahashi, Atsushi Tosakulwong, Nirubol Truitt, Barbara J. Tsironi, Evangelia E. Uitterlinden, Andre G. van Duijn, Cornelia M. Vijaya, Lingam Vingerling, Johannes R. Vithana, Eranga N. Webster, Andrew R. Wichmann, H-Erich Winkler, Thomas W. Wong, Tien Y. Wright, Alan F. Zelenika, Diana Zhang, Ming Zhao, Ling Zhang, Kang Klein, Michael L. Hageman, Gregory S. Lathrop, G. Mark Stefansson, Kari Allikmets, Rando Baird, Paul N. Gorin, Michael B. Wang, Jie Jin Klaver, Caroline C. W. Seddon, Johanna M. Pericak-Vance, Margaret A. Iyengar, Sudha K. Yates, John R. W. Swaroop, Anand Weber, Bernhard H. F. Kubo, Michiaki DeAngelis, Margaret M. Leveillard, Thierry Thorsteinsdottir, Unnur Haines, Jonathan L. Farrer, Lindsay A. Heid, Iris M. Abecasis, Goncalo R. CA AMD Gene Consortium TI Seven new loci associated with age-related macular degeneration SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMPLEMENT FACTOR-H; GENOTYPE IMPUTATION; APOLIPOPROTEIN-E; INFLUENCES RISK; SUSCEPTIBILITY; GENE; VARIANTS; DISEASES; CFH AB Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 x 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 x 10-8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD. C1 [Fritsche, Lars G.; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Fritsche, Lars G.; Chen, Wei; Sim, Xueling; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Chen, Wei] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med,Med Ctr, Div Pediat Pulm Med Allergy & Immunol,Dept Pediat, Pittsburgh, PA USA. [Schu, Matthew; Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Schu, Matthew; Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Biomed Genet, Boston, MA USA. [Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Yu, Yi; Chin, Kimberly A.; Reynolds, Robyn; Seddon, Johanna M.] Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Thorleifsson, Gudmar; Stefansson, Hreinn] deCODE Genet, Reykjavik, Iceland. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Zack, Donald J.; Sahel, Jose-Alain; Leveillard, Thierry] Univ Paris 06, Dept Genet, Inst Vis, UMRS 968, Paris, France. [Zack, Donald J.; Campochiaroll, Peter A.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Neurosci, Baltimore, MD 21205 USA. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Inst Genet Med, Baltimore, MD 21205 USA. [Arakawa, Satoshi; Kubo, Michiaki] RIKEN, CGM, Res Grp Genotyping, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Cipriani, Valentina; Bird, Alan C.; Moore, Anthony T.; Webster, Andrew R.; Yates, John R. W.] Moorfields Eye Hosp, London, England. [Cipriani, Valentina; Bird, Alan C.; Moore, Anthony T.; Sahel, Jose-Alain; Webster, Andrew R.; Yates, John R. W.] UCL, Inst Ophthalmol, London, England. [Ripke, Stephan; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Igo, Robert P., Jr.; Joseph, Peronne; Truitt, Barbara J.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Buitendijk, Gabrielle H. S.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Guymer, Robyn H.; Cain, Melinda S.; Richardson, Andrea J.; Wong, Tien Y.; Baird, Paul N.; Wang, Jie Jin] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Merriam, Joanna E.; Barile, Gaetano R.; Smith, R. Theodore; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Francis, Peter J.; Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97201 USA. [Hannum, Gregory] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Agarwal, Anita] Vanderbilt Univ, Med Ctr, Vanderbilt Eye Inst, Nashville, TN USA. [Agarwal, Anita] Vanderbilt Univ, Sch Med, Dept Ophthalmol & Visual Sci, Nashville, TN 37212 USA. [Armbrecht, Ana Maria; Dhillon, Baljean; Mohand-Saied, Saddek] Univ Edinburgh, Dept Ophthalmol, Edinburgh, Midlothian, Scotland. [Armbrecht, Ana Maria; Dhillon, Baljean; Mohand-Saied, Saddek] Princess Alexandra Eye Pavil, Edinburgh, Midlothian, Scotland. [Sahel, Jose-Alain; Leveillard, Thierry] INSERM, U968, Paris, France. [Mohand-Saied, Saddek; Sahel, Jose-Alain; Leveillard, Thierry] CNRS, UMR 7210, Paris, France. [Aung, Tin; Cheng, Ching-Yu; Cornes, Belinda K.; Vithana, Eranga N.; Wong, Tien Y.] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore. [Aung, Tin; Cheng, Ching-Yu; Vithana, Eranga N.; Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore 117595, Singapore. [Benchaboune, Mustapha; Mohand-Saied, Saddek; Sahel, Jose-Alain] Ctr Invest Clin 503, Ctr Hosp Natl Ophtalmol Quinze Vingts, INSERM Direct Hosp & Org Soins, Paris, France. [Bishop, Paul N.] Univ Manchester, Fac Med & Human Sci, Inst Human Dev, Manchester, Lancs, England. [Bishop, Paul N.] Cent Manchester Univ Hosp Natl Hlth Serv NHS Fdn, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Branham, Kari E.; Heckenlively, John R.; Othman, Mohammad I.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brooks, Matthew; Cojocaru, Radu; Friedman, James S.; Gupta, Neel; Priya, Rinki Ratna; Swaroop, Anand] NEI, Neurobiol Neurodegenerabon & Repair Lab N NNRL, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Brucker, Alexander J.] Penn Presbyterian Med Ctr, Scheie Eye Inst, Philadelphia, PA USA. [Cade, William H.; Naj, Adam C.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Cade, William H.; Naj, Adam C.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA. [Campochiaroll, Peter A.; Scholl, Hendrik P. N.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, US Natl Inst Hlth, Bethesda, MD USA. [Cheng, Ching-Yu] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Cheng, Ching-Yu] Duke Natl Univ Singapore Grad Med Sch, Off Clin Sci, Ctr Quantitat Med, Singapore, Singapore. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Chowers, Itay] Hadassah Hebrew Univ Med Ctr, Dept Ophthalmol, Jerusalem, Israel. [Clayton, David G.; Khan, Jane C.; Shahid, Humma; Yates, John R. W.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Conley, Yvette P.] Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. [Edwards, Albert] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Fagemess, Jesen] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Fagemess, Jesen; Lee, Clara J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Ferreyra, Henry A.; Hughes, Guy; Kozak, Igor; Lee, Clara J.; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [Ferreyra, Henry A.; Hughes, Guy; Kozak, Igor; Lee, Clara J.; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Geirsdottir, Asbjorg; Sigurdsson, Haraldur] Natl Univ Hosp Reykjavik, Dept Ophthalmol, Reykjavik, Iceland. [George, Ronnie J.; Vijaya, Lingam] Vis Res Fdn, Glaucoma Project, Madras, Tamil Nadu, India. [Gieger, Christian; Heid, Iris M.] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Manchen, Inst Genet Epidemiol, Neuherberg, Germany. [Hagstrom, Stephanie A.; Pauer, Gayle J. T.; Peachey, Neal S.] Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA. [Harding, Simon P.] Univ Liverpool, Dept Eye & Vis Sci, Inst Ageing & Chron Dis, Liverpool L69 3BX, Merseyside, England. [Haritoglou, Christos; Rudolph, Guenther] Univ Munich, Augenklin, D-80539 Munich, Germany. [Hoz, Frank G.; Scholl, Hendrik P. N.] Univ Bonn, Dept Ophthalmol, Bonn, Germany. [Hughes, Guy; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Stat, Sch Humanities & Sci, Stanford, CA 94305 USA. [Ishibashi, Tatsuro] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka, Japan. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kamatani, Yoichiro; Lathrop, G. Mark] Ctr Etud Polymorphisme Humain CEPH, Fdn Jean Dausset, Paris, France. [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. [Keilhauer, Claudia N.] Univ Wurzburg, Dept Ophthalmol, D-97070 Wurzburg, Germany. [Khan, Jane C.] Royal Perth Hosp, Dept Ophthalmol, Perth, WA, Australia. [Khan, Jane C.] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Kim, Ivana K.; Schaumberg, Debra A.; Sobrin, Lucia] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kim, Ivana K.; Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Kiyohara, Yutaka; Thorsteinsdottir, Unnur] Kyushu Univ, Grad Sch Med Sci, Dept Environm Med, Fukuoka, Japan. [Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.; Myers, Chelsea E.] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.; Myers, Chelsea E.] Univ Wisconsin, Sch Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Kovach, Jaclyn L.; Schwartz, Stephen G.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Lichtner, Peter; Meitinger, Thomas] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Lotery, Andrew J.] Univ Southampton, Fac Med Clin & Expt Sci, Southampton, Hants, England. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Mohand-Saied, Saddek] Univ Paris 06, Dept Therapeut, Inst Vis, UMRS 968, Paris, France. [Morgan, Denise J.; Morrison, Margaux A.; Stefansson, Kari; DeAngelis, Margaret M.] Univ Utah, Dept Ophthalmol & Visual Sci, John A Moran Eye Ctr, Salt Lake City, UT USA. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo, Japan. [Okada, Yukinori; Takahashi, Atsushi] RIKEN, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Orlin, Anton] Weill Cornell Med Coll, Dept Ophthalmol, New York, NY USA. [Ortube, M. Carolina; Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Ortube, M. Carolina; Gorin, Michael B.] Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Pappas, Chris; Hageman, Gregory S.] Univ Utah, Moran Ctr Translat Med, John A Moran Eye Ctr, Salt Lake City, UT USA. [Park, Kyu Hyung] Seoul Natl Univ, Bundang Hosp, Dept Ophthalmol, Kyeounggi, South Korea. [Peachey, Neal S.; Sturgill-Short, Gwen M.] Louis Stokes Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Poch, Olivier; Ripp, Raymond] IGBMC, Lab Integrat Bioinformat & Genom, Illkirch Graffenstaden, France. [Ryu, Euijung; Tosakulwong, Nirubol] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Sahel, Jose-Alain] Fdn Ophtalmol Adolphe Rothschild, Paris, France. [Sahel, Jose-Alain] Acad Sci Inst France, Paris, France. [Schaumberg, Debra A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Shahid, Humma] Addenbrookes Hosp, Dept Ophthalmol, Cambridge, England. [Sigurdsson, Haraldur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Silvestri, Giuliana] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland. [Sivakumaran, Theru A.] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA. [Smith, R. Theodore] Columbia Univ, Dept Biomed Engn, New York, NY USA. [Souied, Eric H.] Univ Paris Est, Hop Henri Mondor, Ctr Rech Clin Ophthalmol, Hop Intercommunal Creteil, Creteil, France. [Stambolian, Dwight E.] Univ Penn, Dept Ophthalmol & Genet, Philadelphia, PA 19104 USA. [Tsironi, Evangelia E.] Univ Thessaly, Sch Med, Dept Ophthalmol, Larisa, Greece. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Wichmann, H-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Gorin, Michael B.] Univ Munich, Inst Med Informat, Munich, Germany. [Wichmann, H-Erich; Gorin, Michael B.] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany. [Kubo, Michiaki] Univ Munich, Inst Biometry, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Inst Epidemiol, Munich, Germany. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Wright, Alan F.] Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Zelenika, Diana; Lathrop, G. Mark] Ctr Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Zhang, Ming; Zhang, Kang] Sichuan Univ, West China Hosp, Mol Med Res Ctr, Chengdu 610064, Peoples R China. [Zhang, Ming; Zhang, Kang] Sichuan Univ, West China Hosp, Dept Ophthalmol, Chengdu 610064, Peoples R China. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Ctr Clin Invest, Cleveland, OH 44106 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Abecasis, GR (reprint author), Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM jonathan@chgr.mc.vanderbilt.edu; farrer@bu.edu; iris.heid@klinik.uni-regensburg.de; goncalo@umich.edu RI Kubo, Michiaki/N-7947-2015; Abecasis, Goncalo/B-7840-2010; Sahel, Jose-Alain/F-3172-2017; Cipriani, Valentina/A-8549-2012; Cheng, Ching-Yu/K-7017-2013; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Zhao, Ling/D-9005-2015; DeAngelis, e/J-7863-2015; Meitinger, Thomas/O-1318-2015; Klaver, Caroline/A-2013-2016; Kamatani, Yoichiro/N-5513-2015; OI Farrer, Lindsay/0000-0001-5533-4225; george, ronnie/0000-0001-7368-0252; Baird, Paul/0000-0002-1305-3502; Zack, Don/0000-0002-7966-1973; Abecasis, Goncalo/0000-0003-1509-1825; Harding, Simon/0000-0003-4676-1158; Swaroop, Anand/0000-0002-1975-1141; Gieger, Christian/0000-0001-6986-9554; Stefansson, Hreinn/0000-0002-9331-6666; Klein, Ronald/0000-0002-4428-6237; Bishop, Paul/0000-0001-7937-7932; Cipriani, Valentina/0000-0002-0839-9955; Cheng, Ching-Yu/0000-0003-0655-885X; Wang, Jie Jin/0000-0001-9491-4898; Jun, Gyungah/0000-0002-3230-8697; Evangelou, Evangelos/0000-0002-5488-2999; smith, theodore/0000-0002-1693-943X; Weeks, Daniel/0000-0001-9410-7228; Katsanis, Nicholas/0000-0002-2480-0171 FU Medical Research Council [G0000067, MC_U127584475, MR/K006584/1]; NEI NIH HHS [P30 EY014800, R01 EY013435, R01 EY022005]; NHGRI NIH HHS [R01 HG007022] NR 51 TC 281 Z9 282 U1 14 U2 108 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 433 EP 439 DI 10.1038/ng.2578 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600015 PM 23455636 ER PT J AU Li, F Lu, J Cheng, J Wang, LY Matsubara, T Csanaky, IL Klaassen, CD Gonzalez, FJ Ma, XC AF Li, Feng Lu, Jie Cheng, Jie Wang, Laiyou Matsubara, Tsutomu Csanaky, Ivan L. Klaassen, Curtis D. Gonzalez, Frank J. Ma, Xiaochao TI Human PXR modulates hepatotoxicity associated with rifampicin and isoniazid co-therapy SO NATURE MEDICINE LA English DT Article ID PREGNANE-X-RECEPTOR; ERYTHROPOIETIC-PROTOPORPHYRIA; DRUG-INTERACTIONS; GENE-EXPRESSION; LIVER TOXICITY; GENOTYPE; DISEASE; DEFINES; INJURY; MODEL AB Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic. C1 [Li, Feng; Lu, Jie; Wang, Laiyou; Csanaky, Ivan L.; Klaassen, Curtis D.; Ma, Xiaochao] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. [Cheng, Jie; Matsubara, Tsutomu; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ma, XC (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. EM xma2@kumc.edu RI Csanaky, Ivan/N-5312-2015 OI Csanaky, Ivan/0000-0001-7870-4129 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK090305]; National Cancer Institute Intramural Research Program FX This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant number DK090305) and the National Cancer Institute Intramural Research Program. We thank M. Montello for editing the manuscript. NR 21 TC 48 Z9 51 U1 1 U2 10 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 APR PY 2013 VL 19 IS 4 BP 418 EP + DI 10.1038/nm.3104 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100025 PM 23475203 ER PT J AU Han, GW Bian, L Li, FL Cotrim, A Wang, DN Lu, JB Deng, Y Bird, G Sowers, A Mitchell, JB Gutkind, JS Zhao, R Raben, D ten Dijke, P Refaeli, Y Zhang, QH Wang, XJ AF Han, Gangwen Bian, Li Li, Fulun Cotrim, Ana Wang, Donna Lu, Jianbo Deng, Yu Bird, Gregory Sowers, Anastasia Mitchell, James B. Gutkind, J. Silvio Zhao, Rui Raben, David ten Dijke, Peter Refaeli, Yosef Zhang, Qinghong Wang, Xiao-Jing TI Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis SO NATURE MEDICINE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; LOCALLY ADVANCED HEAD; TGF-BETA; NECK-CANCER; SIGNALING PATHWAY; MICE; PALIFERMIN; DISEASE; CHEMOTHERAPY; CHEMORADIOTHERAPY AB We report that K5.Smad7 mice, which express a Smad7 transgene under the control of a keratin 5 promoter, were resistant to radiation-induced oral mucositis, a painful oral ulceration. In addition to nuclear factor kappa B (NF-kappa B) activation, which is known to contribute to oral mucositis, we found activated transforming growth factor beta (TGF-beta) signaling in cells from this condition. Smad7 dampened both pathways to attenuate inflammation, growth inhibition and apoptosis. Additionally, Smad7 promoted oral epithelial migration to close the wound. Further analyses revealed that TGF-beta signaling Smads and their co-repressor C-terminal binding protein 1 (CtBP1) transcriptionally repressed Rac1, and that Smad7 abrogated this repression. Knocking down Rac1 expression in mouse keratinocytes abrogated Smad7-induced migration. Topical application of Smad7 protein conjugated with a cell-permeable Tat tag to oral mucosa showed prophylactic and therapeutic effects on radiation-induced oral mucositis in mice. Thus, we have identified new molecular mechanisms involved in oral mucositis pathogenesis, and our data suggest an alternative therapeutic strategy to block multiple pathological processes in this condition. C1 [Han, Gangwen; Bian, Li; Li, Fulun; Wang, Donna; Wang, Xiao-Jing] Univ Colorado Denver, Dept Pathol, Aurora, CO 80045 USA. [Bian, Li; Lu, Jianbo] Kunming Med Univ, Dept Pathol, Affiliated Hosp 1, Kunming, Peoples R China. [Li, Fulun] Shanghai Univ Tradit Chinese Med, Yueyang Hosp Integrated Tradit Chinese & Western, Dept Dermatol, Shanghai, Peoples R China. [Cotrim, Ana; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. [Deng, Yu; Bird, Gregory; Refaeli, Yosef; Zhang, Qinghong] Univ Colorado Denver, Dept Dermatol, Aurora, CO USA. [Sowers, Anastasia; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Zhao, Rui] Univ Colorado, Dept Mol Genet & Biochem, Aurora, CO USA. [Raben, David] Univ Colorado Denver, Dept Radiat Oncol, Aurora, CO USA. [ten Dijke, Peter] Leiden Univ, Dept Mol Cell Biol, Med Ctr, Leiden, Netherlands. RP Wang, XJ (reprint author), Univ Colorado Denver, Dept Pathol, Anschutz Med Campus, Aurora, CO 80045 USA. EM qinghong.zhang@ucdenver.edu; xj.wang@ucdenver.edu FU NIH [AR061792, DE015953, R01CA115468, R03DA033982, P30CA046934]; Colorado State/University of Colorado Bioscience Discovery Evaluation grant; National Natural Science Foundation of China (NSFC) [81060189]; NSFC [81102596]; Shanghai Rising-Star Program [12QA1403300]; Innovation Program of Shanghai Municipal Education Commission [12YZ067] FX This work was supported by NIH grants AR061792 and DE015953 to X.-J.W., R01CA115468 to Q.Z. and R03DA033982 to R.Z. and Q.Z. and the Colorado State/University of Colorado Bioscience Discovery Evaluation grant to X.-J.W., Q.Z. and Y.R. and was partially supported by NIH grant P30CA046934 to the University of Colorado Cancer Center. L.B. was supported by a grant (81060189) from The National Natural Science Foundation of China (NSFC). F.L. was supported by grants from the NSFC (81102596), The Shanghai Rising-Star Program (12QA1403300) and The Innovation Program of Shanghai Municipal Education Commission (12YZ067). The authors thank S. Said, C. Marshall and C. Liu for searching human oral mucositis clinical samples and C.Y. Li and G. Gang for their input on radiotherapy in patients with oral cancer. The authors also thank P. Garl for proofreading the manuscript. NR 56 TC 18 Z9 19 U1 1 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2013 VL 19 IS 4 BP 421 EP + DI 10.1038/nm.3118 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100026 PM 23475202 ER PT J AU Wang, X Zhao, YJ Zhang, XF Badie, H Zhou, Y Mu, YL Loo, LS Cai, L Thompson, RC Yang, B Chen, YM Johnson, PF Wu, CB Bu, GJ Mobley, WC Zhang, DX Gage, FH Ranscht, B Zhang, YW Lipton, SA Hong, WJ Xu, HX AF Wang, Xin Zhao, Yingjun Zhang, Xiaofei Badie, Hedieh Zhou, Ying Mu, Yangling Loo, Li Shen Cai, Lei Thompson, Robert C. Yang, Bo Chen, Yaomin Johnson, Peter F. Wu, Chengbiao Bu, Guojun Mobley, William C. Zhang, Dongxian Gage, Fred H. Ranscht, Barbara Zhang, Yun-wu Lipton, Stuart A. Hong, Wanjin Xu, Huaxi TI Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome SO NATURE MEDICINE LA English DT Article ID C/EBP-BETA; ALZHEIMERS-DISEASE; SYNDROME PHENOTYPES; POTASSIUM CHANNELS; PARKINSON DISEASE; RETROMER COMPLEX; MEMORY DEFICITS; MOUSE MODEL; CONSOLIDATION; TRAFFICKING AB Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27(-/-) mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27(+/-) mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein beta (C/EBP beta) in Down's syndrome brains and identify C/EBP beta as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBP beta, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis. C1 [Wang, Xin; Zhao, Yingjun; Zhang, Xiaofei; Thompson, Robert C.; Yang, Bo; Chen, Yaomin; Zhang, Dongxian; Zhang, Yun-wu; Lipton, Stuart A.; Xu, Huaxi] Sanford Burnham Med Res Inst, Ctr Neurosci Aging & Stem Cell Res, La Jolla, CA 92037 USA. [Wang, Xin; Zhou, Ying] Sanford Burnham Med Res Inst, Grad Sch Biomed Sci, La Jolla, CA USA. [Zhao, Yingjun; Bu, Guojun; Zhang, Yun-wu; Xu, Huaxi] Xiamen Univ, Fujian Prov Key Lab Neurodegenerat Dis & Aging Re, Coll Med, Xiamen, Peoples R China. [Badie, Hedieh; Ranscht, Barbara] Sanford Burnham Med Res Inst, Tumor Microenvironm Program, La Jolla, CA USA. [Mu, Yangling; Gage, Fred H.] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. [Loo, Li Shen; Cai, Lei; Hong, Wanjin] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. [Johnson, Peter F.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Wu, Chengbiao; Mobley, William C.; Lipton, Stuart A.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Hong, Wanjin] Xiamen Univ, Inst Biomed Res, Sch Pharmaceut Sci, Xiamen, Peoples R China. RP Xu, HX (reprint author), Sanford Burnham Med Res Inst, Ctr Neurosci Aging & Stem Cell Res, La Jolla, CA 92037 USA. EM xuh@sanfordburnham.org RI Chen, Yaomin/H-5205-2013; Chen, Yaomin/I-6192-2013; ASTAR, IMCB/E-2320-2012; Zhao, Yingjun/G-9173-2016; Wang, Xin/A-8119-2017; OI Johnson, Peter/0000-0002-4145-4725 FU US National Institutes of Health [R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197, R01 AG044420, P01 HD29587, P01 ES016738, P30 NS076411]; Alzheimer's Association; American Health Assistance Foundation; National Natural Science Foundation of China [30973150, 81161120496]; 973 Prophase Project [2010CB535004]; Natural Science Funds for Distinguished Young Scholar of Fujian Province [2009J06022]; Program for New Century Excellent Talents in Universities (NCET); Fundamental Research Funds for the Central Universities; Fok Ying Tung Education Foundation; Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research FX We thank P. Slesinger (Mount Sinai School of Medicine) for providing the rabbit SNX27-specific antibody and helpful discussion, A. Roberts and the Scripps behavioral core for mouse behavioral analysis, T. Golde and C. Ceballos (University of Florida) for generating AAV, E. Masliah (University of California, San Diego) for providing human brain specimens, P. Greengard (The Rockfeller University) for providing GluR1 and GluR2 constructs, K. Wright (University of California, San Diego) for helping in the transfer of Ts65Dn mice, S. Huang (Sanford-Burnham Medical Research Institute) for helping with statistical analysis, K. Saylor (US National Institutes of Health) for C/EBP beta knockout mouse breeding and tissue collection and A. Brzozowska-Prechtl and L. Lacarra for technical help. This work was supported in part by US National Institutes of Health grants (R01 AG038710, R01 AG021173, R01 NS046673, R01 AG030197 and R01 AG044420 to H.X.; and P01 HD29587, P01 ES016738, P30 NS076411 to S.A.L.) and grants from the Alzheimer's Association (to H.X. and Y. Zhang), the American Health Assistance Foundation (to H.X.), National Natural Science Foundation of China (30973150 and 81161120496 to Y. Zhang), the 973 Prophase Project (2010CB535004 to Y. Zhang) and Natural Science Funds for Distinguished Young Scholar of Fujian Province (2009J06022 to Y. Zhang). Y. Zhang is supported by the Program for New Century Excellent Talents in Universities (NCET), the Fundamental Research Funds for the Central Universities and Fok Ying Tung Education Foundation. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, US National Cancer Institute and Center for Cancer Research. NR 45 TC 74 Z9 81 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2013 VL 19 IS 4 BP 473 EP + DI 10.1038/nm.3117 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100033 PM 23524343 ER PT J AU Cubas, RA Mudd, JC Savoye, AL Perreau, M van Grevenynghe, J Metcalf, T Connick, E Meditz, A Freeman, GJ Abesada-Terk, G Jacobson, JM Brooks, AD Crotty, S Estes, JD Pantaleo, G Lederman, MM Haddad, EK AF Cubas, Rafael A. Mudd, Joseph C. Savoye, Anne-Laure Perreau, Matthieu van Grevenynghe, Julien Metcalf, Talibah Connick, Elizabeth Meditz, Amie Freeman, Gordon J. Abesada-Terk, Guillermo, Jr. Jacobson, Jeffrey M. Brooks, Ari D. Crotty, Shane Estes, Jacob D. Pantaleo, Giuseppe Lederman, Michael M. Haddad, Elias K. TI Inadequate T follicular cell help impairs B cell immunity during HIV infection SO NATURE MEDICINE LA English DT Article ID ACTIVE-ANTIRETROVIRAL-THERAPY; HUMORAL IMMUNITY; VIRAL-INFECTION; SIV INFECTION; LYMPH-NODES; C-MAF; MEMORY; RESPONSES; INDIVIDUALS; ANTIBODIES AB The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations(1-3). We report here that even though there is an expansion of follicular helper T (T-FH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)(+) germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1-PD-L1 interaction in regulating T-FH cell function. In fact, we show that engagement of PD-1 on T-FH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of T-FH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on T-FH cells. These results demonstrate a role for T-FH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations. C1 [Cubas, Rafael A.; van Grevenynghe, Julien; Metcalf, Talibah; Haddad, Elias K.] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. [Mudd, Joseph C.; Lederman, Michael M.] Case Western Reserve Univ, Div Infect Dis, Ctr AIDS Res, Univ Hosp,Case Med Ctr, Cleveland, OH 44106 USA. [Savoye, Anne-Laure; Perreau, Matthieu; Pantaleo, Giuseppe] Univ Lausanne, Lausanne Univ Hosp, Swiss Vaccine Res Inst, Div Immunol & Allergy, Lausanne, Switzerland. [Connick, Elizabeth; Meditz, Amie] Univ Colorado Denver, Div Infect Dis, Denver, CO USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Abesada-Terk, Guillermo, Jr.] Martin Mem Hlth Syst, Robert & Carol Weissman Canc Ctr, Stuart, FL USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Brooks, Ari D.] Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19104 USA. [Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA. [Crotty, Shane] Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA USA. [Estes, Jacob D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Haddad, EK (reprint author), Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. EM ehaddad@vgtifl.org RI Pantaleo, Giuseppe/K-6163-2016; Perreau, Matthieu/D-6309-2017 FU US National Institutes of Health (NIH) [HHSN272201100017C, NIH-1P01 AI080192, U19AI082630, 2P01 AI056299, R01 AI096966]; Case Western Reserve University Center for AIDS Research [AI 36219]; Cleveland Immunopathogenesis Consortium [AI 76174] FX We thank W. Ryzner, R. Bordi and D. Brown for sample collection. We also thank K. Kusser and Y. Shi from the Flow Cytometry Core at Vaccine & Gene Therapy Institute Florida for their help with sorting all the samples. We are grateful to R. Debernardo (Case Western Reserve University and University Hospitals Case Medical Center) for obtaining the HIV-uninfected lymph nodes and to B. Rodriguez for his help with the infected lymph node samples. This study was supported in part by US National Institutes of Health (NIH) contract HHSN272201100017C, NIH-1P01 AI080192, U19AI082630, 2P01 AI056299 and R01 AI096966. This work was also supported by the Case Western Reserve University Center for AIDS Research (AI 36219) and by the Cleveland Immunopathogenesis Consortium (AI 76174). NR 40 TC 138 Z9 144 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2013 VL 19 IS 4 BP 494 EP + DI 10.1038/nm.3109 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100036 PM 23475201 ER PT J AU Wanat, MJ Bonci, A Phillips, PEM AF Wanat, Matthew J. Bonci, Antonello Phillips, Paul E. M. TI CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors SO NATURE NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; COCAINE SEEKING; STRESS; NEURONS; SYSTEM; ENHANCEMENT; DEPRESSION; NUCLEUS; RELAPSE; PROTEIN AB Stressors affect dopamine-dependent behaviors such as motivation, although the underlying neurobiological mechanism is not well defined. We report that corticotropin-releasing factor (CRF) acts in the ventral tegmental area (VTA) to reduce the motivation to work for food rewards. CRF in the VTA regulates dopamine output in a stimulus- and pathway-specific manner, offering a mechanism by which acute stress selectively regulates information transmission via the VTA to reprioritize motivated behavior. C1 [Wanat, Matthew J.; Phillips, Paul E. M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Wanat, Matthew J.; Phillips, Paul E. M.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Bonci, Antonello] NIDA, Intramural Res Program, Baltimore, MD USA. [Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Bonci, Antonello] Johns Hopkins Sch Med, Solomon H Snyder Neurosci Inst, Baltimore, MD USA. RP Phillips, PEM (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM pemp@uw.edu RI Phillips, Paul/A-4463-2008; Phillips, Paul/E-7813-2013; OI Phillips, Paul/0000-0002-8749-7026; Phillips, Paul/0000-0002-8749-7026; Wanat, Matthew/0000-0003-1643-6557 FU US National Institutes of Health [R01-MH079292, R01-DA016782, T32-AA009455, F32-DA026273]; NARSAD FX We would like to thank S. Ng-Evans for invaluable technical support and C. Akers for technical assistance. We thank N. Hollon, J. Clark and S. Sandberg for scientific discussion. This work was funded by the US National Institutes of Health (R01-MH079292, P.E.M.P.; R01-DA016782, A.B. and P.E.M.P.; T32-AA009455 and F32-DA026273, M.J.W.) and NARSAD (P.E.M.P.). NR 23 TC 31 Z9 31 U1 0 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2013 VL 16 IS 4 BP 383 EP U191 DI 10.1038/nn.3335 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 114EM UT WOS:000316723700005 PM 23416448 ER PT J AU Dillman, AA Hauser, DN Gibbs, JR Nalls, MA McCoy, MK Rudenko, IN Galter, D Cookson, MR AF Dillman, Allissa A. Hauser, David N. Gibbs, J. Raphael Nalls, Michael A. McCoy, Melissa K. Rudenko, Iakov N. Galter, Dagmar Cookson, Mark R. TI mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex SO NATURE NEUROSCIENCE LA English DT Article ID DNA-SEQUENCE DIFFERENCES; LARGE GENE LISTS; HUMAN TRANSCRIPTOME; GLOBAL REGULATION; WIDESPREAD RNA; BRAIN; NETWORKS; GENOME; POINT; CELLS AB The complexity of the adult brain is a result of both developmental processes and experience-dependent circuit formation. One way to look at the differences between embryonic and adult brain is to examine gene expression. Previous studies have used microarrays to address this in a global manner. However, the transcriptome is more complex than gene expression levels alone, as alternative splicing and RNA editing generate a diverse set of mature transcripts. Here we report a high-resolution transcriptome data set of mouse cerebral cortex at embryonic and adult stages using RNA sequencing (RNA-Seq). We found many differences in gene expression, splicing and RNA editing between embryonic and adult cerebral cortex. Each data set was validated technically and biologically, and in each case we found our RNA-Seq observations to have predictive validity. We provide this data set and analysis as a resource for understanding gene expression in the embryonic and adult cerebral cortex. C1 [Dillman, Allissa A.; Hauser, David N.; McCoy, Melissa K.; Rudenko, Iakov N.; Cookson, Mark R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Dillman, Allissa A.; Galter, Dagmar] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Hauser, David N.] Brown Univ, Natl Inst Hlth Grad Partnership Program, Dept Neurosci, Providence, RI 02912 USA. [Gibbs, J. Raphael] NIA, Computat Biol Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Gibbs, J. Raphael] UCL, Inst Neurol, Reta Lila Weston Labs, London, England. [Gibbs, J. Raphael] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Nalls, Michael A.] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Hauser, David/I-4933-2012; Galter, Dagmar/C-4826-2011 OI Hauser, David/0000-0002-9500-5255; Galter, Dagmar/0000-0001-6485-6244 FU US National Institutes of Health, National Institute on Aging [AG000947]; Swedish Research Council; Swedish Brain Power FX The authors would like to thank E. Lindquist for excellent technical assistance. We would also like to thank M. Do for assistance with cloning experiments. This research was supported in part by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging (project AG000947) and by the Swedish Research Council and Swedish Brain Power. NR 40 TC 44 Z9 46 U1 2 U2 30 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2013 VL 16 IS 4 BP 499 EP U178 DI 10.1038/nn.3332 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 114EM UT WOS:000316723700022 PM 23416452 ER PT J AU Cook, MB AF Cook, Michael B. TI EPIDEMIOLOGY Excess cancer in men-a call for an increased research focus SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID SEX DISPARITIES AB A recent report entitled "Excess cancer burden in men" further highlights the stark differences in cancer incidence and mortality rates between sexes, yet the causes of such differences remain largely enigmatic. It is time clinicians, researchers, and funding organizations took notice and necessary action. Cook, M. B. Nat. Rev. Clin. Oncol. 10, 186-188 (2013); published online 12 March 2013; doi:10.1038/nrclinonc.2013.37 C1 NCI, Div Canc Epidemiol & Genet, EPS, Rockville, MD 20852 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, EPS, 6120 Execut Blvd,Room 5014, Rockville, MD 20852 USA. EM michael.cook@nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 NR 8 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD APR PY 2013 VL 10 IS 4 BP 186 EP 188 DI 10.1038/nrclinonc.2013.37 PG 4 WC Oncology SC Oncology GA 116FD UT WOS:000316867300002 PM 23478284 ER PT J AU Wright, CB Zonderman, AB AF Wright, Clinton B. Zonderman, Alan B. TI What can memory tests predict about the aging brain? The freedom to recall SO NEUROLOGY LA English DT Editorial Material ID DEMENTIA C1 [Wright, Clinton B.] Univ Miami, Leonard M Miller Sch Med, Dept Neurol, Evelyn F McKnight Brain Inst, Miami, FL 33124 USA. [Wright, Clinton B.] Univ Miami, Leonard M Miller Sch Med, Dept Epidemiol & Publ Hlth, Evelyn F McKnight Brain Inst, Miami, FL USA. Univ Miami, Leonard M Miller Sch Med, Neurosci Program, Miami, FL USA. [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Lab Populat Sci, Biomed Res Ctr,NIH, Baltimore, MD 21224 USA. RP Wright, CB (reprint author), Univ Miami, Leonard M Miller Sch Med, Dept Neurol, Evelyn F McKnight Brain Inst, Miami, FL 33124 USA. EM cwright@med.miami.edu OI Zonderman, Alan B/0000-0002-6523-4778 NR 10 TC 1 Z9 1 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 14 BP 1274 EP 1275 DI 10.1212/WNL.0b013e31828ab392 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 118AW UT WOS:000316995800007 PM 23468540 ER PT J AU Leischow, SJ Ayo-Yusuf, O Backinger, CL AF Leischow, Scott J. Ayo-Yusuf, Olalekan Backinger, Cathy L. TI Converging Research Needs Across Framework Convention on Tobacco Control Articles: Making Research Relevant to Global Tobacco Control Practice and Policy SO NICOTINE & TOBACCO RESEARCH LA English DT Editorial Material AB Much of the research used to support the ratification of the WHO Framework Convention on Tobacco Control (FCTC) was conducted in high-income countries or in highly controlled environments. Therefore, for the global tobacco control community to make informed decisions that will continue to effectively inform policy implementation, it is critical that the tobacco control community, policy makers, and funders have updated information on the state of the science as it pertains to provisions of the FCTC. Following the National Cancer Institute's process model used in identifying the research needs of the U.S. Food and Drug Administration's relatively new tobacco law, a core team of scientists from the Society for Research on Nicotine and Tobacco identified and commissioned internationally recognized scientific experts on the topics covered within the FCTC. These experts analyzed the relevant sections of the FCTC and identified critical gaps in research that is needed to inform policy and practice requirements of the FCTC. This paper summarizes the process and the common themes from the experts' recommendations about the research and related infrastructural needs. Research priorities in common across Articles include improving surveillance, fostering research communication/collaboration across organizations and across countries, and tracking tobacco industry activities. In addition, expanding research relevant to low- and middle-income countries (LMIC), was also identified as a priority, including identification of what existing research findings are transferable, what new country-specific data are needed, and the infrastructure needed to implement and disseminate research so as to inform policy in LMIC. C1 [Leischow, Scott J.] Univ Arizona, Ctr Canc, Tucson, AZ USA. [Ayo-Yusuf, Olalekan] Univ Pretoria, Oral & Dent Hosp, Sch Dent, Dept Community Dent, ZA-0002 Pretoria, South Africa. [Backinger, Cathy L.] NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. RP Leischow, SJ (reprint author), Mayo Clin, 13400 East Shea Blvd,MCCRB C-301, Scottsdale, AZ 85259 USA. EM leischow.scott@mayo.edu NR 16 TC 4 Z9 4 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD APR PY 2013 VL 15 IS 4 BP 761 EP 766 DI 10.1093/ntr/nts199 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 114XQ UT WOS:000316776700002 PM 22990225 ER PT J AU Harper, M Li, LW Zhao, Y Klebanoff, MA Thorp, JM Sorokin, Y Varner, MW Wapner, RJ Caritis, SN Iams, JD Carpenter, MW Peaceman, AM Mercer, BM Sciscione, A Rouse, DJ Ramin, SM Anderson, GD AF Harper, Margaret Li, Liwu Zhao, Yuan Klebanoff, Mark A. Thorp, John M., Jr. Sorokin, Yoram Varner, Michael W. Wapner, Ronald J. Caritis, Steve N. Iams, Jay D. Carpenter, Marshall W. Peaceman, Alan M. Mercer, Brian M. Sciscione, Anthony Rouse, Dwight J. Ramin, Susan M. Anderson, Garland D. CA Eunice Kennedy Shriver Natl Inst TI Change in Mononuclear Leukocyte Responsiveness in Midpregnancy and Subsequent Preterm Birth SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; OMEGA-3-FATTY-ACID SUPPLEMENTATION; EICOSAPENTAENOIC ACID; CYTOKINE PRODUCTION; PREMATURE LABOR; INFLAMMATION; INFECTION; PREGNANCY; EXPRESSION; INTERLEUKIN-10 AB OBJECTIVE: To estimate the associations of change in immune response with preterm delivery, omega-3 supplementation, and fish diet. METHODS: This was an ancillary study to a randomized trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. In vitro maternal peripheral blood mononuclear leukocyte production of the anti-inflammatory cytokine, interleukin-10, and the proinflammatory cytokine, tumor necrosis factor-alpha, in response to stimulation with lipopolysaccharide, was measured at 16-22 weeks of gestation (baseline) and again at 25-28 weeks of gestation (follow-up) among women with prior spontaneous preterm birth. Changes in concentrations from baseline to follow-up (Delta) were compared separately among groups defined by gestational age category at delivery, fish diet history, and omega-3 compared with placebo treatment assignment with Kruskal-Wallis tests. RESULTS: Interleukin-10 Delta differed by gestational age category among 292 women with paired assays. Concentrations increased less in women delivering between 35 and 36 6/7 weeks of gestation (48.9 pg/mL) compared with women delivering at term (159.3 pg/mL) and decreased by 65.2 pg/mL in women delivering before 35 weeks of gestation (P=.01). Tumor necrosis factor-alpha Delta also differed by gestational age category among 319 women, but the pattern was inconsistent. Those delivering between 35 and 36 6/7 weeks of gestation exhibited decreased concentrations of tumor necrosis factor-alpha at follow-up compared with baseline (-356.0 pg/mL); concentrations increased among women delivering before 35 weeks of gestation and those delivering at term, 132.1 and 86.9 pg/mL (P=.03). Interleukin-10 Delta and tumor necrosis factor-alpha Delta were unaffected by either omega-3 supplementation or fish diet. CONCLUSION: Recurrent preterm birth was associated with decreased peripheral blood mononuclear leukocyte production of interleukin-10 in response to a stimulus during the second trimester. C1 Wake Forest Univ Hlth Sci, Dept Obstet, Winston Salem, NC USA. Wake Forest Univ Hlth Sci, Dept Gynecol, Winston Salem, NC USA. Univ N Carolina, Chapel Hill, NC USA. Wayne State Univ, Detroit, MI USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Columbia Univ, New York, NY USA. Univ Pittsburgh, Pittsburgh, PA USA. Ohio State Univ, Columbus, OH 43210 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Northwestern Univ, Chicago, IL 60611 USA. Case Western Reserve Univ, MetroHlth Med Ctr, Cleveland, OH 44106 USA. Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. Univ Texas Med Branch, Galveston, TX 77555 USA. Virginia Polytech Inst & State Univ, Dept Biol Sci, Div Inflammat Biol & Immunol, Blacksburg, VA 24061 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Harper, M (reprint author), Mt Area Hlth Educ Ctr, 119 Hendersonville Rd, Asheville, NC 28803 USA. EM harper.margaret@gmail.com RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850; Varner, Michael/0000-0001-9455-3973; Li, Liwu/0000-0001-8870-5299 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27860, HD27917, HD40560, HD34208, HD40485, HD21410, HD27915, HD40500, HD40512, HD40544, MO1-RR-000080, HD34136, HD27869, HD40545, HD36801, HD19897] FX The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (HD27860, HD27917, HD40560, HD34208, HD40485, HD21410, HD27915, HD40500, HD40512, HD40544, MO1-RR-000080, HD34136, HD27869, HD40545, HD36801, HD19897) and does not necessarily represent the official views of the NICHD or the National Institutes of Health. NR 42 TC 5 Z9 5 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2013 VL 121 IS 4 BP 805 EP 811 DI 10.1097/AOG.0b013e3182878a80 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112RJ UT WOS:000316610000016 PM 23635681 ER PT J AU Massad, LS Einstein, MH Huh, WK Katki, HA Kinney, WK Schiffman, M Solomon, D Wentzensen, N Lawson, HW AF Massad, L. Stewart Einstein, Mark H. Huh, Warner K. Katki, Hormuzd A. Kinney, Walter K. Schiffman, Mark Solomon, Diane Wentzensen, Nicolas Lawson, Herschel W. CA 2012 ASCCP Consensus Guidelines TI 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ADENOCARCINOMA IN-SITU; SQUAMOUS INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS INFECTION; ATYPICAL GLANDULAR CELLS; OF-AMERICAN-PATHOLOGISTS; UNDETERMINED SIGNIFICANCE; ENDOCERVICAL CURETTAGE; RANDOMIZED-TRIAL; UTERINE CERVIX; YOUNG-WOMEN AB A group of 47 experts representing 23 professional societies, national and international health organizations, and federal agencies met in Bethesda, MD, September 14-15, 2012, to revise the 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines. The group's goal was to provide revised evidence-based consensus guidelines for managing women with abnormal cervical cancer screening tests, cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) following adoption of cervical cancer screening guidelines incorporating longer screening intervals and co-testing. In addition to literature review, data from almost 1.4 million women in the Kaiser Permanente Northern California Medical Care Plan provided evidence on risk after abnormal tests. Where data were available, guidelines prescribed similar management for women with similar risks for CIN 3, AIS, and cancer. Most prior guidelines were reaffirmed. Examples of updates include: Human papillomavirus-negative atypical squamous cells of undetermined significance results are followed with co-testing at 3 years before return to routine screening and are not sufficient for exiting women from screening at age 65 years; women aged 21-24 years need less invasive management, especially for minor abnormalities; postcolposcopy management strategies incorporate co-testing; endocervical sampling reported as CIN 1 should be managed as CIN 1; unsatisfactory cytology should be repeated in most circumstances, even when HPV results from co-testing are known, while most cases of negative cytology with absent or insufficient endocervical cells or transformation zone component can be managed without intensive follow-up. (Obstet Gynecol 2013;121:829-46) DOI: http://10.1097/AOG.0b013e3182883a34 C1 Washington Univ, Sch Med, St Louis, MO 63110 USA. Albert Einstein Coll Med, New York, NY USA. Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Permanente Med Grp Inc, Sacramento, CA USA. Emory Univ, Sch Med, Atlanta, GA USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu NR 93 TC 173 Z9 198 U1 3 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2013 VL 121 IS 4 BP 829 EP 846 DI 10.1097/AOG.0b013e3182883a34 PG 18 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112RJ UT WOS:000316610000019 PM 23635684 ER PT J AU Saade, GR Berghella, V Mercer, BM Wenstrom, KD Spong, CY AF Saade, George R. Berghella, Vincenzo Mercer, Brian M. Wenstrom, Katharine D. Spong, Catherine Y. TI Preventing the First Cesarean Delivery: Summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Berghella, Vincenzo] Thomas Jefferson Univ, Jefferson Med Coll, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. [Mercer, Brian M.] Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Wenstrom, Katharine D.] Women & Infants Hosp Rhode Isl, Dept Obstet & Gynecol, Providence, RI 02908 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Saade, GR (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. NR 2 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2013 VL 121 IS 4 BP 879 EP 879 DI 10.1097/AOG.0b013e31828aa949 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112RJ UT WOS:000316610000034 PM 23635699 ER PT J AU Brown, RS Edwards, D Walsh-Chocolaad, T Childs, RW AF Brown, Ronald S. Edwards, Dean Walsh-Chocolaad, Tracey Childs, Richard W. TI Topical tacrolimus with custom trays in the treatment of severe oral chronic graft-versus-host disease refractory to a potent topical steroid therapy: a case report SO ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY LA English DT Article ID ATOPIC-DERMATITIS; LICHEN-PLANUS; CALCINEURIN INHIBITORS; OINTMENT; MANAGEMENT; EFFICACY; IMMUNOMODULATORS; TRANSPLANTATION; CYCLOSPORINE; LESIONS AB Background. The authors present a case demonstrating the success of topical tacrolimus (TAC) therapy with custom trays in the treatment of oral chronic graft-versus-host disease (cGVHD). The 41-year-old male patient initially responded to topical steroid therapy (clobetasol propionate 0.05% ointment) applied both topically and with flexible carrier trays, but later became refractory to this potent topical agent. Topical TAC therapy with flexible carrier trays and systemic prednisone therapy was initiated. Results. The patient responded favorably with the change to topical TAC therapy with custom trays (and oral prednisone). His oral cGVHD lesions resolved within a period of 4 weeks. The improvement has remained stable at 14 months of follow-up. Clinical implications. This is the first case reported with regard to the successful resolution of steroid recalcitrant cGVHD successfully treated with topical TAC with custom trays. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:e26-e30) C1 [Brown, Ronald S.] Howard Univ, Coll Dent, Dept Oral Diagnost Serv, Washington, DC 20059 USA. [Brown, Ronald S.] Georgetown Univ, Med Ctr, Dept Otolaryngol, Washington, DC 20007 USA. [Brown, Ronald S.; Walsh-Chocolaad, Tracey; Childs, Richard W.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Edwards, Dean] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Brown, RS (reprint author), Howard Univ, Coll Dent, 600 W St,NW,Room 406, Washington, DC 20059 USA. EM rbrown@howard.edu FU Intramural NIH HHS [Z99 HL999999] NR 24 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-4403 J9 OR SURG OR MED OR PA JI Oral Surg. Oral Med. Oral Pathol. Oral Radiol. PD APR PY 2013 VL 115 IS 4 BP E26 EP E30 DI 10.1016/j.oooo.2012.07.487 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 113KR UT WOS:000316666700006 PM 23102802 ER PT J AU Lee, P Brychta, RJ Collins, MT Linderman, J Smith, S Herscovitch, P Millo, C Chen, KY Celi, FS AF Lee, P. Brychta, R. J. Collins, M. T. Linderman, J. Smith, S. Herscovitch, P. Millo, C. Chen, K. Y. Celi, F. S. TI Cold-activated brown adipose tissue is an independent predictor of higher bone mineral density in women SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Bone mineral density; Brown adipose tissue; Human; Metabolism; Thermogenesis ID ADULT HUMANS; VISCERAL FAT; PREMENOPAUSAL; PREVALENCE; OBESITY; MASS; BETA AB In animals, defective brown adipogenesis leads to bone loss. Whether brown adipose tissue (BAT) mass relates to bone mineral density (BMD) in humans is unclear. We determined the relationship between BAT mass and BMD by cold-stimulated positron-emission tomography (PET) and dual-energy X-ray absorptiometry (DXA) in healthy volunteers. Higher BAT mass was associated with higher BMD in healthy women, but not in men, independent of age and body composition. Contrary to the traditional belief that BAT is present only in infants, recent studies revealed significant depots of BAT present in adult humans. In animals, defective brown adipogenesis leads to bone loss. While white adipose tissue mass is a known determinant of BMD in humans, the relationship between BAT and BMD in humans is unclear. We thus examined the relationship between BAT and BMD in healthy adults. BAT volume (ml) and activity (standard uptake value) were determined by F-18-fluorodeoxyglucose PET after overnight mild cold exposure at 19 A degrees C, and BMD was determined by DXA. Among 24 healthy adults (age 28 +/- 1 years, F = 10), BAT volumes were 82.4 +/- 99.5 ml in women and 49.7 +/- 54.5 ml in men. Women manifested significantly higher BAT activity, by 9.4 +/- 8.1 % (p = 0.03), than men. BAT volume correlated positively with total and spine BMD (r (2) = 0.40 and 0.49, respectively, p < 0.02) in women and remained a significant predictor after adjustment for age, fat, and lean body mass (p < 0.05). Total and spine BMD were higher in women who harbored visually detectable BAT on PET images than those without by 11 +/- 2 % (p = 0.02) and 22 +/- 2 % (p < 0.01), respectively. No associations were observed between BAT parameters and BMD in men. This study demonstrated higher BMD among healthy women with more abundant BAT, independent of age and other body compositional parameters. This was not observed in men. The data suggest that brown adipogenesis may be physiologically related to modulation of bone density. C1 [Lee, P.; Brychta, R. J.; Linderman, J.; Smith, S.; Chen, K. Y.; Celi, F. S.] NIDDKD, Diabet Endocrinol & Obes Branch, NIH, CRC, Bethesda, MD 20892 USA. [Collins, M. T.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. [Herscovitch, P.; Millo, C.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Lee, P (reprint author), NIDDKD, Diabet Endocrinol & Obes Branch, NIH, CRC, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM paul.lee2@nih.gov OI Chen, Kong/0000-0002-0306-1904 FU Australian National Health Medical Research Council; Diabetes Australia; Bushell Travelling Fellowship; National Institute of Diabetes and Digestive and Kidney Diseases [Z01-DK047057-02, Z01-DK071044] FX Paul Lee was supported by the Australian National Health Medical Research Council Early Career Fellowship, the Diabetes Australia Fellowship, and the Bushell Travelling Fellowship. This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases: programs Z01-DK047057-02 and Z01-DK071044. NR 19 TC 12 Z9 14 U1 0 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD APR PY 2013 VL 24 IS 4 BP 1513 EP 1518 DI 10.1007/s00198-012-2110-y PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 113BA UT WOS:000316639600038 PM 22890364 ER PT J AU Colloca, L Klinger, R Flor, H Bingel, U AF Colloca, Luana Klinger, Regine Flor, Herta Bingel, Ulrike TI Placebo analgesia: Psychological and neurobiological mechanisms SO PAIN LA English DT Review ID OPIOID ACTIVITY; BRAIN ACTIVITY; PAIN; NETWORK; ACTIVATION; EXPERIENCE; RESPONSES; ANXIETY; ANTICIPATION; VARIABILITY C1 [Colloca, Luana] NIMH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Colloca, Luana] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. [Klinger, Regine] Univ Hamburg, Dept Psychol, Outpatient Clin Behav Therapy, Hamburg, Germany. [Flor, Herta] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Cognit & Clin Neurosci, Mannheim, Germany. [Bingel, Ulrike] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. RP Colloca, L (reprint author), NIMH, Natl Ctr Complementary & Alternat Med, Bldg 10,Room 1C154, Bethesda, MD 20892 USA. EM luana.colloca@nih.gov OI Colloca, Luana/0000-0002-6503-4709; Flor, Herta/0000-0003-4809-5398 FU Intramural Program of the National Center for Complementary and Alternative Medicine and the National Institute of Mental Health; Deutsche Forschungsgemeinschaft [FOR 1328/1, Kl 1350/3-1, Fl 156/33-1, BI 789/2-1]; Bundesministerium fur Bildung und Forschung [01GQ0808] FX This research was funded by the Intramural Program of the National Center for Complementary and Alternative Medicine and the National Institute of Mental Health (L.C.); grants by the Deutsche Forschungsgemeinschaft (FOR 1328/1), (Kl 1350/3-1) (R.K.), (Fl 156/33-1) (H.F.) and (BI 789/2-1) (U.B.); and grants by the Bundesministerium fur Bildung und Forschung (01GQ0808) (U.B.). NR 33 TC 62 Z9 63 U1 4 U2 55 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD APR PY 2013 VL 154 IS 4 BP 511 EP 514 DI 10.1016/j.pain.2013.02.002 PG 4 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 113HW UT WOS:000316658200003 PM 23473783 ER PT J AU Song, LX Bensen, JT Zimmer, C Sleath, B Blackard, B Fontham, E Su, LJ Brennan, CS Mohler, JL Mishel, M AF Song, Lixin Bensen, Jeannette T. Zimmer, Catherine Sleath, Betsy Blackard, Bonny Fontham, Elizabeth Su, L. Joseph Brennan, Christine S. Mohler, James L. Mishel, Merle TI Patient-health care provider communication among patients with newly diagnosed prostate cancer: Findings from a population-based survey SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Prostate cancer; Patient-health care provider communication; Satisfaction with health care services; Structural equation modeling ID QUALITY-OF-LIFE; PHYSICIAN COMMUNICATION; RACIAL-DIFFERENCES; AFRICAN-AMERICAN; SATISFACTION; INFORMATION; DOCTOR; TRUST; PERCEPTIONS; SURVIVORS AB Objective: To examine the multidimensional concept of patient-health care provider (HCP) communication, its effects on patient satisfaction with oncology care services, and related racial differences. Methods: The current analysis draws from a population-based survey sample of 1011 African American and 1034 Caucasian American men with newly diagnosed prostate cancer. The variables of satisfaction with health care services, interpersonal treatment, contextual knowledge of the patient, and prostate cancer communication were analyzed using multiple-group structural equation modeling. Results: Regardless of race, patient-HCP communication was related positively to interpersonal treatment by the HCP, HCP's contextual knowledge of the patient, and prostate cancer communication. More positive patient-HCP communication was related to more satisfaction with health care services. Racial differences were significant in the relationships between patient-HCP communication and prostate cancer communication. Conclusion: Content and interpersonal relationships are important aspects of patient-HCP communication and affect patient satisfaction with oncologic care for prostate cancer. Practice implications: HCPs need to integrate the transfer of information with emotional support and interpersonal connection when they,communicate with men with newly diagnosed prostate cancer. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Song, Lixin; Mishel, Merle] Univ N Carolina, Sch Nursing, Chapel Hill, NC 27599 USA. [Song, Lixin; Bensen, Jeannette T.; Blackard, Bonny] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Bensen, Jeannette T.] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27599 USA. [Zimmer, Catherine] Univ N Carolina, Odum Inst Res Social Sci, Chapel Hill, NC 27599 USA. [Sleath, Betsy] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Fontham, Elizabeth; Brennan, Christine S.] Louisiana State Univ, Hlth Sci Ctr, Sch Publ Hlth, New Orleans, LA USA. [Su, L. Joseph] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Mohler, James L.] Roswell Pk Canc Inst, Dept Urol, Buffalo, NY 14263 USA. RP Song, LX (reprint author), Univ N Carolina, Carrington Hall, Chapel Hill, NC 27599 USA. EM lsong@unc.edu FU Department of Defense contract, DAMD [17-03-2-0052] FX The North Carolina-Louisiana Prostate Cancer Project (PCaP) is carried out as a collaborative study supported by the Department of Defense contract, DAMD #17-03-2-0052. The authors thank the staff, advisory committees and research subjects participating in the PCaP study for their important contributions. NR 44 TC 7 Z9 7 U1 0 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD APR PY 2013 VL 91 IS 1 BP 79 EP 84 DI 10.1016/j.pec.2012.12.002 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 114YJ UT WOS:000316778600012 PM 23332967 ER PT J AU Carol, H Reynolds, CP Kang, MH Keir, ST Maris, JM Gorlick, R Kolb, EA Billups, CA Geier, B Kurmasheva, RT Houghton, PJ Smith, MA Lock, RB AF Carol, Hernan Reynolds, C. Patrick Kang, Min H. Keir, Stephen T. Maris, John M. Gorlick, Richard Kolb, E. Anders Billups, Catherine A. Geier, Brian Kurmasheva, Raushan T. Houghton, Peter J. Smith, Malcolm A. Lock, Richard B. TI Initial Testing of the MDM2 Inhibitor RG7112 by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; preclinical testing; RG7112 ID ACUTE LYMPHOBLASTIC-LEUKEMIA; WILD-TYPE P53; SMALL-MOLECULE ANTAGONISTS; IN-VIVO; CANCER MODELS; SOLID TUMORS; CELL-LINES; CHILDHOOD; NEUROBLASTOMA; MUTATIONS AB Background. RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. Procedures. RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 mu M). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). Results. RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4 mM vs. >10 mu M, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C > 2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. Conclusions. RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation. Pediatr Blood Cancer 2013;60:633-641. (C) 2012 Wiley Periodicals, Inc. C1 [Carol, Hernan; Lock, Richard B.] Univ New S Wales, Childrens Canc Inst Australia Med Res, Sydney, NSW, Australia. [Reynolds, C. Patrick; Kang, Min H.] Texas Tech Univ, Hlth Sci Ctr, Lubbock, TX 79430 USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Kolb, E. Anders] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Billups, Catherine A.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Geier, Brian; Kurmasheva, Raushan T.; Houghton, Peter J.] Nationwide Childrens Hosp, Columbus, OH USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Lock, RB (reprint author), Childrens Canc Inst Australia, Lowy Canc Res Ctr, Leukaemia Biol Program, High St, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Carol, Hernan/F-5750-2013; Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM-42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM-42216, CA21765, CA108786. NR 54 TC 27 Z9 28 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2013 VL 60 IS 4 BP 633 EP 641 DI 10.1002/pbc.24235 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 108KI UT WOS:000316291400020 PM 22753001 ER PT J AU Fogel, JM Mwatha, A Richardson, P Brown, ER Chipato, T Alexandre, M Moodley, D Elbireer, A Mirochnick, M George, K Mofenson, LM Zwerski, S Coovadia, HM Eshleman, SH AF Fogel, Jessica M. Mwatha, Anthony Richardson, Paul Brown, Elizabeth R. Chipato, Tsungai Alexandre, Michel Moodley, Dhayendre Elbireer, Ali Mirochnick, Mark George, Kathleen Mofenson, Lynne M. Zwerski, Sheryl Coovadia, Hoosen M. Eshleman, Susan H. TI Impact of Maternal and Infant Antiretroviral Drug Regimens on Drug Resistance in HIV-infected Breastfeeding Infants SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE nevirapine resistance; prevention of mother-to-child transmission; extended nevirapine; HIV ID EXTENDED-DOSE NEVIRAPINE; VERTICAL TRANSMISSION; CHILDREN; SINGLE; PROPHYLAXIS; MOTHERS; THERAPY; MILK; AGE; PREVENTION AB Background: The HIV Prevention Trials Network (HPTN) 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP up to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV infection despite prophylaxis. Methods: HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher exact tests were used to evaluate associations between categorical variables. Results: NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in 7 (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8 = 75% in the NVP arm, 1/17 = 5.9% in the placebo arm, P = 0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all 4 of those infants by 6 months of age (4/4 = 100%). In contrast, only 3 (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate antiretroviral treatment developed NVP resistance (P = 0.003). Conclusions: Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants. C1 [Fogel, Jessica M.; Richardson, Paul; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Brown, Elizabeth R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Brown, Elizabeth R.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Chipato, Tsungai] Univ Zimbabwe, Coll Med, Dept Obstet & Gynecol, Harare, Zimbabwe. [Alexandre, Michel] Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, Dar Es Salaam, Tanzania. [Moodley, Dhayendre] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Durban, South Africa. MU JHU Care Ltd, Kampala, Uganda. [Mirochnick, Mark] Boston Univ, Sch Med, Boston, MA 02118 USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Adolescent Maternal AIDS Branch, NIH, Rockville, MD USA. [Zwerski, Sheryl] NIAID, HIV Prevent Branch, NIH, Johannesburg, South Africa. [Coovadia, Hoosen M.] Univ Witwatersrand, Maternal Adolescent & Child Hlth, Johannesburg, South Africa. RP Eshleman, SH (reprint author), Johns Hopkins Med Inst, Dept Pathol, Ross Bldg,Room 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group [U01AI068632]; National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH), of the US National Institutes of Health (NIH); NIAID, NIH [1R01AI087139]; NIH [046]; NIAID [U01AI46749]; NICHD; NIMH; National Institute of Drug Abuse (NIDA) FX This work was funded by: (1) the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group (U01AI068632), which receives support from the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), of the US National Institutes of Health (NIH), and (2) 1R01AI087139 funded by NIAID, NIH. The HIV Prevention Trials Network (HPTN) 046 was funded by the NIH, initially through the HIV Prevention Trials Network (HPTN) and later through the IMPAACT group. The HPTN (U01AI46749) has been funded by the NIAID, NICHD, NIMH and the National Institute of Drug Abuse (NIDA). The study products used in the HPTN 046 trial were provided free of charge by Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT). The authors have no other funding or conflicts of interest to disclose. NR 28 TC 6 Z9 6 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2013 VL 32 IS 4 BP E164 EP E169 DI 10.1097/INF.0b013e31827f44ee PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 113LM UT WOS:000316669200008 PM 23249916 ER PT J AU Patel, MM Pitzer, VE Alonso, WJ Vera, D Lopman, B Tate, J Viboud, C Parashar, UD AF Patel, Manish M. Pitzer, Virginia E. Alonso, Wladimir J. Vera, David Lopman, Ben Tate, Jacqueline Viboud, Cecile Parashar, Umesh D. TI Global Seasonality of Rotavirus Disease SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE rotavirus; seasonality; season; diarrhea; global; surveillance ID HOSPITAL-BASED SURVEILLANCE; AGED LESS-THAN-5 YEARS; GROUP-A ROTAVIRUS; THAN 5 YEARS; WATERBORNE GASTROENTERITIS OUTBREAK; MOLECULAR EPIDEMIOLOGY; ECONOMIC BURDEN; ACUTE DIARRHEA; BUENOS-AIRES; SENTINEL HOSPITALS AB Background: A substantial number of surveillance studies have documented rotavirus prevalence among children admitted for dehydrating diarrhea. We sought to establish global seasonal patterns of rotavirus disease before the introduction of widespread vaccination. Methods: We reviewed studies of rotavirus detection in children with diarrhea published since 1995. We assessed potential relationships between seasonal prevalence and locality by plotting the average monthly proportion of diarrhea cases positive for rotavirus according to geography, country development and latitude. We used linear regression to identify variables that were potentially associated with the seasonal intensity of rotavirus. Results: Among a total of 99 studies representing all 6 geographic regions of the world, patterns of year-round disease were more evident in low- and low-middle income countries compared with upper-middle and high-income countries where disease was more likely to be seasonal. The level of country development was a stronger predictor of strength of seasonality (P = 0.001) than geographic location or climate. However, the observation of distinctly different seasonal patterns of rotavirus disease in some countries with similar geographic location, climate and level of development indicate that a single unifying explanation for variation in seasonality of rotavirus disease is unlikely. Conclusion: While no unifying explanation emerged for varying rotavirus seasonality globally, the country income level was somewhat more predictive of the likelihood of having seasonal disease than other factors. Future evaluation of the effect of rotavirus vaccination on seasonal patterns of disease in different settings may help understand factors that drive the global seasonality of rotavirus disease. C1 [Patel, Manish M.; Vera, David; Lopman, Ben; Tate, Jacqueline; Parashar, Umesh D.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Pitzer, Virginia E.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Pitzer, Virginia E.; Alonso, Wladimir J.; Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Pitzer, Virginia E.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. RP Patel, MM (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,MS A-47, Atlanta, GA 30333 USA. EM mpatel@cdc.gov OI Pitzer, Virginia/0000-0003-1015-2289 FU Bill and Melinda Gates Foundation; RAPIDD program of the Science & Technology Directorate; Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was partially supported by the Bill and Melinda Gates Foundation and the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security and the Fogarty International Center, National Institutes of Health (VEP). The funders had no role in study design, data collection, analysis and interpretation, or writing of the report. Manish Patel had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors have no other funding or conflicts of interest to disclose. NR 128 TC 24 Z9 25 U1 0 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2013 VL 32 IS 4 BP E134 EP E147 DI 10.1097/INF.0b013e31827d3b68 PG 14 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 113LM UT WOS:000316669200003 PM 23190782 ER PT J AU Hong, JS Romero, R Kusanovic, JP Kim, JS Lee, J Jin, M El Azzamy, H Lee, DC Topping, V Ahn, S Jacques, S Qureshi, F Chaiworapongsa, T Hassan, SS Korzeniewski, SJ Than, NG Kim, CJ AF Hong, J. -S. Romero, R. Kusanovic, J. P. Kim, J. -S. Lee, J. Jin, M. El Azzamy, H. Lee, D. -C. Topping, V. Ahn, S. Jacques, S. Qureshi, F. Chaiworapongsa, T. Hassan, S. S. Korzeniewski, S. J. Than, N. G. Kim, C. J. TI "Trophoblast islands of the chorionic connective tissue" (TICCT): A novel placental histologic feature SO PLACENTA LA English DT Article DE Chorioamniotic membranes; Pregnancy; Fetal sex; Cytokeratin-7 ID CORTICOTROPIN-RELEASING HORMONE; HUMAN-FETAL MEMBRANES; INTERLEUKIN-1 RECEPTOR ANTAGONIST; PRETERM BIRTH; PROSTAGLANDIN DEHYDROGENASE; STEM-CELLS; EXTRAVILLOUS TROPHOBLASTS; GESTATIONAL-AGE; AMNIOTIC-FLUID; TERM PLACENTA AB Introduction: We found isolated or clustered trophoblasts in the chorionic connective tissue of the extraplacental membranes, and defined this novel histologic feature as the "trophoblast islands of the chorionic connective tissue" (TICCT). This study was conducted to determine the clinical significance of TICCT. Methods: Immunohistochemistry for cytokeratin-7 was performed on the chorioamniotic membranes (N = 2155) obtained from singleton pregnancies of 1199 uncomplicated term and 956 preterm deliveries. The study groups comprised 1236 African American and 919 Hispanic women. Gestational age ranged from 24(+0) weeks to 41(+6) weeks. Multiple logistic regression analysis was performed to investigate the magnitude of association between patient characteristics and the presence of TICCT. Results: The likelihood of TICCT was significantly associated with advancing gestational age both in term (OR: 1.29,95% CI: 1.16-1.45, p < 0.001) and preterm deliveries (OR: 1.19, 95% CI: 1.07-1.32, p = 0.001). Hispanic women were less likely than African American women to have TICCT across gestation in term (OR: 0.23, 95% CI: 0.18-031, p < 0.001) and preterm pregnancies (OR: 0.41, 95% CI: 0.29-0.58, p < 0.001). Women with a female fetus were significantly more likely to have TICCT than women with a male fetus, in both term (OR: 1.64, 95% CI: 128-2.11, p < 0.001) and preterm gestations (OR: 2.04, 95% CI: 1.46-2.85, p < 0.001). TICCT was 40% less frequent in the presence of chronic placental inflammation [term (OR: 0.60, 95% CI: 0.45-0.81, p = 0.001) and preterm gestations (OR: 0.58, 95% CI: 0.40-0.84, p = 0.003)] and in parous women at term (OR: 0.60, 95% CI: 0.44-0.81, p = 0.001). Conclusions: Our findings suggest that the duration of pregnancy, fetal sex, and parity may influence the behavior of extravillous trophoblast and placental mesenchymal cells. Published by Elsevier Ltd. C1 [Hong, J. -S.; Romero, R.; Kim, J. -S.; Lee, J.; Jin, M.; El Azzamy, H.; Lee, D. -C.; Topping, V.; Chaiworapongsa, T.; Hassan, S. S.; Korzeniewski, S. J.; Than, N. G.; Kim, C. J.] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Hong, J. -S.; Romero, R.; Kim, J. -S.; Lee, J.; Jin, M.; El Azzamy, H.; Lee, D. -C.; Topping, V.; Chaiworapongsa, T.; Hassan, S. S.; Korzeniewski, S. J.; Than, N. G.; Kim, C. J.] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. [Hong, J. -S.] Seoul Natl Univ, Bundang Hosp, Dept Obstet & Gynecol, Gyeonggi Do, South Korea. [Kusanovic, J. P.] Pontificia Univ Catolica Chile, Dept Obstet & Gynecol, Sch Med, Santiago, Chile. [Kusanovic, J. P.] Hosp Dr Sotero del Rio, Ctr Res & Innovat Maternal Fetal Med CIMAF, Santiago, Chile. [Kim, J. -S.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Lee, D. -C.] Kangwon Natl Univ, Sch Biomed Sci, Dept Med Biotechnol, Chunchon, South Korea. [Ahn, S.] Seoul Natl Univ, Bundang Hosp, Med Res Collaborating Ctr, Gyeonggi Do, South Korea. [Jacques, S.; Qureshi, F.] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Chaiworapongsa, T.; Hassan, S. S.; Korzeniewski, S. J.; Than, N. G.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Kim, C. J.] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS,Hutzel Womens Hosp, 3990 John R St, Detroit, MI 48201 USA. EM romeror@mail.nih.gov; ckim@amc.seoul.kr FU 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 FX This work 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, U.S. Department of Health and Human Services. The authors are grateful to the patients who agreed to participate in our studies, the nurses, laboratory staff, and clinicians who made this work possible; and also to Maureen McGerty and Andrea Bernard (Wayne State University) for their critical readings of the manuscript. NR 65 TC 1 Z9 1 U1 0 U2 12 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD APR PY 2013 VL 34 IS 4 BP 360 EP 368 DI 10.1016/j.placenta.2013.01.012 PG 9 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 115WM UT WOS:000316842600012 PM 23453248 ER PT J AU Slingsby, C Wistow, GJ Clark, AR AF Slingsby, Christine Wistow, Graeme J. Clark, Alice R. TI Evolution of crystallins for a role in the vertebrate eye lens SO PROTEIN SCIENCE LA English DT Review DE -crystallin; -crystallin; -crystallin; refractive index; small heat shock protein; chaperone; stress resistance; optics; proteinprotein interactions; cataract ID ALPHA-B-CRYSTALLIN; BETA-GAMMA-CRYSTALLIN; HEAT-SHOCK-PROTEIN; X-RAY-ANALYSIS; MACROMOLECULAR ASSEMBLIES; MOLECULAR CHAPERONE; QUATERNARY DYNAMICS; MYXOCOCCUS-XANTHUS; PHASE-SEPARATION; ASCIDIAN LARVA AB The camera eye lens of vertebrates is a classic example of the re-engineering of existing protein components to fashion a new device. The bulk of the lens is formed from proteins belonging to two superfamilies, the -crystallins and the -crystallins. Tracing their ancestry may throw light on the origin of the optics of the lens. The -crystallins belong to the ubiquitous small heat shock proteins family that plays a protective role in cellular homeostasis. They form enormous polydisperse oligomers that challenge modern biophysical methods to uncover the molecular basis of their assembly structure and chaperone-like protein binding function. It is argued that a molecular phenotype of a dynamic assembly suits a chaperone function as well as a structural role in the eye lens where the constraint of preventing protein condensation is paramount. The main cellular partners of -crystallins, the - and -crystallins, have largely been lost from the animal kingdom but the superfamily is hugely expanded in the vertebrate eye lens. Their structures show how a simple Greek key motif can evolve rapidly to form a complex array of monomers and oligomers. Apart from remaining transparent, a major role of the partnership of -crystallins with - and -crystallins in the lens is to form a refractive index gradient. Here, we show some of the structural and genetic features of these two protein superfamilies that enable the rapid creation of different assembly states, to match the rapidly changing optical needs among the various vertebrates. C1 [Slingsby, Christine; Clark, Alice R.] Univ London Birkbeck Coll, Inst Struct & Mol Biol, Dept Biol Sci, London WC1E 7HX, England. [Wistow, Graeme J.] NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Slingsby, C (reprint author), Univ London Birkbeck Coll, Inst Struct & Mol Biol, Dept Biol Sci, Malet St, London WC1E 7HX, England. EM C.Slingsby@mail.cryst.bbk.ac.uk OI Clark, Alice/0000-0002-1701-9010 FU Medical Research Council, UK [G0801846]; European Synchrotron Radiation Facility (Grenoble, France); Diamond Light Source (Oxfordshire, UK); Soleil, France; BIOSTRUCT-X FX Grant sponsor: Medical Research Council, UK; Grant number: G0801846; Grant sponsor: European Synchrotron Radiation Facility (Grenoble, France); Grant sponsor: Diamond Light Source (Oxfordshire, UK); Grant sponsor: Soleil, France (partially funded through BIOSTRUCT-X). NR 95 TC 31 Z9 31 U1 2 U2 52 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD APR PY 2013 VL 22 IS 4 BP 367 EP + DI 10.1002/pro.2229 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112WC UT WOS:000316623900001 PM 23389822 ER PT J AU Meleth, AD Toy, BC Nigam, D Agron, E Murphy, RP Chew, EY Wong, WT AF Meleth, Annal D. Toy, Brian C. Nigam, Divya Agron, Elvira Murphy, Robert P. Chew, Emily Y. Wong, Wai T. TI PREVALENCE AND PROGRESSION OF PIGMENT CLUMPING ASSOCIATED WITH IDIOPATHIC MACULAR TELANGIECTASIA TYPE 2 SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article DE imaging; macular telangiectasia; microperimetry; ocular coherence tomography; retinal pigment ID OPTICAL COHERENCE TOMOGRAPHY; JUXTAFOVEOLAR RETINAL TELANGIECTASIS; RETINITIS-PIGMENTOSA; MACTEL PROJECT; AUTOFLUORESCENCE; MIGRATION; EYE AB Purpose: The purpose of this study was to investigate pigment clumping in idiopathic macular telangiectasia Type 2 for its incidence, development, and progression during the course of the disease. Methods: Patients with a diagnosis of idiopathic macular telangiectasia Type 2 and >12 months of follow-up were reviewed retrospectively. Measurements of the area of pigment clumping were performed and correlated with visual acuity and findings on spectral domain optical coherence tomography and microperimetry (MP-1). Results: Fifty-three eyes in 27 patients with a mean follow-up of 42.5 +/- 14.2 months (range 12-79 months) were included. At study baseline, 16 eyes (30%) had evidence of pigment clumping without associated neovascular changes. During follow-up, 8 of 33 additional study eyes (24%) without previous pigment clumping developed it in Stage 3 (Gass-Blodi classification) disease. Pigment clumping increased in overall area as a function of follow-up time. Pigment clumping was associated with increased intraretinal reflectivity on optical coherence tomography and development of scotomas on microperimetry. Conclusion: Pigment clumping commonly develops in Stage 3 idiopathic macular telangiectasia Type 2 disease, enlarges in area continuously over time, and is associated with declining visual function. Longitudinal measurements of the total area of pigment clumping may be helpful in following disease progression and may constitute a useful outcome measure for interventional clinical studies. RETINA 33:762-770, 2013 C1 [Meleth, Annal D.; Toy, Brian C.; Nigam, Divya; Agron, Elvira; Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Murphy, Robert P.] Retina Grp Washington, Chevy Chase, MD USA. [Wong, Wai T.] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), 6 Ctr Dr,6-217, Bethesda, MD 20892 USA. EM wongw@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU National Eye Institute Intramural Research Program; Lowy Medical Foundation, Sydney, Australia FX Supported by a funding from the National Eye Institute Intramural Research Program and the Lowy Medical Foundation, Sydney, Australia. NR 25 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD APR PY 2013 VL 33 IS 4 BP 762 EP 770 DI 10.1097/IAE.0b013e3182695bb3 PG 9 WC Ophthalmology SC Ophthalmology GA 115GZ UT WOS:000316801900011 PM 23064429 ER PT J AU Stefansdottir, H Arnar, DO Aspelund, T Sigurdsson, S Jonsdottir, MK Hjaltason, H Launer, LJ Gudnason, V AF Stefansdottir, Hrafnhildur Arnar, David O. Aspelund, Thor Sigurdsson, Sigurdur Jonsdottir, Maria K. Hjaltason, Haukur Launer, Lenore J. Gudnason, Vilmundur TI Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts SO STROKE LA English DT Article; Proceedings Paper CT International Stroke Conference CY JAN 31-FEB 03, 2012 CL New Orleans, LA DE atrial fibrillation; brain imaging; cognition; cerebral infarct ID AGES-REYKJAVIK; BLOOD-FLOW; STROKE; POPULATION; DEMENTIA; VULNERABILITY; PREVALENCE; LOCATION; MEMORY; ADULTS AB Background and Purpose-Atrial fibrillation (AF) has been associated with cognitive decline independent of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population. Methods-This is a cross-sectional analysis of 4251 nondemented participants (mean age, 76+/-5 years) in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study. Medical record data were collected for the presence, subtype, and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with magnetic resonance imaging. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic factors, cardiovascular risk factors, and cerebral infarcts. Results-Participants with AF had lower total brain volume compared with those without AF (P<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter hyperintensities (P<0.001 and P=0.008, respectively), but not of white matter hyperintensities (P=0.49). Participants with AF scored lower on tests of memory. Conclusions-AF is associated with smaller brain volume, and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts. (Stroke. 2013;44:1020-1025.) C1 [Stefansdottir, Hrafnhildur; Arnar, David O.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Arnar, David O.] Landspitali Natl Univ Hosp Iceland, Dept Med, Cardiovasc Res Ctr, IS-101 Reykjavik, Iceland. [Aspelund, Thor; Sigurdsson, Sigurdur; Jonsdottir, Maria K.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Jonsdottir, Maria K.] Univ Iceland, Fac Psychol, Reykjavik, Iceland. [Hjaltason, Haukur] Landspitali Natl Univ Hosp Iceland, Dept Neurol, IS-101 Reykjavik, Iceland. [Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Stefansdottir, Hrafnhildur] Univ Iowa Hosp & Clin, Dept Internal Med, Iowa City, IA 52242 USA. RP Arnar, DO (reprint author), Landspitali Natl Univ Hosp Iceland, IS-101 Reykjavik, Iceland. EM davidar@landspitali.is; vilmundur@hjarta.is RI Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU Landspitali; National University Hospital of Iceland Science Fund; Helga Jonsdottir and Sigvaldi Kristjansson Memorial Fund; National Institutes of Health [N01-AG-1-2100]; National Institute on Aging Intramural Research Program; Icelandic Heart Association; Althingi (the Icelandic Parliament) FX This work was supported by the Landspitali, The National University Hospital of Iceland Science Fund, and the Helga Jonsdottir and Sigvaldi Kristjansson Memorial Fund. The Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by National Institutes of Health contract N01-AG-1-2100, the National Institute on Aging Intramural Research Program, the Icelandic Heart Association, and Althingi (the Icelandic Parliament). NR 31 TC 24 Z9 25 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD APR PY 2013 VL 44 IS 4 BP 1020 EP + DI 10.1161/STROKEAHA.12.679381 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 113NE UT WOS:000316673900025 PM 23444303 ER PT J AU White, AM MacInnes, E Hingson, RW Pan, IJ AF White, Aaron M. MacInnes, Erin Hingson, Ralph W. Pan, I-Jen TI Hospitalizations for Suicide-Related Drug Poisonings and Co-occurring Alcohol Overdoses in Adolescents (Ages 1217) and Young Adults (Ages 1824) in the United States, 19992008: Results from the Nationwide Inpatient Sample SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID EMERGENCY-DEPARTMENT; EPIDEMIOLOGIC SURVEY; SELF-HARM; USE DISORDERS; CONSUMPTION; BEHAVIOR; DEPRESSION; IDEATION; SURVEILLANCE; PREVENTION AB Drug poisoning is the leading method of suicide-related deaths among females and third among males in the United States. Alcohol can increase the severity of drug poisonings, yet the prevalence of alcohol overdoses in suicide-related drug poisonings (SRDP) remains unclear. Data from the Nationwide Inpatient Sample was examined to determine rates of inpatient hospital stays for SRDP and co-occurring alcohol overdoses in adolescents (ages 1217) and young adults (ages 1824) between 1999 and 2008. Among adolescents, there were 14,615 hospitalizations for drug poisonings in 2008, of which 72% (10,462) were suicide-related at a cost of $43 million. Rates of SRDP in this age group decreased between 1999 and 2008. The prevalence of co-occurring alcohol overdoses increased from 5% in 1999 to 7% in 2008. Among young adults, there were 32,471 hospitalizations for drug poisonings in 2008, of which 64% (20,746) were suicide-related at a cost of $110 million. Rates of SRDP did not change significantly between 1999 and 2008. The prevalence of co-occurring alcohol overdoses increased from 14% in 1999 to 20% in 2008. Thus, while rates of SRDP decreased for adolescents and remained unchanged for young adults, the prevalence of co-occurring alcohol overdoses increased for both age groups. Such hospitalizations provide important opportunities to employ intervention techniques to prevent further suicide attempts. C1 [White, Aaron M.; Hingson, Ralph W.] NIAAA, Div Epidemiol & Prevent Res, NIH, Bethesda, MD 20892 USA. [MacInnes, Erin] Amer Assoc Suicidol, Washington, DC USA. [Pan, I-Jen] CSR Inc, Arlington, VA USA. RP White, AM (reprint author), NIAAA, 5635 Fishers Lane,MSC 9304,Room 2074, Bethesda, MD 20892 USA. EM whitea4@mail.nih.gov NR 50 TC 8 Z9 8 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD APR PY 2013 VL 43 IS 2 BP 198 EP 212 DI 10.1111/sltb.12008 PG 15 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 115PN UT WOS:000316824500008 PM 23356834 ER PT J AU Costello, EJ Eaves, L Sullivan, P Kennedy, M Conway, K Adkins, DE Angold, A Clark, SL Erkanli, A McClay, JL Copeland, W Maes, HH Liu, YF Patkar, AA Silberg, J van den Oord, E AF Costello, E. Jane Eaves, Lindon Sullivan, Patrick Kennedy, Martin Conway, Kevin Adkins, Daniel E. Angold, A. Clark, Shaunna L. Erkanli, Alaattin McClay, Joseph L. Copeland, William Maes, Hermine H. Liu, Youfang Patkar, Ashwin A. Silberg, Judy van den Oord, Edwin TI Genes, Environments, and Developmental Research: Methods for a Multi-Site Study of Early Substance Abuse SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article DE genomewide association study; environment; development; multi-site ID GENOME-WIDE ASSOCIATION; FALSE DISCOVERY RATE; GREAT SMOKY MOUNTAINS; ALCOHOL-CONSUMPTION; DEPRESSIVE SYMPTOMS; YOUNG ADULTHOOD; WHITE YOUTH; DISORDERS; METAANALYSIS; ADOLESCENCE AB The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables. C1 [Costello, E. Jane; Angold, A.; Erkanli, Alaattin; Copeland, William; Patkar, Ashwin A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27701 USA. [Eaves, Lindon; Maes, Hermine H.; Silberg, Judy; van den Oord, Edwin] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Sullivan, Patrick] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Kennedy, Martin] Univ Otago, Dept Pathol, North Dunedin, New Zealand. [Conway, Kevin] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Adkins, Daniel E.; Clark, Shaunna L.; McClay, Joseph L.] Virginia Commonwealth Univ, Sch Pharm, Ctr Biomarker Res & Personalized Med, Richmond, VA USA. [Liu, Youfang] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC USA. RP Costello, EJ (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Suite 22,Brightleaf Sq,905 West Main St, Durham, NC 27701 USA. EM jcostell@psych.duhs.duke.edu RI McClay, Joseph/C-9931-2009; copeland, william/N-5413-2014; OI McClay, Joseph/0000-0002-3628-2447; Conway, Kevin/0000-0002-7638-339X; Kennedy, Martin/0000-0002-6445-8526 FU NIDA [R01DA024413]; [K01MH093731]; [K23MH080230] FX Work on this project was carried out with support from NIDA (R01DA024413). Dr Adkins was supported by K01MH093731, and Dr Copeland by K23MH080230. We are grateful to all the study participants who contributed to this work. NR 73 TC 3 Z9 3 U1 3 U2 38 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1832-4274 EI 1839-2628 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD APR PY 2013 VL 16 IS 2 BP 505 EP 515 DI 10.1017/thg.2013.6 PG 11 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 115MX UT WOS:000316817500001 PM 23461817 ER PT J AU Dawson, DA Goldstein, RB Grant, BF AF Dawson, Deborah A. Goldstein, Rise B. Grant, Bridget F. TI Prospective correlates of drinking cessation: variation across the life-course SO ADDICTION LA English DT Article DE Drinking cessation; former drinkers; sick quitters ID NATIONAL EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION SAMPLE; ALCOHOL-USE DISORDER; DRUG-USE DISORDERS; DSM-IV ALCOHOL; UNITED-STATES; HEAVY DRINKING; SUBSTANCE USE; GENDER-DIFFERENCES; SOCIAL DRINKERS AB Aims To assess age variation in correlates of drinking cessation. Design Prospective study of a US general population sample. Setting Face-to-face household interviews. Participants Past-yearmonthly drinkers interviewed at baseline and 3-year follow-up (n=14885). Measurements Baseline values and selected changes over follow-up in alcohol consumption, alcohol use disorder (AUD), socio-demographic and health characteristics, other substance use and psychiatric comorbidity were used to predict drinking cessation in three age groups. Findings Correlates of drinking cessation varied over the life-course, with pregnancy/presence of an infant, nicotine or drug use disorder, incident AUD, cluster A personality disorder, liver disease and incident retirement being important at younger ages and high-school graduation, family income$70000, volume of ethanol intake, Asian race/ethnicity, mood disorder and incident cardiovascular disease being significant at older ages. Age-invariant correlates included smoking cessation over follow-up, odds ratio (OR)=2.82 [95% confidence interval (CI): 1.624.92] to 3.45 (2.205.39); college education, OR=0.42 (0.270.65) to 0.54 (0.360.83); black and Hispanic race/ethnicity, OR=1.74 (1.182.29) to 1.88 (1.212.93) and 1.58 (1.111.25) to 1.73 (0.833.63), respectively, and months since last drink, OR=1.24 (1.131.36) to 1.29 (1.191.39). Conclusions Factors associated with ceasing alcohol use in US adults appear to differ over the life-course, reflecting age variation in both their prevalence and impact and supporting the importance of role transitions and health problems (the sick quitter' effect). The most consistent correlates of drinking cessation included factors reflecting ability/inability to give up potentially addictive substances and factors associated with perceived acceptability of drinking and subgroup-specific drinking contexts that might facilitate/impede continued drinking. C1 [Dawson, Deborah A.] Kelly Govt Serv, Bethesda, MD 20816 USA. [Dawson, Deborah A.; Goldstein, Rise B.; Grant, Bridget F.] NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. RP Dawson, DA (reprint author), Kelly Govt Serv, 5111 Duvall Dr, Bethesda, MD 20816 USA. EM deborah.anne.dawson@gmail.com OI Goldstein, Rise/0000-0002-9603-9473 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services FX This research was supported in part by the Intramural Program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism.; The study on which this paper is based, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), is sponsored by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services, with supplemental support from the National Institute on Drug Abuse. NR 59 TC 11 Z9 11 U1 2 U2 38 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 EI 1360-0443 J9 ADDICTION JI Addiction PD APR PY 2013 VL 108 IS 4 BP 712 EP 722 DI 10.1111/add.12079 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 108VA UT WOS:000316323100015 PM 23216848 ER PT J AU Djamshidian, A Sanotsky, Y Matviyenko, Y O'Sullivan, SS Sharman, S Selikhova, M Fedoryshyn, L Filts, Y Bearn, J Lees, AJ Averbeck, BB AF Djamshidian, Atbin Sanotsky, Yanosh Matviyenko, Yuriy O'Sullivan, Sean S. Sharman, Stephen Selikhova, Marianna Fedoryshyn, Ludmyla Filts, Yuriy Bearn, Jenny Lees, Andrew J. Averbeck, Bruno B. TI Increased reflection impulsivity in patients with ephedrone-induced Parkinsonism SO ADDICTION LA English DT Article DE Beads task; ephedrone-induced Parkinsonism; reflection impulsivity; risk-taking; substance abuse; working memory ID DECISION-MAKING; PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; DISEASE; RISK; USERS; AMPHETAMINE; MECHANISMS; MANGANESE; ABUSE AB Aims To examine a syndrome of chronic manganism that occurs in drug addicts in eastern Europe who use intravenous methcathinone (ephedrone) contaminated with potassium permanganate. In many cases the basal ganglia, especially the globus pallidus and the putamen, are damaged irreversibly. Routine neuropsychological assessment has revealed no cognitive deficits, despite widespread abnormalities on brain imaging studies and severe extrapyramidal motor handicap on clinical examination. Design Casecontrol study. Setting Ephedrone patients and patients with opioid dependence were recruited from Lviv, Ukraine. Participants We tested 15 patients with ephedrone-induced toxicity, 13 opiate-dependent patients who were receiving opioid replacement therapy and 18 matched healthy volunteers. Measurements The beads task', an information-gathering task to assess reflection impulsivity, was used and feedback learning, working memory and risk-taking were also assessed. Findings Opiate-dependent patients differed from controls on three of four tasks, whereas ephedrone patients differed from controls on only one task. More specifically, both patient groups were more impulsive and made more irrational choices on the beads task than controls (P<0.001). However, ephedrone patients had no deficits in working memory (0.1) or risk-taking (0.1) compared with controls. Opioid-dependent patients had significantly worse working memory (P<0.001) and were significantly more risk-prone than controls (P=0.002). Conclusions Ephedrone patients may have similar deficits in information-gathering and decision-making to opiate-dependent patients, with preservation of working memory and risk-taking. This may reflect specific damage to anterior cingulate basal ganglia loops. C1 [Djamshidian, Atbin; O'Sullivan, Sean S.; Selikhova, Marianna; Averbeck, Bruno B.] Univ London, Dept Mol Neurosci, London, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Selikhova, Marianna; Lees, Andrew J.] Univ London, Reta LilaWeston Inst Neurol Studies, London, England. [Sanotsky, Yanosh; Matviyenko, Yuriy; Fedoryshyn, Ludmyla] Univ Clin Lviv, Dept Neurol, Lvov, Ukraine. [Averbeck, Bruno B.] UCL, Sobell Dept Motor Neurosci & Movement Disorders, Inst Neurol, London, England. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Filts, Yuriy] Lviv Reg Clin Psychiat Hosp, Lvov, Ukraine. [Sharman, Stephen] UCL, Dept Neuropsychiat, Inst Neurol, London, England. [Bearn, Jenny] South London & Maudsley NHS Fdn Trust, Acute Assessment Unit, Maudsley Hosp, London, England. RP Averbeck, BB (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49 Room 1B80,49 Convent Dr MSC 4415, Bethesda, MD 20892 USA. EM andrew.lees@ucl.ac.uk; averbeckbb@mail.nih.gov RI Lees, Andrew/A-6605-2009; O'Sullivan, Sean/C-9333-2012; OI O'Sullivan, Sean/0000-0002-0583-7956; Djamshidian, Atbin/0000-0001-7174-6000; Sharman, Steve/0000-0001-9816-7981 FU PSP Association; Weston Trust-the Reta Lila Howard Foundation; Wellcome; NIH; NIH, NIMH FX SOS received honoraria from Britannia Pharmaceuticals, otherwise none. AJL: consultancies: Genus; honoraria: Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion; grants: PSP Association, Weston Trust-the Reta Lila Howard Foundation; otherwise none. BBA: grants: Wellcome, and the Intramural Research Program of the NIH; otherwise none. Other authors: none.; The authors wish to thank the patients and families who participated in the study. This research was supported in part by the Intramural Research Program of the NIH, NIMH. NR 50 TC 9 Z9 9 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2013 VL 108 IS 4 BP 771 EP 779 DI 10.1111/add.12080 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 108VA UT WOS:000316323100023 PM 23228208 ER PT J AU Kawamoto, EM Vasconcelos, AR Degaspari, S Bohmer, AE Scavone, C Marcourakis, T AF Kawamoto, Elisa Mitiko Vasconcelos, Andrea Rodrigues Degaspari, Sabrina Boehmer, Ana Elisa Scavone, Cristoforo Marcourakis, Tania TI Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system SO AGE LA English DT Article DE Nitric oxide; Aging; Cyclic GMP; TBARS; Peripheral markers ID ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; RAT-BRAIN; NEURODEGENERATIVE DISEASES; DIRECT PROJECTION; AMMONS HORN; STRESS; SYNTHASE; ACCUMULATION; POTENTIATION AB Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study age-related disorders and new anti-aging therapies. C1 [Marcourakis, Tania] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, BR-05508900 Sao Paulo, Brazil. [Kawamoto, Elisa Mitiko; Vasconcelos, Andrea Rodrigues; Degaspari, Sabrina; Boehmer, Ana Elisa; Scavone, Cristoforo] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci ICB 1, BR-05508900 Sao Paulo, Brazil. [Kawamoto, Elisa Mitiko] NIA, Lab Neurosci, NIH, Baltimore, MD 21224 USA. RP Scavone, C (reprint author), Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci ICB 1, Ave Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, Brazil. EM cristoforo.scavone@gmail.com RI Marcourakis, Tania/D-6667-2012; OI Vasconcelos, Andrea/0000-0001-7549-6408; Scavone, Cristoforo/0000-0002-1206-0882 FU FAPESP; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES); Universidade de Sao Paulo; CNPq; Neuroscience Research Support Centers from University of Sao Paulo (NAPNA) FX The authors thank Larissa de Sa Lima for technical support and Fernando Kok for his helpful comments. E. M. K. and A. E. B. are supported by postdoc fellowship from FAPESP; A. R. V and S. D. are Ph.D. student research fellowship from FAPESP and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), respectively, and L. S. L. is supported by grants from Universidade de Sao Paulo. Work in the laboratory of the authors was supported by FAPESP, CNPq and Neuroscience Research Support Centers from University of Sao Paulo (NAPNA). C. S. and T. M. are research fellows of CNPq. The authors report no biomedical financial interests or potential conflicts of interest. NR 53 TC 6 Z9 7 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 EI 1574-4647 J9 AGE JI Age PD APR PY 2013 VL 35 IS 2 BP 331 EP 342 DI 10.1007/s11357-011-9365-7 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 105JX UT WOS:000316065200006 PM 22278206 ER PT J AU Soerensen, M Dato, S Tan, QH Thinggaard, M Kleindorp, R Beekman, M Suchiman, HED Jacobsen, R McGue, M Stevnsner, T Bohr, VA de Craen, AJM Westendorp, RGJ Schreiber, S Slagboom, PE Nebel, A Vaupel, JW Christensen, K Christiansen, L AF Soerensen, Mette Dato, Serena Tan, Qihua Thinggaard, Mikael Kleindorp, Rabea Beekman, Marian Suchiman, H. Eka D. Jacobsen, Rune McGue, Matt Stevnsner, Tinna Bohr, Vilhelm A. de Craen, Anton J. M. Westendorp, Rudi G. J. Schreiber, Stefan Slagboom, P. Eline Nebel, Almut Vaupel, James W. Christensen, Kaare Christiansen, Lene TI Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity SO AGE LA English DT Article DE Human longevity; Candidate gene association study; Case-control data; Longitudinal data ID APOLIPOPROTEIN-E GENOTYPE; GENOME-WIDE ASSOCIATION; CONVERTING ENZYME GENE; EXCEPTIONAL LONGEVITY; ITALIAN CENTENARIANS; FRENCH CENTENARIANS; COGNITIVE DECLINE; CANDIDATE GENES; LEIDEN 85-PLUS; SIRT3 GENE AB In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2) = 0.55) with rs429358 of the APOE-epsilon 4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected = 0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N = 563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity. C1 [Soerensen, Mette; Dato, Serena; Tan, Qihua; Thinggaard, Mikael; Jacobsen, Rune; McGue, Matt; Vaupel, James W.; Christensen, Kaare; Christiansen, Lene] Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, DK-5000 Odense C, Denmark. [Soerensen, Mette; Tan, Qihua; Christensen, Kaare; Christiansen, Lene] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark. [Soerensen, Mette; Tan, Qihua; Christensen, Kaare; Christiansen, Lene] Odense Univ Hosp, Dept Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark. [Dato, Serena] Univ Calabria, Dept Cell Biol, I-87036 Cosenza, Italy. [Kleindorp, Rabea; Schreiber, Stefan; Nebel, Almut] Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, D-24105 Kiel, Germany. [Kleindorp, Rabea; Schreiber, Stefan; Nebel, Almut] Univ Kiel, D-24105 Kiel, Germany. [Beekman, Marian; Suchiman, H. Eka D.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands. [Beekman, Marian; Suchiman, H. Eka D.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands. [McGue, Matt] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Stevnsner, Tinna; Bohr, Vilhelm A.] Aarhus Univ, Dept Mol Biol, Danish Aging Res Ctr, DK-8000 Aarhus C, Denmark. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [de Craen, Anton J. M.; Westendorp, Rudi G. J.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands. [Vaupel, James W.] Max Planck Inst Demog Res, D-18057 Rostock, Germany. RP Soerensen, M (reprint author), Univ Southern Denmark, Inst Publ Hlth, Danish Aging Res Ctr, JB Winsloews Vej 9B, DK-5000 Odense C, Denmark. EM msoerensen@health.sdu.dk RI Nebel, Almut/E-4196-2010; Schreiber, Stefan/B-6748-2008; Soerensen, Mette/O-1817-2015; Lindahl-Jacobsen, Rune/J-2985-2012; Christensen, Kaare/C-2360-2009; Slagboom, P. Eline/R-4790-2016; Andersen, Mette Adalheidur/D-5608-2017; Suchiman, H. Eka D./F-5024-2017; OI dato, serena/0000-0003-2589-7929; Schreiber, Stefan/0000-0003-2254-7771; Lindahl-Jacobsen, Rune/0000-0002-4622-9826; Christensen, Kaare/0000-0002-5429-5292; Slagboom, P. Eline/0000-0002-2875-4723; Suchiman, H. Eka D./0000-0002-7168-5516; Soerensen, Mette/0000-0001-5268-3366; Beekman, Marian/0000-0003-0585-6206 FU Max Planck Institute for Demographic Research (Rostock, Germany); EU funds from the European Regional Development Fund; National Institute on Aging [P01 AG08761]; Novo Nordisk Foundation; Aase and Ejnar Danielsen Foundation; Augustinus Foundation; Brodrene Hartmann Foundation; King Christian the 10th foundation; Einer Willumsens Mindelegat Foundation; Dutch grant from the Netherlands Consortium for Healthy Ageing [050-060-810]; VELUX Foundation FX This study was financially supported by the Max Planck Institute for Demographic Research (Rostock, Germany), the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the National Institute on Aging (P01 AG08761), the Novo Nordisk Foundation, the Aase and Ejnar Danielsen Foundation, the Augustinus Foundation, the Brodrene Hartmann Foundation, the King Christian the 10th foundation, the Einer Willumsens Mindelegat Foundation, and by a Dutch grant from the Netherlands Consortium for Healthy Ageing (grant 050-060-810) in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The Danish Aging Research Center is supported by a grant from the VELUX Foundation. Susanne Knudsen, Steen Gregersen, Ulla Munk, Shuxia Li, Anne Mette Hedegaard Nielsen, Marlene Graff Sorensen, and Lene Elnegaard are thanked for excellent technical work. NR 73 TC 25 Z9 25 U1 1 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD APR PY 2013 VL 35 IS 2 BP 487 EP 500 DI 10.1007/s11357-011-9373-7 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 105JX UT WOS:000316065200019 PM 22234866 ER PT J AU Holly, AC Melzer, D Pilling, LC Henley, W Hernandez, DG Singleton, AB Bandinelli, S Guralnik, JM Ferrucci, L Harries, LW AF Holly, Alice C. Melzer, David Pilling, Luke C. Henley, William Hernandez, Dena G. Singleton, Andrew B. Bandinelli, Stefania Guralnik, Jack M. Ferrucci, Luigi Harries, Lorna W. TI Towards a gene expression biomarker set for human biological age SO AGING CELL LA English DT Article DE biological aging; mRNA expression; cell senescence; predictive model ID PHYSICAL PERFORMANCE BATTERY; SERUM-ALBUMIN; INCHIANTI; MORTALITY; MUSCLE; WOMEN; MEN AB We have previously described a statistical model capable of distinguishing young (age <65years) from old (age 75years) individuals. Here we studied the performance of a modified model in three populations and determined whether individuals predicted to be biologically younger than their chronological age had biochemical and functional measures consistent with a younger biological age. Those with younger' gene expression patterns demonstrated higher muscle strength and serum albumin, and lower interleukin-6 and blood urea concentrations relative to biologically older' individuals (odds ratios 2.09, 1.64, 0.74, 0.74; P=2.4x102, 3.5x104, 1.8x102, 1.5x102, respectively). We conclude that our expression signature of age is robust across three populations and may have utility for estimation of biological age. C1 [Holly, Alice C.; Harries, Lorna W.] Univ Exeter, Exeter Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Melzer, David; Pilling, Luke C.] Univ Exeter, Exeter Med Sch, Exeter EX2 5DW, Devon, England. [Henley, William] Univ Exeter, Exeter Med Sch, Inst Hlth Serv Res, Exeter EX2 4SG, Devon, England. [Hernandez, Dena G.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. RP Melzer, D (reprint author), Exeter Med Sch, Barrack Rd, Exeter EX2 5DW, Devon, England. EM David.Melzer@pms.ac.uk RI Pilling, Luke/E-4917-2013; Harries, Lorna/D-2241-2014; Singleton, Andrew/C-3010-2009; OI Pilling, Luke/0000-0002-3332-8454; Melzer, David/0000-0002-0170-3838 FU National institute on Aging; University of Exeter Medical School; Exeter Peninsula NIHR Clinical Research Facility; National Institute for Health Research (NIHR); National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) FX This work was supported by the intramural program of the National institute on Aging, internal funds of the University of Exeter Medical School and the Exeter Peninsula NIHR Clinical Research Facility and the National Institute for Health Research (NIHR).; We thank the people and participants who contributed to the InCHIANTI, Exeter 10000 and SAFHS studies. William Henley was supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. NR 15 TC 4 Z9 4 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD APR PY 2013 VL 12 IS 2 BP 324 EP 326 DI 10.1111/acel.12044 PG 3 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 108VE UT WOS:000316323500017 PM 23311345 ER PT J AU Stockman, JK Lucea, MB Draughon, JE Sabri, B Anderson, JC Bertrand, D Campbell, DW Callwood, GB Campbell, JC AF Stockman, Jamila K. Lucea, Marguerite B. Draughon, Jessica E. Sabri, Bushra Anderson, Jocelyn C. Bertrand, Desiree Campbell, Doris W. Callwood, Gloria B. Campbell, Jacquelyn C. TI Intimate partner violence and HIV risk factors among African-American and African-Caribbean women in clinic-based settings SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article DE HIV; AIDS; intimate partner violence; Caribbean; African descent; women ID US VIRGIN-ISLANDS; SEXUAL RISK; DOMESTIC VIOLENCE; RECEIVING CARE; MEN; PERPETRATION; HIV/AIDS; BEHAVIOR; HEALTH; ABUSE AB Despite progress against intimate partner violence (IPV) and HIV/AIDS in the past two decades, both epidemics remain major public health problems, particularly among women of color. The objective of this study was to assess the relationship between recent IPV and HIV risk factors (sexual and drug risk behaviors, sexually transmitted infections [STIs], condom use, and negotiation) among women of African descent. We conducted a comparative casecontrol study in women's health clinics in Baltimore, MD, USA and St. Thomas and St. Croix, US Virgin Islands (USVI). Women aged 1855 years who experienced physical and/or sexual IPV in the past two years (Baltimore, n=107; USVI, n=235) were compared to women who never experienced any form of abuse (Baltimore, n=207; USVI, n=119). Logistic regression identified correlates of recent IPV by site. In both sites, having a partner with concurrent sex partners was independently associated with a history of recent IPV (Baltimore, AOR: 3.91, 95% CI: 1.798.55 and USVI, AOR: 2.25, 95% CI: 1.114.56). In Baltimore, factors independently associated with recent IPV were lifetime casual sex partners (AOR: 1.99, 95% CI: 1.113.57), exchange sex partners (AOR: 5.26, 95% CI: 1.9214.42), infrequent condom use during vaginal sex (AOR: 0.24, 95% CI: 0.080.72), and infrequent condom use during anal sex (AOR: 0.29, 95% CI: 0.090.93). In contrast, in the USVI, having a concurrent sex partner (AOR: 3.33, 95% CI: 1.467.60), frequent condom use during vaginal sex (AOR: 1.97, 95% CI: 1.063.65), frequent condom use during anal sex (AOR: 6.29, 95% CI: 1.5725.23), drug use (AOR: 3.16, 95% CI: 1.0010.06), and a past-year STI (AOR: 2.68, 95% CI: 1.255.72) were associated with recent IPV history. The divergent results by site warrant further investigation into the potential influence of culture, norms, and intentions on the relationships examined. Nonetheless, study findings support a critical need to continue the development and implementation of culturally tailored screening for IPV within HIV prevention and treatment programs. C1 [Stockman, Jamila K.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. [Lucea, Marguerite B.; Draughon, Jessica E.; Sabri, Bushra; Anderson, Jocelyn C.; Campbell, Jacquelyn C.] Johns Hopkins Univ, Dept Community Publ Hlth, Sch Nursing, Baltimore, MD USA. [Bertrand, Desiree; Campbell, Doris W.; Callwood, Gloria B.] Univ Virgin Islands, Caribbean Exploratory NIMHD Res Ctr, St Thomas, VI USA. RP Stockman, JK (reprint author), Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. EM jstockman@ucsd.edu OI Draughon Moret, Jessica/0000-0002-2597-021X FU NICHD NIH HHS [T32 HD064428, T32HD064428]; NIDA NIH HHS [K01DA031593, K01 DA031593]; NIMH NIH HHS [F31 MH088850, R25MH080664, R25 MH080664, F31MH088850]; NIMHD NIH HHS [L60MD003701, P20MD002286, P20 MD002286, L60 MD006272, L60 MD003701] NR 39 TC 7 Z9 7 U1 2 U2 20 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD APR 1 PY 2013 VL 25 IS 4 BP 472 EP 480 DI 10.1080/09540121.2012.722602 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 105LK UT WOS:000316071200011 PM 23006050 ER PT J AU Ben Mortenson, W Demers, L Fuhrer, MJ Jutai, JW Lenker, J DeRuyter, F AF Ben Mortenson, W. Demers, Louise Fuhrer, Marcus J. Jutai, Jeffrey W. Lenker, James DeRuyter, Frank TI Effects of an Assistive Technology Intervention on Older Adults with Disabilities and Their Informal Caregivers An Exploratory Randomized Controlled Trial SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Assistive Technology; Informal Caregiving; Older Adults; Community Dwelling ID LONG-TERM-CARE; DEVICE USE; HOME-CARE; RELIABILITY; VALIDITY; LIFE AB Mortenson WB, Demers L, Fuhrer MJ, Jutai JW, Lenker J, DeRuyter F: Effects of an assistive technology intervention on older adults with disabilities and their informal caregivers: An exploratory randomized controlled trial. Am J Phys Med Rehabil 2013;92:297-306. Objective: The aim of this study was to demonstrate experimentally that an assistive technology (AT) intervention improves older AT users' activity performance and satisfaction with activity performance and decreases their caregivers' sense of burden. Design: This study was a delayed intervention, randomized control trial. Baseline data were collected on 44 community-dwelling AT user-caregiver dyads in Vancouver, British Columbia, and Montreal, Quebec. The primary outcome measures for AT users were the satisfaction and accomplishment scales from the Assessment of Life Habits. The primary outcome measure for caregivers was the Caregiver Assistive Technology Outcome Measure, which assessed burden associated with dyad-identified problematic activities. Results: After the intervention, assistance users in the immediate intervention group reported significantly increased satisfaction with activity performance (P < 0.001) and improved accomplishment scores (P = 0.014). Informal caregivers in the immediate intervention group experienced significantly decreased burden with the dyad-identified problematic activity (P = 0.013). Participants in the delayed intervention group experienced similar benefits after the intervention. Improvements for both groups were mostly maintained 4 mos after the conclusion of the intervention. Conclusions: This is the first experimental study to demonstrate that the provision of AT decreases caregiver burden. If confirmed and extended by subsequent research, the findings have significant policy and practice implications and may enable health care providers to advocate for improved access to AT provision and the related follow-up services. C1 [Ben Mortenson, W.; Demers, Louise] Inst Univ Geriatrie Montreal, Ctr Rech, Montreal, PQ, Canada. [Ben Mortenson, W.] Simon Fraser Univ, Gerontol Res Ctr, Vancouver, BC, Canada. [Demers, Louise] Univ Montreal, Ecole Readaptat, Montreal, PQ, Canada. [Fuhrer, Marcus J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jutai, Jeffrey W.] Univ Ottawa, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada. [Jutai, Jeffrey W.] Bruyere Res Inst, Ottawa, ON, Canada. [Lenker, James] SUNY Buffalo, Dept Rehabil Sci, New York, NY USA. [DeRuyter, Frank] Duke Univ, Dept Surg Speech Pathol & Audiol, Durham, NC USA. RP Demers, L (reprint author), Univ Montreal, Sch Rehabil, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. RI Mortenson, William/L-7441-2013; OI Mortenson, William/0000-0002-0183-6163; Jutai, Jeffrey/0000-0002-7294-1323 FU National Institute on Disability and Rehabilitation Research [H133A060062]; Canadian Institutes of Health Research (CIHR) [232262]; CIHR postdoctoral fellowship in the area of Aging and Mobility from the Institute of Aging FX Supported by the National Institute on Disability and Rehabilitation Research through a grant to the Consortium on Assistive Technology Outcomes Research (http://www.outcomes.org/, grant H133A060062) and by Canadian Institutes of Health Research (CIHR) (grant 232262). Personal financial support for Dr Mortenson was provided by a CIHR postdoctoral fellowship in the area of Aging and Mobility from the Institute of Aging. Support was also provided to Dr Demers by the Fonds de recherche en sante du Quebec. Portions of the findings from this study were presented at three conferences: (1) Demers L, Mortenson W, Plante M, Raymond M-H & CATOR. Impacts des aides techniques aupres des usagers et de leurs proches-aidants: Resultats preliminaires. Congres International Francophone de Geriatrie et Gerontologie, Nice, France, October 19-21, 2010; (2) Mortenson WB, Demers L, Roy L, Lenker J, Jutai J, Fuhrer M, DeRuyter F. Efficacy of a user-caregiver assistive technology intervention: Preliminary results. Canadian Association of Occupational Therapists National Conference, May 26-29, 2010; and (3) Mortenson WB, Demers L, Jutai J, Fuhrer MJ, Lenker J, DeRuyter F. How assistive technology use by older individuals with disabilities impacts their informal caregivers. International Federation on Ageing. 11th Global Conference on Ageing. Prague, Czech Republic, May 28-June 1, 2012. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. NR 20 TC 0 Z9 0 U1 3 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD APR PY 2013 VL 92 IS 4 BP 297 EP 306 DI 10.1097/PHM.0b013e31827d65bf PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 109ZT UT WOS:000316411800002 ER PT J AU Lu, PJ Williams, WW Li, J Dorell, C Yankey, D Kepka, D Dunne, EF AF Lu, Peng-jun Williams, Walter W. Li, Jun Dorell, Christina Yankey, David Kepka, Deanna Dunne, Eileen F. TI Human Papillomavirus Vaccine Initiation and Awareness US Young Men in the 2010 National Health Interview Survey SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; CERVICAL-CANCER; HPV VACCINE; ADULT VACCINATION; ADOLESCENT MALES; WOMEN; COVERAGE; DISPARITIES; PREVENTION; CARE AB Background: In 2009, the quadrivalent human papillomavirus (HPV) vaccine was licensed by the U.S. Food and Drug Administration for use in men/boys aged 9-26 years. In 2009, the Advisory Committee on Immunization Practices (ACIP) provided a permissive recommendation allowing HPV vaccine administration to this group. Purpose: To assess HPV vaccination initiation and coverage, evaluate awareness of HPV and HPV vaccine, and identify factors independently associated with such awareness among men aged 18-26 years. Methods: Data from the 2010 National Health Interview Survey were analyzed in 2011. Results: In 2010, HPV vaccination initiation among men aged 18-26 years was 1.1%. Among the 1741 men interviewed in this age group, nearly half had heard of HPV (51.8%). Overall, about one third of these men had heard of the HPV vaccine (34.8%). Factors independently associated with a higher likelihood of awareness of both HPV and HPV vaccine among men aged 18-26 years included having non-Hispanic white race/ethnicity; a higher education level; a U.S. birthplace; more physician contacts; private health insurance; received other vaccines; and reported risk behaviors related to sexually transmitted diseases, including HIV. Conclusions: HPV vaccination initiation among men aged 18-26 years in 2010 was low. HPV and HPV vaccine awareness were also low, and messages in this area directed to men are needed. Since ACIP published a recommendation for routine use of HPV4 among men/boys in December 2011, continued monitoring of HPV vaccination uptake among men aged 18-26 years is useful for evaluating the vaccination campaigns, and planning and implementing strategies to increase coverage. (Am J Prey Med 2013:44(4):330-338) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Lu, Peng-jun; Williams, Walter W.; Dorell, Christina; Yankey, David] CDC, Immunizat Serv Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Li, Jun] CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Dunne, Eileen F.] CDC, Div Sexually Transmitted Dis Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. [Kepka, Deanna] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Lu, PJ (reprint author), CDC, Natl Ctr Immunizat & Resp Dis, 1600 Clifton Rd,NE,Mail Stop A-19, Atlanta, GA 30333 USA. EM lhp8@cdc.gov NR 49 TC 9 Z9 9 U1 3 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2013 VL 44 IS 4 BP 330 EP 338 DI 10.1016/j.amepre.2012.11.027 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 111GM UT WOS:000316509800002 PM 23498097 ER PT J AU Ballard-Barbash, R Siddiqi, SM Berrigan, DA Ross, SA Nebeling, LC Dowling, EC AF Ballard-Barbash, Rachel Siddiqi, Sameer M. Berrigan, David A. Ross, Sharon A. Nebeling, Linda C. Dowling, Emily C. TI Trends in Research on Energy Balance Supported by the National Cancer Institute SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; OBESITY RESEARCH; SURVIVORS; RECOMMENDATIONS; INTERVENTIONS; METAANALYSIS; PREVENTION; OUTCOMES; BURDEN; HEALTH AB Over the past decade, the body of research linking energy balance to the incidence, development, progression, and treatment of cancer has grown substantially. No prior NIH portfolio analyses have focused on energy balance within one institute. This portfolio analysis describes the growth of National Cancer Institute (NCI) grant research on energy balance-related conditions and behaviors from 2004 to 2010 following the release of an NCI research priority statement in 2003 on energy balance and cancer-related research. Energy balance grants from fiscal years (FY) 2004 to 2010 were identified using multiple search terms and analyzed between calendar years 2008 and 2010. Study characteristics related to cancer site, design, population, and energy balance area (physical activity, diet, and weight) were abstracted. From FY2004 to FY2010, the NCI awarded 269 energy balance-relevant grants totaling $518 million. In FY2010, 4.2% of NCI's total research project grants budget was allocated to energy balance research, compared to 2.1% in FY2004. The NCI more than doubled support for investigator-initiated research project grants (R01) and increased support for cooperative agreement (U01, U54) and exploratory research (R21) grants. In the portfolio, research examining energy balance areas in combination accounted for 41.6%, and observational and interventional studies were equally represented (38.3% and 37.2%, respectively). Breast cancer was the most commonly studied cancer. Inclusion of minorities rose, and funding specific to cancer survivors more than doubled. From FY2004 to FY2010, NCI's investment in energy balance and related health behavior research showed growth in funding and diversity of mechanisms, topics, and disciplines growth that reflects new directions in this field. (Am J Prey Med 2013;44(4):416-423) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Ballard-Barbash, Rachel; Siddiqi, Sameer M.; Berrigan, David A.] NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Nebeling, Linda C.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Ballard-Barbash, R (reprint author), NCI, Div Canc Control & Populat Sci, EPN 4005,6130 Executive Blvd MSC 7344, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 28 TC 6 Z9 6 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2013 VL 44 IS 4 BP 416 EP 423 DI 10.1016/j.amepre.2012.11.033 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 111GM UT WOS:000316509800014 PM 23498109 ER PT J AU Therkelsen, KE Pedley, A Speliotes, EK Massaro, JM Murabito, J Hoffmann, U Fox, CS AF Therkelsen, Kate E. Pedley, Alison Speliotes, Elizabeth K. Massaro, Joseph M. Murabito, Joanne Hoffmann, Udo Fox, Caroline S. TI Intramuscular Fat and Associations With Metabolic Risk Factors in the Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE epidemiology; intramuscular fat; metabolism; obesity ID INDUCED INSULIN-RESISTANCE; VISCERAL ADIPOSE-TISSUE; MUSCLE LIPID-CONTENT; SKELETAL-MUSCLE; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-DISEASE; HUMAN OBESITY; ACCUMULATION; CHOLESTEROL; SENSITIVITY AB Objective-Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors. Approach and Results-Participants (n=2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle, and the muscle attenuation (MA) in Hounsfield units was averaged. We examined the association between MA and metabolic risk factors in multivariable models, and additionally adjusted for body mass index (BMI) and visceral adipose tissue (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% confidence interval, 1.10-1.64) increase in the odds of diabetes mellitus, a 1.40 (95% confidence interval, 1.22-1.61) increase in the odds of high triglycerides, and a 1.29 (95% confidence interval, 1.12-1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low high density lipoprotein and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT. Conclusions-MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men. (Arterioscler Thromb Vasc Biol. 2013;33:863-870.) C1 [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Therkelsen, Kate E.; Pedley, Alison; Murabito, Joanne; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Speliotes, Elizabeth K.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Speliotes, Elizabeth K.] Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 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. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; [K23 DK080145-01] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. Additionally, Dr Speliotes is supported through K23 DK080145-01. NR 35 TC 20 Z9 20 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2013 VL 33 IS 4 BP 863 EP U541 DI 10.1161/ATVBAHA.112.301009 PG 19 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 105ZE UT WOS:000316110400029 PM 23349188 ER PT J AU Schuck, RN Theken, KN Edin, ML Caughey, M Bass, A Ellis, K Tran, B Steele, S Simmons, BP Lih, FB Tomer, KB Wu, MC Hinderliter, AL Stouffer, GA Zeldin, DC Lee, CR AF Schuck, Robert N. Theken, Katherine N. Edin, Matthew L. Caughey, Melissa Bass, Almasa Ellis, Kyle Tran, Bryant Steele, Savanna Simmons, Brian P. Lih, Fred B. Tomer, Kenneth B. Wu, Michael C. Hinderliter, Alan L. Stouffer, George A. Zeldin, Darryl C. Lee, Craig R. TI Cytochrome P450-derived eicosanoids and vascular dysfunction in coronary artery disease patients SO ATHEROSCLEROSIS LA English DT Article DE Soluble epoxide hydrolase; Epoxyeicosatrienoic acid; 20-Hydroxyeicosatetraenoic acid; Inflammation; Endothelial function ID SOLUBLE EPOXIDE HYDROLASE; C-REACTIVE PROTEIN; 20-HYDROXYEICOSATETRAENOIC ACID; CARDIOVASCULAR-DISEASE; GENETIC-VARIATION; BLOOD-PRESSURE; ATHEROSCLEROSIS; INFLAMMATION; INHIBITION; HUMANS AB Objective: Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP omega-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease. Methods: Plasma epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHET), and 20-hydroxyeicosatetraenoic acid (20-HETE) levels were quantified by HPLC-MS/MS in 106 patients with stable, angiographically-confirmed CAD. Relationships between biomarkers of CYP-mediated eicosanoid metabolism and vascular function phenotypes were evaluated by Pearson's correlation. Results: A significant inverse association was observed between 20-HETE levels (a biomarker of CYP omega-hydroxylase metabolism) and brachial artery flow-mediated dilation (r = -0.255, p = 0.010). An inverse association was also observed between 14,15-EET: DHET ratios (a biomarker of sEH metabolism) and both monocyte chemoattractant protein-1 levels (r = -0.252, p = 0.009) and a consolidated cellular adhesion molecule 'score' reflecting the levels of E-selectin and P-selectin (r = -0.216, p = 0.027). No associations with C-reactive protein or epithelial neutrophil-activating protein-78 levels were observed. Conclusions: Collectively, these findings demonstrate that enhanced CYP omega-hydroxylase and sEH metabolic function are associated with more advanced endothelial dysfunction and vascular inflammation, respectively, in patients with established atherosclerotic cardiovascular disease. These findings lay the foundation for future clinical research in this area. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Schuck, Robert N.; Theken, Katherine N.; Bass, Almasa; Ellis, Kyle; Tran, Bryant; Steele, Savanna; Simmons, Brian P.; Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Caughey, Melissa; Hinderliter, Alan L.; Stouffer, George A.] Univ N Carolina, Sch Med, Div Cardiol, Dept Biostat, Chapel Hill, NC 27599 USA. [Wu, Michael C.] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Caughey, Melissa; Hinderliter, Alan L.; Stouffer, George A.; Lee, Craig R.] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27599 USA. [Edin, Matthew L.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Lee, CR (reprint author), Univ N Carolina, Eshelman Sch Pharm, 2317 Kerr Hall,CB 7569, Chapel Hill, NC 27599 USA. EM craig_lee@unc.edu RI Tomer, Kenneth/E-8018-2013; OI Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301; Wu, Michael C./0000-0002-3357-6570 FU NIH/NHLBI [T32 HL069768]; American Heart Association [11PRE7240059]; American Foundation for Pharmaceutical Education; North Carolina Translational and Clinical Sciences Institute; Intramural Research Program of the NIH/NIEHS [Z01 ES050167, Z01 ES025034]; NIH/NCRR [KL2RR025746]; NIH/NCATS FX This publication was made possible by a predoctoral training program in Integrative Vascular Biology supported by the NIH/NHLBI (T32 HL069768) and a predoctoral fellowship from the American Heart Association (11PRE7240059) to Dr. Schuck, a predoctoral fellowship from the American Foundation for Pharmaceutical Education to Dr. Theken, a Beginning Grant-in-Aid from the American Heart Association and a pilot grant from the North Carolina Translational and Clinical Sciences Institute to Dr. Lee, funds from the Intramural Research Program of the NIH/NIEHS to Dr. Tomer (Z01 ES050167) and Dr. Zeldin (Z01 ES025034), and by grant KL2RR025746 from the NIH/NCRR and NIH/NCATS. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 30 TC 25 Z9 26 U1 0 U2 9 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 APR PY 2013 VL 227 IS 2 BP 442 EP 448 DI 10.1016/j.atherosclerosis.2013.01.034 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 112OZ UT WOS:000316603100040 PM 23466098 ER PT J AU Rahman, GM Shanker, S Lewin, NE Kedei, N Hill, CS Prasad, BVV Blumberg, PM Das, J AF Rahman, Ghazi M. Shanker, Sreejesh Lewin, Nancy E. Kedei, Noemi Hill, Colin S. Prasad, B. V. Venkataram Blumberg, Peter M. Das, Joydip TI Identification of the activator-binding residues in the second cysteine-rich regulatory domain of protein kinase C theta (PKC theta) SO BIOCHEMICAL JOURNAL LA English DT Article DE activator-binding residues; diacylglycerol; crystal structure; membrane translocation; phorbol ester; phospholipid; protein kinase C; tryptophan ID T-CELL-ACTIVATION; SITE-DIRECTED MUTAGENESIS; CATION-PI INTERACTIONS; PHORBOL ESTER BINDING; C1B DOMAIN; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; ALPHA ACTIVITY; DIACYLGLYCEROL; DELTA AB PKC (protein kinase C) theta is predominantly expressed in T-cells and is critically involved in immunity. Design of PKC theta-selective molecules to manage autoimmune disorders by targeting its activator-binding C1 domain requires the knowledge of its structure and the activator-binding residues. The C1 domain consists of twin C1 domains, C1A and C1B, of which C1B plays a critical role in the membrane translocation and activation of PKC theta. In the present study we determined the crystal structure of PKC theta C1B to 1.63 angstrom (1 angstrom = 0.1 nm) resolution, which showed that Trp(253) at the rim of the activator-binding pocket was orientated towards the membrane, whereas in PKC delta C1B the homologous tryptophan residue was orientated away from the membrane. This particular orientation of Trp(253) affects the size of the activator-binding pocket and the membrane affinity. To further probe the structural constraints on activator-binding, five residues lining the activator-binding site were mutated (Y239A, T243A, W253G, L255G and Q258G) and the binding affinities of the PKC theta C1B mutants were measured. These mutants showed reduced binding affinities for phorbol ester [PDBu (phorbol 12,13-dibutyrate)] and diacylglycerol [DOG (sn-1,2-dioctanoylglycerol), SAG (sn-1-stearoyl 2-arachidonyl glycerol)]. All five full-length PKC theta mutants exhibited reduced phorbol-ester-induced membrane translocation compared with the wild-type. These results provide insights into the PKC theta activator-binding domain, which will aid in future design of PKC theta-selective molecules. C1 [Rahman, Ghazi M.; Das, Joydip] Univ Houston, Coll Pharm, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA. [Shanker, Sreejesh; Prasad, B. V. Venkataram] Baylor Coll Med, Verna Marrs Mclean Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Lewin, Nancy E.; Kedei, Noemi; Hill, Colin S.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Prasad, B. V. Venkataram] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Das, J (reprint author), Univ Houston, Coll Pharm, Dept Pharmacol & Pharmaceut Sci, Houston, TX 77204 USA. EM jdas@uh.edu FU University of Houston; National Institutes of Health, Center for Cancer Research, National Cancer Institute [Z1A BC 005270] FX This research was supported in part by Startup funds from the University of Houston (to J.D.) and by the Intramural Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute [project number Z1A BC 005270]. NR 71 TC 10 Z9 10 U1 2 U2 21 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD APR 1 PY 2013 VL 451 BP 33 EP 44 DI 10.1042/BJ20121307 PN 1 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 111PK UT WOS:000316533000004 PM 23289588 ER PT J AU Balasubramanian, R Maruoka, H Jayasekara, PS Gao, ZG Jacobson, KA AF Balasubramanian, Ramachandran Maruoka, Hiroshi Jayasekara, P. Suresh Gao, Zhan-Guo Jacobson, Kenneth A. TI AMP-activated protein kinase as regulator of P2Y(6) receptor-induced insulin secretion in mouse pancreatic beta-cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Nucleotides; G protein-coupled receptor; Insulin; AMPK; Diabetes; P2Y(6) receptor ID ENDOTHELIAL-CELLS; COUPLED RECEPTORS; HELA-CELLS; RAT-LIVER; GLUCOSE; METFORMIN; METABOLISM; NUCLEOTIDES; PATHWAYS; CASCADE AB 5'-AMP-activated protein kinase (AMPK) and its pharmacological modulators have been targeted for treating type.2 diabetes. Extracellular uridine 5'-diphosphate (UDP) activates P2Y(6) receptors (P2Y(6)Rs) in pancreatic beta-cells to release insulin and reduce apoptosis, which would benefit diabetes. Here, we studied the role of P2Y(6)R in activation of AMPK in MING mouse pancreatic beta-cells and insulin secretion. Treatment with a potent P2Y(6)R dinucleotide agonist MRS2957 (500 nM) activated AMPK, which was blocked by P2Y(6)R-selective antagonist MRS2578. Also, MRS2957 induced phosphorylation of acetylcoenzyme A carboxylase (ACC), a marker of AMPK activity. Calcium chelator BAPTA-AM, calmodulin-dependent protein kinase kinase (CaMKK) inhibitor STO-069 and IP3 receptor antagonist 2-APB attenuated P2Y(6)R-mediated AMPK phosphorylation revealing involvement of intracellular Ca2+ pathways. P2Y(6)R agonist induced insulin secretion at high glucose, which was reduced by AMPK siRNA. Thus, P2Y(6)R has a crucial role in beta-cell function, suggesting its potential as a therapeutic target in diabetes. Published by Elsevier Inc. C1 [Balasubramanian, Ramachandran; Maruoka, Hiroshi; Jayasekara, P. Suresh; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIDDK, National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Research Program of NIDDK, National Institutes of Health, Bethesda, MD, USA. We thank Prof. T. K. Harden (Univ. of North Carolina) for helpful discussions. NR 49 TC 10 Z9 10 U1 0 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD APR 1 PY 2013 VL 85 IS 7 BP 991 EP 998 DI 10.1016/j.bcp.2012.11.029 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 110DO UT WOS:000316423000014 PM 23333427 ER PT J AU Modi, HR Basselin, M Taha, AY Li, LO Coleman, RA Bialer, M Rapoport, SI AF Modi, Hiren R. Basselin, Mireille Taha, Arneer Y. Li, Lei O. Coleman, Rosalind A. Bialer, Meir Rapoport, Stanley I. TI Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: A potential drug for bipolar disorder SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE Bipolar disorder; Valproic acid; Arachidonic acid; Acyl-CoA synthetase 4; Mood stabilizer; Propylisopropylacetic acid; Uncompetitive inhibition ID CYTOSOLIC PHOSPHOLIPASE A(2); CENTRAL-NERVOUS-SYSTEM; DOCOSAHEXAENOIC ACID; BRAIN PHOSPHOLIPIDS; UNANESTHETIZED RAT; ADMINISTRATION INCREASES; TOPIRAMATE MONOTHERAPY; ANTIEPILEPTIC ACTIVITY; FRONTAL-CORTEX; I DISORDER AB Background: Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic add (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic add (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain long-chain acyl-CoA synthetase (Acsl)4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl4 catalyzed acylation, and thus have a potential anti-BD action. Methods: Rat Acsl4-flag protein was expressed in Escherichia coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics. Results: Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a K-i of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect. Conclusions: PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients. Published by Elsevier B.V. C1 [Modi, Hiren R.; Basselin, Mireille; Taha, Arneer Y.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, Lab Neurosci, NIH, Bethesda, MD 20892 USA. [Li, Lei O.; Coleman, Rosalind A.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Bialer, Meir] Hebrew Univ Jerusalem, Sch Pharm, Fac Med, Dept Pharmaceut, IL-91120 Jerusalem, Israel. RP Modi, HR (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Rm 15126 9000 Rockville Pike, Bethesda, MD 20892 USA. EM modihr@mail.nih.gov RI Taha, Ameer/E-1979-2013 FU Intramural Program of the National Institute on Aging, NIH; NIH [DK 59935]; American Heart Association-Mid-Atlantic Region FX This work was supported by the Intramural Program of the National Institute on Aging, NIH, by NIH Grant DK 59935 (RAC), and by a post-doctoral fellowship from the American Heart Association-Mid-Atlantic Region (L O. L). We also thank the Chemical Synthesis and Drug Supply Program of the National Institute of Mental Health (Research Triangle Park, NC, USA) for supplying us with propylisopropylacetamide (PID). NR 75 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 EI 0006-3002 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD APR PY 2013 VL 1831 IS 4 BP 880 EP 886 DI 10.1016/j.bbalip.2013.01.008 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 110JK UT WOS:000316438200022 PM 23354024 ER PT J AU Lee, JG Ye, YH AF Lee, Jin-Gu Ye, Yihong TI Bag6/Bat3/Scythe: A novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation SO BIOESSAYS LA English DT Review DE Bag6; Bat3; Scythe; chaperone; holdase; ER-associated degradation; ERAD; proteasome; protein quality control; tail-anchored protein biogenesis; ubiquitin ID TAIL-ANCHORED PROTEINS; RETICULUM-ASSOCIATED DEGRADATION; UBIQUITIN-LIKE DOMAIN; CLASS-III REGION; ENDOPLASMIC-RETICULUM; MEMBRANE INSERTION; POLYUBIQUITIN CHAINS; CONJUGATING ENZYME; STRUCTURAL BASIS; BAT3 PROMOTES AB Upon emerging from the ribosome exiting tunnel, polypeptide folding occurs immediately with the assistance of both ribosome-associated and free chaperones. While many chaperones known to date are dedicated folding catalysts, recent studies have revealed a novel chaperoning system that functions at the interface of protein biogenesis and quality control by using a special holdase activity in order to sort and channel client proteins to distinct destinations. The key component, Bag6/Bat3/Scythe, can effectively shield long hydrophobic segments exposed on the surface of a polypeptide, preventing aggregation or inappropriate interactions before a triaging decision is made. The biological consequences of Bag6-mediated chaperoning are divergent for different substrates, ranging from membrane integration to proteasome targeting and destruction. Accordingly, Bag6 can act in various cellular contexts in order to execute many essential cellular functions, while dysfunctions in the Bag6 system can cause severe cellular abnormalities that may be associated with some pathological conditions. C1 [Lee, Jin-Gu; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ye, YH (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov FU NIDDK; Intramural Research Program of the NIDDK; NIH Intramural AIDS Targeted Antiviral Program (IATAP) FX The authors' research is supported by both the Intramural Research Program of the NIDDK and a grant from the NIH Intramural AIDS Targeted Antiviral Program (IATAP) to Y.Y. NR 81 TC 22 Z9 23 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0265-9247 EI 1521-1878 J9 BIOESSAYS JI Bioessays PD APR PY 2013 VL 35 IS 4 BP 377 EP 385 DI 10.1002/bies.201200159 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 108FD UT WOS:000316276300014 PM 23417671 ER PT J AU Tobin, LA Xie, YL Tsokos, M Chung, SI Merz, AA Arnold, MA Li, G Malech, HL Kwong, KF AF Tobin, Lisa A. Xie, Yili Tsokos, Maria Chung, Su I. Merz, Allison A. Arnold, Michael A. Li, Guang Malech, Harry L. Kwong, King F. TI Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization in vivo SO BIOMATERIALS LA English DT Article DE Nanoparticle; Calcium phosphate; In vivo delivery; Endocytosis; Cancer; siRNA ID SMALL INTERFERING RNA; INTRACELLULAR TRAFFICKING; VASCULAR-PERMEABILITY; DNA NANOPARTICLES; DELIVERY; TUMORS; EXPRESSION; PARTICLES; XENOGRAFT; PATHWAYS AB The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects. Published by Elsevier Ltd. C1 [Tobin, Lisa A.; Xie, Yili; Chung, Su I.; Merz, Allison A.; Kwong, King F.] NCI, Thorac Oncol Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Tsokos, Maria; Arnold, Michael A.; Li, Guang] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Tsokos, Maria] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Sch Med, Boston, MA 02215 USA. [Tsokos, Maria] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol, Sch Med, Boston, MA 02215 USA. [Arnold, Michael A.] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH USA. [Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Kwong, King F.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kwong, KF (reprint author), NCI, NIH, 10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM kwongk2@mail.nih.gov OI Malech, Harry/0000-0001-5874-5775; Arnold, Michael/0000-0002-6921-3720 FU US National Institutes of Health, National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, and Center for Cancer Research. We thank Dr. Robert Blumenthal and Professor Matthias Epple for reviewing the manuscript and providing comments and suggestions. We also thank AK Patri, JD Clogston, L Lim, P Mannan, and SH Garfield for their technical support. NR 31 TC 12 Z9 12 U1 1 U2 63 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD APR PY 2013 VL 34 IS 12 BP 2980 EP 2990 DI 10.1016/j.biomaterials.2013.01.046 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 105AV UT WOS:000316038900013 PM 23369215 ER PT J AU Master, Z Resnik, DB AF Master, Zubin Resnik, David B. TI Incorporating Exclusion Clauses into Informed Consent for Biobanking SO CAMBRIDGE QUARTERLY OF HEALTHCARE ETHICS LA English DT Article ID STORED BIOLOGICAL SAMPLES; RESEARCH PARTICIPANTS; GENOMIC RESEARCH; CANCER-PATIENTS; FUTURE-RESEARCH; HUMAN TISSUE; ETHICS; MODEL; VIEWS; FRAMEWORK C1 [Master, Zubin] Albany Med Coll, Alden March Bioeth Inst, Albany, NY 12208 USA. [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Master, Z (reprint author), Albany Med Coll, Alden March Bioeth Inst, Albany, NY 12208 USA. FU Cancer Stem Cell Consortium; AllerGen Network; Interdisciplinary Chronic Disease Collaboration; Stem Cell Network FX We are grateful to Professor Timothy Caulfield, Drs. Bill Schrader and Bruce Androphy, and the anonymous reviewer for insightful comments on the manuscript. This research was supported in part by a generous grant from the Cancer Stem Cell Consortium, the AllerGen Network, the Interdisciplinary Chronic Disease Collaboration, and the Stem Cell Network. The majority of the work for this paper was done while ZM was at the Health Law and Science Policy Group at the University of Alberta. This research is also the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH); however, the statements, opinions, or conclusions contained herein do not necessarily represent those of NIEHS, NIH, or the U.S. government. NR 56 TC 7 Z9 7 U1 1 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0963-1801 J9 CAMB Q HEALTHC ETHIC JI Camb. Q. Healthc. Ethics PD APR PY 2013 VL 22 IS 2 BP 203 EP 212 DI 10.1017/S0963180112000576 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Social Sciences, Biomedical SC Health Care Sciences & Services; Biomedical Social Sciences GA 107BH UT WOS:000316189200009 PM 23507182 ER PT J AU Matsuno, RK Sherman, ME Visvanathan, K Goodman, MT Hernandez, BY Lynch, CF Ioffe, OB Horio, D Platz, C Altekruse, SF Pfeiffer, RM Anderson, WF AF Matsuno, Rayna K. Sherman, Mark E. Visvanathan, Kala Goodman, Marc T. Hernandez, Brenda Y. Lynch, Charles F. Ioffe, Olga B. Horio, David Platz, Charles Altekruse, Sean F. Pfeiffer, Ruth M. Anderson, William F. TI Agreement for tumor grade of ovarian carcinoma: analysis of archival tissues from the surveillance, epidemiology, and end results residual tissue repository SO CANCER CAUSES & CONTROL LA English DT Article DE Epidemiology; Ovarian cancer; Tumor grade; SEER; Kappa coefficient ID SEROUS CARCINOMA; PROGNOSTIC-SIGNIFICANCE; EPITHELIAL CARCINOMA; BREAST-CANCER; 2-TIER SYSTEM; CELL-TYPE; LOW KAPPA; PATHOGENESIS; SUBTYPES; PARADOXES AB Emerging data suggest that ovarian cancers differ by tumor grade. However, the reliability of microscopic grade from paraffin tissue in the general medical community and as reflected in population-based cancer registries is unknown. We examined grade agreement between two gynecologic pathologists and the Surveillance Epidemiology and End Results Residual Tissue Repository (SEER). Grade agreement was assessed with percent observer agreement and kappa coefficients for 664 invasive ovarian carcinomas, using previously defined three-tier and two-tier grading systems. A random subset of ovarian carcinomas was selected to compare intra- and inter-pathologist agreement. Five hundred and eighty-six of SEER's 664 tumors were confirmed invasive. Percent agreement was 49 % with fair kappa coefficient = 0.25 (95 % CI: 0.20-0.30) for the 664 tumors. Agreement improved slightly when restricted to the 586 confirmed invasive cancers; it was better for high grade than low grade tumors, for two-tier than three-tier grading systems, and within (66 %) than between study pathologists (43 %). Grade was not a robust independent predictor of ovarian cancer-specific survival. Grade agreement was fair between SEER and study pathologists irrespective of grading system. Recorded grade in SEER should be used with caution and is probably not a reliable metric for ovarian cancer epidemiology. C1 [Matsuno, Rayna K.; Sherman, Mark E.; Pfeiffer, Ruth M.; Anderson, William F.] NCI, DHHS, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Matsuno, Rayna K.; Goodman, Marc T.; Hernandez, Brenda Y.; Horio, David] Univ Hawaii, Ctr Canc, Dept Epidemiol, Honolulu, HI 96822 USA. [Matsuno, Rayna K.; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Ioffe, Olga B.] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Platz, Charles] Univ Iowa Hosp & Clin, Dept Pathol, Iowa City, IA 52242 USA. [Altekruse, Sean F.] NCI, DHHS, NIH, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Anderson, WF (reprint author), NCI, DHHS, NIH, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8036, Rockville, MD 20852 USA. EM wanderso@mail.nih.gov FU National Institutes of Health, National Cancer Institute [R01CA58598, N01CN67001, N01-PC-35137, N01-PC-35143] FX This research was supported by the National Institutes of Health, National Cancer Institute Intramural Research Program, R01CA58598, N01CN67001, N01-PC-35137, and N01-PC-35143. NR 33 TC 7 Z9 7 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 749 EP 757 DI 10.1007/s10552-013-0157-5 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900013 PM 23378140 ER PT J AU Villasenor, A Ballard-Barbash, R Ambs, A Bernstein, L Baumgartner, K Baumgartner, R Ulrich, CM Hollis, BW McTiernan, A Neuhouser, ML AF Villasenor, Adriana Ballard-Barbash, Rachel Ambs, Anita Bernstein, Leslie Baumgartner, Kathy Baumgartner, Richard Ulrich, Cornelia M. Hollis, Bruce W. McTiernan, Anne Neuhouser, Marian L. TI Associations of serum 25-hydroxyvitamin D with overall and breast cancer-specific mortality in a multiethnic cohort of breast cancer survivors SO CANCER CAUSES & CONTROL LA English DT Article DE 25-Hydroxyvitamin D; Overall mortality; Breast cancer-specific mortality; Vitamin D ID VITAMIN-D DEFICIENCY; PREVENTION; INSUFFICIENCY; METASTASIS; ENDOCRINE; DISEASE; GROWTH; SEX AB Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations. In the Health, Eating, Activity, and Lifestyle study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast cancer-specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast cancer-specific mortality. After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6 %) women as serum 25(OH)D deficient (< 20 ng/mL), 189 (32.2 %) as insufficient (20-30 ng/mL), and 185 (36.2 %) as sufficient (> 30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR = 0.58; 95 % CI 0.36-0.96); however, multivariate adjustments attenuated the association (HR = 0.90; 95 % CI 0.50-1.61). No association was found between serum 25(OH)D and breast cancer-specific mortality (sufficient: HR = 1.21; 95 % CI 0.52-2.80) in multivariate models. In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements, or both should be evaluated in future larger studies with additional endpoints from breast cancer patients. C1 [Villasenor, Adriana; McTiernan, Anne; Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Villasenor, Adriana; McTiernan, Anne; Neuhouser, Marian L.] Univ Washington, Seattle, WA 98195 USA. [Villasenor, Adriana] Univ Calif San Diego, Moores UCSD Canc Ctr, La Jolla, CA 92109 USA. [Ballard-Barbash, Rachel; Ambs, Anita] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Div Populat Sci, Duarte, CA 91010 USA. [Baumgartner, Kathy; Baumgartner, Richard] Univ Louisville, Dept Epidemiol & Populat Hlth, Louisville, KY 40292 USA. [Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Heidelberg, Germany. [Ulrich, Cornelia M.] German Canc Res Ctr, Heidelberg, Germany. [Hollis, Bruce W.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Villasenor, A (reprint author), Univ Calif San Diego, Moores UCSD Canc Ctr, 3855 Hlth Sci Dr,0901, La Jolla, CA 92109 USA. EM a1villasenor@ucsd.edu FU National Cancer Institute [NO1-CN-75036-20, NO1-CN-05228, NO1-PC-67010, U54-CA116847, R25-CA094880]; National Institutes of Health [MO1-RR-0037]; University of New Mexico; NCRR [MO1-RR-0997]; National Institute of Child Health and Human Development [N01-HD-3-3175]; California Department of Health Services [050Q-8709-S1528] FX The authors would like to thank the HEAL participants for their ongoing dedication to this study. This study was supported through National Cancer Institute contracts NO1-CN-75036-20, NO1-CN-05228, NO1-PC-67010, U54-CA116847 and training grant R25-CA094880. A portion of this work was conducted through support by the National Institutes of Health grant MO1-RR-0037, and University of New Mexico grant, NCRR MO1-RR-0997. Data collection for the Women's CARE Study at the University of Southern California was supported by contract N01-HD-3-3175 from the National Institute of Child Health and Human Development and patient identification was supported in part by contract 050Q-8709-S1528 from the California Department of Health Services. NR 43 TC 19 Z9 19 U1 1 U2 23 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 759 EP 767 DI 10.1007/s10552-013-0158-4 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900014 PM 23361338 ER PT J AU Amalou, H Wood, BJ AF Amalou, Hayet Wood, Bradford J. TI Intratumoral Gene Therapy Injections with a Multipronged, Multi-Side Hole Needle for Rectal Carcinoma SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 [Amalou, Hayet; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, MSC 182, Bethesda, MD 20892 USA. EM bwood@nih.gov FU Intramural NIH HHS [ZIA CL040011-04] NR 3 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD APR PY 2013 VL 36 IS 2 BP 561 EP 562 DI 10.1007/s00270-012-0396-y PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 107GB UT WOS:000316202000039 PM 22535244 ER PT J AU Amalou, H Wood, BJ AF Amalou, Hayet Wood, Bradford J. TI Hippocrates Predicted Renal Cryoablation Bleeding Risk in Patients Receiving Anticoagulation SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID RADIOFREQUENCY; COMPLICATIONS C1 [Amalou, Hayet; Wood, Bradford J.] NIH, Ctr Intervent Oncol Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), NIH, Ctr Intervent Oncol Radiol & Imaging Sci, MSC 1182,10 Ctr Dr, Bethesda, MD 20892 USA. EM bwood@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD APR PY 2013 VL 36 IS 2 BP 563 EP 564 DI 10.1007/s00270-012-0368-2 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 107GB UT WOS:000316202000040 PM 22414986 ER PT J AU Kouprina, N Earnshaw, WC Masumoto, H Larionov, V AF Kouprina, Natalay Earnshaw, William C. Masumoto, Hiroshi Larionov, Vladimir TI A new generation of human artificial chromosomes for functional genomics and gene therapy SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Human artificial chromosomes; HAC; Gene expression; Gene delivery vector ID TRANSFORMATION-ASSOCIATED RECOMBINATION; MICROCELL-MEDIATED TRANSFER; PLURIPOTENT STEM-CELLS; DE-NOVO CENTROMERES; HUMAN SOMATIC-CELLS; HUMAN Y-CHROMOSOME; TRANSGENE EXPRESSION; HAC VECTOR; CONDITIONAL CENTROMERE; LENTIVIRAL VECTOR AB Since their description in the late 1990s, human artificial chromosomes (HACs) carrying a functional kinetochore were considered as a promising system for gene delivery and expression with a potential to overcome many problems caused by the use of viral-based gene transfer systems. Indeed, HACs avoid the limited cloning capacity, lack of copy number control and insertional mutagenesis due to integration into host chromosomes that plague viral vectors. Nevertheless, until recently, HACs have not been widely recognized because of uncertainties of their structure and the absence of a unique gene acceptor site. The situation changed a few years ago after engineering of HACs with a single loxP gene adopter site and a defined structure. In this review, we summarize recent progress made in HAC technology and concentrate on details of two of the most advanced HACs, 21HAC generated by truncation of human chromosome 21 and alphoid(tetO)-HAC generated de novo using a synthetic tetO-alphoid DNA array. Multiple potential applications of the HAC vectors are discussed, specifically the unique features of two of the most advanced HAC cloning systems. C1 [Kouprina, Natalay; Larionov, Vladimir] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH8 9YL, Midlothian, Scotland. [Masumoto, Hiroshi] Kazusa DNA Res Inst, Kisarazu, Chiba, Japan. RP Kouprina, N (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov FU Intramural Research Program of the NIH NCI Center for Cancer Research; Ministry of Education, Science, Sports and Culture of Japan; Wellcome Trust [073915]; [077707]; [092076] FX This study was supported by the Intramural Research Program of the NIH NCI Center for Cancer Research (V. L.). This study was also supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan (H. M.) and by The Wellcome Trust, of which W. C. E. is a Principal Research Fellow (grant number 073915). The Wellcome Trust Centre for Cell Biology is supported by core grant numbers 077707 and 092076. NR 96 TC 28 Z9 28 U1 4 U2 47 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD APR PY 2013 VL 70 IS 7 BP 1135 EP 1148 DI 10.1007/s00018-012-1113-3 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 111BT UT WOS:000316493300001 PM 22907415 ER PT J AU Gerlitz, G Reiner, O Bustin, M AF Gerlitz, Gabi Reiner, Orly Bustin, Michael TI Microtubule dynamics alter the interphase nucleus SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE Microtubules; Nuclear envelope; Lamins; Chromatin; Dynein ID HUTCHINSON-GILFORD PROGERIA; ENVELOPE BREAKDOWN; LAMIN-A; CYTOPLASMIC DYNEIN; MEMBRANE PROTEIN; CELLS; ORGANIZATION; CHROMOSOMES; COMPLEXES; DYNACTIN AB Microtubules are known to drive chromosome movements and to induce nuclear envelope breakdown during mitosis and meiosis. Here we show that microtubules can enforce nuclear envelope folding and alter the levels of nuclear envelope-associated heterochromatin during interphase, when the nuclear envelope is intact. Microtubule reassembly, after chemically induced depolymerization led to folding of the nuclear envelope and to a transient accumulation of condensed chromatin at the site nearest the microtubule organizing center (MTOC). This microtubule-dependent chromatin accumulation next to the MTOC is dependent on the composition of the nuclear lamina and the activity of the dynein motor protein. We suggest that forces originating from simultaneous polymerization of microtubule fibers deform the nuclear membrane and the underlying lamina. Whereas dynein motor complexes localized to the nuclear envelope that slide along the microtubules transfer forces and/or signals into the nucleus to induce chromatin reorganization and accumulation at the nuclear membrane folds. Thus, our study identified a molecular mechanism by which mechanical forces generated in the cytoplasm reshape the nuclear envelope, alter the intranuclear organization of chromatin, and affect the architecture of the interphase nucleus. C1 [Gerlitz, Gabi; Bustin, Michael] NCI, Prot Sect, Lab Metab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Gerlitz, Gabi; Reiner, Orly] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Gerlitz, Gabi] Ariel Univ Ctr Samaria, Dept Mol Biol, IL-44837 Ariel, Israel. RP Gerlitz, G (reprint author), Ariel Univ Ctr Samaria, Dept Mol Biol, IL-44837 Ariel, Israel. EM gabi.gerlitz@gmail.com RI Reiner, Orly/E-9455-2010; Bustin, Michael/G-6155-2015 OI Reiner, Orly/0000-0001-7560-9599; FU National Institutes of Health, Center for Cancer Research, National Cancer Institute FX We thank Trina A. Schroer (Department of Biology, Johns Hopkins University, Baltimore, MD, USA), Michael W. Davidson (National High Magnetic Field Laboratory and Department of Biological Science, Florida State University, Tallahassee, FL, USA) and Tom Misteli (NCI, NIH, MD, USA) for providing the plasmids, Valarie A. Barr (LCMB, NCI, NIH) for help with the confocal microscopy, and Kunio Nagashima and Christina M. Burks (Electron Microscope Laboratory, Advanced Technology Program, SAIC-Frederick, Inc. NCI, NIH, Frederick, MD, USA) for help with the TEM analysis. This work was supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. NR 52 TC 12 Z9 12 U1 0 U2 24 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD APR PY 2013 VL 70 IS 7 BP 1255 EP 1268 DI 10.1007/s00018-012-1200-5 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 111BT UT WOS:000316493300008 PM 23117601 ER PT J AU Harel, A Kravitz, DJ Baker, CI AF Harel, Assaf Kravitz, Dwight J. Baker, Chris I. TI Deconstructing Visual Scenes in Cortex: Gradients of Object and Spatial Layout Information SO CEREBRAL CORTEX LA English DT Article DE fMRI; LOC; PPA; RSC; scene recognition ID PARAHIPPOCAMPAL PLACE AREA; LATERAL OCCIPITAL COMPLEX; HUMAN OCCIPITOTEMPORAL CORTEX; MONKEY RETROSPLENIAL CORTEX; CONTEXTUAL ASSOCIATIONS; CORTICAL AFFERENTS; TEMPORAL CORTEX; HUMAN BRAIN; RECOGNITION; REPRESENTATIONS AB Real-world visual scenes are complex cluttered, and heterogeneous stimuli engaging scene- and object-selective cortical regions including parahippocampal place area (PPA), retrosplenial complex (RSC), and lateral occipital complex (LOC). To understand the unique contribution of each region to distributed scene representations, we generated predictions based on a neuroanatomical framework adapted from monkey and tested them using minimal scenes in which we independently manipulated both spatial layout (open, closed, and gradient) and object content (furniture, e.g., bed, dresser). Commensurate with its strong connectivity with posterior parietal cortex, RSC evidenced strong spatial layout information but no object information, and its response was not even modulated by object presence. In contrast, LOC, which lies within the ventral visual pathway, contained strong object information but no background information. Finally, PPA, which is connected with both the dorsal and the ventral visual pathway, showed information about both objects and spatial backgrounds and was sensitive to the presence or absence of either. These results suggest that 1) LOC, PPA, and RSC have distinct representations, emphasizing different aspects of scenes, 2) the specific representations in each region are predictable from their patterns of connectivity, and 3) PPA combines both spatial layout and object information as predicted by connectivity. C1 [Harel, Assaf; Kravitz, Dwight J.; Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Harel, A (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM assaf.harel@nih.gov OI Baker, Chris/0000-0001-6861-8964; Harel, Assaf/0000-0002-4899-6156 FU National Institute of Mental Health FX National Institute of Mental Health Intramural Research Program. NR 60 TC 41 Z9 44 U1 3 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2013 VL 23 IS 4 BP 947 EP 957 DI 10.1093/cercor/bhs091 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 108EY UT WOS:000316275800019 PM 22473894 ER PT J AU Haring, R Teng, ZY Xanthakis, V Coviello, A Sullivan, L Bhasin, S Murabito, JM Wallaschofski, H Vasan, RS AF Haring, Robin Teng, Zhaoyang Xanthakis, Vanessa Coviello, Andrea Sullivan, Lisa Bhasin, Shalender Murabito, Joanne M. Wallaschofski, Henri Vasan, Ramachandran S. TI Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all-cause mortality in elderly men from the Framingham Heart Study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID LOW SERUM TESTOSTERONE; HORMONE-BINDING GLOBULIN; POPULATION-BASED COHORT; ENDOGENOUS TESTOSTERONE; METABOLIC SYNDROME; PREDICT MORTALITY; ESTRADIOL LEVELS; OLDER MEN; HEALTH; RISK AB Background Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date. Methods We prospectively evaluated 254 elderly men (mean age, 75 center dot 5years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5- and 10-year follow-up. Results We observed no association between baseline concentrations of sex steroids, gonadotrophins and their trajectories with incident clinical CVD over 5- and 10-year follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5years (hazard ratio per quartile increment, 0 center dot 74; 95% confidence interval, 0 center dot 560 center dot 98), correction for multiple statistical testing (P<0 center dot 005) rendered this association statistically nonsignificant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotrophins or their trajectories and mortality. Conclusion Investigating longitudinal trajectory patterns of serial sex steroid and gonadotrophin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men from the community. C1 [Haring, Robin; Xanthakis, Vanessa; Coviello, Andrea; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. [Haring, Robin; Wallaschofski, Henri] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Teng, Zhaoyang; Xanthakis, Vanessa; Sullivan, Lisa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Xanthakis, Vanessa; Murabito, Joanne M.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Coviello, Andrea; Bhasin, Shalender] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Haring, R (reprint author), Univ Med Greifswald, Inst Clin Chem & Lab Med, Ferdinand Sauerbruch Str, D-17475 Greifswald, Germany. EM robin.haring@uni-greifswald.de OI Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI [NO1-HC25195] FX The present study was supported in part by contract NO1-HC25195 from the NHLBI. NR 24 TC 36 Z9 37 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD APR PY 2013 VL 78 IS 4 BP 629 EP 634 DI 10.1111/cen.12013 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 107PC UT WOS:000316229400023 PM 22901104 ER PT J AU McMahon, DK Zheng, L Hitti, J Chan, ES Halvas, EK Hong, FY Kabanda, J Taulo, F Kumarasamy, N Bonhomme, J Wallis, CL Klingman, KL Hughes, MD Mellors, JW AF McMahon, Deborah K. Zheng, Lu Hitti, Jane Chan, Ellen S. Halvas, Elias K. Hong, Feiyu Kabanda, Joseph Taulo, Frank Kumarasamy, Nagalingeswaran Bonhomme, Jerry Wallis, Carole L. Klingman, Karin L. Hughes, Michael D. Mellors, John W. TI Greater Suppression of Nevirapine Resistance With 21-vs 7-Day Antiretroviral Regimens After Intrapartum Single-Dose Nevirapine for Prevention of Mother-to-Child Transmission of HIV SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE nevirapine; mother-to-child transmission; pregnancy; resistance; HIV ID PREGNANT-WOMEN; SUBTYPE-C; MUTATIONS; HIVNET-012; EMERGENCE; VARIANTS; THERAPY; PLASMA AB Background. Nevirapine (NVP) resistance emerges in up to 70% of women exposed to single-dose (sd) NVP for prevention of mother-to-child transmission of human immunodeficiency virus (HIV). Methods. HIV-infected pregnant women were randomized to receive sdNVP and either zidovudine/lamivudine (3TC), tenofovir/emtricitabine (FTC), or lopinavir/ritonavir for either 7 or 21 days. The primary endpoint was the emergence of new NVP resistance mutations as detected by standard population genotype at 2 and 6 weeks after treatment. Low-frequency NVP- or 3TC/FTC-resistant mutants at codons 103, 181, and 184 were sought using allele-specific polymerase chain reaction (ASP). Results. Among 484 women randomized, 422 (87%) received study treatment. Four hundred twelve (98%) women had primary endpoint results available; of these, 5 (1.2%) had new NVP resistance detected by population genotype: 4 of 215 in the 7-day arms (1.9%; K103N in 4 women with Y181C, Y188C, or G190A in 3 of 4) and 1 of 197 (0.5%; V108I) in the 21-day arms (P = .37). Among women with ASP results, new NVP resistance mutations emerged significantly more often in the 7-day arms (13/74 [18%]) than in the 21-day arms (3/66 [5%], P = .019). 3TC/FTC-resistant mutants (M184V/I) emerged infrequently (7/134 [5%]), and their occurrence did not differ by arm. Conclusions. Three short-term antiretroviral strategies, begun simultaneously with the administration of sdNVP, resulted in a low rate (1.2%) of new NVP-resistance mutations when assessed at 2 and 6 weeks following completion of study treatment by standard genotype. ASP revealed that 21-day regimens were significantly better than 7-day regimens at preventing the emergence of minor NVP resistance variants. Clinical Trials Registration. NCT00099632. C1 [McMahon, Deborah K.; Halvas, Elias K.; Hong, Feiyu; Mellors, John W.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Zheng, Lu; Chan, Ellen S.; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hitti, Jane] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Kabanda, Joseph] Joint Clin Res Ctr, Kampala, Uganda. [Taulo, Frank] Univ Malawi, Obstet & Gynecol Dept, Blantyre, Malawi. [Kumarasamy, Nagalingeswaran] YRGCARE Med Ctr, Madras, Tamil Nadu, India. [Bonhomme, Jerry] Ctr GHESKIO, Port Au Prince, Haiti. [Wallis, Carole L.] Univ Witwatersrand, Johannesburg, South Africa. [Klingman, Karin L.] NIH, Div AIDS, Bethesda, MD 20892 USA. RP McMahon, DK (reprint author), Univ Pittsburgh, 3520 5th Ave,Keystone Bldg,Ste 510, Pittsburgh, PA 15213 USA. EM mcmahond@pitt.edu FU AIDS Clinical Trials Group; US National Institute of Allergy and Infectious Diseases, National Institutes of Health (ACTG network leadership grant) [1U01AI068636-01]; US National Institute of Allergy and Infectious Diseases, National Institutes of Health (ACTG statistical and data analysis center grant) [1U01AI068634-01]; National Institute of Allergy and Infectious Diseases (University of Pittsburgh clinical trials unit grant) [1U01 AI069494-01]; Virology Support Laboratory of the AIDS Clinical Trials Group Central Group [204VC009, 1 U01A10 68636-01] FX The study was supported by the AIDS Clinical Trials Group funded by the US National Institute of Allergy and Infectious Diseases, National Institutes of Health (ACTG network leadership grant 1U01AI068636-01; ACTG statistical and data analysis center grant 1U01AI068634-01); the National Institute of Allergy and Infectious Diseases (University of Pittsburgh clinical trials unit grant 1U01 AI069494-01); and the Virology Support Laboratory Subcontract 204VC009 of the AIDS Clinical Trials Group Central Group (grant 1 U01A10 68636-01). NR 16 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2013 VL 56 IS 7 BP 1044 EP 1051 DI 10.1093/cid/cis1219 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 106TG UT WOS:000316167000021 PM 23300238 ER PT J AU Raju, TNK AF Raju, Tonse N. K. TI Timing of umbilical cord clamping after birth for optimizing placental transfusion SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE anemia; intracranial hemorrhage; iron-deficiency anemia; necrotizing enterocolitis; neonatal jaundice; preterm; sepsis; serum ferritin; umbilical cord clamping ID RANDOMIZED CONTROLLED-TRIAL; 29 WEEKS GESTATION; INFANTS BORN; TERM INFANTS; CEREBRAL OXYGENATION; IRON STATUS; BLOOD-FLOW; MILKING; OBSTETRICIANS; CONSENSUS AB Purpose of review A brief delay in clamping the umbilical cord after birth offers health benefits to the newborn, with no adverse effects to the mother or her infant. Yet, in most obstetric practice, the cord is clamped soon after birth. A summary of the current evidence on delayed cord clamping and some reasons for the disconnect between the evidence and practice are discussed here, along with the recommendations from professional organizations and societies about this practice. Recent findings In term infants, umbilical cord clamping between 30 and 180 s after birth results in higher concentrations of hemoglobin and hematocrit during the neonatal period, and increased serum ferritin levels and a lower incidence of iron-deficiency anemia at 4-6 months of age. These are important benefits for children in low and middle income countries where iron-deficiency anemia is highly prevalent. In preterm infants, delayed cord clamping for at least 30 s increases the concentrations of hemoglobin and hematocrit, improves mean systemic blood pressure, urine output, and cardiac function, and decreases the need for vasopressors and blood transfusions during the neonatal period. It also decreases the prevalence of necrotizing enterocolitis, sepsis, and intraventricular hemorrhage (all grades). Milking of the unclamped umbilical cord toward the infant soon after birth also has similar beneficial effects. In some studies, more infants in the delayed cord clamping groups required phototherapy for jaundice. Summary Many professional organizations, societies, and experts recommend at least a 30-s delay before clamping the umbilical cord, especially after preterm births. The value of this practice for term births in resource-rich settings has not been evaluated. C1 [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Raju, TNK (reprint author), 6100 Execut Blvd,4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 35 TC 28 Z9 33 U1 2 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2013 VL 25 IS 2 BP 180 EP 187 DI 10.1097/MOP.0b013e32835d2a9e PG 8 WC Pediatrics SC Pediatrics GA 105YV UT WOS:000316109500005 PM 23407180 ER PT J AU Bharti, K AF Bharti, K. TI DEVELOPING CELL-BASED THERAPY FOR MACULAR DEGENERATION USING IPS CELL DERIVED RPE TISSUE ON BIODEGRADABLE SCAFFOLDS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Bharti, K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 31 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 53 BP S19 EP S19 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700054 ER PT J AU Cruz, CR Micklethwaite, KP Savoldo, B Lam, S Ku, S Krance, RA Dioufouf, O Leen, AM Kamble, RT Kennedy-Nasser, A Barrett, J Shpall, E Heslop, HE Rooney, CM Brenner, MK Bollard, CM Dotti, G AF Cruz, C. R. Micklethwaite, K. P. Savoldo, B. Lam, S. Ku, S. Krance, R. A. Dioufouf, O. Leen, A. M. Kamble, R. T. Kennedy-Nasser, A. Barrett, J. Shpall, E. Heslop, H. E. Rooney, C. M. Brenner, M. K. Bollard, C. M. Dotti, G. TI INFUSION OF CD19-DIRECTED/MULTIVIRUS SPECIFIC-CYTOTOXIC T LYMPHOCYTES AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR B CELL MALIGNANCIES SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Cruz, C. R.; Micklethwaite, K. P.; Savoldo, B.; Lam, S.; Ku, S.; Krance, R. A.; Dioufouf, O.; Leen, A. M.; Kamble, R. T.; Kennedy-Nasser, A.; Heslop, H. E.; Rooney, C. M.; Brenner, M. K.; Bollard, C. M.; Dotti, G.] Baylor Coll Med, Houston, TX 77030 USA. [Barrett, J.] NIH, Bethesda, MD 20892 USA. [Shpall, E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 10 BP S7 EP S7 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700011 ER PT J AU Frank, JA Tebebi, P Venkatash, P Chetta, J Burks, S AF Frank, J. A. Tebebi, P. Venkatash, P. Chetta, J. Burks, S. TI ENHANCING HOMING PERMEABILITY AND RETENTIONS OF STEM CELLS (SC) TO TARGETED TISSUES NONINVASIVELY BY PULSE FOCUSED ULTRASOUND (PFUS): POTENTIAL APPLICATION IN REGENERATIVE MEDICINE SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Frank, J. A.; Tebebi, P.; Venkatash, P.; Chetta, J.; Burks, S.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 23 BP S10 EP S11 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700024 ER PT J AU Hanley, PJ Cruz, RY Melenhorst, J Scheinberg, P Blaney, J Savoldo, B Dotti, G Heslop, H Rooney, C Shpall, EJ Barrett, JA Rodgers, J Bollard, CM AF Hanley, P. J. Cruz, R. Y. Melenhorst, J. Scheinberg, P. Blaney, J. Savoldo, B. Dotti, G. Heslop, H. Rooney, C. Shpall, E. J. Barrett, J. A. Rodgers, J. Bollard, C. M. TI NAIVE T-CELL-DERIVED CTL RECOGNIZE ATYPICAL EPITOPES OF CMVPP65 WITH HIGHER AVIDITY THAN CMV-SEROPOSITIVE DONOR-DERIVED CTL - A BASIS FOR TREATMENT OF POST-TRANSPLANT VIRAL INFECTION BY ADOPTIVE TRANSFER OF T-CELLS FROM VIRUS-NAIVE DONORS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Hanley, P. J.; Cruz, R. Y.; Blaney, J.; Savoldo, B.; Dotti, G.; Heslop, H.; Rooney, C.; Rodgers, J.; Bollard, C. M.] Baylor Coll Med, Houston, TX 77030 USA. [Melenhorst, J.; Scheinberg, P.] NHLBI, NIH, Washington Dc, DC USA. [Shpall, E. J.] MD Anderson, Houston, TX USA. [Barrett, J. A.] NIH, Washington Dc, DC USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 18 BP S9 EP S9 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700019 ER PT J AU Ku, S Kennedy-Nasser, AA Hazrat, Y Melenhorst, J Barrett, A Ito, S Durett, AG Foster, A Savoldo, B Yvon, E Heslop, HE Carrum, G Kamble, RT Brenner, MK Krance, RA Bollard, CM AF Ku, S. Kennedy-Nasser, A. A. Hazrat, Y. Melenhorst, J. Barrett, A. Ito, S. Durett, A. G. Foster, A. Savoldo, B. Yvon, E. Heslop, H. E. Carrum, G. Kamble, R. T. Brenner, M. K. Krance, R. A. Bollard, C. M. TI ULTRA LOW-DOSE IL-2 MEDIATED EXPANSION OF REGULATORY T CELLS AS GVHD PROPHYLAXIS FOR RECIPIENTS OF ALLOGENEIC HEMATOPOIETIC STEM CELLS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Ku, S.; Kennedy-Nasser, A. A.; Hazrat, Y.; Durett, A. G.; Savoldo, B.; Heslop, H. E.; Carrum, G.; Kamble, R. T.; Brenner, M. K.; Krance, R. A.; Bollard, C. M.] Baylor Coll Med, Houston, TX 77030 USA. [Melenhorst, J.] Univ Penn, Philadelphia, PA 19104 USA. [Barrett, A.; Ito, S.] NIH, Bethesda, MD 20892 USA. [Foster, A.] Bellicum Pharmaceut, Houston, TX USA. [Yvon, E.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 140 BP S41 EP S42 PG 2 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700138 ER PT J AU Nam, J Onitsuka, I Hatch, J Uchida, Y Ray, S Huang, SY Li, WL Zang, H Ruiz-Lozano, P Mukouyama, YS AF Nam, Joseph Onitsuka, Izumi Hatch, John Uchida, Yutaka Ray, Saugata Huang, Siyi Li, Wenling Zang, Heesuk Ruiz-Lozano, Pilar Mukouyama, Yoh-suke TI Coronary veins determine the pattern of sympathetic innervation in the developing heart SO DEVELOPMENT LA English DT Article DE NGF; Cardiac innervation; Coronary development; Sympathetic axons; Vascular smooth muscle ID NERVE GROWTH-FACTOR; VASCULAR DEVELOPMENT; SMOOTH-MUSCLE; NEURONS; CELLS; MICE; GUIDANCE; NGF; DIFFERENTIATION; EPHRIN-B2 AB Anatomical congruence of peripheral nerves and blood vessels is well recognized in a variety of tissues. Their physical proximity and similar branching patterns suggest that the development of these networks might be a coordinated process. Here we show that large diameter coronary veins serve as an intermediate template for distal sympathetic axon extension in the subepicardial layer of the dorsal ventricular wall of the developing mouse heart. Vascular smooth muscle cells (VSMCs) associate with large diameter veins during angiogenesis. In vivo and in vitro experiments demonstrate that these cells mediate extension of sympathetic axons via nerve growth factor (NGF). This association enables topological targeting of axons to final targets such as large diameter coronary arteries in the deeper myocardial layer. As axons extend along veins, arterial VSMCs begin to secrete NGF, which allows axons to reach target cells. We propose a sequential mechanism in which initial axon extension in the subepicardium is governed by transient NGF expression by VSMCs as they are recruited to coronary veins; subsequently, VSMCs in the myocardium begin to express NGF as they are recruited by remodeling arteries, attracting axons toward their final targets. The proposed mechanism underlies a distinct, stereotypical pattern of autonomic innervation that is adapted to the complex tissue structure and physiology of the heart. C1 [Nam, Joseph; Onitsuka, Izumi; Hatch, John; Uchida, Yutaka; Li, Wenling; Zang, Heesuk; Mukouyama, Yoh-suke] NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. [Ray, Saugata; Ruiz-Lozano, Pilar] Sanford Burnham Med Res Inst, Dev & Aging Program, La Jolla, CA 92037 USA. [Huang, Siyi] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ruiz-Lozano, Pilar] Stanford Univ, Sch Med, Palo Alto, CA 94305 USA. RP Mukouyama, YS (reprint author), NHLBI, Lab Stem Cell & Neurovasc Biol, Genet & Dev Biol Ctr, NIH, Bldg 10-6C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukoyamay@mail.nih.gov FU National Heart, Lung and Blood Institute, National Institutes of Health (NIH) [HL006116]; NIH [HL065484, HL086879] FX This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute, National Institutes of Health (NIH) [HL006116 to Y.-s.M.] and was also supported by NIH grants [HL065484 and HL086879 to P.R.-L.]. Deposited in PMC for release after 12 months. NR 33 TC 22 Z9 22 U1 1 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD APR 1 PY 2013 VL 140 IS 7 BP 1475 EP 1485 DI 10.1242/dev.087601 PG 11 WC Developmental Biology SC Developmental Biology GA 105TU UT WOS:000316096400011 PM 23462468 ER PT J AU Driver, EC Sillers, L Coate, TM Rose, MF Kelley, MW AF Driver, Elizabeth Carroll Sillers, Laura Coate, Thomas M. Rose, Matthew F. Kelley, Matthew W. TI The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Inner ear; Development; Cell fate; Organ of Corti ID DEVELOPING NERVOUS-SYSTEM; EAR SENSORY EPITHELIA; MOUSE INNER-EAR; REGULATES DEVELOPMENT; DOWN-REGULATION; NOTCH LIGANDS; NULL MICE; MATH1; EXPRESSION; ORGAN AB The organ of Corti, located within the mammalian cochlea, contains a precise mosaic of hair cells (HC) and supporting cells (SC), the patterning of which is critical for auditory function. Progenitors of HCs and SCs are found in the same post-mitotic region of the cochlear duct during early stages of cochlear development, and both HCs and SCs are absent in mice lacking the transcription factor Atoh1. Based on existing data, Atoh1 is thought to be the earliest determinant of HC fate, and to have a cell-autonomous role in HC differentiation, but the lineage of Atoh1-positive cells within the cochlear duct remains unclear. To address this issue, we used an inducible Atoh1(Cre)*(PR) allele to permanently mark Atoh1-expressing cells at different developmental time points. We found that up to 30% of cells from the Atoh1-lineage develop as SCs, and that the number of Atoh1-positive SCs decreases both spatially and temporally in a pattern consistent with ongoing commitment. Modulation of Notch signaling, necessary for formation of the HC-SC mosaic, changes the percentage of cells from the Atoh1-lineage that develop as either HCs or SCs. The HC-SC ratio is also affected by morphogenesis of the cochlea, as inhibiting the outgrowth of the cochlear duct increases the number of Atoh1-lineage cells that develop as SCs. Our results demonstrate that the Atoh1-lineage is established early in cochlear development, but also show that expression of Atoh1 does not absolutely result in commitment to a HC fate. Published by Elsevier Inc. C1 [Driver, Elizabeth Carroll; Sillers, Laura; Coate, Thomas M.; Kelley, Matthew W.] NIDCD, Lab Cochlear Dev, NIH, Bethesda, MD 20892 USA. [Rose, Matthew F.] Baylor Coll Med, Program Dev Biol, Houston, TX 77030 USA. RP Driver, EC (reprint author), NIDCD, Lab Cochlear Dev, NIH, Bldg 35,Room 2A-205, Bethesda, MD 20892 USA. EM drivere@nidcd.nih.gov; coatet@nidcd.nih.gov; kelleymt@nidcd.nih.gov OI Rose, Matthew/0000-0002-1148-4130; Driver, Elizabeth/0000-0002-5618-1053 FU Howard Hughes Medical Institute; Intramural Research Program at the National Institute on Deafness and Other Communication Disorders FX We thank H. Zoghbi for sharing reagents prior to publication, T. Okano for help with statistical analysis, and S. Raft, S. Maricich, and M. Kelly for critical comments on the manuscript. This work was supported by The Howard Hughes Medical Institute (M.F.R.), and the Intramural Research Program at the National Institute on Deafness and Other Communication Disorders. NR 51 TC 35 Z9 35 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD APR 1 PY 2013 VL 376 IS 1 BP 86 EP 98 DI 10.1016/j.ydbio.2013.01.005 PG 13 WC Developmental Biology SC Developmental Biology GA 106QA UT WOS:000316158600009 PM 23318633 ER PT J AU Bar-Haim, Y Pine, DS AF Bar-Haim, Yair Pine, Daniel S. TI Cognitive training research and the search for a transformative, translational, developmental cognitive neuroscience SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Editorial Material C1 [Bar-Haim, Yair] Tel Aviv Univ, Tel Aviv, Israel. [Pine, Daniel S.] NIMH, Bethesda, MD 20892 USA. RP Bar-Haim, Y (reprint author), Tel Aviv Univ, Tel Aviv, Israel. EM yair1@post.tau.ac.il FU Intramural NIH HHS [Z99 MH999999] NR 1 TC 5 Z9 5 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD APR PY 2013 VL 4 SI SI BP 1 EP 2 DI 10.1016/j.dcn.2013.02.001 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 113FJ UT WOS:000316651600001 PM 23485515 ER PT J AU Britton, JC Bar-Haim, Y Clementi, MA Sankin, LS Chen, G Shechner, T Norcross, MA Spiro, CN Lindstrom, KM Pine, DS AF Britton, Jennifer C. Bar-Haim, Yair Clementi, Michelle A. Sankin, Lindsey S. Chen, Gang Shechner, Tomer Norcross, Maxine A. Spiro, Carolyn N. Lindstrom, Kara M. Pine, Daniel S. TI Training-associated changes and stability of attention bias in youth: Implications for Attention Bias Modification Treatment for pediatric anxiety SO DEVELOPMENTAL COGNITIVE NEUROSCIENCE LA English DT Article DE Dot-probe; Attention training; Test-retest reliability; fMRI ID TEST-RETEST RELIABILITY; PREFRONTAL CORTEX ACTIVATION; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; ANGRY FACES; SELECTIVE ATTENTION; SOCIAL ANXIETY; CLINICAL-TRIAL; DISORDERS; THREAT AB Attention Bias Modification Treatment (ABMT), an emerging treatment for anxiety disorders, is thought to modify underlying, stable patterns of attention. Therefore, ABMT research should take into account the impact of attention bias stability on attention training response, especially in pediatric populations. ABMT research typically relies on the dot-probe task, where individuals detect a probe following an emotional-neutral stimulus pair. The current research presents two dot-probe experiments relevant to ABMT and attention-bias stability. In Experiment 1, anxious youth receiving 8-weeks of cognitive-behavioral therapy (CBT) were randomly assigned to ABMT that trains attention towards happy faces (n = 18) or placebo (n = 18). Two additional comparison groups, anxious youth receiving only CBT (n = 17) and healthy comparison youth (n = 16), were studied. Active attention training towards happy faces did not augment clinician-rated response to CBT; however, individuals receiving training exhibited reductions on self-report measures of anxiety earlier than individuals receiving CBT only. In Experiment 2, healthy youth (n = 12) completed a dot-probe task twice while undergoing functional magnetic resonance imaging. Intra-class correlation demonstrated stability of neural activation in response to attention bias in the ventrolateral prefrontal cortex and amygdala. Together, these two studies investigate the ways in which attention-bias stability may impact future work on ABMT. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Britton, Jennifer C.; Clementi, Michelle A.; Sankin, Lindsey S.; Shechner, Tomer; Norcross, Maxine A.; Spiro, Carolyn N.; Lindstrom, Kara M.; Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. [Bar-Haim, Yair] Tel Aviv Univ, Sch Psychol Sci, IL-69978 Tel Aviv, Israel. [Chen, Gang] NIMH, Sci & Stat Comp Core, Bethesda, MD 20814 USA. RP Britton, JC (reprint author), Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. EM j.britton@miami.edu; yair1@post.tau.ac.il; mclementi@uh.edu; LindseySankin2016@u.northwestern.edu; gangchen@mail.nih.gov; shechnert@mail.nih.gov; norcrossm@gmail.com; spirocn@mail.nih.gov; karalindstrom@gmail.com; pined@mail.nih.gov RI Britton, Jennifer/J-4501-2013 FU National Institute of Mental Health (NIMH), National Institutes of Health; National Alliance of Research on Schizophrenia and Depression (NARSAD) FX This research was supported in part by the Intramural Research Program of the National Institute of Mental Health (NIMH), National Institutes of Health and the National Alliance of Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (JCB). A version of these findings was presented at the Anxiety Disorders Association of America annual conference in April 2012. The imaging data partially overlap with data presented in Thomason et al. (2010). We thank the clinicians in the Section on Development and Affective Neuroscience Program at the NIMH for their assistance. NR 50 TC 38 Z9 39 U1 4 U2 42 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1878-9293 J9 DEV COGN NEUROS-NETH JI Dev. Cogn. Neurosci. PD APR PY 2013 VL 4 SI SI BP 52 EP 64 DI 10.1016/j.dcn.2012.11.001 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 113FJ UT WOS:000316651600006 PM 23200784 ER EF