FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Loos, RJF Lindgren, CM Li, SX Wheeler, E Zhao, JH Prokopenko, I Inouye, M Freathy, RM Attwood, AP Beckmann, JS Berndt, SI Bergmann, S Bennett, AJ Bingham, SA Bochud, M Brown, M Cauchi, S Connell, JM Cooper, C Smith, GD Day, I Dina, C De, S Dermitzakis, ET Doney, ASF Elliott, KS Elliott, P Evans, DM Farooqi, IS Froguel, P Ghori, J Groves, CJ Gwilliam, R Hadley, D Hall, AS Hattersley, AT Hebebrand, J Heid, IM Herrera, B Hinney, A Hunt, SE Jarvelin, MR Johnson, T Jolley, JDM Karpe, F Keniry, A Khaw, KT Luben, RN Mangino, M Marchini, J McArdle, WL McGinnis, R Meyre, D Munroe, PB Morris, AD Ness, AR Neville, MJ Nica, AC Ong, KK O'Rahilly, S Owen, KR Palmer, CNA Papadakis, K Potter, S Pouta, A Qi, L Randall, JC Rayner, NW Ring, SM Sandhu, MS Scherag, A Sims, MA Song, K Soranzo, N Speliotes, EK Syddall, HE Teichmann, SA Timpson, NJ Tobias, JH Uda, M Vogel, CIG Wallace, C Waterworth, DM Weedon, MN Willer, CJ Wraight, VL Yuan, X Zeggini, E Hirschhorn, JN Strachan, DP Ouwehand, WH Caulfield, MJ Samani, NJ Frayling, TM Vollenweider, P Waeber, G Mooser, V Deloukas, P McCarthy, MI Wareham, NJ Barroso, I AF Loos, Ruth J. F. Lindgren, Cecilia M. Li, Shengxu Wheeler, Eleanor Zhao, Jing Hua Prokopenko, Inga Inouye, Michael Freathy, Rachel M. Attwood, Antony P. Beckmann, Jacques S. Berndt, Sonja I. Bergmann, Sven Bennett, Amanda J. Bingham, Sheila A. Bochud, Murielle Brown, Morris Cauchi, Stephane Connell, John M. Cooper, Cyrus Smith, George Davey Day, Ian Dina, Christian De, Subhajyoti Dermitzakis, Emmanouil T. Doney, Alex S. F. Elliott, Katherine S. Elliott, Paul Evans, David M. Farooqi, I. Sadaf Froguel, Philippe Ghori, Jilur Groves, Christopher J. Gwilliam, Rhian Hadley, David Hall, Alistair S. Hattersley, Andrew T. Hebebrand, Johannes Heid, Iris M. Herrera, Blanca Hinney, Anke Hunt, Sarah E. Jarvelin, Marjo-Riitta Johnson, Toby Jolley, Jennifer D. M. Karpe, Fredrik Keniry, Andrew Khaw, Kay-Tee Luben, Robert N. Mangino, Massimo Marchini, Jonathan McArdle, Wendy L. McGinnis, Ralph Meyre, David Munroe, Patricia B. Morris, Andrew D. Ness, Andrew R. Neville, Matthew J. Nica, Alexandra C. Ong, Ken K. O'Rahilly, Stephen Owen, Katharine R. Palmer, Colin N. A. Papadakis, Konstantinos Potter, Simon Pouta, Anneli Qi, Lu Randall, Joshua C. Rayner, Nigel W. Ring, Susan M. Sandhu, Manjinder S. Scherag, Andre Sims, Matthew A. Song, Kijoung Soranzo, Nicole Speliotes, Elizabeth K. Syddall, Holly E. Teichmann, Sarah A. Timpson, Nicholas J. Tobias, Jonathan H. Uda, Manuela Vogel, Carla I. Ganz Wallace, Chris Waterworth, Dawn M. Weedon, Michael N. Willer, Cristen J. Wraight, Vicki L. Yuan, Xin Zeggini, Eleftheria Hirschhorn, Joel N. Strachan, David P. Ouwehand, Willem H. Caulfield, Mark J. Samani, Nilesh J. Frayling, Timothy M. Vollenweider, Peter Waeber, Gerard Mooser, Vincent Deloukas, Panos McCarthy, Mark I. Wareham, Nicholas J. Barroso, Ines CA Prostate Lung Colorectal Ovarian KORA Nurses' Health Study Diabetes Genetics Initiative SardiNIA Study Wellcome Trust Case Control Consor FUSION TI Common variants near MC4R are associated with fat mass, weight and risk of obesity SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MELANOCORTIN-4 RECEPTOR GENE; EARLY-ONSET OBESITY; FRAMESHIFT MUTATION; ADULT OBESITY; FTO GENE; EXPRESSION; DEFICIENCY; CHILDHOOD; DOMINANT AB To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits. C1 [Lindgren, Cecilia M.; Prokopenko, Inga; Bennett, Amanda J.; Elliott, Katherine S.; Evans, David M.; Groves, Christopher J.; Herrera, Blanca; Randall, Joshua C.; Rayner, Nigel W.; Timpson, Nicholas J.; Zeggini, Eleftheria; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Loos, Ruth J. F.; Li, Shengxu; Zhao, Jing Hua; Sandhu, Manjinder S.; Sims, Matthew A.; Wareham, Nicholas J.] Addenbrookes Hosp, MRC, Epidemiol Unit, Cambridge CB2 0QQ, England. [Loos, Ruth J. F.; Li, Shengxu; Zhao, Jing Hua; Farooqi, I. Sadaf; Ong, Ken K.; O'Rahilly, Stephen; Sims, Matthew A.; Wraight, Vicki L.; Wareham, Nicholas J.] Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 0QQ, England. [Lindgren, Cecilia M.; Prokopenko, Inga; Bennett, Amanda J.; Groves, Christopher J.; Herrera, Blanca; Karpe, Fredrik; Neville, Matthew J.; Owen, Katharine R.; Randall, Joshua C.; Rayner, Nigel W.; McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Wheeler, Eleanor; Inouye, Michael; Attwood, Antony P.; Dermitzakis, Emmanouil T.; Ghori, Jilur; Gwilliam, Rhian; Hunt, Sarah E.; Keniry, Andrew; McGinnis, Ralph; Nica, Alexandra C.; Potter, Simon; Soranzo, Nicole; Deloukas, Panos; Barroso, Ines] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Freathy, Rachel M.; Hattersley, Andrew T.; Weedon, Michael N.; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Freathy, Rachel M.; Hattersley, Andrew T.; Weedon, Michael N.; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Attwood, Antony P.; Jolley, Jennifer D. M.; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Attwood, Antony P.; Jolley, Jennifer D. M.; Ouwehand, Willem H.] Cambridge Ctr, NHS Blood & Transplant, Cambridge, England. [Beckmann, Jacques S.; Bergmann, Sven; Johnson, Toby] Univ Lausanne, Dept Med Genet, CH-1011 Lausanne, Switzerland. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Bergmann, Sven; Johnson, Toby] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Bingham, Sheila A.] MRC, Dunn Human Nutr Unit, Cambridge CB2 0XY, England. [Bochud, Murielle; Johnson, Toby] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland. [Brown, Morris] Univ Cambridge, Clin Pharmacol Unit, Addenbrookes Hosp, Cambridge, England. [Cauchi, Stephane; Dina, Christian; Froguel, Philippe; Meyre, David] Inst Pasteur, CNRS, Inst Biol 8090, F-5900 Lille, France. [Connell, John M.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Cooper, Cyrus; Day, Ian; Syddall, Holly E.] Univ Southampton, MRC, Epidemiol Resource Ctr, Southampton SO16 6YD, Hants, England. [Smith, George Davey; Evans, David M.; Timpson, Nicholas J.] Univ Bristol, MRC, Ctr Causal Analyses Translat Epidemiol, Bristol BS8 2PR, Avon, England. [De, Subhajyoti; Teichmann, Sarah A.] MRC, Mol Biol Lab, Cambridge CB2 2QH, England. [Doney, Alex S. F.; Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Diabet Res Grp, Div Med & Therapeut, Dundee DD1 9SY, Scotland. [Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Elliott, Paul] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, FIN-90014 Oulu, Finland. [Farooqi, I. Sadaf; O'Rahilly, Stephen; Wraight, Vicki L.] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London W12 0NN, England. [Hadley, David; Papadakis, Konstantinos; Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England. [Hall, Alistair S.] Univ Leeds, LIGHT Res Inst, Fac Med & Hlth, Leeds LS2 9JT, W Yorkshire, England. [Hebebrand, Johannes; Hinney, Anke; Vogel, Carla I. Ganz] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, D-45147 Essen, Germany. [Heid, Iris M.] GSF, Inst Epidemiol, D-85764 Neuherberg, Germany. [Heid, Iris M.] Univ Munich, IBE Chair Epidemiol, D-81377 Munich, Germany. [Jarvelin, Marjo-Riitta; Pouta, Anneli] Natl Publ Hlth Inst, Dept Child & Adolescent Hlth, Oulu 90221, Finland. [Khaw, Kay-Tee; Luben, Robert N.; Sandhu, Manjinder S.] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 2SR, England. [Mangino, Massimo; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester LE3 9QP, Leics, England. [Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [McArdle, Wendy L.; Ring, Susan M.] Univ Bristol, Dept Social Med, Bristol BS8 2PR, Avon, England. [Munroe, Patricia B.; Wallace, Chris; Caulfield, Mark J.] Barts & London Queen Marys Sch Med & Dent, Barts & London Genome Ctr, William Harvey Res Inst, London EC1M 6BQ, England. [Ness, Andrew R.] Univ Bristol, Dept Oral & Dent Sci, Bristol Dent Sch, Bristol BS1 2LY, Avon, England. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Populat Pharmacogenet Grp, Dundee DD1 9SY, Scotland. [Pouta, Anneli] Univ Hosp, Dept Obstet & Gynaecol, Oulu 90221, Finland. [Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Scherag, Andre] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, D-45122 Essen, Germany. [Song, Kijoung; Waterworth, Dawn M.; Yuan, Xin; Mooser, Vincent] Med Genet Clin Pharmacol & Discovery Med, King Of Prussia, PA 19406 USA. [Speliotes, Elizabeth K.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Speliotes, Elizabeth K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Speliotes, Elizabeth K.; Hirschhorn, Joel N.] MIT, Broad Inst, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Tobias, Jonathan H.] Univ Bristol, Bristol BS2 8AE, Avon, England. [Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, I-09100 Cagliari, Italy. [Willer, Cristen J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Vollenweider, Peter; Waeber, Gerard] CHU Vaudois, Dept Med & Internal Med, CH-1011 Lausanne, Switzerland. Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. GSF, Inst Human Genet, D-85764 Neuherberg, Germany. Tech Univ Munich, Inst Human Genet, D-81671 Munich, Germany. Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Diabet & Endocrinol Res Unit, S-20502 Malmo, Sweden. Univ Helsinki, Dept Med, Helsinki Univ Hosp, Helsinki 00029, Finland. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21244 USA. Natl Publ Hlth Inst, Diabet Unit, Dept Epidemiol & Hlth Promot, SF-00300 Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. S Ostrobothnia Cent Hosp, Seinajoki 60220, Finland. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. RP McCarthy, MI (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM mark.mccarthy@drl.ox.ac.uk; nick.wareham@mrc-epid.cam.ac.uk; ib1@sanger.ac.uk RI Colaus, PsyColaus/K-6607-2013; Ness, Andy/M-7612-2013; Tobias, Jon/E-2832-2014; Berryman, Katie/J-4236-2014; Dina, Christian/D-3535-2015; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Burton, Paul/H-7527-2016; Study, GoDARTS/K-9448-2016; mangino, massimo/F-5134-2011; Davey Smith, George/A-7407-2013; Dermitzakis, Emmanouil/B-7687-2013; HILL, Adrian/C-1306-2008; Genetic Epidemiology, Innsbruck Med.Univ./C-2095-2008; Evans, David/H-6325-2013; Palmer, Colin/C-7053-2008; Morris, Andrew/C-2837-2009; Abecasis, Goncalo/B-7840-2010; Bochud, Murielle/A-3981-2010; Meyre, David/D-7315-2011; Beckmann, Jacques S /A-9772-2008; Li, Shengxu/D-8915-2012; Hinney, Anke/D-6953-2011; Hadley, David/I-6902-2012; Deloukas, Panos/B-2922-2013 OI Zeggini, Eleftheria/0000-0003-4238-659X; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Monsalve, Beatriz Elena/0000-0002-5994-866X; Lango Allen, Hana/0000-0002-7803-8688; Hunt, Sarah/0000-0002-8350-1235; Brown, Matthew A/0000-0003-0538-8211; Abecasis, Goncalo/0000-0003-1509-1825; Wallace, Chris/0000-0001-9755-1703; Karpe, Fredrik/0000-0002-2751-1770; Eyre, Stephen/0000-0002-1251-6974; Evans, David/0000-0003-0663-4621; Timpson, Nicholas/0000-0002-7141-9189; Bergmann, Sven/0000-0002-6785-9034; Dunger, Professor David/0000-0002-2566-9304; Teichmann, Sarah/0000-0002-6294-6366; Luben, Robert/0000-0002-5088-6343; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Scherag, Andre/0000-0002-9406-4704; Hayes, Richard/0000-0002-0918-661X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Farooqi, Sadaf/0000-0001-7609-3504; Ness, Andy/0000-0003-3548-9523; Tobias, Jon/0000-0002-7475-3932; Dina, Christian/0000-0002-7722-7348; Prokopenko, Inga/0000-0003-1624-7457; mangino, massimo/0000-0002-2167-7470; Davey Smith, George/0000-0002-1407-8314; Freathy, Rachel/0000-0003-4152-2238; Willer, Cristen/0000-0001-5645-4966; Palmer, Colin/0000-0002-6415-6560; Bochud, Murielle/0000-0002-5727-0218; Beckmann, Jacques S /0000-0002-9741-1900; Hinney, Anke/0000-0001-5659-0706; Deloukas, Panos/0000-0001-9251-070X FU British Heart Foundation; Cancer Research UK; Department of Health [DHCS/07/07/008]; Medical Research Council [MC_U105630924, , G0000934, G0000934(68341), G0400874, G0401527, G0600331, G0600705, G0601261, G0701863, G9521010, G9521010(63660), G9824984, G9828345, MC_QA137934, MC_U105161047, MC_U106179472, MC_U106188470, MC_U147585824, MC_UP_A620_1014, U.1475.00.002.00001.01 (85824)]; NIDDK NIH HHS [F32 DK079466, F32 DK079466-01, K23 DK080145, K23 DK080145-01, P30 DK040561, P30 DK040561-13, R01 DK072193]; Wellcome Trust [, 068545, 076113, 077016, 079557, 084713, 090532] NR 30 TC 750 Z9 781 U1 16 U2 87 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 JUN PY 2008 VL 40 IS 6 BP 768 EP 775 DI 10.1038/ng.140 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 305XV UT WOS:000256212000019 PM 18454148 ER PT J AU Liu, YZ Zhang, P Li, J Kulkarni, AB Perruche, S Chen, WJ AF Liu, Yongzhong Zhang, Pin Li, Jun Kulkarni, Ashok B. Perruche, Sylvain Chen, WanJun TI A critical function for TGF-beta signaling in the development of natural CD4(+)CD25(+)Foxp3(+) regulatory T cells SO NATURE IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; NEONATAL-PERIOD; SELF-TOLERANCE; CUTTING EDGE; REG CELLS; IN-VITRO; INTERLEUKIN-2; MECHANISMS; MICE; AUTOIMMUNITY AB The molecular mechanisms directing the development of 'natural' CD4(+)CD25(+)Foxp3(+) regulatory T cells (T-reg cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-beta receptor I (T beta RI) in T cells blocked the appearance of CD4(+)CD25(+)Foxp3(+) thymocytes at postnatal days 3-5. Paradoxically, however, beginning 1 week after birth, the same T beta RI-mutant mice showed accelerated expansion of thymic CD4(+)CD25(+)Foxp3(+) populations. This rapid recovery of Foxp3(+) thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in T beta RI-mutant mice resulted in a complete absence of CD4(+)CD25(+)Foxp3(+) cells from the thymus and periphery. Thus, transforming growth factor-beta signaling is critical to the thymic development of natural CD4(+)CD25(+)Foxp3(+) T-reg cells. C1 [Liu, Yongzhong; Zhang, Pin; Li, Jun; Perruche, Sylvain; Chen, WanJun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Kulkarni, Ashok B.] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Chen, WJ (reprint author), Natl Inst Dent & Craniofacial Res, Mucosal Immunol Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM wchen@mail.nih.gov RI Li, Jun/N-6267-2015 FU Intramural NIH HHS NR 51 TC 261 Z9 278 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2008 VL 9 IS 6 BP 632 EP 640 DI 10.1038/ni.1607 PG 9 WC Immunology SC Immunology GA 303VB UT WOS:000256067900013 PM 18438410 ER PT J AU Appay, V Douek, DC Price, DA AF Appay, Victor Douek, Daniel C. Price, David A. TI CD8(+) T cell efficacy in vaccination and disease SO NATURE MEDICINE LA English DT Review ID PRIME-BOOST IMMUNIZATION; IMMUNODEFICIENCY VIRUS-INFECTION; TUMOR-INFILTRATING LYMPHOCYTES; BLOOD MONONUCLEAR-CELLS; VIVO ANTITUMOR EFFICACY; HIGH-AVIDITY CTL; IN-VIVO; HIV-INFECTION; MELANOMA PATIENTS; PROTECTIVE IMMUNITY AB Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8(+) T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of clearly defined correlates of protection and the inherent difficulties that hinder full characterization of the determinants of successful T cell immunity in humans. Recent data from the disparate fields of infectious disease and tumor immunology have converged, with an emphasis on the functional attributes of individual antigen-specific T cell clonotypes, to provide a better understanding of CD8(+) T cell efficacy. This new knowledge paves the way to the design of more effective T cell vaccines and highlights the importance of comprehensive immunomonitoring. C1 [Appay, Victor] Univ Paris 06, Hop Pitie Salpetriere, Ave Grp, Inst Natl Sante & Rech Med U543, F-75013 Paris, France. [Douek, Daniel C.; Price, David A.] US Natl Inst Hlth, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, Wales. RP Appay, V (reprint author), Univ Paris 06, Hop Pitie Salpetriere, Ave Grp, Inst Natl Sante & Rech Med U543, 91 Blvd Hop, F-75013 Paris, France. EM appay@chups.jussieu.fr RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G0501963, ] NR 100 TC 194 Z9 198 U1 1 U2 16 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 JUN PY 2008 VL 14 IS 6 BP 623 EP 628 DI 10.1038/nm.f.1774 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 309NY UT WOS:000256468700027 PM 18535580 ER PT J AU Buettner, C Muse, ED Cheng, A Chen, L Scherer, T Pocai, A Su, K Cheng, B Li, X Harvey-White, J Schwartz, GJ Kunos, G Rossetti, L AF Buettner, Christoph Muse, Evan D. Cheng, Andrew Chen, Linghong Scherer, Thomas Pocai, Alessandro Su, Kai Cheng, Bob Li, Xiasong Harvey-White, Judith Schwartz, Gary J. Kunos, George Rossetti, Luciano TI Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms SO NATURE MEDICINE LA English DT Article ID HORMONE-SENSITIVE LIPASE; DIET-INDUCED OBESITY; HUMAN FAT-CELLS; PPAR-GAMMA; ENERGY-BALANCE; PHOSPHATIDYLINOSITOL 3-KINASE; PARASYMPATHETIC INNERVATION; TRANSCRIPTIONAL ACTIVATION; SYMPATHETIC DENERVATION; ENDOCANNABINOID SYSTEM AB Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids. C1 [Buettner, Christoph; Chen, Linghong; Scherer, Thomas; Su, Kai; Cheng, Bob] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Muse, Evan D.; Cheng, Andrew; Rossetti, Luciano] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. [Cheng, Andrew; Pocai, Alessandro; Li, Xiasong; Schwartz, Gary J.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Muse, Evan D.; Pocai, Alessandro; Li, Xiasong; Rossetti, Luciano] Albert Einstein Coll Med, Ctr Diabet Res & Training, Bronx, NY 10461 USA. [Harvey-White, Judith; Kunos, George] US Natl Inst Hlth, US Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD 20892 USA. RP Buettner, C (reprint author), Mt Sinai Sch Med, Dept Med, 1 Gustave L Levy Pl,Box 1005, New York, NY 10029 USA. EM christoph.buettner@mssm.edu RI su, kai/F-2072-2011 FU Intramural NIH HHS [Z01 AA000351-07]; NIDDK NIH HHS [DK026687, DK048321, DK066618, DK074873, K08 DK074873, P30 DK026687, R01 DK048321, R01 DK066618, R01 DK083658, R37 DK048321] NR 50 TC 162 Z9 167 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2008 VL 14 IS 6 BP 667 EP 675 DI 10.1038/nm1775 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 309NY UT WOS:000256468700033 PM 18516053 ER PT J AU Neuman, KC Nagy, A AF Neuman, Keir C. Nagy, Attila TI Single-molecule force spectroscopy: optical tweezers, magnetic tweezers and atomic force microscopy SO NATURE METHODS LA English DT Review ID SCANNING-TUNNELING-MICROSCOPY; RNA-POLYMERASE MOLECULES; MUSCLE PROTEIN TITIN; DNA-MOLECULES; DIELECTRIC PARTICLES; MECHANICAL STABILITY; UNWINDING MECHANISM; UNFOLDING PATHWAYS; KINESIN MOLECULES; PROBE MICROSCOPY AB Single-molecule force spectroscopy has emerged as a powerful tool to investigate the forces and motions associated with biological molecules and enzymatic activity. The most common force spectroscopy techniques are optical tweezers, magnetic tweezers and atomic force microscopy. Here we describe these techniques and illustrate them with examples highlighting current capabilities and limitations. C1 [Neuman, Keir C.] NHLBI, Mol Biophys Lab, NIH, Bethesda, MD 20892 USA. [Nagy, Attila] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Neuman, KC (reprint author), NHLBI, Mol Biophys Lab, NIH, Bldg 50,50 S Dr, Bethesda, MD 20892 USA. EM neumankc@mail.nih.gov RI Neuman, Keir/F-7400-2011 OI Neuman, Keir/0000-0002-0863-5671 FU Intramural NIH HHS [Z01 HL001056-01, Z01 HL001056-02] NR 148 TC 793 Z9 812 U1 62 U2 465 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUN PY 2008 VL 5 IS 6 BP 491 EP 505 DI 10.1038/NMETH.1218 PG 15 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 307GU UT WOS:000256308200012 PM 18511917 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI How to succeed in science: a concise guide for young biomedical scientists. Part II: making discoveries SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review AB Making discoveries is the most important part of being a scientist, and also the most fun. Young scientists need to develop the experimental and mental skill sets that enable them to make discoveries, including how to recognize and exploit serendipity when it strikes. Here, I provide practical advice to young scientists on choosing a research topic, designing, performing and interpreting experiments and, last but not least, on maintaining your sanity in the process. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS [Z01 AI001055-01] NR 3 TC 1 Z9 1 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD JUN PY 2008 VL 9 IS 6 BP 491 EP 494 DI 10.1038/nrm2390 PG 4 WC Cell Biology SC Cell Biology GA 304LL UT WOS:000256110900017 PM 18401347 ER PT J AU Heekeren, HR Marrett, S Ungerleider, LG AF Heekeren, Hauke R. Marrett, Sean Ungerleider, Leslie G. TI The neural systems that mediate human perceptual decision making SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID DORSOLATERAL PREFRONTAL CORTEX; DEVELOPING OCULOMOTOR COMMANDS; OBSESSIVE-COMPULSIVE DISORDER; HUMAN EXTRASTRIATE CORTEX; HUMAN BRAIN; CORTICAL MICROSTIMULATION; SUPERIOR COLLICULUS; FRONTAL-CORTEX; VISUAL-MOTION; PSYCHOPHYSICAL PERFORMANCE AB Perceptual decision making is the act of choosing one option or course of action from a set of alternatives on the basis of available sensory evidence. Thus, when we make such decisions, sensory information must be interpreted and translated into behaviour. Neurophysiological work in monkeys performing sensory discriminations, combined with computational modelling, has paved the way for neuroimaging studies that are aimed at understanding decision-related processes in the human brain. Here we review findings from human neuroimaging studies in conjunction with data analysis methods that can directly link decisions and signals in the human brain on a trial-by-trial basis. This leads to a new view about the neural basis of human perceptual decision-making processes. C1 [Heekeren, Hauke R.] Max Planck Inst Human Dev, Neurocognit Decis Making Grp, D-14195 Berlin, Germany. [Heekeren, Hauke R.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Heekeren, Hauke R.] Charite, Neurosci Res Ctr, D-13353 Berlin, Germany. [Heekeren, Hauke R.] Charite, Berlin Neuroimaging Ctr, D-13353 Berlin, Germany. [Marrett, Sean] NIMH, Funct Magnet Resonance Imaging Facil, Bethesda, MD 20892 USA. [Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Heekeren, HR (reprint author), Max Planck Inst Human Dev, Neurocognit Decis Making Grp, Lentzeallee 94, D-14195 Berlin, Germany. EM heekeren@mpib-berlin.mpg.de RI Heekeren, Hauke/B-7739-2008; OI Heekeren, Hauke/0000-0001-7912-6826; Marrett, Sean/0000-0001-8179-6511 FU Intramural NIH HHS NR 105 TC 343 Z9 345 U1 10 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD JUN PY 2008 VL 9 IS 6 BP 467 EP 479 DI 10.1038/nrn2374 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 312WA UT WOS:000256701900015 PM 18464792 ER PT J AU Kitazawa, T Hirama, R Masunaga, K Nakamura, T Asakawa, K Cao, J Teraoka, H Unno, T Komori, SI Yamada, M Wess, J Taneike, T AF Kitazawa, Takio Hirama, Ryuichi Masunaga, Kozue Nakamura, Tatsuro Asakawa, Koichi Cao, Jinshan Teraoka, Hiroki Unno, Toshihiro Komori, Sei-ichi Yamada, Masahisa Wess, Juergen Taneike, Tetsuro TI Muscarinic receptor subtypes involved in carbachol-induced contraction of mouse uterine smooth muscle SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article; Proceedings Paper CT 5th International Symposium on Receptor Mechanisms, Signal Transduction and Drug Effects CY MAY 10-11, 2007 CL Shizuoka, JAPAN DE mouse uterus; M-2 receptor; M-3 receptor; carbachol; contraction ID GUINEA-PIG UTERUS; KNOCKOUT MICE; ACETYLCHOLINE-RECEPTORS; PHARMACOLOGICAL CHARACTERIZATION; URINARY-BLADDER; RAT MYOMETRIUM; M-3; EXPRESSION; PREGNANCY; LACKING AB Functional muscarinic acetylcholine receptors present in the mouse uterus were characterized by pharmacological and molecular biological studies using control (DDY and wild-type) mice, muscarinic M-2 or M-3 single receptor knockout (M2KO, M3KO), and M-2 and M-3 receptor double knockout mice (M-2/M3KO). Carbachol (10 nM-100 mu M) increased muscle tonus and phasic contractile activity of uterine strips of control mice in a concentration-dependent manner. The maximum carbachol-induced contractions (E-max) differed between cervical and ovarian regions of the uterus. The stage of the estrous cycle had no significant effect on carbachol concentration-response relationships. Tetrodotoxin did not decrease carbachol-induced contractions, but the muscarinic receptor antagonists (11-[[2-[(diethylaminomethyl)-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b[2,3-b][1,4]benzodiazepin6-one (AF-DX116), N-[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4] benzodiazepine-11-carboxamide (AF-DX384), 4-diphenylacetoxy-N-methyl-piperidine(4-DAMP), para-fluoro-hexa hydro-sila-diphenidol (p-F-HHSiD), himbacine, methoctramine, pirenzepine, and tropicamide) inhibited carbachol-induced contractions in a competitive fashion. The pK(b) values for these muscarinic receptor antagonists correlated well with the known pK(i) values of these antagonists for the M-3 muscarinic receptor. In uterine strips isolated from mice treated with pertussis toxin (100 mu g/kg, i.p. for 96 h), E-max values for carbachol were significantly decreased, but effective concentration that caused 50% of E-max values (EC50) remained unchanged. In uterine strips treated with 4-DAMP mustard (30 nM) and AF-DX116 (1 mu M), followed by subsequent washout of AF-DX116, neither carbachol nor N,N,N,-trimethyl-4-(2-oxo-1-pyrolidinyl)-2-butyn-1-ammonium iodide (oxotremorine-M) caused any contractile responses. Both M-2 and M-3 muscarinic receptor messenger RNAs were detected in the mouse uterus via reverse transcription polymerase chain reaction. Carbachol also caused contraction of uterine strips isolated from M2KO mice, but the concentration-response curve was shifted to the right and downward compared with that for the corresponding wild-type mice. On the other hand, uterine strips isolated from M3KO and M-2/M-3 double KO mice were virtually insensitive to carbachol. In conclusion, although both M-2 and M-3 muscarinic receptors were expressed in the mouse uterus, carbachol-induced contractile responses were predominantly mediated by the M-3 receptor. Activation of M-2 receptors alone did not cause uterine contractions; however, M-2 receptor activation enhanced M-3 receptor-mediated contractions in the mouse uterus. C1 [Kitazawa, Takio; Hirama, Ryuichi; Masunaga, Kozue; Nakamura, Tatsuro; Asakawa, Koichi; Cao, Jinshan; Taneike, Tetsuro] Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 0698501, Japan. [Teraoka, Hiroki] Rakuno Gakuen Univ, Sch Vet Med, Dept Toxicol, Ebetsu, Hokkaido 0698501, Japan. [Unno, Toshihiro; Komori, Sei-ichi] Gifu Univ, Pharmacol Lab, Fac Appl Biol Sci, Gifu 5011193, Japan. [Yamada, Masahisa] RIKEN Brain Sci Inst, Yamada Res Unit, Wako, Saitama 3510198, Japan. [Wess, Juergen] NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Kitazawa, T (reprint author), Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 0698501, Japan. EM tko-kita@rakuno.ac.jp NR 34 TC 16 Z9 17 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD JUN PY 2008 VL 377 IS 4-6 BP 503 EP 513 DI 10.1007/s00210-007-0223-1 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 316DN UT WOS:000256929200024 PM 18071676 ER PT J AU Gonzales, P Pisitkun, T Knepper, MA AF Gonzales, Patricia Pisitkun, Trairak Knepper, Mark A. TI Urinary exosomes: is there a future? SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE aquaporin-2; exosomes; polycystic kidney disease; protein mass spectrometry; urine; vasopressin ID BIOMARKERS; IDENTIFICATION; DISCOVERY; PROTEIN; DISEASE C1 [Gonzales, Patricia; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, NIH, Kidney & Electrolyte Metab Lab, 10 Ctr Dr,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural NIH HHS [NIH0010140011, Z01 HL001285-21]; NHLBI NIH HHS [HL001285] NR 12 TC 30 Z9 32 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD JUN PY 2008 VL 23 IS 6 BP 1799 EP 1801 DI 10.1093/ndt/gfn058 PG 3 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 305JC UT WOS:000256173300007 PM 18310721 ER PT J AU Sampson, JH Akabani, G Archer, GE Berger, MS Coleman, RE Friedman, AH Friedman, HS Greer, K Herndon, JE Kunwar, S McLendon, RE Paolino, A Petry, NA Provenzale, JM Reardon, DA Wong, TZ Zalutsky, MR Pastan, I Bigner, DD AF Sampson, John H. Akabani, Gamal Archer, Gerald E. Berger, Mitchel S. Coleman, R. Edward Friedman, Allan H. Friedman, Henry S. Greer, Kim Herndon, James E., II Kunwar, Sandeep McLendon, Roger E. Paolino, Alison Petry, Neil A. Provenzale, James M. Reardon, David A. Wong, Terence Z. Zalutsky, Michael R. Pastan, Ira Bigner, Darell D. TI Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors SO NEURO-ONCOLOGY LA English DT Article DE brain neoplasms; convection; drug delivery systems; epidermal growth factor receptor; immunotoxins ID CONVECTION-ENHANCED DELIVERY; IL4-PSEUDOMONAS EXOTOXIN NBI-3001; PSEUDOMONAS EXOTOXIN; NEUROTROPHIC FACTOR; THERAPEUTIC AGENTS; HUMAN GLIOMAS; PHASE-I; MICROINFUSION; EFFICACY; PROTEIN AB The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of I-123-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused I-123-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of I-123-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses <= 100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients. C1 [Sampson, John H.; Archer, Gerald E.; Friedman, Allan H.; Friedman, Henry S.; Reardon, David A.] Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. [Sampson, John H.; McLendon, Roger E.; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Akabani, Gamal; Coleman, R. Edward; Greer, Kim; Petry, Neil A.; Provenzale, James M.; Wong, Terence Z.; Zalutsky, Michael R.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Herndon, James E., II] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Berger, Mitchel S.; Kunwar, Sandeep] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Paolino, Alison] Emory Univ, Dept Neurol Surg, Atlanta, GA 30322 USA. [Pastan, Ira] NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Box 3050,,Room 220,Sands Bldg, Durham, NC 27710 USA. EM john.sampson@duke.edu RI Coleman, Ralph/A-7865-2009 FU Intramural NIH HHS; NCI NIH HHS [P50 CA097257, P50-CA097257, R01 CA097611, CA11898, R37 CA011898]; NCRR NIH HHS [K23 RR016065, K23 RR16065, MO1 RR 30, S10 RR15697]; NINDS NIH HHS [2P50-NS20023, P50 NS020023] NR 59 TC 91 Z9 91 U1 0 U2 5 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 320 EP 329 DI 10.1215/15228517-2008-012 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900010 PM 18403491 ER PT J AU Chandramohan, V Pegram, CN Szafranski, SE Keir, ST Pastan, I Kuan, CT Bigner, DD AF Chandramohan, Vidyalakshmi Pegram, Charles N. Szafranski, Scott E. Keir, Stephen T. Pastan, Ira Kuan, Chien-Tsun Bigner, Darell D. TI Dual-specific antibody, D2C7 (SCDSFV)-PE38KDEL for brain tumor therapy SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Chandramohan, Vidyalakshmi; Pegram, Charles N.; Szafranski, Scott E.; Keir, Stephen T.; Kuan, Chien-Tsun; Bigner, Darell D.] Duke Univ, Med Ctr, Pediat Brain Tumor Fdn Inst, Durham, NC USA. [Pastan, Ira] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 379 EP 379 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900045 ER PT J AU Choi, MR Rushing, E Santi, MR Cornelison, R Macdonald, T AF Choi, Mi Rim Rushing, Elisabeth Santi, Mary Rita Cornelison, Robert Macdonald, Tobey TI Expression of the notch pathway effectors HES-1 and HES-5 is associated with favorable outcome in medulloblastoma SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Choi, Mi Rim; Santi, Mary Rita; Macdonald, Tobey] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Cornelison, Robert] Natl Inst Hlth, Bethesda, MD USA. [Rushing, Elisabeth] Armed Forces Inst Pathol, Washington, DC 20306 USA. RI MacDonald, Tobey/D-4554-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 381 EP 381 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900052 ER PT J AU Hayward, R Bent, R Steffen-Smith, E Wiest, J Warren, K AF Hayward, Robert Bent, Robyn Steffen-Smith, Emilie Wiest, Jonathan Warren, Katherine TI Use of imaging in response criteria for pediatric patients with diffuse intrinsic pontine gliomas (DIPGs) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Hayward, Robert; Warren, Katherine] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 394 EP 395 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900098 ER PT J AU Steffen-Smith, E Albert, P Warren, K AF Steffen-Smith, Emilie Albert, Paul Warren, Katherine TI Metabolite patterns in pontine gliomas postradiation: Comparison of single and multivoxel spectroscopic techniques SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Steffen-Smith, Emilie; Albert, Paul; Warren, Katherine] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 430 EP 431 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900220 ER PT J AU Jakacki, R Dombi, E Goldman, S Allen, J Pollack, I Geyer, R Widemann, B AF Jakacki, Regina Dombi, Eva Goldman, Stewart Allen, Jeffrey Pollack, Ian Geyer, Russell Widemann, Brigitte TI Phase I trial of pegylated interferon alpha-2B for children and young adults with neurofibromatosis type 1 and unresectable plexiform neurofibromas SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Jakacki, Regina] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Goldman, Stewart] Childrens Mem Hosp, Chicago, IL 60614 USA. [Allen, Jeffrey] NYU, New York, NY USA. [Pollack, Ian] Univ Pittsburgh, Pittsburgh, PA USA. [Widemann, Brigitte] NIH, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 463 EP 463 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900329 ER PT J AU Fouladi, M Blaney, S Onar, A Poussaint, TY Schaiquevich, P Stewart, C Gajjar, A Dancey, J Kun, L Boyett, J Gilbertson, R AF Fouladi, Maryam Blaney, Susan Onar, Arzu Poussaint, Tina Young Schaiquevich, Paula Stewart, Clinton Gajjar, Amar Dancey, Janet Kun, Larry Boyett, James Gilbertson, Richard TI A phase I trial of lapatinib in children with refractory CNS malignancies: A pediatric brain tumor consortium study SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 13th International Symposium on Pediatric Neuro-Oncology CY JUN 29-JUL 02, 2008 CL Chicago, IL C1 [Fouladi, Maryam; Onar, Arzu; Schaiquevich, Paula; Stewart, Clinton; Gajjar, Amar; Kun, Larry; Boyett, James; Gilbertson, Richard] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Blaney, Susan] Baylor Coll Med, Houston, TX 77030 USA. [Poussaint, Tina Young] Childrens Hosp Boston, Boston, MA USA. [Boyett, James] Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD JUN PY 2008 VL 10 IS 3 BP 506 EP 507 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 316UJ UT WOS:000256974900475 ER PT J AU Duan, WZ Peng, Q Masuda, N Ford, E Tryggestad, E Ladenheim, B Zhao, M Cadet, JL Wong, J Ross, CA AF Duan, Wenzhen Peng, Qi Masuda, Naoki Ford, Eric Tryggestad, Erik Ladenheim, Bruce Zhao, Ming Cadet, Jean Lud Wong, John Ross, Christopher A. TI Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE SSRL; serotonin; BDNF; Huntington's disease; neurogenesis ID NEUROTROPHIC FACTOR; CELL-PROLIFERATION; HIPPOCAMPAL NEUROGENESIS; NEURONAL DEGENERATION; SYNAPTIC PLASTICITY; DIETARY RESTRICTION; ADULT NEUROGENESIS; CEREBRAL-ISCHEMIA; STRIATAL NEURONS; X-IRRADIATION AB Huntington's disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntington's disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients. (C) 2008 Elsevier Inc. All rights reserved. C1 [Duan, Wenzhen; Peng, Qi; Masuda, Naoki; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Div Neurobiol, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Ford, Eric; Tryggestad, Erik; Wong, John] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21218 USA. [Ladenheim, Bruce; Cadet, Jean Lud] Natl Inst Drug Abuse, Mol Neuropsychiat Branch, Baltimore, MD 21224 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Duan, WZ (reprint author), Johns Hopkins Univ, Sch Med, Div Neurobiol, Dept Psychiat & Behav Sci, CMSC 8-121,600 N Wolfe St, Baltimore, MD 21287 USA. EM wduan2@jhmi.edu RI Ross, Christopher/H-8395-2013 FU NINDS NIH HHS [R21 NS055942, NS 16375] NR 73 TC 75 Z9 75 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2008 VL 30 IS 3 BP 312 EP 322 DI 10.1016/j.nbd.2008.01.015 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 306WM UT WOS:000256278600004 PM 18403212 ER PT J AU Burnett, BG Andrews, J Ranganathan, S Fischbeck, KH Di Prospero, NA AF Burnett, Barrington G. Andrews, Jaime Ranganathan, Srikanth Fischbeck, Kenneth H. Di Prospero, Nicholas A. TI Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics SO NEUROBIOLOGY OF DISEASE LA English DT Article DE profilin; Huntington's disease; polyglutamine; actin; ubiquitin proteasome system ID HUNTINGTONS-DISEASE; DROSOPHILA HOMOLOG; MOLECULAR-CLONING; TRANSGENIC MICE; PROTEIN; GENE; MOUSE; NEURODEGENERATION; POLYMERIZATION; AGGREGATION AB Huntington's disease is caused by polyglutamine expansion in the huntingtin protein. Huntingtin directly interacts with profilin, a major actin monomer sequestering protein and a key integrator of signals leading to actin polymerization. We observed a progressive loss of profilin in the cerebral cortex of Huntington's disease patients, and in cell culture and Drosaphila models of polyglutamine disease. This loss of profilin is likely due to increased degradation through the ubiquitin proteasome system. Profilin loss reduces the F/G actin ratio, indicating a shift in actin polymerization. Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. These results indicate a link between huntingtin and profilin and implicate profilin in Huntington's disease pathogenesis. (C) 2008 Elsevier Inc. All rights reserved. C1 [Burnett, Barrington G.; Andrews, Jaime; Ranganathan, Srikanth; Fischbeck, Kenneth H.; Di Prospero, Nicholas A.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Burnett, BG (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 35,Room 2A1008, Bethesda, MD 20892 USA. EM burnettb@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 44 TC 19 Z9 19 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD JUN PY 2008 VL 30 IS 3 BP 365 EP 374 DI 10.1016/j.nbd.2008.02.007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 306WM UT WOS:000256278600009 PM 18417352 ER PT J AU Adermark, L Lovinger, DM AF Adermark, Louise Lovinger, David M. TI Electrophysiological properties and gap junction coupling of striatal astrocytes SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE astroglia; basal ganglia; carbenoxolone; glia; patch clamp ID RAT-HEART-CELLS; PRIMARY CULTURES; BRAIN-REGIONS; ASTROGLIAL CELLS; BASAL GANGLIA; GLIAL-CELLS; WHOLE-CELL; COMMUNICATION; HIPPOCAMPUS; PERMEABILITY AB The striatum is the biggest nucleus of the basal ganglia and receives input from almost all cortical regions, substantia. nigra and the thalamus. Striatal neuronal circuitry is well characterized, but less is known about glial physiology. To this end, we evaluated astrocyte electrophysiological properties using whole-cell patch-clamp recording in dorsal striatal brain slices from P15 to P21 rat. The majority of cells (95%) were passive astrocytes that do not express any detectable voltage-gated channels. Passive astrocytes were subcategorized into three groups based on time-dependent current properties. The observed proportion of the different astrocyte subtypes did not change within the age range evaluated here, but was modulated during reduction of specific conductances and gap junction coupling. Striatal astrocytes were extensively interconnected and closure of gap junctions with octanol (1 mM), carbenoxolone (100 mu M) or increased intracellular calcium (2 mM), significantly altered intrinsic properties. When simultaneously blocking potassium channels and gap junction coupling almost no passive conductance was detected, implying that the major currents in striatal astrocytes derive from potassium and gap junction conductance. Uncoupling of the syncytium reduced currents activated in response to a hyperpolarizing pulse, suggesting that changes in gap junction coupling alters astrocyte electrophysiological responses. Our findings indicate that the prevalent gap junction coupling is vital for astrocyte function in the striatum, and that whole-cell recordings will be distorted by currents activated in neighboring cells. Published by Elsevier B.V. C1 [Adermark, Louise; Lovinger, David M.] NIAAA, NIH, Lab Integrat Neurosci, Sect Synapt Pharmacol, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIAAA, NIH, Lab Integrat Neurosci, Sect Synapt Pharmacol, 5625 Fishers Lane,TS-13, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov RI Adermark, Louise/D-2297-2014 OI Adermark, Louise/0000-0002-7165-9908 FU Intramural NIH HHS [Z01 AA000407-06] NR 44 TC 17 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD JUN PY 2008 VL 52 IS 7 BP 1365 EP 1372 DI 10.1016/j.neuint.2008.02.006 PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 305EL UT WOS:000256160500008 PM 18396351 ER PT J AU Yao, J Zhang, ZF Antani, S Long, R Thoma, G AF Yao, Jian Zhang, Zhongfei (Mark) Antani, Sameer Long, Rodney Thoma, George TI Automatic medical image annotation and retrieval SO NEUROCOMPUTING LA English DT Article DE medical image; image retrieval; image annotation; semi-supervised learning; active learning; error-correcting output coding ID RELEVANCE-FEEDBACK AB The demand for automatically annotating and retrieving medical images is growing faster than ever. In this paper, we present a novel medical image retrieval method for a special medical image retrieval problem where the images in the retrieval database can be annotated into one of the pre-defined labels. Even more, a user may query the database with an image that is close to but not exactly what he/she expects. The retrieval consists of the deducible retrieval and the traditional retrieval. The deducible retrieval is a special semantic retrieval and is to retrieve the label that a user expects while the traditional retrieval is to retrieve the images in the database which belong to this label and are most similar to the query image in appearance. The deducible retrieval is achieved using SEMI-supervised Semantic Error-Correcting output Codes (SEMI-SECC). The active learning method is also exploited to further reduce the number of the required ground truthed training images. Relevance feedbacks (RFs) are used in both retrieval steps: in the deducible retrieval, RF acts as a short-term memory feedback and helps identify the label that a user expects; in the traditional retrieval, RF acts as a long-term memory feedback and helps ground truth the unlabelled training images in the database. The experimental results on IMAGECLEF 2005 [< http://ir.shef.ac.uk/imageclef2005/>] annotation data set clearly show the strength and the promise of the presented methods. (C) 2008 Elsevier B.V. All rights reserved. C1 [Yao, Jian; Zhang, Zhongfei (Mark)] SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. [Antani, Sameer; Long, Rodney; Thoma, George] Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Yao, J (reprint author), SUNY Binghamton, Dept Comp Sci, Binghamton, NY 13902 USA. EM jian_yao1414@yahoo.com OI Antani, Sameer/0000-0002-0040-1387 NR 27 TC 8 Z9 10 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2008 VL 71 IS 10-12 BP 2012 EP 2022 DI 10.1016/j.neucom.2007.10.021 PG 11 WC Computer Science, Artificial Intelligence SC Computer Science GA 322ZH UT WOS:000257413300025 ER PT J AU Fan, Y Resnick, SM Wu, XY Davatzikos, C AF Fan, Yong Resnick, Susan M. Wu, Xiaoying Davatzikos, Christos TI Structural and functional biomarkers of prodromal Alzheimer's disease: A high-dimensional pattern classification study SO NEUROIMAGE LA English DT Article DE Alzheimer's disease; MCI; high-dimensional pattern classification; MRI; PET; voxel-based analysis; diagnosis of AD ID MILD COGNITIVE IMPAIRMENT; VOXEL-BASED MORPHOMETRY; MACHINE LEARNING-METHODS; GRAY-MATTER LOSS; HIPPOCAMPAL VOLUME; TEMPORAL-LOBE; EARLY-ONSET; DIAGNOSTIC PERFORMANCE; SCHIZOPHRENIA-PATIENTS; ELASTIC REGISTRATION AB This work builds upon previous studies that reported high sensitivity and specificity in classifying individuals with mild cognitive impairment (MCI), which is often a prodromal phase of Alzheimer's disease (AD), via pattern classification of MRI scans. The current study integrates MRI and PET O-15 water scans from 30 participants in the Baltimore Longitudinal Study of Aging, and tests the hypothesis that joint evaluation of structure and function can yield higher classification accuracy than either alone. Classification rates of up to 100% accuracy were achieved via leave-one-out cross-validation, whereas conservative estimates of generalization performance in new scans, evaluated via bagging cross-validation, yielded an area under the receiver operating characteristic (ROC) curve equal to 0.978 (97.8%), indicating excellent diagnostic accuracy. Spatial maps of regions determined to contribute the most to the classification implicated many temporal, prefrontal, orbitofrontal, and parietal regions. Detecting complex patterns of brain abnormality in early stages of cognitive impairment has pivotal importance for the detection and management of AD. (c) 2008 Elsevier Inc. All rights reserved. C1 [Fan, Yong; Wu, Xiaoying; Davatzikos, Christos] Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. [Resnick, Susan M.] NIA, Lab Personal & Cognit, Bethesda, MD 20892 USA. RP Davatzikos, C (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, 3600 Market St,Suite 380, Philadelphia, PA 19104 USA. EM christos@rad.upenn.edu OI Fan, Yong/0000-0001-9869-4685 FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124, R01 AG014971, R01 AG014971-09, R01-AG14971] NR 83 TC 159 Z9 163 U1 3 U2 22 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2008 VL 41 IS 2 BP 277 EP 285 DI 10.1016/j.neuroimage.2008.02.043 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 306TQ UT WOS:000256271100011 PM 18400519 ER PT J AU Stranahan, AM Lee, K Mattson, MP AF Stranahan, Alexis M. Lee, Kim Mattson, Mark P. TI Central mechanisms of HPA axis regulation by voluntary exercise SO NEUROMOLECULAR MEDICINE LA English DT Article DE stress; wheel running; glucocorticoid; hippocampus; hypothalamus ID PITUITARY-ADRENOCORTICAL AXIS; WHEEL-RUNNING ACTIVITY; HIPPOCAMPAL PROGENITOR PROLIFERATION; SPONTANEOUSLY HYPERTENSIVE-RATS; SPRAGUE-DAWLEY RATS; NEUROTROPHIC FACTOR; ADULT NEUROGENESIS; DENTATE GYRUS; PARAVENTRICULAR NUCLEUS; PROTEIN EXPRESSION AB Stress exerts complex effects on the brain and periphery, dependent on the temporal profile and intensity of the stressor. The consequences of a stressful event can also be determined by other characteristics of the stressor, such as whether it is predictable and controllable. While the traditional view has focused primarily on the negative effects of stress on a variety of somatic systems, emerging data support the idea that certain forms of stress can enhance cellular function. Here we review the current literature on the hypothalamic-pituitary-adrenal (HPA) axis regulation by wheel running, a voluntary and controllable stressor with a distinct temporal profile. While running indeed activates a number of systems related to the stress response, other mechanisms exist to reduce the reactivity to this stressor, with possible crosstalk between running and other forms of stress. C1 [Stranahan, Alexis M.; Lee, Kim; Mattson, Mark P.] NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, Intramural Res Program,Gerontol Res Ctr, Baltimore, MD 21224 USA. [Stranahan, Alexis M.] Princeton Univ, Dept Psychol, Program Neurosci, Princeton, NJ 08544 USA. RP Mattson, MP (reprint author), NIA, Cellular & Mol Neurosci Sect, Neurosci Lab, Intramural Res Program,Gerontol Res Ctr, Nathan Shock Dr 5600, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012; OI Lee, Kim/0000-0002-5675-1896 FU Intramural NIH HHS; NIA NIH HHS [F31 AG024690, F31 AG024690-01, F31 AG024690-02, F31 AG024690-03, F31 AG024690-04] NR 73 TC 63 Z9 63 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2008 VL 10 IS 2 BP 118 EP 127 DI 10.1007/s12017-008-8027-0 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 315XK UT WOS:000256913300007 PM 18273712 ER PT J AU van Praag, H AF van Praag, Henriette TI Neurogenesis and exercise: Past and future directions SO NEUROMOLECULAR MEDICINE LA English DT Review DE neurogenesis; exercise; hippocampus; learning and memory; growth factors; angiogenesis ID ADULT HIPPOCAMPAL NEUROGENESIS; GROWTH-FACTOR-I; NEWLY GENERATED NEURONS; LONG-TERM POTENTIATION; MAGNETIC-RESONANCE-SPECTROSCOPY; ENHANCED SYNAPTIC PLASTICITY; HUNTINGTONS-DISEASE MICE; TRANSGENIC MOUSE MODEL; DENTATE GYRUS; ALZHEIMERS-DISEASE AB Research in humans and animals has shown that exercise improves mood and cognition. Physical activity also causes a robust increase in neurogenesis in the dentate gyrus of the hippocampus, a brain area important for learning and memory. The positive correlation between running and neurogenesis has raised the hypothesis that the new hippocampal neurons may mediate, in part, improved learning associated with exercise. The present review gives an overview of research pertaining to exercise-induced cell genesis, its possible relevance to memory function and the cellular mechanisms that may be involved in this process. C1 NIA, Sect Neuroplast & Behav, Neurosci Lab, GRC,NIH, Baltimore, MD 21224 USA. RP van Praag, H (reprint author), NIA, Sect Neuroplast & Behav, Neurosci Lab, GRC,NIH, Rm 4E14,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vanpraagh@mail.nih.gov RI van Praag, Henriette/F-3939-2015 OI van Praag, Henriette/0000-0002-5727-434X FU Intramural NIH HHS NR 167 TC 221 Z9 223 U1 10 U2 61 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD JUN PY 2008 VL 10 IS 2 BP 128 EP 140 DI 10.1007/s12017-008-8028-z PG 13 WC Neurosciences SC Neurosciences & Neurology GA 315XK UT WOS:000256913300008 PM 18286389 ER PT J AU O'Sullivan, GJ Dunleavy, M Hakansson, K Clementi, M Kinsella, A Croke, DT Drago, J Fienberg, AA Greengard, P Sibley, DR Fisone, G Henshall, DC Waddington, JL AF O'Sullivan, Gerard J. Dunleavy, Mark Hakansson, Kerstin Clementi, Mario Kinsella, Anthony Croke, David T. Drago, John Fienberg, Allen A. Greengard, Paul Sibley, David R. Fisone, Gilberto Henshall, David C. Waddington, John L. TI Dopamine D(1) vs D(5) receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling SO NEUROPHARMACOLOGY LA English DT Article DE dopamine D(1)-like receptors; seizures; adenylate cyclase; DARPP-32; ERK1/2; knockout ID ETHOLOGICALLY BASED RESOLUTION; DENDRITIC K+ CHANNELS; BEHAVIORAL TOPOGRAPHY; AMPA RECEPTOR; AGONIST RESPONSES; ADENYLYL-CYCLASE; KNOCKOUT MICE; MUTANT MICE; KINASE ERK; CELL-DEATH AB Recent reports have shown that the selective dopamine D(1)-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D(1) vs D(5) receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D(1), D(5) and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D(1) knockouts. In both heterozygous and homozygous D(5) knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D(1)-like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D(1), and to a lesser extent D(5), receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822. (C) 2008 Elsevier Ltd. All rights reserved. C1 [O'Sullivan, Gerard J.; Hakansson, Kerstin; Kinsella, Anthony; Croke, David T.; Waddington, John L.] Royal Coll Surgeons Ireland, Mol & Cellular Therapeut & RCSI Res Inst, Dublin 2, Ireland. [Dunleavy, Mark; Henshall, David C.] Royal Coll Surgeons Ireland, Dept physiol & Med Phys, Dublin 2, Ireland. [Hakansson, Kerstin; Clementi, Mario; Fisone, Gilberto] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Drago, John] Univ Melbourne, Howard Florey Inst, Melbourne, Vic 3010, Australia. [Fienberg, Allen A.] Intracellular Therapies Inc, New York, NY 10032 USA. [Greengard, Paul] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. [Sibley, David R.] NINDS, NIH, Mol Neuropharmacol Sect, Bethesda, MD 20892 USA. RP Waddington, JL (reprint author), Royal Coll Surgeons Ireland, Mol & Cellular Therapeut & RCSI Res Inst, 123 St Stephens Green, Dublin 2, Ireland. EM jwadding@rcsi.ie RI Dunleavy, Mark/B-4260-2012; Henshall, David/C-3364-2012; OI Dunleavy, Mark/0000-0001-5916-9722; Henshall, David/0000-0001-6237-9632 FU NIDA NIH HHS [DA10044, P01 DA010044, P01 DA010044-04]; NIMH NIH HHS [MH074866, P50 MH074866, P50 MH074866-01] NR 51 TC 18 Z9 20 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2008 VL 54 IS 7 BP 1051 EP 1061 DI 10.1016/j.neuropharm.2008.02.011 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 312EO UT WOS:000256652100003 PM 18367215 ER PT J AU Hu, XQ Lovinger, DM AF Hu, Xiang-Qun Lovinger, David M. TI The L293 residue in transmembrane domain 2 of the 5-HT(3A) receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole SO NEUROPHARMACOLOGY LA English DT Article DE 5-HT(3A) receptor; allosteric modulation; Gating; desensitization; structure-function; electrophysiology ID GATED ION-CHANNEL; N1E-115 NEUROBLASTOMA-CELLS; ACETYLCHOLINE-RECEPTOR; GLYCINE RECEPTORS; GABA(A) RECEPTORS; POINT MUTATION; AGONIST; PORE; SEROTONIN; ALCOHOL AB Allosteric modulation of ligand-gated ion channels can play important roles in shaping synaptic transmission. The function of the 5-hydroxytryptamine (serotonin) type 3 (5-HT(3)) receptor, a member of the Cys-loop ligand-gated ion channel superfamily, is modulated by a variety of compounds such as alcohols, anesthetics and 5-hydroxyindole (5-HI). In this study, the molecular determinants of allosteric modulation by 5-HI were explored in N1E-115 neuroblastoma cells expressing the native 5-HT(3) receptor and HEK 293 cells transfected with the recombinant 5-HT(3A) receptor using molecular biology and whole-cell patch-clamp techniques. 5-HI potentiated 5-HT-activated currents in both N1E-115 cells and HEK 293 cells, and significantly decreased current desensitization and deactivation. Substitution of Leu293 (L293, L15') in the second transmembrane domain (TM2) with cysteine (L293C) or serine (L293S) abolished 5-HI modulation. Other mutations in the TM2 domain, such as D298A and T284F, failed to after 5-HI modulation. The L293S mutation enhanced dopamine efficacy and converted 5-HI into a partial agonist at the mutant receptor. These data suggest that 5-HI stabilizes the 5-HT3A receptor in the open state by decreasing both desensitization and 5-HT unbinding/channel closing; and L293 is a common site for both channel gating and allosteric modulation by 5-HI. Our observations also indicate existence of a second 5-HI recognition site on the 5-HT3A receptor, which may overlap with the 5-HT binding site and is not involved in the positive modulation by 5-HI. These findings support the idea that there are two discrete sites for 5-HI allosteric modulation and direct activation in the 5-HT3A receptor. Published by Elsevier Ltd. C1 [Hu, Xiang-Qun; Lovinger, David M.] Natl Inst Alcohol Abuse & Alcoholism, Lab Integrat Neurosci, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Lab Integrat Neurosci, Natl Inst Hlth, 5625 Fishers Lane,Room TS-13A, Bethesda, MD 20852 USA. EM lovindav@mail.nih.gov FU Intramural NIH HHS [Z01 AA000407-06] NR 41 TC 11 Z9 11 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2008 VL 54 IS 8 BP 1153 EP 1165 DI 10.1016/j.neuropharm.2008.03.009 PG 13 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 317FF UT WOS:000257004600001 PM 18436267 ER PT J AU Ide, S Minami, M Ishihara, K Uhl, GR Satoh, M Sora, I Ikeda, K AF Ide, Soichiro Minami, Masabumi Ishihara, Kumatoshi Uhl, George R. Satoh, Masamichi Sora, Ichiro Ikeda, Kazutaka TI Abolished thermal and mechanical antinociception but retained visceral chemical antinociception induced by butorphanol in mu-opioid receptor knockout mice SO NEUROPHARMACOLOGY LA English DT Article DE opioid receptor; knockout mice; butorphanol; antinociception ID MORPHINE-INDUCED ANALGESIA; DEPENDENCE; AGONIST; GENE; PAIN; SENSITIVITY; ANTAGONISTS; WITHDRAWAL; TOLERANCE; BINDING AB Butorphanol is hypothesized to induce analgesia via opioid pathways, although the precise mechanisms for its effects remain unknown. In this study, we investigated the role of the mu-opioid receptor (MOP) in thermal, mechanical, and visceral chemical antinociception induced by butorphanol using MOP knockout (KO) mice. Butorphanol-induced thermal antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from our butorphanol-induced mechanical antinociception experiments, assessed by the Randall-Selitto test, were similar to the results obtained from the thermal antinociception experiments in these mice. Interestingly, however, butorphanol retained its ability to induce significant visceral chemical antinociception, assessed by the writhing test, in homozygous MOP-KO mice. The butorphanol-induced visceral chemical antinociception that was retained in homozygous MOP-KO mice was completely blocked by pretreatment with nor-binaltorphimine, a K-Opioid receptor (KOP) antagonist. In vitro binding and cyclic adenosine monophosphate assays also showed that butorphanol possessed higher affinity for KOPs and MOPs than for delta-opioid receptors. These results molecular pharmacologically confirmed previous studies implicating MOPs, and partially KOPs, in mediating butorphanol-induced analgesia. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Ide, Soichiro; Sora, Ichiro; Ikeda, Kazutaka] Tokyo Inst Psychiat, Div Psychobiol, Setagaya Ku, Tokyo 1568585, Japan. [Ide, Soichiro; Ishihara, Kumatoshi] Hiroshima Int Univ, Fac Pharmaceut Sci, Neuropharmacol Lab, Hiroshima, Japan. [Minami, Masabumi] Hokkaido Univ, Grad Sch Pharmaceut Sci, Dept Pharmacol, Sapporo, Hokkaido 0600812, Japan. [Uhl, George R.; Sora, Ichiro] Natl Inst Drug Abuse, Baltimore, MD 21224 USA. [Satoh, Masamichi] Yasuda Womens Univ, Dept Pharm, Hiroshima 7310153, Japan. [Sora, Ichiro] Tohoku Univ, Dept Biol Psychiat, Grad Sch Med, Sendai, Miyagi 9808574, Japan. RP Ikeda, K (reprint author), Tokyo Inst Psychiat, Div Psychobiol, Setagaya Ku, 2-1-8 Kamikitazawa, Tokyo 1568585, Japan. EM ikedak@prit.go.jp RI Ide, Soichiro/D-5472-2012; Minami, Masabumi/A-3883-2012; Ikeda, Kazutaka/I-4694-2013 OI Minami, Masabumi/0000-0002-0144-0679; Ikeda, Kazutaka/0000-0001-8342-0278 FU Intramural NIH HHS [Z01 DA000165-13, Z01 DA000406-10] NR 28 TC 7 Z9 8 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUN PY 2008 VL 54 IS 8 BP 1182 EP 1188 DI 10.1016/j.neuropharm.2008-03.008 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 317FF UT WOS:000257004600004 PM 18417173 ER PT J AU Maurice, T Duclot, F Meunier, J Naert, G Givalois, L Meffre, J Celerier, A Jacquet, C Copois, V Mechti, N Ozato, K Gongora, C AF Maurice, Tangui Duclot, Florian Meunier, Johann Naert, Gaelle Givalois, Laurent Meffre, Julie Celerier, Aurelie Jacquet, Chantal Copois, Virginie Mechti, Nadir Ozato, Keiko Gongora, Celine TI Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE histone acetylase PCAF; short-term memory; spatial memory; stress; age ID RUBINSTEIN-TAYBI-SYNDROME; TRANSCRIPTIONAL COACTIVATORS P300; RAT HIPPOCAMPUS; CBP; PROTEIN; ACETYLTRANSFERASES; ACTIVATION; MECHANISMS; EXPRESSION; RETENTION AB Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress. C1 [Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaelle; Givalois, Laurent; Celerier, Aurelie] Univ Montpellier 2, INSERM, U710, F-34095 Montpellier 5, France. [Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaelle; Givalois, Laurent] EPHE, F-75006 Paris, France. [Maurice, Tangui; Duclot, Florian; Meunier, Johann; Naert, Gaelle; Givalois, Laurent; Meffre, Julie] INSERM, U710, Montpellier, France. [Meffre, Julie; Celerier, Aurelie] CNRS, FRE2693, Montpellier, France. [Jacquet, Chantal] Inst Genet Mol Montpellier, CNRS, UMR 5535, Montpellier, France. [Copois, Virginie; Mechti, Nadir; Gongora, Celine] CNRS, UMR 5160, Montpellier, France. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Maurice, T (reprint author), Univ Montpellier 2, INSERM, U710, Pl Eugene Bataillon, F-34095 Montpellier 5, France. EM Tangui.Maurice@univ-montp2.fr RI Duclot, Florian/E-4669-2013 OI Duclot, Florian/0000-0003-0121-5807 NR 38 TC 89 Z9 90 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2008 VL 33 IS 7 BP 1584 EP 1602 DI 10.1038/sj.npp.1301551 PG 19 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 301LM UT WOS:000255897700009 PM 17805310 ER PT J AU Xi, ZX Spiller, K Pak, AC Gilbert, J Dillon, C Li, X Peng, XQ Gardner, EL AF Xi, Zheng-Xiong Spiller, Krista Pak, Arlene C. Gilbert, Jeremy Dillon, Christopher Li, Xia Peng, Xiao-Qing Gardner, Eliot L. TI Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cocaine; cannabinoid; AM 251; SR141716; self-administration; brain reward ID CB1 RECEPTOR ANTAGONISTS; AGONIST WIN 55,212-2; NUCLEUS-ACCUMBENS; KNOCKOUT MICE; PROGRESSIVE-RATIO; SYNAPTIC-TRANSMISSION; ANIMAL-MODELS; ENDOGENOUS CANNABINOIDS; LOCOMOTOR-ACTIVITY; BASAL GANGLIA AB Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1-10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30-70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1-3 mg/kg) also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/ kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications. C1 [Xi, Zheng-Xiong; Spiller, Krista; Pak, Arlene C.; Gilbert, Jeremy; Dillon, Christopher; Li, Xia; Peng, Xiao-Qing; Gardner, Eliot L.] Natl Inst Drug Abuse, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Neuropsychopharmacol Sect, Chem Biol Res Branch, Intramural Res Program,NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU Intramural NIH HHS NR 69 TC 49 Z9 50 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2008 VL 33 IS 7 BP 1735 EP 1745 DI 10.1038/sj.npp.1301552 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 301LM UT WOS:000255897700022 PM 17728698 ER PT J AU Cummings, DM Belluscio, L AF Cummings, Diana M. Belluscio, Leonardo TI Charting plasticity in the regenerating maps of the mammalian olfactory bulb SO NEUROSCIENTIST LA English DT Review DE olfactory system; map; sensory neurons; olfactory bulb; intrabulbar map ID INTRABULBAR ASSOCIATIONAL SYSTEM; GATED CHANNEL SUBUNIT; ODORANT RECEPTORS; GENERATED NEURONS; SENSORY MAP; TOPOGRAPHIC ORGANIZATION; GLOMERULAR REFINEMENT; TARGETED DELETION; MICE DEFICIENT; GRANULE CELLS AB The anatomical organization of a neural system can offer a glimpse into its functional logic. The basic premise is that by understanding how something is put together one can figure out how it works. Unfortunately, organization is not always represented purely at an anatomical level and is sometimes best revealed through molecular or functional studies. The mammalian olfactory system exhibits organizational features at all these levels including 1) anatomically distinct structural layers in the olfactory bulb, 2) molecular maps based upon odorant receptor expression, and 3) functional local circuits giving rise to odor columns that provide a contextual logic for an intrabulbar map. In addition, various forms of cellular plasticity have been shown to play an integral role in shaping the structural properties of most neural systems and must be considered when assessing each system's anatomical organization. Interestingly, the olfactory system invokes an added level of complexity for understanding organization in that it regenerates both at the peripheral and the central levels. Thus, olfaction offers a rare opportunity to study both the structural and the functional properties of a regenerating sensory system in direct response to environmental stimuli. In this review, we discuss neural organization in the form of maps and explore the relationship between regeneration and plasticity. C1 [Cummings, Diana M.; Belluscio, Leonardo] Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Belluscio, L (reprint author), Natl Inst Neurol Disorders & Stroke, Dev Neural Plast Unit, Porter Neurosci Res Ctr, Bldg 35,Room 3A-116,35 Convent Dr,MSC 3703, Bethesda, MD 20892 USA. EM belluscl@ninds.nih.gov FU Intramural NIH HHS [ZIA NS003002-07] NR 65 TC 5 Z9 5 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD JUN PY 2008 VL 14 IS 3 BP 251 EP 263 DI 10.1177/1073858408315026 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 299UV UT WOS:000255781400012 PM 18420836 ER PT J AU Kim, J Hoffman, DA AF Kim, Jinhyun Hoffman, Dax A. TI Potassium channels: Newly found players in synaptic plasticity SO NEUROSCIENTIST LA English DT Article DE potassium channel; Kv4.2; SK; trafficking; synaptic plasticity ID CA2+-ACTIVATED K+ CHANNELS; HIPPOCAMPAL PYRAMIDAL NEURONS; LONG-TERM POTENTIATION; DEPENDENT PROTEIN-KINASE; GATED ION CHANNELS; SMALL-CONDUCTANCE; NMDA-RECEPTOR; SK CHANNELS; AFTER-HYPERPOLARIZATION; DENDRITIC SPINES AB One of the major issues for modern neuroscience research concerns the molecular and cellular mechanisms that underlie the acquisition, storage, and recollection of memories by the brain. Regulation of the strength of individual synaptic inputs (synaptic plasticity) has, for decades, been the front-running candidate mechanism for cellular information storage, with some direct supporting evidence recently obtained. Research into the molecular mechanisms responsible for changing synaptic strength has, to date, primarily focused on trafficking and properties of the neurotransmitter receptors themselves (AMPARs and NMDARs). However, recent evidence indicates that, subsequent to receptor activation, synaptic inputs are subject to regulation by synaptically located K+ channels. It is therefore critical to understand the biophysical properties and subcellular localization (density and distribution) of these channels and how their properties are modulated. Here we will review recent findings showing that two different classes of K+ channels (A-type and small conductance, Ca2+-activated K+ channels), beyond their traditional role in regulating action potential firing, contribute to the regulation of synaptic strength in the hippocampus. In addition, we discuss how modulation of these channels' properties and expression might contribute to synaptic plasticity. C1 [Kim, Jinhyun; Hoffman, Dax A.] NICHD, Mol Neurophysiol & Biophys Unit, LCSN, NIH, Bethesda, MD 20892 USA. RP Hoffman, DA (reprint author), NICHD, Mol Neurophysiol & Biophys Unit, LCSN, NIH, 35 Lincoln Dr Room 3C-905, Bethesda, MD 20892 USA. EM hoffmand@mail.nih.gov RI Hoffman, Dax/E-5155-2011 OI Hoffman, Dax/0000-0001-6999-2157 FU Intramural NIH HHS [Z99 HD999999, Z01 HD008755-05] NR 73 TC 46 Z9 46 U1 1 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-8584 J9 NEUROSCIENTIST JI Neuroscientist PD JUN PY 2008 VL 14 IS 3 BP 276 EP 286 DI 10.1177/1073858408315041 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 299UV UT WOS:000255781400014 PM 18413784 ER PT J AU Bock, NA Paiva, FF Silva, AC AF Bock, Nicholas A. Paiva, Fernando F. Silva, Afonso C. TI Fractionated manganese-enhanced MRI SO NMR IN BIOMEDICINE LA English DT Article DE rodent; central nervous system; MRI; manganese; contrast agent ID RESONANCE-IMAGING MEMRI; IN-VIVO; CHLORIDE EXPOSURE; T-1-WEIGHTED MRI; MOUSE-BRAIN; RAT-BRAIN; NEUROTOXICITY; ACTIVATION; INJECTION; MNCL2 AB We investigated the use of manganese-enhanced MRI (MEMRI) with fractionated doses as a way to retain the unique properties of manganese as a neuronal contrast agent while lessening its toxic effects in animals. First, we followed the signal enhancement on T-1-weighted images of the brains of rats receiving 30 mg/kg fractions of MnCl2 center dot 4H(2)O every 48 h and found that the signal increased in regions with consecutive fractionated doses and ultimately saturated. Second, we used T, mapping to test whether the amount of MRI-visible manganese that accumulated depended on the concentration of manganese in the fractions. For a fixed cumulative dose of 180 mg/kg MnCl2 center dot 4H(2)O, increasing fraction doses of 6 x 30 mg/kg, 3 x 60 mg/kg, 2 x 90 mg/kg and 1 x 180 mg/kg produced progressively shorter T, values. The adverse systemic health effects, including complications at the injection site and poor animal well-being, also rose with the fraction dose. Thus, fractionated MEMRI can be used to balance the properties of manganese as a contrast agent in animals against its toxic effects. Published in 2007 by John Wiley & Sons, Ltd. C1 [Bock, Nicholas A.; Paiva, Fernando F.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Bock, NA (reprint author), NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room BD109, Bethesda, MD 20892 USA. EM bockn@mail.nih.gov RI Silva, Afonso/A-7129-2009; Paiva, Fernando/C-1429-2012 OI Paiva, Fernando/0000-0002-8989-9707 FU Intramural NIH HHS [Z01 NS003041-02] NR 28 TC 43 Z9 47 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JUN PY 2008 VL 21 IS 5 BP 473 EP 478 DI 10.1002/nbm.1211 PG 6 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 319NX UT WOS:000257171800006 PM 17944008 ER PT J AU Kim, S Barnett, AS Pierpaoli, C Chi-Fishman, G AF Kim, Sungheon Barnett, Alan S. Pierpaoli, Carlo Chi-Fishman, Gloria TI Three-dimensional mapping of lingual myoarchitecture by diffusion tensor MRI SO NMR IN BIOMEDICINE LA English DT Article; Proceedings Paper CT 13th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine CY MAY 07-13, 2005 CL Miami Beach, FL SP Int Soc Magnet Resonance Med DE diffusion tensor imaging; tongue; muscle; segmentation; lingual myoarchitecture ID BOVINE TONGUE; FIBER ARCHITECTURE; HUMAN BRAIN; ORIENTATION; VALIDATION; MORPHOLOGY; TISSUE; TIME; VIVO; NMR AB This study was performed to assess the feasibility of investigating the complex lingual myoarchitecture through segmentation of muscles from diffusion tensor imaging (DTI) data. The primary eigenvectors were found to be adequate for delineating the superior and inferior longitudinalis, genioglossus, and hyoglossus. The tertiary eigenvector orientations effectively revealed the homogeneous and systematic change of muscle orientation in the tongue core. In the longitudinalis near the tongue tip, the secondary eigenvectors were oriented in the radial direction. Lingual muscles were segmented using two methods: modified directional correlation (DC) and tensor coherence (TC) methods. The DC method, based on one eigenvector, was found to be inadequate for lingual muscle segmentation, whereas the TC method, based on the tensor shape and orientation, was used successfully to segment most lingual muscles. The segmentation result was used to report the diffusion tensor properties of individual lingual muscles. Also found was a continuous change in skewness of the intrinsic tongue core from negative in the anterior region to positive in the posterior region. DTI and the proposed segmentation method provide an adequate means of imaging and visualizing the complex, compartmentalized musculature of the tongue. The potential for in vivo research and clinical applications is demonstrated. Copyright (C) 2007 John Wiley & Sons, Ltd. C1 [Kim, Sungheon] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Barnett, Alan S.] NIMH, NIH, Bethesda, MD USA. [Pierpaoli, Carlo] NICHHD, NIH, Bethesda, MD USA. [Chi-Fishman, Gloria] NIH, Clin Res Ctr, Dept Rehabil Med, Phys Disabil Branch, Bethesda, MD USA. RP Kim, S (reprint author), Univ Penn, Dept Radiol, 423 Guardian Dr,Blockley Hall B6, Philadelphia, PA 19104 USA. EM Sungheon.Kim@uphs.upenn.edu RI Pierpaoli, Carlo/E-1672-2011 FU Intramural NIH HHS NR 30 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD JUN PY 2008 VL 21 IS 5 BP 479 EP 488 DI 10.1002/nbm.1215 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 319NX UT WOS:000257171800007 PM 17952877 ER PT J AU Paap, B Wilson, DM Sutherland, BM AF Paap, Brigitte Wilson, David M., III Sutherland, Betsy M. TI Human abasic endonuclease action on multilesion abasic clusters: implications for radiation-induced biological damage SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; CHINESE-HAMSTER CELLS; ESCHERICHIA-COLI; DNA-DAMAGE; IONIZING-RADIATION; MAMMALIAN-CELLS; EXONUCLEASE-III; EXCISION-REPAIR; MAJOR HUMAN; SITE AB Clustered damagestwo or more closely opposed abasic sites, oxidized bases or strand breaksare induced in DNA by ionizing radiation and by some radiomimetic drugs. They are potentially mutagenic or lethal. High complexity, multilesion clusters (three or more lesions) are hypothesized as repair-resistant and responsible for the greater biological damage induced by high linear energy transfer radiation (e.g. charged particles) than by low linear energy transfer X- or gamma-rays. We tested this hypothesis by assessing human abasic endonuclease Ape1 activity on two- and multiple-lesion abasic clusters. We constructed cluster-containing oligonucleotides using a central variable cassette with abasic site(s) at specific locations, and 5 and 3 terminal segments tagged with visually distinctive fluorophores. The results indicate that in two- or multiple-lesion clusters, the spatial arrangement of uni-sided positive [in which the opposing strand lesion(s) is 3 to the base opposite the reference lesion)] or negative polarity [opposing strand lesion(s) 5 to the base opposite the reference lesion] abasic clusters is key in determining Ape1 cleavage efficiency. However, no bipolar clusters (minimally three-lesions) were good Ape1 substrates. The data suggest an underlying molecular mechanism for the higher levels of biological damage associated with agents producing complex clusters: the induction of highly repair-resistant bipolar clusters. C1 [Paap, Brigitte; Sutherland, Betsy M.] Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Sutherland, BM (reprint author), Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. EM bms@bnl.gov FU Intramural NIH HHS; NCI NIH HHS [R01 CA086897, R01 CA86897] NR 40 TC 34 Z9 34 U1 0 U2 3 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 JUN PY 2008 VL 36 IS 8 BP 2717 EP 2727 DI 10.1093/nar/gkn118 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 299ML UT WOS:000255759600026 PM 18353858 ER PT J AU Tharakaraman, K Bodenreider, O Landsman, D Spouge, JL Marino-Ramirez, L AF Tharakaraman, Kannan Bodenreider, Olivier Landsman, David Spouge, John L. Marino-Ramirez, Leonardo TI The biological function of some human transcription factor binding motifs varies with position relative to the transcription start site SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FULL-LENGTH HUMAN; GENE ONTOLOGY; TRANSPOSABLE ELEMENTS; REGULATORY SEQUENCES; INTERACTION NETWORKS; HUMAN PROMOTERS; PROTEIN; IDENTIFICATION; INFORMATION; SPECIFICITY AB A number of previous studies have predicted transcription factor binding sites (TFBSs) by exploiting the position of genomic landmarks like the transcriptional start site (TSS). The studies methods are generally too computationally intensive for genome-scale investigation, so the full potential of positional regulomics to discover TFBSs and determine their function remains unknown. Because databases often annotate the genomic landmarks in DNA sequences, the methodical exploitation of positional regulomics has become increasingly urgent. Accordingly, we examined a set of 7914 human putative promoter regions (PPRs) with a known TSS. Our methods identified 1226 eight-letter DNA words with significant positional preferences with respect to the TSS, of which only 608 of the 1226 words matched known TFBSs. Many groups of genes whose PPRs contained a common word displayed similar expression profiles and related biological functions, however. Most interestingly, our results included 78 words, each of which clustered significantly in two or three different positions relative to the TSS. Often, the gene groups corresponding to different positional clusters of the same word corresponded to diverse functions, e.g. activation or repression in different tissues. Thus, different clusters of the same word likely reflect the phenomenon of positional regulation, i.e. a words regulatory function can vary with its position relative to a genomic landmark, a conclusion inaccessible to methods based purely on sequence. Further integrative analysis of words co-occurring in PPRs also yielded 24 different groups of genes, likely identifying cis-regulatory modules de novo. Whereas comparative genomics requires precise sequence alignments, positional regulomics exploits genomic landmarks to provide a poor mans alignment. By exploiting the phenomenon of positional regulation, it uses position to differentiate the biological functions of subsets of TFBSs sharing a common sequence motif. C1 [Tharakaraman, Kannan; Landsman, David; Spouge, John L.; Marino-Ramirez, Leonardo] Natl Canc Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. [Bodenreider, Olivier] Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Marino-Ramirez, L (reprint author), Natl Canc Biotechnol Informat, Computat Biol Branch, 8600 Rockville Pike,MSC 6075, Bethesda, MD 20894 USA. EM marino@ncbi.nlm.nih.gov RI Landsman, David/C-5923-2009; Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU Intramural NIH HHS [Z99 LM999999] NR 44 TC 17 Z9 18 U1 0 U2 1 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 JUN PY 2008 VL 36 IS 8 BP 2777 EP 2786 DI 10.1093/nar/gkn137 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 299ML UT WOS:000255759600031 PM 18367472 ER PT J AU Turner, KB Brinson, RG Yi-Brunozzi, HY Rausch, JW Miller, JT Le Grice, SFJ Marino, JP Fabris, D AF Turner, Kevin B. Brinson, Robert G. Yi-Brunozzi, Hye Young Rausch, Jason W. Miller, Jennifer T. Le Grice, Stuart F. J. Marino, John P. Fabris, Daniele TI Structural probing of the HIV-1 polypurine tract RNA : DNA hybrid using classic nucleic acid ligands SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ION-CYCLOTRON RESONANCE; IONIZATION MASS-SPECTROMETRY; REVERSE-TRANSCRIPTASE; NUCLEOCAPSID PROTEIN; RNA/DNA HYBRIDS; RIBONUCLEASE-H; BINDING; RECOGNITION; TYPE-1 AB The interactions of archetypical nucleic acid ligands with the HIV-1 polypurine tract (PPT) RNA:DNA hybrid, as well as analogous DNA:DNA, RNA:RNA and swapped hybrid substrates, were used to probe structural features of the PPT that contribute to its specific recognition and processing by reverse transcriptase (RT). Results from intercalative and groove-binding ligands indicate that the wild-type PPT hybrid does not contain any strikingly unique groove geometries and/or stacking arrangements that might contribute to the specificity of its interaction with RT. In contrast, neomycin bound preferentially and selectively to the PPT near the 5(rA)(4):(dT)(4) tract and the 3 PPT-U3 junction. Nuclear magnetic resonance data from a complex between HIV-1 RT and the PPT indicate RT contacts within the same regions highlighted on the PPT by neomycin. These observations, together with the fact that the sites are correctly spaced to allow interaction with residues in the ribonuclease H (RNase H) active site and thumb subdomain of the p66 RT subunit, suggest that despite the long cleft employed by RT to make contact with nucleic acids substrates, these sites provide discrete binding units working in concert to determine not only specific PPT recognition, but also its orientation on the hybrid structure. C1 [Turner, Kevin B.; Fabris, Daniele] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Brinson, Robert G.; Marino, John P.] Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. [Brinson, Robert G.; Marino, John P.] Natl Inst Stand & Technol, Rockville, MD USA. [Brinson, Robert G.; Yi-Brunozzi, Hye Young; Rausch, Jason W.; Miller, Jennifer T.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. RP Fabris, D (reprint author), Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. EM marino@umbi.umd.edu; fabris@umbc.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM643208, R01 GM059107, GM59107] NR 58 TC 17 Z9 17 U1 1 U2 3 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 JUN PY 2008 VL 36 IS 8 BP 2799 EP 2810 DI 10.1093/nar/gkn129 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 299ML UT WOS:000255759600033 PM 18400780 ER PT J AU Lyakhov, IG Krishnamachari, A Schneider, TD AF Lyakhov, Ilya G. Krishnamachari, Annangarachari Schneider, Thomas D. TI Discovery of novel tumor suppressor p53 response elements using information theory SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-BINDING SITE; ESCHERICHIA-COLI; HUMAN GENOME; SEQUENCE LOGOS; TARGET GENES; TRANSCRIPTIONAL REPRESSION; MOLECULAR MACHINES; PROMOTER; DATABASE; P63 AB An accurate method for locating genes under tumor suppressor p53 control that is based on a well-established mathematical theory and built using naturally occurring, experimentally proven p53 sites is essential in understanding the complete p53 network. We used a molecular information theory approach to create a flexible model for p53 binding. By searching around transcription start sites in human chromosomes 1 and 2, we predicted 16 novel p53 binding sites and experimentally demonstrated that 15 of the 16 (94%) sites were bound by p53. Some were also bound by the related proteins p63 and p73. Thirteen of the adjacent genes were controlled by at least one of the proteins. Eleven of the 16 sites (69%) had not been identified previously. This molecular information theory approach can be extended to any genetic system to predict new sites for DNA-binding proteins. C1 [Schneider, Thomas D.] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Krishnamachari, Annangarachari] Jawaharlal Nehru Univ, Bioinformat Ctr, New Delhi 110067, India. [Lyakhov, Ilya G.] NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21701 USA. RP Schneider, TD (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM toms@ncifcrf.gov OI Schneider, Thomas/0000-0002-9841-1531 FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 50 TC 24 Z9 26 U1 1 U2 6 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 JUN PY 2008 VL 36 IS 11 BP 3828 EP 3833 DI 10.1093/nar/gkn189 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319UC UT WOS:000257188700029 PM 18495754 ER PT J AU Arana, ME Seki, M Wood, RD Rogozin, IB Kunkel, TA AF Arana, Mercedes E. Seki, Mineaki Wood, Richard D. Rogozin, Igor B. Kunkel, Thomas A. TI Low-fidelity DNA synthesis by human DNA polymerase theta SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HIV-1 REVERSE-TRANSCRIPTASE; UNIQUE ERROR SIGNATURE; SOMATIC HYPERMUTATION; TRANSLESION SYNTHESIS; ESCHERICHIA-COLI; IMMUNOGLOBULIN GENES; FRAMESHIFT MUTATIONS; EXCISION-REPAIR; HUMAN-CELLS; IG GENES AB Human DNA polymerase theta (pol theta or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol theta may synthesize DNA with low fidelity. Here, we show that when copying undamaged DNA, pol theta generates single base errors at rates 10- to more than 100-fold higher than for other family A members. Pol theta adds single nucleotides to homopolymeric runs at particularly high rates, exceeding 1% in certain sequence contexts, and generates single base substitutions at an average rate of 2.4 x 10(-3), comparable to inaccurate family Y human pol kappa (5.8 x 10(-3)) also implicated in TLS. Like pol kappa, pol theta is processive, implying that it may be tightly regulated to avoid deleterious mutagenesis. Pol theta also generates certain base substitutions at high rates within sequence contexts similar to those inferred to be copied by pol theta during SHM of immunoglobulin genes in mice. Thus, pol theta is an exception among family A polymerases, and its low fidelity is consistent with its proposed roles in TLS and SHM. C1 [Arana, Mercedes E.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Arana, Mercedes E.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, Natl Inst Hlth, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Seki, Mineaki; Wood, Richard D.] Univ Pittsburgh, Sch Med, Hillman Canc Ctr, Dept Pharmacol, Pittsburgh, PA 15213 USA. [Rogozin, Igor B.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, Natl Inst Hlth, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Wood, Richard/E-7855-2011 OI Wood, Richard/0000-0002-9495-6892 FU Intramural NIH HHS; NCI NIH HHS [CA101980, R01 CA101980]; NIEHS NIH HHS [Z01 ES065070] NR 62 TC 58 Z9 61 U1 1 U2 2 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 JUN PY 2008 VL 36 IS 11 BP 3847 EP 3856 DI 10.1093/nar/gkn310 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319UC UT WOS:000257188700031 PM 18503084 ER PT J AU Kirk, M Lea, D Skirton, H AF Kirk, Maggie Lea, Dale Skirton, Heather TI Genomic health care: Is the future now? SO NURSING & HEALTH SCIENCES LA English DT Article DE genetics; genomics; health care; nursing ID GENETICS EDUCATION; NURSES; KNOWLEDGE; PROGRAMS; MIDWIVES AB In some areas of health care, genomics is having a steadily increasing impact on clinical practice. Yet, in other areas, genomic developments are considered to be at the periphery of care. Health-care professionals from such areas might feel that the potential of genomics is exaggerated. To explore this issue, genetic nurse specialists were invited to submit case studies and to identify barriers and facilitators in incorporating genomics into mainstream nursing practice. Twenty-five cases were submitted and a total of 10 barriers and seven facilitators were identified. These cases were presented as a basis for debate in a session conducted at the 2006 Annual Conference of the International Society of Nurses in Genetics. The majority of delegates agreed that genomics would have a profound effect on health care and nursing within the next 5 years, particularly in oncology. That nurses do not see genomics as being relevant to their practice was identified as the greatest barrier, by a narrow majority. Specialist nurses in any field have a role in acting as agents of change, educators, and consultants to non-specialists. It is clear that genetics nurse specialists still have a considerable challenge in raising awareness about the relevance of genomics to mainstream nursing practice. C1 [Kirk, Maggie] Univ Glamorgan, Fac Hlth Sport & Sci, NHS Natl Genet Educ & Dev Ctr, Pontypridd CF37 1DL, M Glam, Wales. [Skirton, Heather] Univ Plymouth, Fac Hlth & Social Work, Sch Nursing & Community Studies, Plymouth PL4 8AA, Devon, England. [Lea, Dale] NHGRI, Educ & Community Involvement Branch, Bethesda, MD 20892 USA. RP Kirk, M (reprint author), Univ Glamorgan, Fac Hlth Sport & Sci, NHS Natl Genet Educ & Dev Ctr, Pontypridd CF37 1DL, M Glam, Wales. EM mkirk@glam.ac.uk RI Kirk, Maggie/G-9333-2012; OI Kirk, Maggie/0000-0003-1745-7106; Skirton, Heather/0000-0002-3639-5265 FU Department of Health; Intramural NIH HHS NR 44 TC 11 Z9 11 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1441-0745 J9 NURS HEALTH SCI JI Nurs. Health Sci. PD JUN PY 2008 VL 10 IS 2 BP 85 EP 92 DI 10.1111/j.1442-2018.2008.00374.x PG 8 WC Nursing SC Nursing GA 310SI UT WOS:000256550100003 PM 18466380 ER PT J AU Moon, HS Lee, HG Chung, CS Choi, YJ Cho, CS AF Moon, Hyun-Seuk Lee, Hong-Gu Chung, Chung-Soo Choi, Yun-Jaie Cho, Chong-Su TI Physico-chemical modifications of conjugated linoleic acid for ruminal protection and oxidative stability SO NUTRITION & METABOLISM LA English DT Review ID MILK-FAT SYNTHESIS; RADICAL SCAVENGING PROPERTIES; REDUCES BODY-FAT; DAIRY-COWS; OVERWEIGHT SUBJECTS; LIPID-ACCUMULATION; ADIPOSE-TISSUE; CALCIUM SALTS; NITRIC-OXIDE; WEIGHT-LOSS AB Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of octadecadienoic acid [linoleic acid (LA), 18: 2n-6]. Although ruminant milk and meat products represent the largest natural source of CLA and therefore, their concentration in ruminant lipids are of interest to human health, chemical or physical modifications of CLA should be needed as a means to enhance oxidative stability, to improve post-ruminal bioavailability, and to increase the clinical application. In fact, CLA are rapidly decomposed to form furan fatty acids when its are oxidized in air, and the effectiveness of dietary supplements of CLA may be related to the extent that their metabolisms by rumen bacteria are avoided. For these reasons, many scientists have examined the effect of manufacturing and protection on the stability of CLA in ruminants and food products. In this review, physico-chemical modifications of CLA for ruminal protection such as calcium salt (Ca), formaldehyde protection (FP), lipid encapsulation (LE), and amide linkage (AL), and for oxidative stability such as green tea catechin (GTC), cyclodextrin (CD), arginine (Arg), amylase, and PEGylation are proposed. C1 [Choi, Yun-Jaie; Cho, Chong-Su] Seoul Natl Univ, Sch Agr Biotechnol, Seoul 151921, South Korea. [Moon, Hyun-Seuk] NIAAA, Mol Signalling Lab, NIH, Bethesda, MD 20892 USA. [Lee, Hong-Gu] Pusan Natl Univ, Special Anim Biotechnol Ctr, Miryang 627706, South Korea. [Lee, Hong-Gu] Pusan Natl Univ, Sch Bioresources, Miryang 627706, South Korea. [Chung, Chung-Soo] Chungbuk Natl Univ, Coll Agr Life & Environm Sci, Cheongju 361763, South Korea. RP Cho, CS (reprint author), Seoul Natl Univ, Sch Agr Biotechnol, Seoul 151921, South Korea. EM moonh2@mail.nih.gov; hglee66@snu.ac.kr; chungpig@hotmail.com; cyjcow@snu.ac.kr; chocs@plaza.snu.ac.kr RI Choi, Yunjaie /B-4697-2014; Moon, Hyun-Seuk/G-8576-2015 OI Moon, Hyun-Seuk/0000-0002-5216-2090 NR 79 TC 7 Z9 8 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD JUN 1 PY 2008 VL 5 AR 16 DI 10.1186/1743-7075-5-16 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 325TO UT WOS:000257611400001 PM 18513443 ER PT J AU Siervo, M Wells, JCK Cizza, G AF Siervo, Mario Wells, Jonathan C. K. Cizza, Giovanni TI Evolutionary theories, psychosocial stress and the modern obesity epidemic SO OBESITY AND METABOLISM-MILAN LA English DT Review DE human evolution; seasonality; stress response; visceral adiposity ID BODY-MASS INDEX; ACTIVATED PROTEIN-KINASE; WORK STRESS; SOCIOECONOMIC-STATUS; METABOLIC SYNDROME; EATING BEHAVIOR; SECULAR TRENDS; INDUSTRIAL-REVOLUTION; NUTRITION TRANSITION; AGONISTIC BEHAVIOR AB The thrifty genotype hypothesis of Neel theorises that a set of genes have been selected during evolution to confer an adaptive advantage. In modern times, characterized by unlimited food availability, these genes may have become metabolically harmful and may be contributing to the secular trends in weight gain and epidemic of type 2 diabetes and metabolic syndrome. These genes remain to be identified. We suggest the existence of cellular energy sensing mechanisms controlling the regulation of energy balance and we hypothesise the existence of different physiological pathways regulating anabolic or catabolic pathways. We propose that the adaptive energetic and neuro-endocrine responses that have characterized the evolution of the Homo genus exposed to uncertainty in energy supply can be explained by models of conservation of energy based upon the laws of thermodynamics. We have applied these models to modern humans to shed some light on the increased prevalence in obesity. Fluctuations in the availability of food, due to environmental and climatic perturbations, were most likely strong selective forces for the transmission of genes important for survival. However, in modern times where changes in food availability due to seasonality are attenuated, the decrease in physical activity and increase in energy intake, features of our times, are not conferring a selective advantage. Modern times are characterized by increased emotional stress and decreased sleep duration and the consequent activation of the hypothalamic-pituitary-adrenal axis, and sympatho-adrenal system which, in turn, may induce accumulation of visceral fat and metabolic syndrome. We propose that the neuroendocrine stress system evolved to enhance chances of survival for our ancestors, but in today's plentifully provisioned societies, where sedentariness and mental stress have become typical traits of modem humans, the chronic activation of the stress responses may underpin some of the metabolic characteristics of the insulin resistance syndrome. C1 [Siervo, Mario] Elsie Widdowson Lab, MRC Human Nutr Res, Cambridge CB1 9NL, England. [Wells, Jonathan C. K.] Inst Child Hlth, Childrens Nutr Res Ctr, London, England. [Cizza, Giovanni] NIDDK, NIH, Bethesda, MD USA. RP Siervo, M (reprint author), Elsie Widdowson Lab, MRC Human Nutr Res, Fulbourn Rd, Cambridge CB1 9NL, England. EM Mario.Siervo@mrc-hnr.cam.ac.uk RI Wells, Jonathan/A-4604-2009 OI Wells, Jonathan/0000-0003-0411-8025 NR 136 TC 5 Z9 5 U1 3 U2 17 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1825-3865 EI 1826-7572 J9 OBES METAB-MILAN JI Obes. Metab.-Milan PD JUN PY 2008 VL 4 IS 2 BP 131 EP 142 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 339HO UT WOS:000258568900008 ER PT J AU Martin-Johnston, MK Okoji, OY Armstrong, A AF Martin-Johnston, Meredith K. Okoji, Olanma Y. Armstrong, Alicia TI Therapeutic amenorrhea in patients at risk for thrombocytopenia SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Article ID INHERITED BLEEDING DISORDERS; LEVONORGESTREL INTRAUTERINE SYSTEM; STEM-CELL TRANSPLANTATION; MYOMA-RELATED MENORRHAGIA; VENOUS THROMBOEMBOLISM; LUPUS-ERYTHEMATOSUS; ENDOMETRIAL RESECTION; PREMENOPAUSAL WOMEN; MALIGNANT-DISEASE; RANDOMIZED-TRIAL AB To examine the need for and evaluate the method of menses suppression in women at risk for thrombocytopenia. A systematic review of the published literature in MEDLINE using the search terms thrombocytopenia, menorrhagia, therapeutic amenorrhea, progestin intrauterine device, combination oral contraceptive-extended and cyclic, gonadotropin releasing hormone agonist, danazol, and progestins. There are an increased number of reproductive age women at risk for thrombocytopenia who would benefit from menses suppression. A number of effective medical regimens are available. In patients who fail medical therapy, endometrial ablation appears to be effective in women with thrombocytopenia. As a result of the increased number of women at risk for thrombocytopenia, there is a need for therapeutic amenorrhea. The type of regimen selected depends upon the patients need for contraception and the ability to tolerate estrogen-containing medications. For women who fail medical therapy, there are surgical options, which are associated with less morbidity than hysterectomy. C1 [Martin-Johnston, Meredith K.] Illinois Masonic Med Ctr, Chicago, IL 60657 USA. [Okoji, Olanma Y.] George Washington Univ, Sch Med, Washington, DC USA. [Armstrong, Alicia] NIH, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. RP Martin-Johnston, MK (reprint author), Illinois Masonic Med Ctr, Chicago, IL 60657 USA. FU Intramural NIH HHS [Z99 HD999999] NR 74 TC 7 Z9 7 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUN PY 2008 VL 63 IS 6 BP 395 EP 402 DI 10.1097/OGX.0b013e3181706620 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 306EY UT WOS:000256232300003 PM 18492296 ER PT J AU Massad, LS Jeronimo, J Schiffman, M AF Massad, L. Stewart Jeronimo, Jose Schiffman, Mark CA NIH ASCCP Res Grp TI Interobserver agreement in the assessment of components of colposcopic grading SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; UNDETERMINED SIGNIFICANCE; MANAGEMENT; LESIONS; IMAGES; TRIAL; INDEX; WOMEN AB OBJECTIVE: To estimate the reproducibility of the assessment of visual characteristics of cervical lesions used to judge lesion grade from colposcopy. METHODS: Digitized cervical images from 862 women enrolled in the ASCUS-LSIL Triage Study were obtained after application of 5% acetic acid. Each image was later assessed online by two randomly assigned evaluators from a pool of 20 experienced colposcopists. Interobserver agreement beyond chance was assessed by kappa statistics. RESULTS: Of 862 evaluable images with paired assessments, 607 were considered to have an acetowhite lesion by both evaluators, 171 by one, and 84 by neither. Kappa values (95% confidence intervals) for agreement were 0.22 (0.17-0.27) for color, 0.24 (0.18-0.30) for margins, 0.22 (0.16-0.29) for mosaicism, 0.17 (0.11-0.23) for punctation, 0.11 (0.00-0.22) for atypical vessels, and 0.26 (0.22-0.31) for modified Reid Index score. CONCLUSION: Characteristics used to assign colposcopic grade are poorly reproducible when used to assess static cervical images from women with borderline cytology results. C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Pl, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu NR 15 TC 36 Z9 37 U1 0 U2 1 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 JUN PY 2008 VL 111 IS 6 BP 1279 EP 1284 DI 10.1097/AOG.0b013e31816baed1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 305PX UT WOS:000256191400005 PM 18515509 ER PT J AU Carroll, MA Vidaeff, AC Mele, L Wapner, RJ Mercer, B Peaceman, AM Sorokin, Y Dudly, DJ Spong, CY Leveno, KJ Harper, M Caritis, SN Miodovnik, M Thorp, JM Moawad, A O'Sullivan, MJ Carpenter, MW Rouse, DJ Sibai, B AF Carroll, Mary A. Vidaeff, Alex C. Mele, Lisa Wapner, Ronald J. Mercer, Brian Peaceman, Alan M. Sorokin, Yoram Dudly, Donald J. Spong, Catherine Y. Leveno, Kenneth J. Harper, Margaret Caritis, Steve N. Miodovnik, Menachem Thorp, John M. Moawad, Atef O'Sullivan, Maiy J. Carpenter, Marshall W. Rouse, Dwight J. Sibai, Baha TI Bone metabolism in pregnant women exposed to single compared with multiple courses of corticosteroids SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 53rd Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 22-25, 2006 CL Toronto, CANADA SP Soc Gynecol Invest ID ANTENATAL CORTICOSTEROIDS; BIOCHEMICAL MARKERS; PRETERM DELIVERY; I COLLAGEN; TURNOVER; OSTEOPOROSIS; LACTATION; DENSITY; SERUM; UK AB OBJECTIVE: To compare markers of maternal bone metabolism between women who received a single compared with multiple Courses of antenatal corticosteroids. METHODS: This is an analysis of serum samples from a previously reported randomized, placebo-controlled, multicenter trial. Women at risk for preterm delivery after an initial course of corticosteroids were randomly assigned to weekly courses of betamethasone (active) or placebo. Serum levels of carboxy terminal propeptide of type I procollagen (PICP) and cross-linked carboxy terminal telopeptide of type I Collagen (ICTP) were measured to assess the rate of bone formation and resorption, respectively, at three time points. The placebo group (n = 93) was compared with the active group, receiving four or more courses of betamethasone (n = 112). RESULTS: There were significant (P < .001) increases in PICP and ICTP between baseline and delivery in both groups. Cross-linked carboxy terminal telopeptide of type I Collagen, but not PICP, was lower with corticosteroid exposure immediately before administration of the fourth study course (P < .001). No significant differences in PICP and ICTP were seen between groups at delivery. CONCLUSION: Increasing levels of PICP and ICTP with advancing gestation are consistent with physiologic changes in maternal bone metabolism. Multiple courses of corticosteroids for fetal maturation are not associated with persistent or cumulative effects on maternal bone metabolism as measured by PICP and ICTP. C1 George Washington Univ, Ctr Biostat, Rockville, MD USA. Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. NICHHD, Bethesda, MD 20892 USA. Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. Wake Forest Univ, Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27109 USA. Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. Univ Miami, Dept Obstet & Gynecol, Miami, FL 33152 USA. Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. RP Vidaeff, AC (reprint author), Univ Texas Houston, Sch Med, Dept Obstet Gynecol & Reprod Sci, 6431 Fannin,Suite 3-604, Houston, TX 77030 USA. EM alex.c.vidaeff@uth.tmc.edu OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850 FU NCRR NIH HHS [M01 RR000080, M01 RR000080-45, M01-RR-000080]; NICHD NIH HHS [U10 HD034122-05, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, U01 HD036801, U10 HD021410, U10 HD021410-22, U10 HD021414-15, U10 HD027860, U10 HD027860-15, U10 HD027861-10, U10 HD027869, U10 HD027869-10, U10 HD027905, U10 HD027905-10, U10 HD027915, U10 HD027915-18, U10 HD027917, U10 HD027917-18, U10 HD034116, U10 HD034116-13, U10 HD034122, U10 HD034136, U10 HD034136-07, U10 HD034208, U10 HD034208-12, U10 HD036801, U10 HD036801-11, U10 HD040485, U10 HD040485-09, U10 HD040500, U10 HD040500-08, U10 HD040512, U10 HD040512-09, U10 HD040544, U10 HD040544-09, U10 HD040545, U10 HD040545-09, U10 HD040560, U10 HD040560-09, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 30 TC 5 Z9 5 U1 0 U2 4 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 JUN PY 2008 VL 111 IS 6 BP 1352 EP 1358 DI 10.1097/AOG.0b013e318173573b PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 305PX UT WOS:000256191400015 PM 18515519 ER PT J AU Massad, LS Seaberg, EC Wright, RL Darragh, T Lee, YC Colie, C Burk, R Strickler, HD Watts, DH AF Massad, L. Stewart Seaberg, Eric C. Wright, Rodney L. Darragh, Teresa Lee, Yi-Chun Colie, Christine Burk, Robert Strickler, Howard D. Watts, D. Heather TI Squamous cervical lesions in women with human immunodeficiency virus - Long-term follow-up SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID HIV-INFECTED WOMEN; INTRAEPITHELIAL LESIONS; HUMAN-PAPILLOMAVIRUS; INTERAGENCY HIV; CANCER; RISK; PREVALENCE; ABNORMALITIES; TYPE-1 AB OBJECTIVE: To estimate the frequency of and trends in abnormal Pap test results in women with human immunodeficiency virus (HIV) and HIV-uninfected women. METHODS: In a cohort study of HIV-infected and uninfected women, Pap tests were obtained every 6 months. Results of atypical squamous cells of undetermined significance (ASC-US) or worse were considered abnormal. RESULTS: Over a median of 8.4 years, 23,843 Pap tests were obtained from 1,931 HIV-positive women with 6,828 Pap tests from 533 HIV-negative women (13 women seroconverted during the study). Among women with HIV, Pap test results were ASC-US in 4,462 (19%), low-grade squamous intraepithelial lesion (LSIL) in 3,199 (13%), high-grade squamous intraepithelial lesion (HSIL) in 267 (1%), and cancer in 11 (0.05%). The incidence of abnormal Pap test results was 179 in 1,000 person-years for HIV-positive and 75 in 1,000 person-years for HIV-negative women (incidence rate ratio 2.4, 95% confidence interval 2.0-2.8). The incidence of HSIL or cancer was 4.4 in 1,000 person-years for HIV-positive and 1.3 in 1,000 person-years for HIV-negative women (incidence rate ratio 3.4, 95% confidence interval 1.2-9.5). CONCLUSION: Among women with HIV in a cervical cancer prevention program, Pap test abnormalities are common, but high-grade abnormalities are infrequent. C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Georgetown Univ, Washington, DC USA. Albert Einstein Coll Med, Bronx, NY USA. NICHHD, Bethesda, MD 20892 USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Pl, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu FU NCRR NIH HHS [M01-RR-00071, M01-RR-00083, M01-RR-00079]; NIAID NIH HHS [U01-AI-34993, U01-AI-31834, U01-AI-34994, U01-AI-35004, U01-AI-42590, U01-AI-34989]; NICHD NIH HHS [U01-HD-32632] NR 23 TC 32 Z9 32 U1 0 U2 0 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 JUN PY 2008 VL 111 IS 6 BP 1388 EP 1393 DI 10.1097/AOG.0b013e3181744619 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 305PX UT WOS:000256191400019 PM 18515523 ER PT J AU Thurman, AR Holden, AEC Shain, RN Perdue, S Piper, JM AF Thurman, Andrea Ries Holden, Alan E. C. Shain, Rochelle N. Perdue, Sondra Piper, Jeanna M. TI Preventing recurrent sexually transmitted diseases in minority adolescents - A randomized controlled trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID AFRICAN-AMERICAN WOMEN; RISK-REDUCTION INTERVENTIONS; PARTNER NOTIFICATION; FEMALE ADOLESCENTS; STD PREVALENCE; SAFER CHOICES; HIV; SEX; BEHAVIORS; PREGNANCY AB OBJECTIVE: To compare the efficacy of a randomized controlled trial of the Sexual Awareness For Everyone (SAFE) behavioral intervention on teenagers (aged 14 to 18 years) compared with adult rates of reinfection with Neiserria gonorrhea or Chlamydia trachomatis cervicitis, and to identify behaviors associated with recurrent infection. METHODS: Mexican-American and African-American females with a nonviral sexually transmitted disease (STD) were enrolled in SAFE or assigned to the control group. All participants were interviewed and examined at baseline, 6, and 12 months. The primary outcome variable was reinfection with N. gonorrhea or C. trachomatis. Secondary outcomes were changes in risky sexual behavior. RESULTS: Teens randomized to participation in SAFE had a statistically lower incidence of recurrent N. gonorrhea and C. trachomatis at 0 to 6 months (52%, P = .04) and cumulatively (39%, P = .04) compared with teens in the control group. Cumulatively, teens as a group had higher rates of reinfection (33.1%) than adults (14.4%) (P < .001). Adolescent reinfection was explained by unprotected sex with untreated partners (adjusted odds ratio [OR] 5.58), nonmonogamy (adjusted OR 5.14), and rapid partner turnover (adjusted OR 2.02). In adults, reinfection was predicted by unprotected sex with untreated partners (adjusted OR 4.90), unsafe sex (adjusted OR 2.18), rapid partner turnover (adjusted OR 3.13), and douching after sex (adjusted OR 2.14). CONCLUSION: Sexual Awareness for Everyone significantly reduced recurrent STDs in teenagers. Adults and teens randomized to the SAFE intervention had significant decreases in high-risk sexual behaviors as compared with those in the control group. Although not specifically designed for teens, the SAFE intervention worked very well in this high-risk population. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, ClinicalTrials.gov, HSC2004415H. C1 [Thurman, Andrea Ries] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Thurman, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, 7703 Floyd Curl Dr,Mail Code 7836, San Antonio, TX 78229 USA. EM thurmana@uthscsa.edu FU NIAID NIH HHS [U01 AI40029] NR 38 TC 23 Z9 24 U1 4 U2 7 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 JUN PY 2008 VL 111 IS 6 BP 1417 EP 1425 DI 10.1097/AOG.0b013e318177143a PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 305PX UT WOS:000256191400023 PM 18515527 ER PT J AU Mikolajczyk, RT Zhang, J AF Mikolajczyk, Rafael T. Zhang, Jun TI Evaluation of logistic regression reporting in current obstetrics and gynecology literature - In reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter ID SELECTION C1 [Mikolajczyk, Rafael T.; Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Mikolajczyk, RT (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2008 VL 111 IS 6 BP 1447 EP 1448 DI 10.1097/AOG.0b013e31817afef0 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 305PX UT WOS:000256191400037 ER PT J AU Christiani, DC Mehta, AJ Yu, CL AF Christiani, D. C. Mehta, A. J. Yu, C-L TI Genetic susceptibility to occupational exposures SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID CHRONIC BERYLLIUM DISEASE; DIISOCYANATE-INDUCED ASTHMA; ISOCYANATE-INDUCED ASTHMA; COTTON TEXTILE WORKERS; HLA CLASS-II; BLADDER-CANCER; LONGITUDINAL CHANGES; PULMONARY-FUNCTION; ETHICAL ISSUES; ASSOCIATION AB Because of their high prevalence in the general population, genetic variants that determine susceptibility to environmental exposures may contribute greatly to the development of occupational diseases in the setting of specific exposures occurring in the workplace. Studies investigating genetic susceptibilities in the workplace may: ( 1) provide mechanistic insight into the aetiology of disease, in particular the determination of environmentally responsive genes; ( 2) identify susceptible subpopulations with respect to exposure; and ( 3) provide valuable input in setting occupational exposure limits by taking genetic susceptibility into account. Polymorphisms in the NAT2 and the HLA-DPB1(Glu69) genes provide classic examples of how genetic susceptibility markers have a clear role in identifying disease risk in bladder cancer and chronic beryllium disease, respectively. For diseases with more complex and multifactorial aetiology such as occupational asthma and chronic airways disease, susceptibility studies for selected genetic polymorphisms provide additional insight into the biological mechanisms of disease. Even when polymorphisms for genetic susceptibility have a clear role in identifying disease risk, the value of wide scale genetic screening in occupational settings remains limited due to primarily ethical and social concerns. Thus, large scale genetic screening in the workplace is not currently recommended. C1 [Christiani, D. C.; Mehta, A. J.] Harvard Univ, Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Yu, C-L] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU NIEHS NIH HHS [ES00002, P30 ES000002]; NIOSH CDC HHS [T42 OH008416, T42OH008416, R01OH2421, R01 OH002421] NR 62 TC 31 Z9 33 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD JUN PY 2008 VL 65 IS 6 BP 430 EP 436 DI 10.1136/oem.2007.033977 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 302FT UT WOS:000255954900014 PM 18487431 ER PT J AU Angiuoli, SV Gussman, A Klimke, W Cochrane, G Field, D Garrity, G Kodira, CD Kyrpides, N Madupu, R Markowitz, V Tatusova, T Thomson, N White, O AF Angiuoli, Samuel V. Gussman, Aaron Klimke, William Cochrane, Guy Field, Dawn Garrity, George Kodira, Chinnappa D. Kyrpides, Nikos Madupu, Ramana Markowitz, Victor Tatusova, Tatiana Thomson, Nick White, Owen TI Toward an online repository of Standard Operating Procedures (SOPs) for (Meta) genomic annotation SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article; Proceedings Paper CT 4th Genomic Standards Consortium Workshop CY JUN 06-08, 2007 CL Cambridge, ENGLAND ID RESOURCE INTEGRATION CENTER; SEQUENCE; DATABASE; INFORMATION; BIOLOGY; ERRORS; GENES; TOOL AB The methodologies used to generate genome and metagenome annotations are diverse and vary between groups and laboratories. Descriptions of the annotation process are helpful in interpreting genome annotation data. Some groups have produced Standard Operating Procedures ( SOPs) that describe the annotation process, but standards are lacking for structure and content of these descriptions. In addition, there is no central repository to store and disseminate procedures and protocols for genome annotation. We highlight the importance of SOPs for genome annotation and endorse an online repository of SOPs. C1 [Angiuoli, Samuel V.; Gussman, Aaron; White, Owen] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Angiuoli, Samuel V.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Klimke, William; Tatusova, Tatiana] NIH, Natl Ctr Biotechnol Informat, Baltimore, MD USA. [Cochrane, Guy] EMBL European Bioinformat Inst, Cambridge, England. [Field, Dawn] Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Sect, Oxford, England. [Garrity, George] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Kodira, Chinnappa D.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Kyrpides, Nikos] Joint Genome Inst, Dept Energy, Walnut Creek, CA USA. [Madupu, Ramana] J Craig Venter Inst, Rockville, MD USA. [Markowitz, Victor] Univ Calif Berkeley, Lawrence Berkeley Lab, Biol Data Management & Technol Ctr, Berkeley, CA 94720 USA. [Thomson, Nick] Wellcome Trust Sanger Inst, Pathogen Sequencing Unit, Cambridge, England. RP Angiuoli, SV (reprint author), Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. EM sangiuoli@som.umaryland.edu RI Field, Dawn/C-1653-2010; Garrity, George/F-7551-2013; Angiuoli, Samuel/H-7340-2014; Kyrpides, Nikos/A-6305-2014; OI Garrity, George/0000-0002-4465-7034; Kyrpides, Nikos/0000-0002-6131-0462; Cochrane, Guy/0000-0001-7954-7057; Angiuoli, Samuel/0000-0001-9525-4350 FU PHS HHS [HHSN2662004000386] NR 31 TC 102 Z9 104 U1 3 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2008 VL 12 IS 2 BP 137 EP 141 DI 10.1089/omi.2008.0017 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 321PT UT WOS:000257319700005 PM 18416670 ER PT J AU Sansone, SA Rocca-Serra, P Brandizi, M Brazma, A Field, D Fostel, J Garrow, AG Gilbert, J Goodsaid, F Hardy, N Jones, P Lister, A Miller, M Morrison, N Rayner, T Sklyar, N Taylor, C Tong, W Warner, G Wiemann, S AF Sansone, Susanna-Assunta Rocca-Serra, Philippe Brandizi, Marco Brazma, Alvis Field, Dawn Fostel, Jennifer Garrow, Andrew G. Gilbert, Jack Goodsaid, Federico Hardy, Nigel Jones, Phil Lister, Allyson Miller, Michael Morrison, Norman Rayner, Tim Sklyar, Nataliya Taylor, Chris Tong, Weida Warner, Guy Wiemann, Stefan CA RSBI Working Grp TI The first RSBI (ISA-TAB) workshop: "Can a Simple Format Work for Complex Studies?" SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article; Proceedings Paper CT 4th Genomic Standards Consortium Workshop CY JUN 06-08, 2007 CL Cambridge, ENGLAND ID MINIMUM INFORMATION; MICROARRAY DATA; DATA STANDARDS; GENOMICS AB This article summarizes the motivation for, and the proceedings of, the first ISA-TAB workshop held December 6-8, 2007, at the EBI, Cambridge, UK. This exploratory workshop, organized by members of the Microarray Gene Expression Data (MGED) Society's Reporting Structure for Biological Investigations (RSBI) working group, brought together a group of developers of a range of collaborative systems to discuss the use of a common format to address the pressing need of reporting and communicating data and metadata from biological, biomedical, and environmental studies employing combinations of genomics, transcriptomics, proteomics, and metabolomics technologies along with more conventional methodologies. The expertise of the participants comprised database development, data management, and hands-on experience in the development of data communication standards. The workshop's outcomes are set to help formalize the proposed Investigation, Study, Assay (ISA)-TAB tab-delimited format for representing and communicating experimental metadata. This article is part of the special issue of OMICS on the activities of the Genomics Standards Consortium (GSC). C1 [Sansone, Susanna-Assunta; Rocca-Serra, Philippe; Brandizi, Marco; Brazma, Alvis; Jones, Phil; Rayner, Tim; Sklyar, Nataliya; Taylor, Chris] EMBL EBI, Cambridge CB10 1SD, England. [Field, Dawn; Morrison, Norman] NERC, Ctr Ecol & Hydrol, Oxford OX1 3SR, England. [Fostel, Jennifer] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Garrow, Andrew G.; Warner, Guy] Unilever Safety & Environm Assurance Ctr, Bedford, England. [Gilbert, Jack] Plymouth Marine Lab, Plymouth, Devon, England. [Goodsaid, Federico] US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hardy, Nigel] Aberystwyth Univ, Dept Comp Sci, Ceredigion, Wales. [Lister, Allyson] Univ Newcastle, CISBAN, Newcastle Upon Tyne, Tyne & Wear, England. [Lister, Allyson] Univ Newcastle, Sch Comp Sci, Newcastle Upon Tyne, Tyne & Wear, England. [Miller, Michael] Rosetta Biosoftware, Seattle, WA USA. [Morrison, Norman] NERC, Bioinformat Ctr NEBC, Ctr Ecol & Hydrol, Oxford OX1 3SR, England. [Morrison, Norman] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. [Tong, Weida] US FDA, Natl Ctr Toxicol Res, Ctr Toxicoinformat, Jefferson, AR 72079 USA. [Wiemann, Stefan] German Canc Res Ctr, D-6900 Heidelberg, Germany. RP Sansone, SA (reprint author), EMBL EBI, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England. EM sansone@ebi.ac.uk; rocca@ebi.ac.uk RI Field, Dawn/C-1653-2010; Wiemann, Stefan/E-4424-2013; OI Wiemann, Stefan/0000-0003-4683-3174; Lister, Allyson/0000-0002-7702-4495; Sansone, Susanna-Assunta/0000-0001-5306-5690; Brandizi, Marco/0000-0002-5427-2496; Rayner, Tim/0000-0002-6992-5592; Brazma, Alvis/0000-0001-5988-7409 FU Biotechnology and Biological Sciences Research Council [BB/E025080/1] NR 28 TC 53 Z9 53 U1 0 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD JUN PY 2008 VL 12 IS 2 BP 143 EP 149 DI 10.1089/omi.2008.0019 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 321PT UT WOS:000257319700006 PM 18447634 ER PT J AU Alsheich-Bartok, O Haupt, S Alkalay-Snir, I Saito, S Appella, E Haupt, Y AF Alsheich-Bartok, O. Haupt, S. Alkalay-Snir, I. Saito, S. Appella, E. Haupt, Y. TI PML enhances the regulation of p53 by CK1 in response to DNA damage SO ONCOGENE LA English DT Article DE PML; CK1; p53; Mdm2; threonine 18 phosphorylation ID ACUTE PROMYELOCYTIC LEUKEMIA; NUCLEAR-BODIES; PROTEIN-KINASE; HUMAN CANCERS; PHOSPHORYLATION; MDM2; BINDING; UBIQUITINATION; DEGRADATION; INHIBITOR AB In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modi. cations of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation. C1 [Alsheich-Bartok, O.; Haupt, S.; Alkalay-Snir, I.; Haupt, Y.] Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, Dept Immunol, IL-91120 Jerusalem, Israel. [Saito, S.; Appella, E.] NCI, Cell Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Haupt, Y (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, Dept Immunol, IL-91120 Jerusalem, Israel. EM haupt@md.huji.ac.il NR 30 TC 34 Z9 35 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2008 VL 27 IS 26 BP 3653 EP 3661 DI 10.1038/sj.onc.1211036 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 312HH UT WOS:000256659300002 PM 18246126 ER PT J AU Wagner, S Carpentier, I Rogov, V Kreike, M Ikeda, F Lohr, F Wu, CJ Ashwell, JD Dotsch, V Dikic, I Beyaert, R AF Wagner, S. Carpentier, I. Rogov, V. Kreike, M. Ikeda, F. Loehr, F. Wu, C-J Ashwell, J. D. Doetsch, V. Dikic, I. Beyaert, R. TI Ubiquitin binding mediates the NF-kappa B inhibitory potential of ABIN proteins SO ONCOGENE LA English DT Article DE ABIN; NF-kappa B; ubiquitin; TNF; protein-protein interaction ID ADENOVIRAL GENE-TRANSFER; A20-BINDING INHIBITOR; NEMO/IKK-GAMMA; KINASE COMPLEX; ACTIVATION; ALPHA; A20; IKK; RIP AB Deregulated nuclear factor kappa B (NF-kappa B) activation plays an important role in inflammation and tumorigenesis. ABIN proteins have been characterized as negative regulators of NF-kappa B signaling. However, their mechanism of NF-kappa B inhibition remained unclear. With the help of a yeast two-hybrid screen, we identified ABIN proteins as novel ubiquitin-interacting proteins. The minimal ubiquitin-binding domain (UBD) corresponds to the ABIN homology domain 2 (AHD2) and is highly conserved in ABIN-1, ABIN-2 and ABIN-3. Moreover, this region is also present in NF-kappa B essential modulator/I kappa B kinase gamma (NEMO/IKK gamma) and the NEMO-like protein optineurin, and is therefore termed UBD in ABIN proteins and NEMO (UBAN). Nuclear magnetic resonance studies of the UBAN domain identify it as a novel type of UBD, with the binding surface on ubiquitin being significantly different from the binding surface of other UBDs. ABIN-1 specifically binds ubiquitinated NEMO via a bipartite interaction involving its UBAN and NEMO-binding domain. Mutations in the UBAN domain led to a loss of ubiquitin binding and impaired the NF-kappa B inhibitory potential of ABINs. Taken together, these data illustrate an important role for ubiquitin binding in the negative regulation of NF-kappa B signaling by ABINs and identify UBAN as a novel UBD. C1 [Carpentier, I.; Kreike, M.; Beyaert, R.] Univ Ghent VIB, Dept Mol Biomed Res, Unit Mol Signal Transduct Inflammat, B-9052 Ghent, Belgium. [Carpentier, I.; Kreike, M.; Beyaert, R.] Univ Ghent, Dept Mol Biol, Zwijnaarde, Belgium. [Wagner, S.; Ikeda, F.; Dikic, I.] Univ Frankfurt, Sch Med, Inst Biochem 2, Frankfurt, Germany. [Rogov, V.; Loehr, F.; Doetsch, V.] Univ Frankfurt, Inst Biophys Chem, Frankfurt, Germany. [Rogov, V.] Russian Acad Sci, Inst Prot Res, Pushchino 142292, Russia. [Wu, C-J; Ashwell, J. D.] NCI, Lab Immune Cell Biol, NIH, Bethesda, MD 20892 USA. RP Beyaert, R (reprint author), Univ Ghent VIB, Dept Mol Biomed Res, Unit Mol Signal Transduct Inflammat, Technologiepk 927, B-9052 Ghent, Belgium. EM ivan.dikic@biochem2.de; rudi.beyaert@dmbr.ugent.be RI Doetsch, Volker/D-5697-2011; Wagner, Sebastian/B-9056-2012; Beyaert, Rudi/B-2589-2009; Dikic, Ivan/O-4650-2015; OI Dikic, Ivan/0000-0001-8156-9511; Ikeda, Fumiyo/0000-0003-0407-2768 NR 21 TC 122 Z9 129 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN PY 2008 VL 27 IS 26 BP 3739 EP 3745 DI 10.1038/sj.onc.1211042 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 312HH UT WOS:000256659300011 PM 18212736 ER PT J AU Klein, ML Ferris, FL Armstrong, J Hwang, TS Chew, EY Bressler, SB Chandra, SR AF Klein, Michael L. Ferris, Frederick L., III Armstrong, Jane Hwang, Thomas S. Chew, Emily Y. Bressler, Susan B. Chandra, Suresh R. CA AREDS Res Grp TI Retinal precursors and the development of geographic atrophy in age-related macular degeneration SO OPHTHALMOLOGY LA English DT Article ID FUNDUS AUTOFLUORESCENCE PATTERNS; PIGMENT EPITHELIUM; CHOROIDAL NEOVASCULARIZATION; PROGRESSION; DISEASE; DRUSEN; FORM AB Purpose: To determine specific retinal precursor lesions and sequence of events preceding the onset of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). Design: Retrospective review. Participants: All participants in the Age-Related Eye Disease Study (AREDS) at 2 clinical centers (Devers Eye Institute, Portland, Oregon, and University of Wisconsin, Madison, Wisconsin) in whom GA initially appeared in at least one eye a minimum of 4 years after the baseline study visit. Methods: All stereoscopic fundus photographs taken before the appearance of GA in the involved (study) eye were reviewed. Fundus features at the site of future GA were graded and recorded. Three graders reviewed photographs, with independent grading and adjudication by mutual agreement. Features graded included drusen (classified by size and confluence), focal hyperpigmentation, hypopigmentation, and refractile deposits. The time between first appearance of these features and initial appearance of GA was recorded. Main Outcome Measure: Appearance of GA. Results: Of all AREDS participants at the 2 sites, 95 eyes of 77 developed GA at least 4 years after entrance into the study. Average time from baseline to initial appearance of GA was 6.6 years (range, 4-11). Drusen were found in 100% of eyes at the site of later developing GA, drusen >1 25 mu m in diameter in 96% of eyes, confluent drusen in 94%, hyperpigmentation in 96%, drusen > 250 mu m in 83%, hypopigmentation in 82%, and refractile deposits in 23%. Time from lesion appearance to onset of GA varied by lesion type, ranging from 5.9 years for drusen confluence to 2.5 years for hypopigmentation or refractile deposits. Lesions generally followed a uniform sequence of appearance. Conclusions: By focusing on the location of initial GA appearance and then retrospectively analyzing prior photographs, we were able to identify specific precursor lesions and the most common sequence of events leading to GA formation in eyes with AMD. The progression was usually characterized by large drusen formation and development of hyperpigmentation, followed by regression of drusen, appearance of hypopigmentation, and ultimately development of GA, sometimes preceded by the appearance of refractile deposits. C1 [Klein, Michael L.; Hwang, Thomas S.] Oregon Hlth & Sci Univ, Macular Degenerat Ctr, Casey Eye Inst, Portland, OR 97239 USA. [Klein, Michael L.; Hwang, Thomas S.] Legacy Good Samaritan Hosp, Devers Eye Inst, Portland, OR USA. [Klein, Michael L.; Armstrong, Jane] Med Ctr, Portland, OR USA. [Ferris, Frederick L., III; Chew, Emily Y.] NEI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Armstrong, Jane] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Fundus Photograph Reading Ctr, Madison, WI USA. [Bressler, Susan B.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Chandra, Suresh R.] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Madison, WI USA. RP Klein, ML (reprint author), Oregon Hlth & Sci Univ, Macular Degenerat Ctr, Casey Eye Inst, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. FU Intramural NIH HHS [Z99 EY999999, ZIA EY000489-01] NR 22 TC 83 Z9 85 U1 1 U2 7 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 JUN PY 2008 VL 115 IS 6 BP 1026 EP 1031 DI 10.1016/j.ophtha.2007.08.030 PG 6 WC Ophthalmology SC Ophthalmology GA 306XX UT WOS:000256282800016 PM 17981333 ER PT J AU Lloyd-Smith, JO Poss, M Grenfell, BT AF Lloyd-Smith, James O. Poss, Mary Grenfell, Bryan T. TI HIV-1/parasite co-infection and the emergence of new parasite strains SO PARASITOLOGY LA English DT Article DE HIV/AIDS; emerging infectious diseases; mathematical model; population heterogeneity; drug resistance; zoonosis; immunosuppression ID HIV-POSITIVE PATIENTS; SUB-SAHARAN AFRICA; DRUG-RESISTANCE; INFECTIOUS-DISEASES; MALARIA; TRANSMISSION; LEISHMANIA; EVOLUTION; UGANDA; ADULTS AB HIV-1 and parasitic infections co-circulate in many populations, and in a few well-studied examples HIV-1 co-infection is known to amplify parasite transmission. There are indications that HIV-1 interacts significantly with many other parasitic infections within individual hosts, but the population-level impacts of co-infection are not well-characterized. Here we consider how alteration of host immune status due to HIV-1 infection may influence the emergence of novel parasite strains. We review clinical and epidemiological evidence from five parasitic diseases (malaria, leishmaniasis, schistosomiasis, trypanosomiasis and strongyloidiasis) with emphasis on how HIV-1 co-infection alters individual susceptibility and infectiousness for the parasites. We then introduce a simple modelling framework that allows us to project how these individual-level properties might influence population-level dynamics. We find that HIV-1 can facilitate invasion by parasite strains in many circumstances and we identify threshold values of HIV-1 prevalence that allow otherwise unsustainable parasite strains to invade successfully. Definitive evidence to test these predicted effects is largely lacking, and we conclude by discussing challenges in interpreting available data and priorities for future studies. C1 [Lloyd-Smith, James O.; Poss, Mary; Grenfell, Bryan T.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Grenfell, Bryan T.] US Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lloyd-Smith, JO (reprint author), Penn State Univ, Ctr Infect Dis Dynam, 208 Mueller Lab, University Pk, PA 16802 USA. EM jlloydsmith@psu.edu RI Lloyd-Smith, James/K-4080-2012 OI Lloyd-Smith, James/0000-0001-7941-502X FU NIGMS NIH HHS [GM83606] NR 51 TC 23 Z9 23 U1 2 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0031-1820 J9 PARASITOLOGY JI Parasitology PD JUN PY 2008 VL 135 IS 7 BP 795 EP 806 DI 10.1017/S0031182008000292 PG 12 WC Parasitology SC Parasitology GA 330CO UT WOS:000257917300005 PM 18371236 ER PT J AU Lock, R Carol, H Houghton, PJ Morton, CL Kolb, EA Gorlick, R Reynolds, CP Maris, JM Keir, ST Wu, JR Smith, MA AF Lock, Richard Carol, Hernan Houghton, Peter J. Morton, Christopher L. Kolb, E. Anders Gorlick, Richard Reynolds, C. Patrick Maris, John M. Keir, Stephen T. Wu, Jianrong Smith, Malcolm A. TI Initial testing (stage 1) of the BH3 mimetic ABT-263 by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ABT-263; Bcl-2; developmental therapeutics; preclinical testing ID GLUCOCORTICOID-INDUCED APOPTOSIS; BCL-2 FAMILY PROTEINS; HEMATOPOIETIC PROGENITORS; CANCER MODELS; IN-VIVO; BIM; INHIBITOR; CHEMOTHERAPY; SURVIVAL; DOMAINS AB Background. ABT-263 is a potent (K(i) < 1 nM) small-molecule BH3 mimetic that inhibits the antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w. The Structurally related Bcl-2 inhibitor ABT-737 exhibits single-agent preclinical activity against lymphoma, small-cell lung carcinoma, and chronic lymphocytic leukemia and displays synergistic cytotoxicity with chemotherapeutics and radiation. Methods. ABT-263 was tested at concentrations ranging from 1.0 nM to 10.0 mu M using 23 cell lines from the PPTP in vitro panel and was tested in 44 xenograft models representing nine distinct histologies using daily gavage administration of ABT-263 (100 mg/kg) or vehicle for 21 days. Results. ABT-263 was active against approximately one-half of the cell lines of the PPTP in vitro panel. The median IC(50) for all of the lines in the panel was 1.91 mu M. ABT-263 induced significant prolongation of the EFS distribution in 9 of 35 (26%) of the solid tumor xenografts, and in 5 of 6 (83%) of the evaluable ALL xenografts. ABT-263 induced no objective responses in the solid tumor panels, but induced CRs in 3 of 6 evaluable xenografts in the ALL panel, including two that were maintained for an additional 3 weeks following treatment cessation. Conclusions. ABT-263 demonstrated in vitro activity against a range of cell lines, with the ALL cell lines showing the greatest sensitivity. ABT-263 demonstrated limited single agent in vivo activity against the PPTP's solid tumor panels but showed significant activity against xenografts in the ALL panel. C1 [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Houghton, Peter J.; Morton, Christopher L.; Wu, Jianrong] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Kolb, E. Anders; Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 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. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Lock, R (reprint author), Childrens Canc Inst Australia, POB 81,High St, Randwick, NSW 2031, Australia. EM rlock@ccia.unsw.edu.au RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [P30 CA021765, CA108786, CA21765, N01-CM-42216] NR 31 TC 86 Z9 86 U1 0 U2 1 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2008 VL 50 IS 6 BP 1181 EP 1189 DI 10.1002/pbc.21433 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288TL UT WOS:000255008600015 PM 18085673 ER PT J AU Kolb, EA Gorlick, R Houghton, PJ Morton, CL Lock, R Carol, H Reynolds, CP Maris, JM Keir, ST Billups, CA Smith, MA AF Kolb, E. Anders Gorlick, Richard Houghton, Peter J. Morton, Christopher L. Lock, Richard Carol, Hernan Reynolds, C. Patrick Maris, John M. Keir, Stephen T. Billups, Catherine A. Smith, Malcolm A. TI Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; IGF-1R; preclinical testing; SCH 717454 ID GROWTH-FACTOR-I; BREAST-CANCER CELLS; INSULIN-RECEPTOR; EWINGS-SARCOMA; MALIGNANT PHENOTYPE; HUMAN NEUROBLASTOMA; OSTEOSARCOMA CELLS; ANTITUMOR-ACTIVITY; XENOGRAFT MODELS; DOWN-REGULATION AB Background SCH 717454 (19D12) is a fully human antibody directed against the insulin-like growth factor 1 receptor (IGF-1R), which is implicated in the growth and metastatic phenotype of a broad range of malignancies. The activity of SCH 717454 was evaluated against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. SCH 717454 was tested against the PPTP in vitro panel at concentrations ranging from 0.01 to 100 nM and was tested against the PPTP in vivo panel at a dose of 0.5 mg per mouse administered twice weekly for 4 weeks via intraperitoneal injection. Results. SCH 717454 was ineffective at retarding growth of cell lines in the in vitro panel. in vivo, SCH 717454 significantly increased event-free survival in 20 of 35 (57%) solid tumor xenograft models with tumor regressions in one Ewing sarcoma model (complete response) and 2 osteosarcoma models (maintained complete responses). Using the time to event activity measure, SCH 717454 had intermediate (n=9) or high ml) activity against 31 evaluable solid tumor xenografts, including xenografts from the rhabdoid tumor, Ewing, rhabdomyosarcoma, glioblastoma, neuroblastoma, and osteosarcoma panels. SCH 717454 showed little activity against the 8 xenografts of the acute lymphoblastic leukemia panel. Conclusions. SCH 717454 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels. Further characterization of the molecular predictors of response and of the activity of combinations of SCH 717454 with other anticancer agents are anticipated. C1 [Kolb, E. Anders; Gorlick, Richard] Childrens Hosp Montefiore, Albert Einstein Coll Med, Bronx, NY USA. [Lock, Richard; Carol, Hernan] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Houghton, Peter J.; Morton, Christopher L.; Billups, Catherine A.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 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. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Kolb, EA (reprint author), Alfred I DuPont Hosp Children, Div Hematol & Oncol, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM eakolb@nemours.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [CA21765, N01 CM042216, N01-CM-42216] NR 62 TC 113 Z9 121 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2008 VL 50 IS 6 BP 1190 EP 1197 DI 10.1002/pbc.21450 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288TL UT WOS:000255008600016 PM 18260118 ER PT J AU Kolb, EA Gorlick, R Houghton, PJ Morton, CL Lock, RB Tajbakhsh, M Reynolds, CP Maris, JM Keir, ST Billups, CA Smith, MA AF Kolb, E. Anders Gorlick, Richard Houghton, Peter J. Morton, Christopher L. Lock, Richard B. Tajbakhsh, Mayamin Reynolds, C. Patrick Maris, John M. Keir, Stephen T. Billups, Catherine A. Smith, Malcolm A. TI Initial testing of dasatinib by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE dasatinib; developmental therapeutics; preclinical testing ID CHRONIC MYELOID-LEUKEMIA; SRC KINASE-ACTIVITY; C-SRC; IMATINIB-RESISTANT; CANCER CELLS; LYMPHOBLASTIC-LEUKEMIA; HUMAN OSTEOSARCOMA; IN-VIVO; BMS-354825; LYN AB Background Dasatinib, a dual inhibitor of the src and abl tyrosine kinases, was recently approved by the Federal Drug Administration for the treatment of imatinib mesylate-resistant chronic myeloid leukemia. Procedures. Dasatinib was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 0.1 nM to 1.0 mu M and was tested in vivo at a dose of 50 mg/kg administered orally twice daily 5 days per week for 4 weeks for the solid tumor xenografts and once daily for the acute lymphoblastic leukemia (ALL) xenografts. Results. Dasatinib was selectively active against the cell lines of the PPTP in vitro panel, reaching an IC50 in 6 of the 22 lines. The most sensitive were the AML line Kasumi-1, which has a gain-of-function c-Kit mutation (Asn822Lys), and the rhabdoid tumor line CHLA-266 (IC50 approximately 10 nM for each). In the in vivo panel, dasatinib induced significant differences in EFS distribution in 8 of 32 (25%) solid tumor models and 3 of 7 ALL models. Using the time to event activity measure, dasatinib had intermediate activity against 1 of 27 (4%) evaluable solid tumor xenografts and 3 of 7 ALL xenografts. One xenograft in the ALL panel, a Philadelphia chromosome positive (Ph+) ALL xenograft, demonstrated a complete response. Conclusions. Dasatinib was active at low nanomolar concentrations against a small subset of the PPTP's in vitro panel. Dasatinib had limited in vivo activity against the PPTP solid tumor xenografts, but was highly active against a Ph+ ALL xenograft and also had anti-leukemia activity against two other xenografts. C1 [Kolb, E. Anders; Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Houghton, Peter J.; Morton, Christopher L.; Billups, Catherine A.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Lock, Richard B.; Tajbakhsh, Mayamin] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 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. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Kolb, EA (reprint author), Alfred I DuPont Hosp Children, Wilmington, DE 19803 USA. EM eakolb@nemours.org RI Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [N01 CM042216, CA108786, CA21765, N01-CM-42216] NR 44 TC 46 Z9 47 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN PY 2008 VL 50 IS 6 BP 1198 EP 1206 DI 10.1002/pbc.21368 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 288TL UT WOS:000255008600017 PM 17914733 ER PT J AU Brown, RJ Rother, KI AF Brown, Rebecca J. Rother, Kristina I. TI Effects of beta-cell rest on beta-cell function: a review of clinical and preclinical data SO PEDIATRIC DIABETES LA English DT Review DE diabetes mellitus type 1; diabetes mellitus type 2; diazoxide; insulin; insulin-secreting cells ID TYPE-2 DIABETES-MELLITUS; SELECTIVE SOMATOSTATIN ANALOGS; PROPHYLACTIC INSULIN-TREATMENT; POTASSIUM CHANNEL OPENERS; TERM GLYCEMIC CONTROL; OXIDATIVE STRESS; HUMAN ISLETS; PANCREATIC-ISLETS; RAT MODEL; BB-RATS C1 [Brown, Rebecca J.; Rother, Kristina I.] Natl Inst Diabet Digest & Kidney Dis, Clin Endocrinol Branch, Natl Inst Hlth, Bethesda, MD USA. RP Rother, KI (reprint author), Bldg 10,Room 8C-432A, Bethesda, MD 20892 USA. EM kristinar@mail.nih.gov FU Intramural NIH HHS [Z01 DK047049-02, Z99 DK999999, ZIA DK047049-03, Z01 DK047049-01, ZIA DK047049-04] NR 67 TC 29 Z9 31 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD JUN PY 2008 VL 9 IS 3 BP 14 EP 22 DI 10.1111/j.1399-5448.2007.00272.x PN 2 PG 9 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 307YM UT WOS:000256355500003 PM 18221429 ER PT J AU Nesterova, G Gahl, W AF Nesterova, Galina Gahl, William TI Nephropathic cystinosis: late complications of a multisystemic disease SO PEDIATRIC NEPHROLOGY LA English DT Review DE cystinosis; nephropathic; complications; lysosomal storage; transport ID NONCIRRHOTIC PORTAL-HYPERTENSION; LEUKOCYTE GRANULAR FRACTIONS; GENETIC METABOLIC-DISORDER; ORAL CYSTEAMINE THERAPY; CHRONIC-RENAL-FAILURE; TERM-FOLLOW-UP; AGE 10 YEARS; INFANTILE CYSTINOSIS; DIABETES-MELLITUS; INTELLECTUAL-DEVELOPMENT AB Cystinosis is a rare autosomal recessive disorder due to impaired transport of cystine out of cellular lysosomes. Its estimated incidence is 1 in 100,000 live births. End-stage renal disease (ESRD) is the most prominent feature of cystinosis and, along with dehydration and electrolyte imbalance due to renal tubular Fanconi syndrome, has accounted for the bulk of deaths from this disorder. Prior to renal transplantation and cystine-depleting therapy with cysteamine for children with nephropathic cystinosis, their lifespan was approximately 10 years. Now, cystinotic patients have survived through their fifth decade, but the unremitting accumulation of cystine has created significant non-renal morbidity and mortality. In this article we review the classic presentation of nephropathic cystinosis and the natural history, diagnosis, and treatment of the disorder's systemic involvement. We also emphasize the role of oral cysteamine therapy in preventing the late complications of cystinosis. C1 [Nesterova, Galina; Gahl, William] NHGRI, NIH, Human Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. RP Gahl, W (reprint author), NHGRI, NIH, Human Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov FU Intramural NIH HHS NR 133 TC 61 Z9 62 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUN PY 2008 VL 23 IS 6 BP 863 EP 878 DI 10.1007/s00467-007-0650-8 PG 16 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 294NV UT WOS:000255413700003 PM 18008091 ER PT J AU Klein, MI Bergel, E Gibbons, L Coviello, S Bauer, G Benitez, A Serra, ME Delgado, MF Melendi, GA Rodriguez, S Kleeberger, SR Polack, FP AF Klein, M. Ines Bergel, Eduardo Gibbons, Luz Coviello, Silvina Bauer, Gabriela Benitez, Alicia Serra, M. Elina Delgado, M. Florencia Melendi, Guillermina A. Rodriguez, Susana Kleeberger, Steven R. Polack, Fernando P. TI Differential gender response to respiratory infections and to the protective effect of breast milk in preterm infants SO PEDIATRICS LA English DT Article DE lower respiratory infection; breast milk; respiratory syncytial virus; prematurity; gender ID SYNCYTIAL VIRUS-INFECTION; YOUNG-CHILDREN; 1ST YEAR; HUMAN METAPNEUMOVIRUS; INFLUENZA VACCINES; TRACT ILLNESS; HIGH-RISK; DISEASE; MEASLES; SERUM AB OBJECTIVE. The protective role of breastfeeding against severe acute lung disease in infants is well established, but its mechanism is unclear. Most hypotheses assume that breastfeeding confers similar passive protection to every infant; however, a few observations have suggested that the benefits of breast milk against severe lung disease may differ according to gender. The objective of this study was to determine whether the effect of breastfeeding on susceptibility to severe acute lung disease among infants at high risk is different for girls and boys. METHODS. A cohort was analyzed prospectively by use of 2 different strategies: (1) predictors of first episode of rehospitalization by univariate and multivariate analyses using robust Poisson regression and (2) mean number of rehospitalizations between groups using multiple regression negative binomial models. RESULTS. A total of 119 high-risk, very low birth weight infants were enrolled. Breast milk protected girls but not boys against severe acute lung disease. The interaction between breastfeeding and gender was clinically and statistically significant, even after adjustment for variables that can affect severity of acute lung disease. Disease was most severe in formula-fed girls (versus formula-fed boys). CONCLUSIONS. Breastfeeding decreased the risk for severe acute lung disease in girls but not in boys. These findings suggest that breast milk protection is not universally conferred by passive transfer of humoral immunity (which should be gender indifferent), show that respiratory symptoms may be amenable to nonspecific modulation, and identify nonbreastfed preterm infant girls as an at-risk group for severe acute lung disease. C1 [Melendi, Guillermina A.; Polack, Fernando P.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Polack, Fernando P.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Polack, Fernando P.] Johns Hopkins Univ, Dept Int Hlth, Baltimore, MD 21205 USA. [Kleeberger, Steven R.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. [Klein, M. Ines; Coviello, Silvina; Serra, M. Elina; Delgado, M. Florencia; Melendi, Guillermina A.; Polack, Fernando P.] Fdn INFANT, Buenos Aires, DF, Argentina. [Bergel, Eduardo; Gibbons, Luz] Inst Efectividad Clin & Sanitaria, Buenos Aires, DF, Argentina. [Bergel, Eduardo] Dept Reprod Hlth & Res, World Bank Special Programme Res Dev & Res Traini, World Hlth Org, United Nat Populat Fund,United Nat Dev Programme, Geneva, Switzerland. [Bauer, Gabriela; Rodriguez, Susana] Hosp Pediat Juan P Garrahan, High Risk Clin, Buenos Aires, DF, Argentina. RP Polack, FP (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, 615 N Wolfe St,E5202, Baltimore, MD 21205 USA. EM fpolack@jhsph.edu FU Intramural NIH HHS [Z01 ES100557-06]; NIAID NIH HHS [R21 AI054952, R01 AI054952, AI-054952] NR 42 TC 20 Z9 22 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2008 VL 121 IS 6 BP E1510 EP E1516 DI 10.1542/peds.2007-1757 PG 7 WC Pediatrics SC Pediatrics GA 307IX UT WOS:000256313700007 PM 18519454 ER PT J AU Hsu, PYJ Kotin, RM Yang, YW AF Hsu, Paul Yueh-Jen Kotin, Robert M. Yang, Ya-Wun TI Glucose- and metabolically regulated hepatic insulin gene therapy for diabetes SO PHARMACEUTICAL RESEARCH LA English DT Article DE diabetes mellitus; insulin; polyethylenimine; recombinant adeno-associated virus; regulated gene therapy ID RECOMBINANT ADENOASSOCIATED VIRUS; BETA-CELLS; PROINSULIN; EXPRESSION; SECRETION; DELIVERY; VECTORS; GLUCOKINASE; CALCIUM; LIVER AB Purpose. The purpose of this study was to examine glucose- and metabolically modulation of insulin secretion by rAAV-mediated gene delivery in vitro and in vivo. Materials and methods. A recombinant adeno-associated virus vector (rAAV) containing a furin-mutated human insulin gene, driven by the rat insulin I promoter, was used in this study. Glucose-responsive secretion of human insulin was determined by treating rAAV-transduced Huh7 human hepatoma cells with varying concentrations of glucose, with or without insulin secretagogues. Glucose- and metabolically modulated secretion of human insulin in the streptozotocin (STZ)-induced diabetic mice was assessed by intrahepatic administration of rAAV-polyethylenimine (PEI) complexes, followed by intraperitoneal glucose tolerance test (IPGTT), with or without theophylline. Results. Glucose- and metabolically controlled human insulin secretion was obtained in the rAAV-transduced Huh7 cells. Treatment of STZ-induced diabetic animals with rAAV-polyethylenimine (rAAV-PEI) complexes resulted in production of human insulin and amelioration of hyperglycemia. Co-administration of glucose and theophylline in these animals augmented the secretion of human insulin, demonstrating metabolic modulation of insulin secretion in vivo. Immunohistochemical examination of the liver sections of rAAV-treated mice confirmed the production of human insulin. Conclusions. Glucose- and metabolically controlled hepatic insulin gene therapy was obtained both in vitro and in vivo. C1 [Hsu, Paul Yueh-Jen; Yang, Ya-Wun] Natl Taiwan Univ, Sch Pharm, Coll Med, Taipei 100, Taiwan. [Kotin, Robert M.] NHLBI, Lab Biochem Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Yang, YW (reprint author), Natl Taiwan Univ, Sch Pharm, Coll Med, 1 Jen Ai Rd,Sect 1, Taipei 100, Taiwan. EM ywyang@ntu.edu.tw RI kotin, robert/B-8954-2008 NR 36 TC 9 Z9 11 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES JI Pharm. Res. PD JUN PY 2008 VL 25 IS 6 BP 1460 EP 1468 DI 10.1007/s11095-008-9539-x PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 299KG UT WOS:000255753900022 PM 18293064 ER PT J AU Takabe, K Paugh, SW Milstien, S Spiegel, S AF Takabe, Kazuaki Paugh, Steven W. Milstien, Sheldon Spiegel, Sarah TI "Inside-Out" signaling of sphingosine-1-phosphate: Therapeutic targets SO PHARMACOLOGICAL REVIEWS LA English DT Review ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; PROTEIN-COUPLED RECEPTOR; NOVO RENAL-TRANSPLANTATION; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; ENDOTHELIAL BARRIER FUNCTION; KINASE INHIBITOR SUPPRESSES; RANDOMIZED CONTROLLED-TRIAL; MAST-CELL DEGRANULATION; GENE-DEFICIENT MICE; BREAST-CANCER CELLS AB Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody. C1 [Paugh, Steven W.; Spiegel, Sarah] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Sch Med, Richmond, VA 23298 USA. [Takabe, Kazuaki] Virginia Commonwealth Univ, Dept Surg, Sch Med, Div Surg Oncol, Richmond, VA 23298 USA. [Milstien, Sheldon] NIMH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Sch Med, 1101 E Marshall St,2011 Sanger Hall, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Paugh, Steven/A-7739-2008 OI Paugh, Steven/0000-0001-5697-9228 FU Intramural NIH HHS; NCI NIH HHS [R01 CA061774, R01 CA061774-15, R01CA61774]; NIAID NIH HHS [T32 AI007407, R01 AI050094, R01 AI050094-06A2, R01AI50094, T32AI007407]; NICHD NIH HHS [1K12HD055881-01, K12 HD055881]; NIGMS NIH HHS [5T32GM008695-08, R37 GM043880, R37 GM043880-18, R37GM043880, T32 GM008695] NR 198 TC 334 Z9 349 U1 3 U2 24 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 2008 VL 60 IS 2 BP 181 EP 195 DI 10.1124/pr.107.07113 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 323IG UT WOS:000257439200003 PM 18552276 ER PT J AU Miller, DS Bauer, B Hartz, AMS AF Miller, David S. Bauer, Bjoern Hartz, Anika M. S. TI Modulation of P-glycoprotein at the blood-brain barrier: Opportunities to improve central nervous system pharmacotherapy SO PHARMACOLOGICAL REVIEWS LA English DT Review ID PREGNANE-X-RECEPTOR; MICROVESSEL ENDOTHELIAL-CELLS; MULTIDRUG-RESISTANCE GENE; NECROSIS-FACTOR-ALPHA; CANALICULAR ABC TRANSPORTERS; INFLAMMATORY-BOWEL-DISEASE; RAT-BRAIN; UP-REGULATION; DRUG-TRANSPORTER; IN-VIVO AB Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin ( ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic. C1 [Miller, David S.; Bauer, Bjoern; Hartz, Anika M. S.] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Bauer, Bjoern] Univ Minnesota, Coll Pharm, Duluth, MN 55812 USA. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Duluth, MN 55812 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov FU Intramural NIH HHS [Z01 ES080048-17, Z01 ES080060-08, Z99 ES999999] NR 121 TC 177 Z9 182 U1 3 U2 27 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD JUN PY 2008 VL 60 IS 2 BP 196 EP 209 DI 10.1124/pr.107.07109 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 323IG UT WOS:000257439200004 PM 18560012 ER PT J AU Thanos, PK Michaelides, M Ho, CW Wang, GJ Newman, AH Heidbreder, CA Ashby, CR Gardner, EL Volkow, ND AF Thanos, Panayotis K. Michaelides, Michael Ho, Christopher W. Wang, Gene-Jack Newman, Amy H. Heidbreder, Christian A. Ashby, Charles R., Jr. Gardner, Eliot L. Volkow, Nora D. TI The effects of two highly selective dopamine D(3) receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE hunger; ingestive behavior; operant conditioning; anorexia; anorexigenic ID DRUG-SEEKING BEHAVIOR; ENHANCED BRAIN REWARD; NUCLEUS-ACCUMBENS; ZUCKER RATS; MOTIVATED BEHAVIOR; COCAINE-SEEKING; MESSENGER-RNA; INDUCED REINSTATEMENT; MESOLIMBIC DOPAMINE; EXPRESSION AB In the current study, we examined the effect of the selective D(3) receptor antagonists SB-277011A and NGB 2904 on operant food self-administration (FSA) in Zucker obese and lean rats. Obese (Ob) and lean (Le) Zucker rats were maintained under a restricted feeding regimen (70% of ad-libitum rat chow) and were trained to lever press for food during daily, 2 hour fixed-ratio 4 (FR4) schedules. Once rats reached a stable baseline for FSA, they were injected with vehicle until a stable FSA criterion was achieved. Animals then received daily injections of different random doses of SB-277011A (3, 10, and 30 mg/kg i.p.), and NGB-2904 (0.3, 1 and 3 mg/kg i.p.). SB-277011A produced a significant decrease in both food intake and active lever responses in both Ob and Le rats. In contrast, NGB-2904 did not decrease food intake levels or lever presses for food in Ob and Le rats. These results suggest that along with its involvement in seeking behavior for drugs of abuse, the D(3) dopamine receptor may also be involved in seeking behavior for natural reinforcers such as food. (C) 2008 Elsevier Inc. All rights reserved. C1 [Thanos, Panayotis K.; Michaelides, Michael; Ho, Christopher W.; Wang, Gene-Jack] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Michaelides, Michael] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Thanos, Panayotis K.] SUNY Stony Brook, Neurosci Program, Stony Brook, NY 11794 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Newman, Amy H.; Gardner, Eliot L.] NIDA, Intramural Res Program, NIH, Baltimore, MD USA. [Ashby, Charles R., Jr.] St Johns Univ, Jamaica, NY 11439 USA. [Ho, Christopher W.] GlaxoSmithKline Inc, Verona, Italy. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, 30 Bell Ave, Upton, NY 11973 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU Intramural NIH HHS [Z01 AA000551-04] NR 78 TC 32 Z9 33 U1 1 U2 5 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 JUN PY 2008 VL 89 IS 4 BP 499 EP 507 DI 10.1016/j.pbb.2008.02.003 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 302ZH UT WOS:000256008200002 PM 18329700 ER PT J AU Foreman, MM Hanania, T Stratton, SC Wilcox, KS White, HS Stables, JR Eller, M AF Foreman, Mark M. Hanania, Taleen Stratton, Sharon C. Wilcox, Karen S. White, H. Steve Stables, James R. Eller, Mark TI In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE JZP-4; lamotrigine; anticonvulsant; mood stabilizer; antidepressant; mania; epilepsy; bipolar disorder ID ANTIEPILEPTIC DRUGS; ELECTRICAL STIMULATION; BEHAVIORAL DESPAIR; LAMOTRIGINE; SEIZURE; RATS; CHLORDIAZEPOXIDE; DEXAMPHETAMINE; VALPROATE; EPILEPSY AB JZP-4 is a potent calcium and sodium channel blocker, which is currently being evaluated in patients as an anticonvulsant and mood stabilizer. in the current studies, JZP-4 was evaluated in a variety of animal models for anticonvulsant, antimania and antidepressant activity. In the mouse and rat maximal electroshock models, JZP-4 was slightly more potent than LTG. In the mouse pentylenetetrazole induced seizures model, JZP-4 was approximately twice as potent as lamotrigine in prolonging the time to clonus. In the mouse 6-Hz model for drug resistant or refractory epilepsy, JZP-4 had potent anticonvulsant activity at all current intensities, whereas LTG was active at only the lowest current intensity. In the mouse amphetamine-chlordiazepoxide model for antimanic effects, JZP-4, but not LTG, produced dose-related and significant effects at 3 and 10 mg/kg i.p. In the rat forced swim model of antidepressant activity, JZP-4 (30 mg/kg i.p.) produced a significant reduction in immobility and an increase in climbing behavior. LTG (30 mg/kg i.p.) produced similar effects but these effects did not achieve statistical significance. The specificity of this antidepressant response was confirmed in the rat locomotor test. In this test, JZP-4 produced dose-related and significant reductions in locomotor activity, indicating that it was not a CNS stimulant. LTG produced no significant effects in the rat locomotor test. The studies have demonstrated that JZP-4 has greater potency and efficacy than LTG in models of refractory epilepsy, antidepressant activity and antimania activity. The variance between the effects of LTG and JZP-4 may be related to the greater potency at sodium channels or the additional pharmacological actions of JZP-4 on calcium channels. (C) 2008 Elsevier Inc. All rights reserved. C1 [Foreman, Mark M.; Eller, Mark] Jazz Pharmaceut, Palo Alto, CA 94304 USA. [Wilcox, Karen S.; White, H. Steve] Univ Utah, Salt Lake City, UT 84112 USA. [Stables, James R.] NINDS, Bethesda, MD 20892 USA. RP Foreman, MM (reprint author), Jazz Pharmaceut, 3180 Porter Dr, Palo Alto, CA 94304 USA. EM mforeman@jazzphanna.com NR 51 TC 15 Z9 15 U1 1 U2 7 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 JUN PY 2008 VL 89 IS 4 BP 523 EP 534 DI 10.1016/j.pbb.2008.02.007 PG 12 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 302ZH UT WOS:000256008200005 PM 18377968 ER PT J AU Wolski, SC Kuper, J Hanzelmann, P Truglio, JJ Croteau, DL Van Houten, B Kisker, C AF Wolski, Stefanie C. Kuper, Jochen Haenzelmann, Petra Truglio, James J. Croteau, Deborah L. Van Houten, Bennett Kisker, Caroline TI Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD SO PLOS BIOLOGY LA English DT Article ID MEDIATED CHARGE-TRANSPORT; ELECTRON-DENSITY MAPS; DNA-REPAIR; DAMAGE RECOGNITION; XERODERMA-PIGMENTOSUM; ATP HYDROLYSIS; OPEN COMPLEX; MECHANISM; PROTEIN; TRANSCRIPTION AB DNA damage recognition by the nucleotide excision repair pathway requires an initial step identifying helical distortions in the DNA and a proofreading step verifying the presence of a lesion. This proofreading step is accomplished in eukaryotes by the TFIIH complex. The critical damage recognition component of TFIIH is the XPD protein, a DNA helicase that unwinds DNA and identifies the damage. Here, we describe the crystal structure of an archaeal XPD protein with high sequence identity to the human XPD protein that reveals how the structural helicase framework is combined with additional elements for strand separation and DNA scanning. Two RecA-like helicase domains are complemented by a 4Fe4S cluster domain, which has been implicated in damage recognition, and an alpha-helical domain. The first helicase domain together with the helical and 4Fe4S-cluster-containing domains form a central hole with a diameter sufficient in size to allow passage of a single stranded DNA. Based on our results, we suggest a model of how DNA is bound to the XPD protein, and can rationalize several of the mutations in the human XPD gene that lead to one of three severe diseases, xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. C1 [Wolski, Stefanie C.; Kuper, Jochen; Haenzelmann, Petra; Kisker, Caroline] Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, Wurzburg, Germany. [Truglio, James J.] SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. [Croteau, Deborah L.; Van Houten, Bennett] Natl Inst Environm Hlth Sci, Mol Genet Lab, Natl Inst Hlth, Res Triangle Pk, NC USA. RP Kisker, C (reprint author), Univ Wurzburg, Inst Biol Struct, Rudolf Virchow Ctr Expt Biomed, Wurzburg, Germany. EM caroline.kisker@virchow.uni-wuerzburg.de FU Intramural NIH HHS; Medical Research Council [G0500367] NR 59 TC 120 Z9 127 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD JUN PY 2008 VL 6 IS 6 BP 1332 EP 1342 AR e149 DI 10.1371/journal.pbio.0060149 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 318QA UT WOS:000257105500019 PM 18578568 ER PT J AU Chang, M Rowland, CM Garcia, VE Schrodi, SJ Catanese, JJ Mil, AHMVDHV Ardlie, KG Amos, CI Criswell, LA Kastner, DL Gregersen, PK Kurreeman, FAS Toes, REM Huizinga, TWJ Seldin, MF Begovich, AB AF Chang, Monica Rowland, Charles M. Garcia, Veronica E. Schrodi, Steven J. Catanese, Joseph J. Mil, Annette H. M. van der Helm-van Ardlie, Kristin G. Amos, Christopher I. Criswell, Lindsey A. Kastner, Daniel L. Gregersen, Peter K. Kurreeman, Fina A. S. Toes, Rene E. M. Huizinga, Tom W. J. Seldin, Michael F. Begovich, Ann B. TI A Large-Scale Rheumatoid Arthritis Genetic Study Identifies Association at Chromosome 9q33.2 SO PLOS GENETICS LA English DT Article ID RECEPTOR-ASSOCIATED FACTOR-1; GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; COLLAGEN-INDUCED ARTHRITIS; REED-STERNBERG CELLS; NF-KAPPA-B; LINKAGE DISEQUILIBRIUM; TYROSINE-PHOSPHATASE; AUTOIMMUNE-DISEASES; MONOCLONAL-ANTIBODY AB Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease affecting both joints and extra-articular tissues. Although some genetic risk factors for RA are well-established, most notably HLA-DRB1 and PTPN22, these markers do not fully account for the observed heritability. To identify additional susceptibility loci, we carried out a multi-tiered, casecontrol association study, genotyping 25,966 putative functional SNPs in 475 white North American RA patients and 475 matched controls. Significant markers were genotyped in two additional, independent, white case-control sample sets (661 cases/1322 controls from North America and 596 cases/705 controls from The Netherlands) identifying a SNP, rs1953126, on chromosome 9q33.2 that was significantly associated with RA (OR(common) = 1.28, trend P(comb) = 1.45E- 06). Through a comprehensive fine-scale-mapping SNP-selection procedure, 137 additional SNPs in a 668 kb region from MEGF9 to STOM on 9q33.2 were chosen for follow-up genotyping in a staged-approach. Significant single marker results (P(comb)<0.01) spanned a large 525 kb region from FBXW2 to GSN. However, a variety of analyses identified SNPs in a 70 kb region extending from the third intron of PHF19 across TRAF1 into the TRAF1-C5 intergenic region, but excluding the C5 coding region, as the most interesting (trend Pcomb: 1.45E-06 -> 5.41E-09). The observed association patterns for these SNPs had heightened statistical significance and a higher degree of consistency across sample sets. In addition, the allele frequencies for these SNPs displayed reduced variability between control groups when compared to other SNPs. Lastly, in combination with the other two known genetic risk factors, HLA-DRB1 and PTPN22, the variants reported here generate more than a 45-fold RA-risk differential. C1 [Chang, Monica; Rowland, Charles M.; Garcia, Veronica E.; Schrodi, Steven J.; Catanese, Joseph J.; Begovich, Ann B.] Celera, Alameda, CA USA. [Mil, Annette H. M. van der Helm-van; Kurreeman, Fina A. S.; Toes, Rene E. M.; Huizinga, Tom W. J.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Ardlie, Kristin G.] SeraCare Life Sci, Cambridge, MA USA. [Amos, Christopher I.] Univ Texas Houston, Houston, TX USA. [Criswell, Lindsey A.] Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA USA. [Kastner, Daniel L.] NIH, Bethesda, MD 20892 USA. [Gregersen, Peter K.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Seldin, Michael F.] Univ Calif Davis, Davis, CA 95616 USA. RP Chang, M (reprint author), Celera, Alameda, CA USA. EM ann.begovich@roche.com OI Schrodi, Steven/0000-0003-2304-8528 FU National Arthritis Foundation; National Institutes of Health; National Institute of Arthritis; Musculoskeletal and Skin Diseases; National Institute of Allergy and Infectious Diseases [N01-AR-7-2232, R01-AR44222]; National Center for Research Resources [5 M01 RR-00079]; National Institutes of Health [HG02275]; Dutch Arthritis Foundation FX Collection of the NARAC samples has been funded by a National Arthritis Foundation grant and the National Institutes of Health, acting through the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases (contracts N01-AR-7-2232 and R01-AR44222). These studies were performed in part in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by the National Center for Research Resources (5 M01 RR-00079, U. S. Public Health Service). Support was also provided by the National Institutes of Health through grant HG02275. The Department of Rheumatology, Leiden University Medical Center, received funding from the Dutch Arthritis Foundation. NR 88 TC 46 Z9 49 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2008 VL 4 IS 6 AR e1000107 DI 10.1371/journal.pgen.1000107 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 365MI UT WOS:000260410300007 PM 18648537 ER PT J AU Jordan, JJ Menendez, D Inga, A Nourredine, M Bell, D Resnick, MA AF Jordan, Jennifer J. Menendez, Daniel Inga, Alberto Nourredine, Maher Bell, Douglas Resnick, Michael A. TI Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53 SO PLOS GENETICS LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; SITE-DIRECTED MUTAGENESIS; BINDING DOMAIN PEPTIDES; MASTER REGULATOR P53; FRAUMENI LIKE FAMILY; BETA-STRAND 326-333; TETRAMERIZATION DOMAIN; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; MISSENSE MUTATION AB Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0-13 nucleotides (nt), originally defined by the consensus RRRCWWGYYY (n=0-13) RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs) by wild type (WT) and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi-in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical 1/2-(a single decamer) and 3/4-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1.p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of 1/2- and 3/4-site REs greatly expands the p53 master regulatory network. C1 [Jordan, Jennifer J.; Menendez, Daniel; Inga, Alberto; Nourredine, Maher; Bell, Douglas; Resnick, Michael A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Jordan, Jennifer J.; Resnick, Michael A.] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC USA. [Inga, Alberto] IST, Natl Inst Canc Res, Unit Mol Mutagenesis & DNA Repair, Genoa, Italy. RP Jordan, JJ (reprint author), NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov FU Italian Association for Cancer Research; NIEHS; Department of Defense Breast Cancer Research Program Predoctoral Traineeship Award [BC051212] FX This work was partially supported by the Italian Association for Cancer Research, AIRC (to AI) and intramural research funds from NIEHS. Jennifer Jordan is supported by a Department of Defense Breast Cancer Research Program Predoctoral Traineeship Award (BC051212). NR 111 TC 67 Z9 67 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2008 VL 4 IS 6 AR e1000104 DI 10.1371/journal.pgen.1000104 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 365MI UT WOS:000260410300004 PM 18714371 ER PT J AU Zaas, AK Liao, GC Chien, JW Weinberg, C Shore, D Giles, SS Marr, KA Usuka, J Burch, LH Perera, L Perfect, JR Peltz, G Schwartz, DA AF Zaas, Aimee K. Liao, Guochun Chien, Jason W. Weinberg, Clarice Shore, David Giles, Steven S. Marr, Kieren A. Usuka, Jonathan Burch, Lauranell H. Perera, Lalith Perfect, John R. Peltz, Gary Schwartz, David A. TI Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis SO PLOS GENETICS LA English DT Article ID STEM-CELL TRANSPLANTATION; IN-SILICO; CANDIDA-ALBICANS; BINDING; ACTIVATION; FUMIGATUS; MICE; GENE; ENOLASE; PROTEIN AB Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection. C1 [Zaas, Aimee K.; Perfect, John R.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Liao, Guochun; Usuka, Jonathan; Peltz, Gary] Roche Palo Alto, Palo Alto, CA USA. [Chien, Jason W.; Marr, Kieren A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Weinberg, Clarice; Shore, David; Burch, Lauranell H.; Perera, Lalith; Schwartz, David A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Giles, Steven S.] Univ Wisconsin, Madison, WI USA. [Marr, Kieren A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Zaas, AK (reprint author), Duke Univ, Med Ctr, Durham, NC 27706 USA. EM aimee.zaas@duke.edu RI perera, Lalith/B-6879-2012 OI perera, Lalith/0000-0003-0823-1631 FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences; National Institute of Allergy and Infectious Diseases [K08AI065837] FX This work was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. This work was supported in part by Grant # K08AI065837 ( AKZ) from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. GL, JU and GP are employees of Roche Biosciences. NR 54 TC 77 Z9 78 U1 0 U2 3 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 JUN PY 2008 VL 4 IS 6 AR e1000101 DI 10.1371/journal.pgen.1000101 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 365MI UT WOS:000260410300015 PM 18566672 ER PT J AU Kigozi, G Gray, RH Wawer, MJ Serwadda, D Makumbi, F Watya, S Nalugoda, F Kiwanuka, N Moulton, LH Chen, MZ Sewankambo, NK Wabwire-Mangen, F Bacon, MC Ridzon, R Opendi, P Sempijja, V Settuba, A Buwembo, D Kiggundu, V Anyokorit, M Nkale, J Kighoma, N Charvat, B AF Kigozi, Godfrey Gray, Ronald H. Wawer, Maria J. Serwadda, David Makumbi, Frederick Watya, Stephen Nalugoda, Fred Kiwanuka, Noah Moulton, Lawrence H. Chen, Michael Z. Sewankambo, Nelson K. Wabwire-Mangen, Fred Bacon, Melanie C. Ridzon, Renee Opendi, Pius Sempijja, Victor Settuba, Absolom Buwembo, Denis Kiggundu, Valerian Anyokorit, Margaret Nkale, James Kighoma, Nehemia Charvat, Blake TI The safety of adult male circumcision in HIV-infected and uninfected men in Rakai, Uganda SO PLOS MEDICINE LA English DT Article ID TRIAL; PREVENTION; KISUMU; KENYA; CAMPS AB Background The objective of the study was to compare rates of adverse events (AEs) related to male circumcision ( MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men. Methods and Findings A total of 2,326 HIV-negative and 420 HIV-positive men ( World Health Organization [ WHO] stage I or II and CD4 counts. 350 cells/mm(3)) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1-2 d and 5-9 d, and at 4-6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47-1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05-2.33). Conclusions Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved. C1 [Gray, Ronald H.; Wawer, Maria J.; Moulton, Lawrence H.; Chen, Michael Z.; Charvat, Blake] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Kigozi, Godfrey; Nalugoda, Fred; Kiwanuka, Noah; Sempijja, Victor; Settuba, Absolom; Buwembo, Denis; Kiggundu, Valerian; Anyokorit, Margaret; Nkale, James; Kighoma, Nehemia] Rakai Hlth Sci Program, Entebbe, Uganda. [Serwadda, David; Makumbi, Frederick; Wabwire-Mangen, Fred] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Watya, Stephen] Makerere Univ, Mulago Hosp, Urol Unit, Dept Surg, Kampala, Uganda. [Sewankambo, Nelson K.] Makerere Univ, Dept Med, Kampala, Uganda. [Bacon, Melanie C.] NIAID, NIH, Bethesda, MD 20892 USA. [Ridzon, Renee] Bill & Melinda Gates Fdn, Seattle, WA USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. EM rgray@jhsph.edu OI Sewankambo, Nelson/0000-0001-9362-053X; Moulton, Lawrence/0000-0001-7041-7387 FU FIC NIH HHS [5D43TW001508, D43 TW001508, D43TW00015, T22 TW000015]; Intramural NIH HHS; NIAID NIH HHS [U01 AI051171, U1AI51171] NR 14 TC 58 Z9 59 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2008 VL 5 IS 6 BP 911 EP 918 AR e116 DI 10.1371/journal.pmed.0050116 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 318QB UT WOS:000257105600015 PM 18532873 ER PT J AU Lee, CT Chen, J Hayashi, T Tsai, SY Sanchez, JF Errico, SL Amable, R Su, TP Lowe, RH Huestis, MA Shen, J Becker, KG Geller, HM Freed, WJ AF Lee, Chun-Ting Chen, Jia Hayashi, Teruo Tsai, Shang-Yi Sanchez, Joseph F. Errico, Stacie L. Amable, Rose Su, Tsung-Ping Lowe, Ross H. Huestis, Marilyn A. Shen, James Becker, Kevin G. Geller, Herbert M. Freed, William J. TI A mechanism for the inhibition of neural progenitor cell proliferation by cocaine SO PLOS MEDICINE LA English DT Article ID CYCLIN-A PROMOTER; IN-VITRO; NORCOCAINE NITROXIDE; OXIDATIVE STRESS; GENE-EXPRESSION; HISTAMINE H-2-RECEPTOR; POSTMORTEM BRAIN; CEREBRAL-CORTEX; DOWN-REGULATION; HUMAN-PLACENTA AB Background Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation. Methods and Findings Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum ( ER) stress response, as indicated by increased phosphorylation of eIF2 alpha and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A. Conclusions Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development. C1 [Lee, Chun-Ting; Chen, Jia; Hayashi, Teruo; Tsai, Shang-Yi; Sanchez, Joseph F.; Errico, Stacie L.; Amable, Rose; Su, Tsung-Ping; Freed, William J.] Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. [Lowe, Ross H.; Huestis, Marilyn A.] NIDA, IRP, NIH, DHHS, Baltimore, MD USA. [Shen, James] ScienCell Res Labs, San Diego, CA USA. [Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, NIH,DHHS, Baltimore, MD 21224 USA. [Geller, Herbert M.] NHLBI, Dev Neurobiol Sect, Cell Biol & Physiol Ctr, Div Intramural Res,NIH,DHHS, Bethesda, MD 20892 USA. RP Lee, CT (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. EM clee@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656; Geller, Herbert/0000-0002-7048-6144 NR 76 TC 36 Z9 38 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUN PY 2008 VL 5 IS 6 BP 987 EP 1004 AR e117 DI 10.1371/journal.pmed.0050117 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 318QB UT WOS:000257105600022 PM 18593214 ER PT J AU Takayama, S Thorgeirsson, UP Adamson, RH AF Takayama, Shozo Thorgeirsson, Unnur P. Adamson, Richard H. TI Chemical carcinogenesis studies in nonhuman primates SO PROCEEDINGS OF THE JAPAN ACADEMY SERIES A-MATHEMATICAL SCIENCES LA English DT Review DE chemical carcinogenesis; nonhuman primate; lifetime administration ID COMBINATION CHEMOTHERAPY; HETEROCYCLIC AMINES; CYNOMOLGUS MONKEYS; CANCER; TUMORS; METABOLISM; ACTIVATION; CYCLAMATE; MEIQX; 2-AMINO-3-METHYLIMIDAZO<4,5-F>QUINOLINE AB This review covers chemical carcinogenesis studies in nonhuman primates performed by the National Cancer Institute, USA, to provide hitherto unavailable information on their susceptibility to compounds producing carcinogenic effects in rodents. From autopsy records of 401 breeders and untreated controls, incidences of spontaneous malignant tumors were found to be relatively low in cynomolgus (1.9%) and rhesus monkeys (3.8%), but higher in African green monkeys (8%). Various chemical compounds, and in particular 6 antineoplastic agents, 13 food-related compounds including additives and contaminants, 1 pesticide, 5 N-nitroso compounds, 3 heterocyclic amines, and 7 "classical" rodent carcinogens, were tested during the 34 years period, generally at doses 10-40 times the estimated human exposure. Results were inconclusive in many cases but unequivocal carcinogenicity was demonstrated for IQ, procarbazine, methylnitrosourea and diethylnitrosamine. Furthermore, negative findings for saccharine and cyclamate were in line with results in other species. Thus susceptibility to carcinogens is at least partly shared by nonhuman primates and rodents. C1 [Thorgeirsson, Unnur P.; Adamson, Richard H.] NCI, Bethesda, MD 20892 USA. RP Takayama, S (reprint author), Meiji Seika Kaisha Ltd, Pharmaceut Res Dept, Kohoku Ku, 760 Morooka Cho, Kanagawa 2228567, Japan. EM shozo_takayama0@meiji.co.jp NR 42 TC 3 Z9 3 U1 0 U2 5 PU JAPAN ACAD PI TOKYO PA 7-32, UENO PARK, TAITO-KU, TOKYO, 110-0007, JAPAN SN 0386-2194 J9 P JPN ACAD A-MATH JI Proc. Jpn. Acad. Ser. A-Math. Sci. PD JUN PY 2008 VL 84 IS 6 BP 176 EP 188 DI 10.2183/pjab/84.176 PG 13 WC Mathematics SC Mathematics GA 320FF UT WOS:000257218400004 ER PT J AU Takayama, S Thorgeirsson, UP Adamson, RH AF Takayama, Shozo Thorgeirsson, Unnur P. Adamson, Richard H. TI Chemical carcinogenesis studies in nonhuman primates SO PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES LA English DT Review DE chemical carcinogenesis; nonhuman primate; lifetime administration ID COMBINATION CHEMOTHERAPY; HETEROCYCLIC AMINES; CYNOMOLGUS MONKEYS; CANCER; TUMORS; ACTIVATION; CYCLAMATE; MEIQX; 2-AMINO-3-METHYLIMIDAZO<4,5-F>QUINOLINE; 1-METHYL-1-NITROSOUREA AB This review covers chemical carcinogenesis studies in nonhuman primates performed by the National Cancer Institute, USA, to provide hitherto unavailable information on their susceptibility to compounds producing carcinogenic effects in rodents. From autopsy records of 401 breeders and untreated controls, incidences of spontaneous malignant tumors were found to be relatively low in cynomolgus (1.9%) and rhesus monkeys (3.8%), but higher in African green monkeys (8%). Various chemical compounds, and in particular 6 antineoplastic agents; 13 food-related compounds including additives and contaminants, 1 pesticide, 5 N-nitroso compounds, 3 heterocyclic amines, and 7 "classical" rodent carcinogens; were tested during the 34 years period; generally at doses 1040 times the estimated human exposure. Results were inconclusive in many cases but unequivocal carcinogenicity was demonstrated for IQ, procarbazine, methylnitrosourea and diethylnitrosamine. Furthermore; negative findings for saccharine and cyclamate were in line with results in other species. Thus susceptibility to carcinogens is at least partly shared by nonhuman primates and rodents. C1 [Takayama, Shozo] Meiji Seika Kaisha Ltd, Pharmaceut Res Dept, Kohoku Ku, Kanagawa 2228567, Japan. [Takayama, Shozo] Showa Univ, Sch Med, Tokyo 142, Japan. [Thorgeirsson, Unnur P.; Adamson, Richard H.] NCI, Bethesda, MD 20892 USA. RP Takayama, S (reprint author), Meiji Seika Kaisha Ltd, Pharmaceut Res Dept, Kohoku Ku, 760 Morooka Cho, Kanagawa 2228567, Japan. EM shozo_takayama0@meiji.co.jp NR 42 TC 0 Z9 0 U1 1 U2 6 PU JAPAN ACAD PI TOKYO PA 7-32, UENO PARK, TAITO-KU, TOKYO, 110-0007, JAPAN SN 0386-2208 J9 P JPN ACAD B-PHYS JI Proc. Jpn. Acad. Ser. B-Phys. Biol. Sci. PD JUN PY 2008 VL 84 IS 6 BP 176 EP 188 DI 10.2183/pjab.84.176 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322GF UT WOS:000257362500002 ER PT J AU Olivera, A AF Olivera, Ana TI Unraveling the complexities of sphingosine-1-phosphate function: The mast cell model SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Review DE sphingosine kinase; sphingosine-1-phosphate; mastcells; anaphylaxis ID FC-EPSILON-RI; SPHINGOSINE KINASE TYPE-2; IMMUNOMODULATORY DRUG FTY720; OPERATED CALCIUM-CHANNELS; LYMPHOCYTE EGRESS; DENDRITIC CELLS; CRAC CHANNEL; MEDIATED PHOSPHORYLATION; SPHINGOLIPID METABOLISM; 1-PHOSPHATE METABOLISM AB Sphingosine-1-phosphate (SIP) is a lipid mediator involved in diverse biological processes, from vascular and neural development to the regulation of lymphocyte trafficking. Many of its functions are regulated by five widely expressed S1P G-protein-coupled receptors (S1P(1-5)).S1P is produced mostly intracellularly, thus, much of its potential as an autocrine and paracrine mediator depends on how, when, and where it is generated or secreted out of the cells. However, S1P can also have intracellular activity independent of its receptors, adding to the complexity of S1P function. The mast cell, a major effector cell during an allergic response, has proven instrumental towards understanding the complex regulation and function of S1P. Antigen (Ag) engagement of the IgE receptor in mast cells stimulates sphingosine kinases, which generate S1P and are involved in the activation of calcium fluxes critical for mast cell responses. In addition, mast cells secrete considerable amounts of S1P upon activation, thus affecting the surrounding tissues and recruiting inflammatory cells. Export of S1P is also involved in the autocrine transactivation of S1P receptors present in mast cells. The in vivo response of mast cells, however, is not strictly dependent on their ability to generate S1P, but they are also affected by changes in S1P in the environment previous to Ag challenge. This review will discuss the recent advances towards understanding the intricacies of SI P generation, secretion and regulation in mast cells. In addition, how S1P receptors are activated and their involvement in mast cell functions will also be covered, including new insights on the role of S1P in the mast cell-mediated allergic response of systemic anaphylaxis. Published by Elsevier Inc. C1 NIAMSD, NIH, Lab Immune Cell Signaling, Bethesda, MD 20892 USA. RP Olivera, A (reprint author), NIAMSD, NIH, Lab Immune Cell Signaling, 9 Mem Dr,Bldg 9,Room 1W122, Bethesda, MD 20892 USA. EM oliveraa@mail.nih.gov FU Intramural NIH HHS [Z01 AR041155-01] NR 109 TC 21 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 EI 2212-196X J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD JUN PY 2008 VL 86 IS 1-4 BP 1 EP 11 DI 10.1016/j.prostaglandins.2008.02.005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 313MR UT WOS:000256745200001 PM 18403224 ER PT J AU Yamamoto, T Langham, RG Ronco, P Knepper, MA Thongboonkerd, V AF Yamamoto, Tadashi Langham, Robyn G. Ronco, Pierre Knepper, Mark A. Thongboonkerd, Visith TI Towards standard protocols and guidelines for urine proteomics: A report on the Human Kidney and Urine Proteome Project (HKUPP) symposium and workshop - 6 October 2007, Seoul, Korea and 1 November 2007, San Francisco, CA, USA SO PROTEOMICS LA English DT Article DE HKUPP; HUPO; kidney; urine AB The Human Kidney and Urine Proteome Project (HKUPP) was initiated in 2005 to promote proteomics research in the nephrology field, to better understand kidney functions as well as pathogenic mechanisms of kidney diseases, and to define novel biomarkers and therapeutic targets. This project was first approved in 2005 by the Human Proteome Organisation (HUPO) as a Kidney Disease Initiative under an umbrella of the HUPO Disease Biomarker Initiative (DBI), and more recently was approved as the HKUPP Initiative in 2007. Several sub-projects have been planned to achieve the ultimate goals. The most pressing is the establishment of "standard protocols and guidelines for urine proteome analysis". This sub-project had been extensively discussed during the first HKUPP symposium (during 6(th) HUPO Annual World Congress - October 2007, Seoul, Korea) and second workshop (during 40(th) American Society of Nephrology Renal Week - November 2007, San Francisco , CA, USA). Additional data and references have been collected after the symposium and workshop. An initial draft of standard protocols and guidelines for proteome analysis of non-proteinuric urine (urine protein excretion <= 150 mg/day) will soon be released as the first HKUPP product. C1 [Yamamoto, Tadashi] Grad Sch Med & Dental Sci, Inst Nephrol, Dept Struct Pathol, Chair Human Kidney & Urine Proteome Project,Chuo, Niigata 9518510, Japan. [Langham, Robyn G.] Univ Melbourne, St Vincent Hosp, Dept Med, Melbourne, Vic, Australia. [Ronco, Pierre] Univ Paris 06, INSERM Unit 702, Hop Tenon, Paris, France. [Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Thongboonkerd, Visith] Mahidol Univ, Siriraj Hosp, Fac Med, Off Res & Dev,Med Proteom Unit, Bangkok 10700, Thailand. [Thongboonkerd, Visith] Mahidol Univ, Siriraj Hosp, Fac Med, Off Res & Dev,Med Mol Biol Unit, Bangkok 10700, Thailand. RP Yamamoto, T (reprint author), Grad Sch Med & Dental Sci, Inst Nephrol, Dept Struct Pathol, Chair Human Kidney & Urine Proteome Project,Chuo, 1-757 Asahimachi Dori, Niigata 9518510, Japan. EM tdsymmt@med.niigata-u.ac.jp RI THONGBOONKERD, VISITH /C-6920-2009 FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21] NR 0 TC 36 Z9 37 U1 1 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUN PY 2008 VL 8 IS 11 BP 2156 EP 2159 DI 10.1002/pmic.200800138 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 316PG UT WOS:000256961600001 PM 18528840 ER PT J AU Seurynck-Servoss, SL Baird, CL Miller, KD Pefaur, NB Gonzalez, RM Apiyo, DO Engelmann, HE Srivastava, S Kagan, J Rodland, KD Zangar, RC AF Seurynck-Servoss, Shannon L. Baird, Cheryl L. Miller, Keith D. Pefaur, Noah B. Gonzalez, Rachel M. Apiyo, David O. Engelmann, Heather E. Srivastava, Sudhir Kagan, Jacob Rodland, Karin D. Zangar, Richard C. TI Immobilization strategies for single-chain antibody microarrays SO PROTEOMICS LA English DT Article DE antibody microarray; ELISA; single-chain antibodies ID YEAST SURFACE DISPLAY; ESCHERICHIA-COLI; OVARIAN-CANCER; FV ANTIBODIES; SACCHAROMYCES-CEREVISIAE; FRAGMENTS; AFFINITY; CYTOPLASM; THIOREDOXIN; BIOMARKERS AB Sandwich ELISA microarrays have great potential for validating disease biomarkers. Each ELISA relies on robust-affinity reagents that retain activity when immobilized on a solid surface or when labeled for detection. Single-chain antibodies (scFv) are affinity reagents that have greater potential for high-throughput production than traditional IgG. Unfortunately, scFv are typically less active than IgG following immobilization on a solid surface and not always suitable for use in sandwich ELISAs. We therefore investigated different immobilization strategies and scFv constructs to determine a more robust strategy for using scFv as ELISA reagents. Two promising strategies emerged from these studies: (i) the precapture of epitope-tagged scFv using an antiepitope antibody and (ii) the direct printing of a thioredoxin (TRX)/scFv fusion protein on glass slides. Both strategies improved the stability of immobilized scFv and increased the sensitivity of the scFv ELISA microarray assays, although the antiepitope precapture method introduced a risk of reagent transfer. Using the direct printing method, we show that scFv against prostate-specific antigen (PSA) are highly specific when tested against 21 different IgG-based assays. In addition, the scFv microarray PSA assay gave comparable quantitative results (R-2 = 0.95) to a commercial 96-well ELISA when tested using human serum samples. In addition, we find that TRX-scFv fusions against epidermal growth factor and toxin X have good LOD. Overall, these results suggest that minor modifications of the scFv construct are sufficient to produce reagents that are suitable for use in multiplex assay systems. C1 [Seurynck-Servoss, Shannon L.; Baird, Cheryl L.; Gonzalez, Rachel M.; Apiyo, David O.; Engelmann, Heather E.; Rodland, Karin D.; Zangar, Richard C.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99354 USA. [Miller, Keith D.; Pefaur, Noah B.] Pacific NW Natl Lab, Biotechnol Grp, Richland, WA 99354 USA. [Srivastava, Sudhir; Kagan, Jacob] NCI, Canc Biomarkers Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Zangar, RC (reprint author), Pacific NW Natl Lab, Div Biol Sci, 790 6th St, Richland, WA 99354 USA. EM richard.zangar@pnl.gov RI Baird, Cheryl/F-6569-2011 FU NCI NIH HHS [U01 CA117378, Y1-CN-5014] NR 23 TC 18 Z9 18 U1 1 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUN PY 2008 VL 8 IS 11 BP 2199 EP 2210 DI 10.1002/pmic.200701036 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 316PG UT WOS:000256961600008 PM 18452230 ER PT J AU Gundry, RL Boheler, KR Van Eyk, JE Wollscheid, B AF Gundry, Rebekah L. Boheler, Kenneth R. Van Eyk, Jennifer E. Wollscheid, Bernd TI A novel role for proteomics in the discovery of cell-surface markers on stem cells: Scratching the surface SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE cell surface protein marker; stem cells ID PLASMA-MEMBRANE PROTEINS; HEMATOPOIETIC STEM; MASS-SPECTROMETRY; BONE-MARROW; PROGENITOR CELLS; QUANTITATIVE-ANALYSIS; IN-VITRO; EXPRESSION; DIFFERENTIATION; IDENTIFICATION AB The concept of cell-based therapy has been advocated as a novel approach for treating diseases or conditions where regeneration of cells, tissue and/or potentially organs is required. A promising source for cell-replacement therapies is provided by stem cells, but the success of this approach will ultimately rely on the ability to isolate primary stem or progenitor cells. Cell-surface protein markers will play a critical role in this step. Current methodologies for the identification of cell-surface protein markers rely primarily on antibody availability and flow cytometry, but many cell-surface proteins remain undetectable. Proteomic technologies now offer the possibility to specifically identify and investigate the cell-surface subproteome in a quantitative and discovery-driven manner. Once a cell surface protein marker panel has been identified by MS and the antibodies become available, the panel should permit the identification, tracking, and/or isolation of stem or progenitor cells that may be appropriate for therapeutics. This review provides a context for the use of proteomics in discovering new cell-surface markers for stem cells. C1 [Wollscheid, Bernd] ETH, Inst Mol Syst Biol, NCCR Neuro Ctr Proteom, CH-8093 Zurich, Switzerland. [Boheler, Kenneth R.] NIA, NIH, Baltimore, MD 21224 USA. [Gundry, Rebekah L.; Van Eyk, Jennifer E.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Wollscheid, B (reprint author), ETH, Inst Mol Syst Biol, NCCR Neuro Ctr Proteom, HPT D 77,Wolfgang Pauli Str 16, CH-8093 Zurich, Switzerland. EM wollscheid@imsb.biol.ethz.ch RI Wollscheid, Bernd/E-8909-2010 OI Wollscheid, Bernd/0000-0002-3923-1610 FU Intramural NIH HHS [Z01 AG000847-01]; NHLBI NIH HHS [R01 HL085434, N01 HV028180, P50 HL084946, P50 HL084946-019003, P50 HL084946-029003, P50 HL084946-039003, R01 HL085434-01A2] NR 90 TC 23 Z9 24 U1 1 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2008 VL 2 IS 6 BP 892 EP 903 DI 10.1002/prca.200780122 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319SJ UT WOS:000257183900010 PM 19526049 ER PT J AU Bosley, A Marshall, HN Badralmaa, Y Natarajan, V AF Bosley, Allen Marshall, Heather N. Badralmaa, Yunden Natarajan, Ven TI A method of HIV-1 inactivation compatible with antibody-based depletion of abundant proteins from plasma SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE HIV-1; plasma depletion; plasma proteomics ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEAT INACTIVATION AB We have examined several methods, including heat treatment and treatment with detergents, to inactivate HIV-1 present in plasma to be depleted of abundant proteins utilizing an antibody-based technology. Treatment with Triton X-100 was not compatible with abundant protein depletion with an antibody column and heat treatment alters the composition of the plasma proteome. However, treatment with 1.2% N-octylglucoside for 5 min completely inhibited HIV-1 infectivity. The detergent was easily removed through buffer exchange, and this treatment had no discernable effect on protein depletion. C1 [Bosley, Allen; Marshall, Heather N.; Badralmaa, Yunden; Natarajan, Ven] NCI, Mol Cell Biol Lab, SAIC Frederick, Frederick, MD 21702 USA. RP Natarajan, V (reprint author), NCI, Mol Cell Biol Lab, SAIC Frederick, Bldg 550, Frederick, MD 21702 USA. EM vnatarajan@mail.nih.gov NR 10 TC 1 Z9 1 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD JUN PY 2008 VL 2 IS 6 BP 904 EP 907 DI 10.1002/prca.200780086 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319SJ UT WOS:000257183900011 PM 21136887 ER PT J AU Bevans, M Zabora, J Castro, K Prince, P Shelburne, N Prachenko, O Loscalzo, M BrintzenhofeSzoc, K Soeken, K Wallen, G AF Bevans, Margaret Zabora, James Castro, Kathleen Prince, Patricia Shelburne, Nonniekaye Prachenko, Olena Loscalzo, Matthew BrintzenhofeSzoc, Karlynn Soeken, Karen Wallen, Gwenyth TI An individualized dyadic problem-solving education intervention (PSEI) to improve problem-solving skills of patients and family caregivers during allogeneic hematopoietic stem cell transplantation (a-HSCT) SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Bevans, Margaret; Castro, Kathleen; Prince, Patricia; Shelburne, Nonniekaye; Prachenko, Olena; Soeken, Karen; Wallen, Gwenyth] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Zabora, James; BrintzenhofeSzoc, Karlynn] Catholic Univ Amer, Washington, DC 20064 USA. [Loscalzo, Matthew] Rebecca & John Moores UCSD Canc Ctr, La Jolla, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUN PY 2008 VL 17 SU S BP S160 EP S161 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 329NL UT WOS:000257874200302 ER PT J AU Prince, P Mitchell, SA Soeken, K Prachenko, O Barrett, AJ Castro, K Childs, R Fowler, D Krumlauf, M Savani, B Shelburne, N Bevans, MF AF Prince, Patricia Mitchell, Sandra A. Soeken, Karen Prachenko, Olena Barrett, A. John Castro, Kathleen Childs, Richard Fowler, Daniel Krumlauf, Michael Savani, Bipin Shelburne, Nonniekaye Bevans, Margaret F. TI Spiritual well-being (SpWB) in Hispanic and non-Hispanic survivors of allogeneic hematopoietic stem cell transplantation (HSCT) SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Prince, Patricia; Mitchell, Sandra A.; Soeken, Karen; Prachenko, Olena; Barrett, A. John; Castro, Kathleen; Childs, Richard; Fowler, Daniel; Krumlauf, Michael; Savani, Bipin; Shelburne, Nonniekaye; Bevans, Margaret F.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD JUN PY 2008 VL 17 SU S BP S45 EP S45 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 329NL UT WOS:000257874200085 ER PT J AU Cornwell, BR Echiverri, AM Covington, MF Grillon, C AF Cornwell, Brian R. Echiverri, Aileen M. Covington, Matthew F. Grillon, Christian TI Modality-specific attention under imminent but not remote threat of shock: Evidence from differential prepulse inhibition of startle SO PSYCHOLOGICAL SCIENCE LA English DT Article ID FEAR-POTENTIATED STARTLE; ACOUSTIC STARTLE; CONTEXTUAL FEAR; REFLEX; HUMANS; ANXIETY; MODULATION; PAIN; BENZODIAZEPINES; PREDICTABILITY AB Theories of animal defensive behavior postulate that imminent, predictable threat elicits highly focused attention toward the threat source, whereas remote, unpredictable threat elicits distributed attention to the overall environment. We used threat of shock combined with measurement of prepulse inhibition of the startle reflex to test these claims in humans. Twenty-seven participants experienced periods of threat and safety. Threat and safe periods were short or long, with the short threat periods conveying relatively predictable, imminent shocks and the long threat periods conveying unpredictable shocks. Startle reflexes were elicited with equal numbers of acoustic probes presented alone, preceded by a tactile prepulse, or preceded by an auditory prepulse. We observed enhanced tactile relative to auditory prepulse inhibition during short threat periods only. This finding supports the notion that imminent threat, but not remote threat, elicits attention focused toward the relevant modality, potentially reflecting preparatory activity to minimize the impact of the noxious stimulus. C1 [Cornwell, Brian R.; Covington, Matthew F.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Echiverri, Aileen M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Cornwell, BR (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, 15K N Dr, Bethesda, MD 20892 USA. EM cornwellb@mail.nih.gov FU Intramural NIH HHS [Z01 MH002798-06] NR 38 TC 20 Z9 20 U1 1 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD JUN PY 2008 VL 19 IS 6 BP 615 EP 622 DI 10.1111/j.1467-9280.2008.02131.x PG 8 WC Psychology, Multidisciplinary SC Psychology GA 311YR UT WOS:000256636800014 PM 18578853 ER PT J AU Kavaliers, M Devidze, N Choleris, E Fudge, M Gustafsson, JA Korach, KS Pfaff, DW Ogawa, S AF Kavaliers, Martin Devidze, Nino Choleris, Elena Fudge, Melissa Gustafsson, Jan-Ake Korach, Kenneth S. Pfaff, Donald W. Ogawa, Sonoko TI Estrogen receptors alpha and beta mediate different aspects of the facilitatory effects of female cues on male risk taking SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE boldness; decision making; predator odor; anxiety; fear; social behavior; social recognition; sexual motivation ID ANTIPREDATOR DEFENSIVE BEHAVIOR; MAJOR URINARY PROTEINS; COPULATING MALE RATS; MALE-MICE; GENE DISRUPTION; SEXUAL-BEHAVIOR; INDIVIDUAL-RECOGNITION; LUTEINIZING-HORMONE; SOCIAL INFORMATION; BRIEF EXPOSURE AB Mate risk taking and decision making are affected by sex-related cues, with men making poorer and riskier decisions in the presence of females and, or their cues. In non-human species, female cues can also increase mate risk taking, reducing their responses to predator threat. As estrogen receptors alpha and beta (ER alpha and ER beta) are involved in the mediation of social and sexual responses, we investigated their roles in determining the effects of female-associated cues on mate risk taking. We examined the effects of brief pre-exposure to the odors of either a novel or familiar estrous female on the avoidance of, and aversive responses to, predator threat (cat odor) in ER alpha and ER beta wild type (alpha ERWT, beta ERWT) and gene-deleted (knockout, alpha ERKO, beta ERKO) mate mice. Exposure of alpha ERWT and alpha ERWT mates to the odors of a novel, but not a familiar, estrous female mouse resulted in enhanced risk taking with the mates displaying reduced avoidance of, and analgesic responses to, cat odor. In contrast, alpha ERKO mate mice failed to show any changes in risk taking, while beta ERKO mates, although displaying greater risk taking, did not distinguish between novel and familiar females, displaying similarly reduced avoidance responses to cat odor after exposure to either a novel or familiar female odor. These findings indicate that the gene for ER alpha is associated with the sexual mechanisms (response to estrous female) and the genes for ER beta and ER alpha with the social (recognition of novel female) mechanisms underlying the effects of female cues on mate risk taking. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Kavaliers, Martin; Fudge, Melissa] Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. [Devidze, Nino; Pfaff, Donald W.; Ogawa, Sonoko] Rockefeller Univ, Lab Neurobiol Behav, New York, NY 10021 USA. [Choleris, Elena] Univ Guelph, Dept Psychol, Guelph, ON N1G 2W1, Canada. [Gustafsson, Jan-Ake] Karolinska Inst, Dept Biosci & Nutr, S-14186 Huddinge, Sweden. [Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Ogawa, Sonoko] Univ Tsukuba, Lab Behav Neuroendocrinol, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. RP Kavaliers, M (reprint author), Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. EM kavalier@uwo.ca OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [Z01 ES070065-31]; NIMH NIH HHS [MH36273]; PHS HHS [NIMH 62147] NR 63 TC 16 Z9 16 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD JUN PY 2008 VL 33 IS 5 BP 634 EP 642 DI 10.1016/j.psyneuen.2008.02.003 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 314AX UT WOS:000256782200009 PM 18374493 ER PT J AU Schooler, C Caplan, LJ Revell, AJ Salazar, AM Grafman, J AF Schooler, Carmi Caplan, Leslie J. Revell, Andrew J. Salazar, Andres M. Grafman, Jordan TI Brain lesion and memory functioning: Short-term memory deficit is independent of lesion location SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Article ID PENETRATING HEAD-INJURY; AMNESIA AB We analyzed the effects of patterns of brain lesions from penetrating head injuries on memory performance in participants of the Vietnam Head Injury Study (Grafman et al., 1988). Classes of lesion patterns were determined by mixture modeling (L. K. Muthen & B. O. Muthen, 1998-2004). Memory performance was assessed for short-term memory (STM), semantic memory, verbal episodic memory, and visual episodic memory. The striking finding was that large STM deficits were observed in all classes of brain-injured individuals, regardless of lesion location pattern. These effects persist despite frequent concomitant effects of depressive symptomatology and substance dependence. Smaller deficits in semantic memory, verbal episodic memory, and visual episodic memory depended on lesion location, in a manner roughly consistent with the existing neuropsychological literature. The theoretical and clinical implications of the striking, seemingly permanent STM deficits in individuals with penetrating head injuries are discussed. C1 [Schooler, Carmi; Caplan, Leslie J.; Revell, Andrew J.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Salazar, Andres M.; Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Schooler, C (reprint author), NIMH, Intramural Res Program, 6101 Execut Blvd,Suite 360,Room 362 MSC, Bethesda, MD 20892 USA. EM carmi.schooler@nih.gov; grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS NR 32 TC 4 Z9 4 U1 2 U2 3 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 1069-9384 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD JUN PY 2008 VL 15 IS 3 BP 521 EP 527 DI 10.3758/PBR.15.3.521 PG 7 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 320EZ UT WOS:000257217800004 PM 18567249 ER PT J AU Shin, R Qin, M Liu, ZH Ikemoto, S AF Shin, Rick Qin, Mei Liu, Zhong-Hua Ikemoto, Satoshi TI Intracranial self-administration of MDMA into the ventral striatum of the rat: differential roles of the nucleus accumbens shell, core, and olfactory tubercle SO PSYCHOPHARMACOLOGY LA English DT Article DE intracranial self-administration; reward; reinforcement; ecstasy; dopamine; nucleus accumbens; core; shell; D1 receptors; D2 receptors ID TRIAL PLACE PREFERENCE; CENTRAL-NERVOUS-SYSTEM; ECSTASY MDMA; DOPAMINE D-1; REWARD; COCAINE; RECEPTORS; REINFORCEMENT; METHYLENEDIOXYMETHAMPHETAMINE; ACQUISITION AB Rationale Behavioral and anatomical data suggest that the ventral striatum, consisting of the nucleus accumbens and olfactory tubercle, is functionally heterogeneous. Cocaine and D-amphetamine appear to be more rewarding when administered into the medial olfactory tubercle or medial accumbens shell than into their lateral counterparts, including the accumbens core. Objectives We sought to determine whether rats self-administer the popular recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) into ventrostriatal subregions and whether the medial olfactory tubercle and medial accumbens shell mediate MDMA's positive reinforcing effects more effectively than their lateral counterparts. Results Rats receiving 30 mM MDMA into the medial olfactory tubercle, medial accumbens shell, or accumbens core, but not the lateral tubercle or lateral shell, showed higher self-administration rates than rats receiving vehicle. The medial shell supported more vigorous self-administration of MDMA at higher concentrations than the core or medial olfactory tubercle. In addition, intra-medial shell MDMA self-administration was disrupted by co-administration of the D1 or D2 receptor antagonists SCH 23390 (1-3 mM) or raclopride (3-10 mM). Conclusions Our data suggest that the ventral striatum is functionally heterogeneous. The medial accumbens shell appears to be more important than other ventrostriatal subregions in mediating the positive reinforcing effects of MDMA via both D1- and D2-type receptors. Together with previous data, our data also suggest that unidentified actions of MDMA interfere with the positive reinforcing effects of dopamine in the medial olfactory tubercle. C1 [Shin, Rick; Qin, Mei; Liu, Zhong-Hua; Ikemoto, Satoshi] NIDA, Behav Neurosci Res Branch, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Res Branch, NIH, US Dept HHS, 251 Bayview Blvd,Room 08A711, Baltimore, MD 21224 USA. EM sikemoto@mail.nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU Intramural NIH HHS [Z01 DA000439-08] NR 32 TC 22 Z9 22 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUN PY 2008 VL 198 IS 2 BP 261 EP 270 DI 10.1007/s00213-008-1131-x PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 296KW UT WOS:000255543100012 PM 18389222 ER PT J AU Croft, BY AF Croft, B. Y. TI NCI Cancer Imaging Program efforts and their application to non-conventional radionuclides SO QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article; Proceedings Paper CT 17th International Symposium on Radiopharmaceutical Sciences CY APR 30-MAY 04, 2007 CL Aachen, GERMANY DE research support; diagnostic imaging; radionuclide imaging AB The US National Institute of Health (NIH) National Cancer Institute's Cancer Imaging Program funds research in cancer imaging. The article describes funding initiatives, such as Requests for Application and Program Announcement, funding mechanisms such as the R01 and R21, the Institutes of the NIH that fund imaging research, the application process, the application review process, and on-line resources to assist applicants for research funding for non-conventional radionuclides for imaging and therapy. C1 NCI, Canc Imaging Program, Rockville, MD 20852 USA. RP Croft, BY (reprint author), NCI, Canc Imaging Program, 6130 Execut Blvd,EPN 6064, Rockville, MD 20852 USA. EM bc129b@nih.gov RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 1 TC 0 Z9 0 U1 0 U2 0 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1824-4785 J9 Q J NUCL MED MOL IM JI Q. J. Nucl. Med. Mol. Imag. PD JUN PY 2008 VL 52 IS 2 BP 107 EP 110 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 302KB UT WOS:000255966100002 PM 18043543 ER PT J AU Brechbiel, MW AF Brechbiel, M. W. TI Bifunctional chelates for metal nuclides SO QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article; Proceedings Paper CT 17th International Symposium on Radiopharmaceutical Sciences CY APR 30-MAY 04, 2007 CL Aachen, GERMANY DE radionuclides; radiopharmaceuticals; tomography, emission computed ID MONOCLONAL-ANTIBODIES; IN-VIVO; CONVENIENT SYNTHESIS; ACID; THERAPY; AGENT; DERIVATIVES; PEPTIDE; DTPA; STABILITY AB The use of "non-standard" metallic radionuclides continues to be an expanding field of investigation. Radiolabeling small molecules, peptides, proteins, and up to nano-particles are all areas of active investigation for both diagnostic and therapeutic applications. All require a common variableaethe need for appropriate chelation chemistry for adequate sequestration of the metallic radionuclide that is equal to the intended application. A brief overview of the array of the chelation chemistry options available to researchers and the means for their selection is provided. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Brechbiel, MW (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bldg 10,Room 1B40,10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural NIH HHS [Z01 SC006353-24] NR 46 TC 58 Z9 60 U1 3 U2 7 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1824-4785 J9 Q J NUCL MED MOL IM JI Q. J. Nucl. Med. Mol. Imag. PD JUN PY 2008 VL 52 IS 2 BP 166 EP 173 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 302KB UT WOS:000255966100010 PM 18043537 ER PT J AU DiCarlo, AL Hatchett, RJ Kaminski, JM Ledney, GD Pellmar, TC Okunieff, P Ramakrishnan, N AF DiCarlo, Andrea L. Hatchett, Richard J. Kaminski, Joseph M. Ledney, G. David Pellmar, Terry C. Okunieff, Paul Ramakrishnan, Narayani TI Medical countermeasures for radiation combined injury: Radiation with burn, blast, trauma and/or sepsis. Report of an NIAID Workshop, March 26-27, 2007 SO RADIATION RESEARCH LA English DT Article ID SYNTHETIC TREHALOSE DICORYNOMYCOLATE; SYSTEMIC INFLAMMATORY RESPONSE; TOTAL-BODY IRRADIATION; DELTA-T-CELLS; ENDOTHELIAL DYSFUNCTION; THERMAL-INJURY; X-IRRADIATION; MICE; MORTALITY; FIBROSIS AB Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy. (C) 2008 by Radiation Research Society. C1 [DiCarlo, Andrea L.; Hatchett, Richard J.; Kaminski, Joseph M.; Ramakrishnan, Narayani] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. [Ledney, G. David; Pellmar, Terry C.] Uniformed Serv Univ Hlth Sci, Armed Forces Radiobiol Res Inst, Bethesda, MD 20814 USA. [Okunieff, Paul] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP DiCarlo, AL (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr,Room 4056, Bethesda, MD 20892 USA. EM cohena@niaid.nih.gov NR 85 TC 52 Z9 55 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUN PY 2008 VL 169 IS 6 BP 712 EP 721 DI 10.1667/RR1295.1 PG 10 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 305LJ UT WOS:000256179600012 PM 18494548 ER PT J AU Pawelczyk, E Frank, JA AF Pawelczyk, Edyta Frank, Joseph A. TI Transferrin receptor expression in iron oxide-labeled mesenchymal stem cells SO RADIOLOGY LA English DT Letter ID DIFFERENTIATION CAPACITY; FERUMOXIDES; TRANSFORMATION; NANOPARTICLES; TRAFFICKING; MODEL C1 [Pawelczyk, Edyta; Frank, Joseph A.] NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. RP Pawelczyk, E (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pawelczyke@cc.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2008 VL 247 IS 3 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 303ZL UT WOS:000256079700044 ER PT J AU Lauretani, F Semba, RD Bandinelli, S Dayhoff-Brannigan, M Lauretani, F Corsi, AM Guralnik, JM Ferrucci, L AF Lauretani, Fulvio Semba, Richard D. Bandinelli, Stefania Dayhoff-Brannigan, Margaret Lauretani, Fabrizio Corsi, Anna Maria Guralnik, Jack M. Ferrucci, Luigi TI Carotenoids as protection against disability in older persons SO REJUVENATION RESEARCH LA English DT Article ID HUMAN SKELETAL-MUSCLE; GROWTH-FACTOR-I; CARDIOVASCULAR-DISEASE; MEDITERRANEAN DIET; ENDOTHELIAL DYSFUNCTION; PLASMA-CONCENTRATIONS; ATHEROSCLEROSIS RISK; PHYSICAL PERFORMANCE; MOBILITY LIMITATION; OXIDATIVE STRESS AB The purpose was to examine the relationship of total plasma carotenoids, an indicator of fruit and vegetable intake, with walking speed and severe walking disability in older adults. Nine hundred twenty-eight men and women aged 65 to 102 years from the Invecchiare in Chianti (Aging in the Chianti Area [InCHIANTI]) study, a population-based cohort in Tuscany, Italy, were studied. Plasma carotenoids were measured at enrollment (1998-2000), and walking speed over 4 meters and 400 meters distance were assessed at enrollment and 6 years later (2004-2006). At enrollment, 85 of 928 (9.2%) participants had severe walking disability (defined as being unable to walk or having a walking speed at the 4-meter walking test < 0.4 m/sec). After adjusting for potential confounders, participants with high total plasma carotenoids were significantly less likely to have prevalent severe walking disability (odds ration [OR] 0.59, 95% confidence interval [CI] 0.38-0.90, p = 0.01) and had higher walking speed over 4 meters (,6 = 0.024, standard error [SE] = 0.011, p = 0.03) and over 400 meters (0 = 0.019, SE = 0.010, p = 0.04). Of 621 participants without severe walking disability at enrollment who were seen 6 years later, 68 (11.0%) developed severe walking disability. After adjusting for potential confounders, higher total plasma carotenoids were associated with a significantly lower risk of developing severe walking disability (OR 0.51, 95% CI 0.30-0.86, p = 0.01) and were associated with a less steep decline in 4-meter walking speed over a 6-year follow-up (n = 579; beta = 0.026, SE = 0.012, p = 0.03) and with lower incidence rates of being unable to successfully complete the 400-meter walking test at the 6-year follow-up visit (beta = -0.054, SE = 0.03, p = 0.04). High plasma carotenoids concentrations may be protective against the decline in walking speed and the development of severe walking disability in older adults. C1 [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, Baltimore, MD 21225 USA. [Lauretani, Fulvio; Lauretani, Fabrizio; Corsi, Anna Maria] Tuscany Reg Agcy, Florence, Italy. [Semba, Richard D.] Johns Hopkins Sch Med, Baltimore, MD USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Florence, Italy. [Corsi, Anna Maria] Univ Florence, Thrombosis Ctr, Dept Med & Surg Crit Care, I-50121 Florence, Italy. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, ASTRA Unit, Harbor Hosp 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS; NIA NIH HHS [N01 AG 50002, N01 AG 916413, N01 AG 821336, R01 AG027012, N01 AG916413, N01 AG5-002, R01 AG 027012, Z01 AG000015-50] NR 43 TC 19 Z9 19 U1 0 U2 1 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 JUN PY 2008 VL 11 IS 3 BP 557 EP 563 DI 10.1089/rej.2007.0581 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 322RE UT WOS:000257392200003 PM 18593275 ER PT J AU Jessup, CA Forde, SE AF Jessup, Christine A. Forde, Samantha E. TI Ecology and evolution in microbial systems: the generation and maintenance of diversity in phage-host interactions SO RESEARCH IN MICROBIOLOGY LA English DT Article DE virus; bacteriophage; microbial diversity; microbial interactions; coevolution ID ANTAGONISTIC COEVOLUTION; PARASITOID INTERACTION; BACTERIAL COMMUNITIES; NATURAL COMMUNITIES; VIRUS; PRODUCTIVITY; DISTURBANCE; BACTERIOPHAGE; BIODIVERSITY; ADAPTATION AB Insights gained from studying the interactions between viruses and bacteria have important implications for the ecology and evolution of virus-host interactions in many environments and for pathogen-host and predator-prey interactions in general. Here, we focus on the generation and maintenance of diversity, highlighting recent laboratory and field experiments with microorganisms. (C) 2008 Elsevier Masson SAS. All rights reserved. C1 [Jessup, Christine A.] Univ Oregon, Ctr Ecol & Evolutionary Biol, Eugene, OR 97403 USA. [Forde, Samantha E.] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. RP Jessup, CA (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM cjessup@stanfordalumni.org; forde@biology.ucsc.edu FU National Science Foundation [DEB-0703067, DEB-0515598] FX Thank you to the Fondation des Treilles and the organizers of the meeting "The evolution, diversity and ecology of the dark matter of the biosphere: bacteriophages". This meeting fostered stimulating discussions and led to this review. C.M.J. was supported by the National Science Foundation DEB-0703067. S.E.F. was supported by the National Science Foundation DEB-0515598. NR 62 TC 13 Z9 13 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0923-2508 J9 RES MICROBIOL JI Res. Microbiol. PD JUN PY 2008 VL 159 IS 5 SI SI BP 382 EP 389 DI 10.1016/j.resmic.2008.05.006 PG 8 WC Microbiology SC Microbiology GA 351GX UT WOS:000259413800011 PM 18582563 ER PT J AU Buehler, M Steiner, A Meylan, M Portier, CJ Mevissen, M AF Buehler, M. Steiner, A. Meylan, M. Portier, C. J. Mevissen, M. TI In vitro effects of bethanechol on smooth muscle preparations from abomasal fundus, corpus, and antrum of dairy cows SO RESEARCH IN VETERINARY SCIENCE LA English DT Article DE cows; abomasum; abomasal displacement; muscarinic receptor; bethanechol ID MUSCARINIC RECEPTOR SUBTYPES; GASTROINTESTINAL MOTILITY; MYOELECTRIC ACTIVITY; DISPLACED ABOMASUM; METOCLOPRAMIDE; PHARMACOLOGY; CISAPRIDE; CATTLE; DRUGS; COLON AB Abomasal displacement has been associated with gastric hypomotility. The supply of prokinetic drugs available to address this problem is insufficient. The goal of the study was to investigate the effect of the muscarinic agonist bethanechol (BeCh) on contractility parameters of smooth muscle preparations from several regions of the bovine abomasum (fundus, corpus, and antrum). Cumulative concentration-response curves were constructed using BeCh in vitro with and without pre-incubation with antagonists targeted at M(2) and M(3) muscarinic acetylcholine receptor (mAChR) subtypes. In all preparations investigated, BeCh induced a significant and concentration-dependent increase in all contractility parameters investigated. The maximal attainable effect (V(max)) was more pronounced in circular specimens, and V(max) of antral specimens in circular orientation were significantly lower when compared to the other preparations. Both antagonists caused a rightward shift of the concentration-response curve, suggesting that the effect of BeCh is mediated at least partly by M(2) and M(3) AChRs. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Mevissen, M.] Univ Bern, Vetsuisse Fac, Div Vet Pharmacol & Toxicol, Bern, Switzerland. [Buehler, M.; Steiner, A.; Meylan, M.] Univ Bern, Vetsuisse Fac, Clin Ruminants, Bern, Switzerland. [Portier, C. J.] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Mevissen, M (reprint author), Univ Bern, Vetsuisse Fac, Div Vet Pharmacol & Toxicol, Bern, Switzerland. EM meike.mevissen@vpi.unibe.ch RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 32 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0034-5288 J9 RES VET SCI JI Res. Vet. Sci. PD JUN PY 2008 VL 84 IS 3 BP 444 EP 451 DI 10.1016/j.rvsc.2007.05.012 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 300OD UT WOS:000255832900021 PM 17632190 ER PT J AU Bakalov, VK Bondy, CA AF Bakalov, Vladimir K. Bondy, Carolyn A. TI Fracture risk and bone mineral density in Turner syndrome SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Article DE fracture risk; bone mineral density; Turner syndrome; hormone replacement therapy ID QUANTITATIVE COMPUTED-TOMOGRAPHY; ESTROGEN REPLACEMENT THERAPY; X-RAY ABSORPTIOMETRY; GROWTH-HORMONE; HIP FRACTURE; YOUNG-WOMEN; CORTICAL BONE; OSTEOPOROTIC WOMEN; PROXIMAL RADIUS; SHOX DEFICIENCY AB Bone health is a major lifelong concern in caring for women and girls with Turner syndrome (TS). There is an approximately 25% increase in fracture risk most of which is related to medium or high impact trauma. The long bones, especially of the forearm are predominantly affected. This fact may be due to a selective cortical bone deficiency in TS which is unrelated to hypogonadism. In addition, lack of adequate estrogen replacement can lead to trabecular bone deficiency and increase in vertebral compression fractures after age 45. Evaluation of bone density by dual X-ray absorptiometry (DEXA) is important, however, it should be used judiciously in TS in view of its inherent tendency to underestimate the bone density of people with short stature. Bone size-independent methods, such as QCT or volumetric transformation of DEXA data should be used in individuals shorter than 150 cm. Achieving optimal bone density is of critical importance for fracture prevention in TS, and should be pursued by timely introduction of hormone replacement therapy, adequate dose of estrogens during the young adult life, optimal calcium and vitamin D intake and regular physical exercise. In addition, other measures to prevent fall and trauma should be considered, including optimizing hearing and vision, avoiding contact sports and exercise to improve coordination. C1 [Bakalov, Vladimir K.; Bondy, Carolyn A.] NICHHD, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov NR 50 TC 26 Z9 28 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD JUN PY 2008 VL 9 IS 2 BP 145 EP 151 DI 10.1007/s11154-008-9076-2 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 291LC UT WOS:000255197800006 PM 18415020 ER PT J AU Giroux, E AF Giroux, E. TI Cohort study and multivariate analysis: An epistemological and historical analysis of the Framingham heart study SO REVUE D EPIDEMIOLOGIE ET DE SANTE PUBLIQUE LA French DT Article DE history of medicine; cohort studies; prospective studies; research design; cardiovascular diseases; multivariate analysis; risk factors ID RETROSPECTIVE COHORT; CIGARETTE SMOKING; UNITED-STATES; DISEASE; EPIDEMIOLOGY; RISK; EXPERIENCE; TUBERCULOSIS; EVOLUTION; COMPANY AB Background. - Begun in 1947 and still ongoing, the epidemiological Study of heart disease known as the Framingham study was one of the first prospective studies based on a large cohort and has rapidly been considered as the prototype and model for the cohort study. Nevertheless, an examination of its history reveals that the protocol does not at all correspond to today's standards for this type of study. How, then, can we account for the remarkable reputation of this study? Methods. - This paper consists in an epistemological and historical analysis of the Framingham study that provides some of the answers to this question. In my treatment of the study's methodology, I focus on the issue of how the study population was constituted, and the manner in which the multiple factor analyses were conducted, two issues that are now central to cohort studies and more generally to analytic epidemiology. Results. - I show how the study population of Framingham and its long-term follow-up have contributed significantly to the interpretation of the cohort as a sort of "population-laboratory". The data generated by this study, which have been very widely used by epidemiologists and other researchers, are unparalleled in terms of the amount of detailed clinical information available for such a long follow-up period. Furthermore, multivariate statistical modelling, which has become a standard statistical tool for clinical as well as epidemiological studies was introduced in the context of this study to improve the identification of significant factors in the simultaneous analysis of multiple correlations. Multivariate analysis has since proved crucial in shaping the epidemiological concept of "risk factor" and in analysing multifactorial diseases. Indeed, I suggest that the modern idea of multifactorial diseases depends on the adaptation of this statistical method. Conclusion. - Thus, the Framingham study played a leading role not only in remodelling epidemiology after Second World War, in particular because of its contribution to the establishment of the cohort study as a standard method of investigation in etiological research, but also in constituting the "risk factor approach" to disease. (c) 2008 Elsevier Masson SAS. Tous droits reserves. C1 [Giroux, E.] Univ Lyon 1, Inst Hist & Philosophie Sci & Tech, Paris, France. [Giroux, E.] Off NIH Hist, Bethesda, MD USA. RP Giroux, E (reprint author), 3 Ter Rue St Gervais, F-69008 Lyon, France. EM elodie.giroux@free.fr NR 77 TC 5 Z9 5 U1 1 U2 5 PU MASSON EDITEUR PI MOULINEAUX CEDEX 9 PA 21 STREET CAMILLE DESMOULINS, ISSY, 92789 MOULINEAUX CEDEX 9, FRANCE SN 0398-7620 J9 REV EPIDEMIOL SANTE JI Rev. Epidemiol. Sante Publique PD JUN PY 2008 VL 56 IS 3 BP 177 EP 188 DI 10.1016/j.respe.2008.02.110 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 337QT UT WOS:000258451300004 PM 18547763 ER PT J AU Targanski, I Cherkasova, V AF Targanski, Ilia Cherkasova, Vera TI Analysis of genomic tRNA sets from Bacteria, Archaea, and Eukarya points to anticodon-codon hydrogen bonds as a major determinant of tRNA compositional variations SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE tRNA; extended anticodon; hydrogen bonds ID AMINOACYL-TRANSFER-RNA; TRANSLATIONAL EFFICIENCY; ACTIVE-ROLE; BINDING; RIBOSOME; ACID; LOOP; DISCRIMINATION; ACCOMMODATION; SPECIFICITY AB Analysis of 100 complete sets of the cytoplasmic elongator tRNA genes from Bacteria, Archaea, and Eukarya pointed to correspondences between types of anticodon and composition of the rest of the tRNA body. The number of the hydrogen bonds formed between the complementary nucleotides in the anticodon-codon duplex appeared as a major quantitative parameter determining covariations in all three domains of life. Our analysis has supported and advanced the "extended anticodon'' concept that is based on the argument that the decoding performance of the anticodon is enhanced by selection of a matching anticodon stem-loop sequence, as reported by Yarus in 1982. In addition to the anticodon stem-loop, we have found covariations between the anticodon nucleotides and the composition of the distant regions of their respective tRNAs that include dihydrouridine (D) and thymidyl (T) stem-loops. The majority of the covariable tRNA positions were found at the regions with the increased dynamic potential-such as stem-loop and stem-stem junctions. The consistent occurrences of the covariations on the multigenomic level suggest that the number and pattern of the hydrogen bonds in the anticodon-codon duplex constitute a major factor in the course of translation that is reflected in the fine-tuning of the tRNA composition and structure. C1 [Cherkasova, Vera] NICHHD, Lab Gene Regulat & Dev, Lab Mol Growth Regulat, Natl Inst Hlth, Bethesda, MD 20892 USA. [Targanski, Ilia] BioLing Inc, Rockville, MD 20853 USA. RP Cherkasova, V (reprint author), NICHHD, Lab Gene Regulat & Dev, Lab Mol Growth Regulat, Natl Inst Hlth, Bethesda, MD 20892 USA. EM cherkasv@mail.nih.gov NR 34 TC 3 Z9 3 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD JUN PY 2008 VL 14 IS 6 BP 1095 EP 1109 DI 10.1261/rna.896108 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 303TW UT WOS:000256064800011 PM 18441051 ER PT J AU Estes, JD Haase, AT Schacker, TW AF Estes, Jacob D. Haase, Ashley T. Schacker, Timothy W. TI The role of collagen deposition in depleting CD4+T cells and limiting reconstitution in HIV-1 and SIV infections through damage to the secondary lymphoid organ niche SO SEMINARS IN IMMUNOLOGY LA English DT Review DE HIV pathogenesis; lymphatic tissues; fibrosis; immune reconstitution; naive CD4 cells ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; GROWTH-FACTOR-BETA; CD4(+) T-CELLS; FIBROBLASTIC RETICULAR CELLS; LYMPHATIC TISSUE FIBROSIS; FOLLICULAR DENDRITIC CELLS; GERMINAL-CENTERS; NODE CORTEX; B-CELLS AB The hallmark of HIV/SIV infections is the progressive depletion of CD4+ T cells that ultimately renders the host incapable of defending against AIDS defining opportunistic infections and malignancies. Although many potential mechanisms have been proposed to explain CD4+ T cell loss, we review here the growing evidence that fibrotic 'scarring' and consequent damage to the lymphatic tissue niche contributes to CD4+ T cell decline and limits CD4+ T cell re-population with retroviral therapy. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Schacker, Timothy W.] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA. [Estes, Jacob D.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. RP Schacker, TW (reprint author), Univ Minnesota, Sch Med, Dept Med, MMC 250,516 Delaware St, Minneapolis, MN 55455 USA. EM Schacker@umn.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400, P130-CA79458-01]; NCRR NIH HHS [M01 RR000400, M01 RR00400]; NIAID NIH HHS [R37 AI 28246, R01 AI048484, R01 AI054232, R01 AI056997, R01 AI48484, R56 AI054232, T32 AI007421, 2U01 AI041535, AI056997, AI07421, R01 AI054232-01A2, R01 AI54232-01A2, R37 AI028246, R56 AI054232-06A1]; NIDCR NIH HHS [1R01DE12934-01] NR 76 TC 47 Z9 49 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2008 VL 20 IS 3 BP 181 EP 186 DI 10.1016/j.smim.2008.04.002 PG 6 WC Immunology SC Immunology GA 350AT UT WOS:000259325500005 PM 18595731 ER PT J AU Lederman, MM Margolis, L AF Lederman, Michael M. Margolis, Leonid TI The lymph node in HIV pathogenesis SO SEMINARS IN IMMUNOLOGY LA English DT Review DE CD38; cell cycle; HIV; immune activation; lymph node; microbial translocation; toll like receptors ID CD4(+) T-CELLS; ACQUIRED IMMUNODEFICIENCY SYNDROME; ACTIVE ANTIRETROVIRAL THERAPY; VIRUS TYPE-1 INFECTION; PNEUMOCYSTIS-CARINII PNEUMONIA; PLASMACYTOID DENDRITIC CELLS; SIV INFECTION; IMMUNE ACTIVATION; GASTROINTESTINAL-TRACT; MEDIATED-IMMUNITY AB Since the earliest days of the AIDS epidemic, clinicians and researchers have recognized the importance of lymphoid tissue both in the clinical manifestations of disease and in its pathogenesis. Generalized lymphadenopathy was one of the earliest harbingers of AIDS in the United States and over the past 27 years an increasing body of evidence has implicated the lymphoid organs as central to the pathogenesis of immune deficiency in chronic HIV-1 infection. In this essay, we will review some of the data that have been accumulated and propose a testable model that may reconcile them. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp Cleveland, Ctr AIDS Res, Cleveland, OH 44118 USA. [Margolis, Leonid] NICHHD, Bethesda, MD 20892 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Sch Med, Dept Med, Div Infect Dis,Ctr AIDS Res, 2061 Cornell Rd, Cleveland, OH 44118 USA. EM MXL6@case.edu FU Case Western Reserve University FX The authors would like to acknowledge the Center for AIDS Research at Case Western Reserve University for logistic and financial support and the BBC/CLIC (Bad Boys of Cleveland/Cleveland Immunopathogenesisi Consortium) for helpful discussions and presentations that helped to frame the outline of this pathogenesis model. NR 123 TC 23 Z9 23 U1 1 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2008 VL 20 IS 3 BP 187 EP 195 DI 10.1016/j.smim.2008.06.001 PG 9 WC Immunology SC Immunology GA 350AT UT WOS:000259325500006 PM 18620868 ER PT J AU Chadwick, RS Liao, Z AF Chadwick, Richard S. Liao, Zhijie TI High-frequency oscillations of a sphere in a viscous fluid near a rigid plane SO SIAM REVIEW LA English DT Article DE asymptotic expansions; oscillating boundary layers; wall effects; atomic force microscopy ID ATOMIC-FORCE MICROSCOPE; SLOW MOTION; BRINKMAN MEDIUM; SURFACE; WALL AB High-frequency oscillations of a rigid sphere in an incompressible viscous fluid moving normal to a rigid plane are considered when the ratio of minimum clearance to sphere radius is small. Asymptotic expansions are constructed that permit an analytical estimate of the force acting on the sphere as a result of its motion. An inner expansion, valid in the neighborhood of the minimum gap, reflects the dominance of viscous effects and fluid inertia. An outer expansion, valid outside the gap, reflects the dominance of fluid inertia with a correction for an oscillating viscous boundary layer. The results are applied to the hydrodynamics of the tapping mode of an atomic force microscope and to the dynamic calibration of its cantilevers. C1 [Chadwick, Richard S.; Liao, Zhijie] Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Auditory Mech, NIH, Bethesda, MD 20892 USA. EM chadwick@helix.nih.gov; zhijie.liao@gmail.com FU Intramural NIH HHS [Z01 DC000033-12]; NIDCD NIH HHS [Z01 DC000033] NR 14 TC 4 Z9 4 U1 2 U2 6 PU SIAM PUBLICATIONS PI PHILADELPHIA PA 3600 UNIV CITY SCIENCE CENTER, PHILADELPHIA, PA 19104-2688 USA SN 0036-1445 J9 SIAM REV JI SIAM Rev. PD JUN PY 2008 VL 50 IS 2 BP 313 EP 322 DI 10.1137/06067763X PG 10 WC Mathematics, Applied SC Mathematics GA 303MC UT WOS:000256043600006 PM 19809589 ER PT J AU Earley, CJ Ponnuru, P Wang, XS Patton, SM Connor, JR Beard, JL Taub, DD Allen, RP AF Earley, Christopher J. Ponnuru, Padmavathi Wang, Xinsheng Patton, Stephanie M. Connor, James R. Beard, John L. Taub, Dennis D. Allen, Richard P. TI Altered iron metabolism in lymphocytes from subjects with restless legs syndrome SO SLEEP LA English DT Article DE restless leg syndrome; lymphocytes; ferroportin; DMT1; iron ID SEGREGATION ANALYSIS; FERRITIN LEVELS; TRANSFERRIN; DEFICIENCY; DISEASE; BRAIN; EXPRESSION; TRANSPORT; MODEL; RATS AB Objective: Studies using cerebrospinal fluid, magnetic resonance imaging, and autopsy tissue have implicated a primary role for brain iron insufficiency in restless legs syndrome (RLS). If the abnormalities of brain iron regulation reflect a basic disturbance of iron metabolism, then this might be expressed at least partially in some peripheral systems. Thus the study aim was to determine whether patients with RLS and control subjects show differences in lymphocyte iron regulator proteins. Methods: Fasting morning blood samples were used to obtain common serum measures of iron status and to determine lymphocyte iron management proteins. Twenty-four women with early-onset RLS and 25 control women without RLS symptoms were studied. Results: RLS and control subjects were matched for age, hemoglobin, and serum iron profile. However, transferrin receptor (TfR) and DMT1 (divalent metal transporter 1 protein) levels in lymphocytes were significantly higher for RLS patients than for controls. No significant differences in ferritin subtypes or transferrin levels were found. No significant correlations were found between lymphocyte and serum indices of iron status. Interpretation: RLS lymphocytes showed an increase in ferroportin, implying increased cellular iron excretion, in the face of increased iron need (increased TfR and DMT1). In the absence of changes in H-ferritin, the findings indicate a balance between input and output with no net iron change but probable overall increase in iron turnover. The lack of any significant correlation between serum and lymphocyte iron indices indicates that iron management proteins from lymphocytes are at a minimum an alternative and independent marker of cellular iron metabolism. C1 [Earley, Christopher J.; Allen, Richard P.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Ponnuru, Padmavathi; Wang, Xinsheng; Patton, Stephanie M.; Connor, James R.] Penn State Coll Med, Dept Neurosurg, Hershey, PA USA. [Beard, John L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Taub, Dennis D.] NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Earley, CJ (reprint author), Johns Hopkins Bayview Med Ctr, 5501 Hopkins Bayview Circle,AAC 1B-82, Baltimore, MD 21224 USA. EM cearley@jhmi.edu FU NCRR NIH HHS [M01 RR002719, M01-RR02719]; NIA NIH HHS [P01 AG021190, P01-AG21190] NR 36 TC 16 Z9 17 U1 0 U2 2 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD JUN 1 PY 2008 VL 31 IS 6 BP 847 EP 852 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 307QX UT WOS:000256334500010 PM 18548829 ER PT J AU Bolla, KI Lesage, SR Gamaldo, CE Neubauer, DN Funderburk, FR Cadet, JL David, PM Verdejo-Garcia, A Benbrook, AR AF Bolla, Karen I. Lesage, Suzanne R. Gamaldo, Charlene E. Neubauer, David N. Funderburk, Frank R. Cadet, Jean Lud David, Paula M. Verdejo-Garcia, Antonio Benbrook, Amy R. TI Sleep disturbance in heavy marijuana users SO SLEEP LA English DT Article DE marijuana; sleep; polysomnography; withdrawal ID CANNABIS WITHDRAWAL; CHRONIC-ALCOHOLICS; BRAIN; DELTA-9-TETRAHYDROCANNABINOL; QUESTIONNAIRE; ADOLESCENCE; ABSTINENCE; PATTERNS; INSOMNIA; VALIDITY AB Study Objective: To determine if recently abstinent, heavy marijuana (MJ) users show differences in polysomnographic (PSG) measures compared with a drug-free control group. Design: A group of carefully selected heavy MJ users were chosen for study inclusion and matched to a drug-free control group. Questionnaire data were collected prior to cessation of MJ use. PSG studies were conducted during 2 consecutive nights after discontinuation of MJ use in our core sleep laboratory. Setting: Baltimore Maryland, General Clinical Research Center (GCRC) core sleep lab. Participants: 17 heavy MJ users discontinuing MJ use and 14 drug-free controls. Men and women were studied, 18 to 30 years. The MJ users reported no other drug use and alcohol use was negligible in both groups. Urine was positive for metabolites of cannabis only. Measurements and Results: The MJ users showed differences in PSG measures (lower total sleep times, and less slow wave sleep than the control group) on both nights; they also showed worse sleep efficiency, longer sleep onset, and shorter REM latency than the control group on Night 2. More sleep continuity parameters were significantly worse for the MJ group than the control group on Night 2 versus Night 1, indicating that sleep in the MJ group was relatively worse on Night 2 compared to Night 1. The MJ group did not show improved sleep after an adaptation night as expected. Withdrawal symptoms, craving, and depression did not appear to influence these findings. Conclusions: During discontinuation of heavy MJ use, PSG measures of sleep disturbance were detected in MJ users compared with a drug-free control group, While this preliminary study cannot identify the extent to which these group differences were present before abstinence, poor sleep quality either prior to or after MJ discontinuation could result in treatment failure for MJ users. Further investigation is necessary to determine the association between the use and cessation of MJ and sleep disturbance. C1 [Bolla, Karen I.; Gamaldo, Charlene E.; David, Paula M.; Benbrook, Amy R.] Johns Hopkins Med Inst, Dept Neurol, Bayview Med Ctr, Baltimore, MD 21205 USA. [Bolla, Karen I.; Neubauer, David N.] Johns Hopkins Med Inst, Dept Psychiat & Behav Sci, Bayview Med Ctr, Baltimore, MD 21205 USA. [Bolla, Karen I.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Lesage, Suzanne R.] Univ Maryland, Sleep Disorders Ctr Baltimore, Baltimore, MD 21201 USA. [Funderburk, Frank R.] InCompass Syst, Columbia, MD USA. [Cadet, Jean Lud] NIDA, Intramural Res Program, DHHS, Mol Neuropsychiat Branch,NIH, Baltimore, MD USA. [Verdejo-Garcia, Antonio] Inst Municipal Invest Med Barcelona, Pharmacol Res Inst, Barcelona, Spain. RP Bolla, KI (reprint author), Johns Hopkins Bayview Med Ctr, Dept Neurol, 4940 Eastern Ave,B Bldg,Room 123, Baltimore, MD 21224 USA. EM kbolla@jhmi.edu OI Verdejo-Garcia, Antonio/0000-0001-8874-9339 FU Intramural NIH HHS; NCRR NIH HHS [M01 RR002719, M01 RR02719]; NIDA NIH HHS [DA 17122, R21 DA017122] NR 34 TC 47 Z9 47 U1 3 U2 11 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD JUN 1 PY 2008 VL 31 IS 6 BP 901 EP 908 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 307QX UT WOS:000256334500017 PM 18548836 ER PT J AU Berger, VW AF Berger, Vance W. TI Controversies in clinical trials SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Editorial Material C1 [Berger, Vance W.] Univ Maryland, NCI, Baltimore, MD 21201 USA. [Berger, Vance W.] NCI, Biometr Res Grp, Bethesda, MD USA. RP Berger, VW (reprint author), Univ Maryland, NCI, Baltimore, MD 21201 USA. EM bergerv@mail.nih.go NR 1 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD JUN PY 2008 VL 17 IS 3 BP 229 EP 230 DI 10.1177/0962280207081034 PG 2 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 320OL UT WOS:000257244300001 PM 17925314 ER PT J AU Berger, VW Matthews, JR Grosch, EN AF Berger, Vance W. Matthews, J. Rosser Grosch, Eric N. TI On improving research methodology in clinical trials SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID SELECTION BIAS AB Research plays a vital role within biomedicine. Scientifically appropriate research provides a basis for appropriate medical decisions; conversely, inappropriate research may lead to flawed 'best medical practices' which, when followed, contribute to avoidable morbidity and mortality. Although an all-encompassing definition of 'appropriate medical research' is beyond the scope of this article, the concept clearly entails (among other things) that research methods be continually revised and updated as better methods become available. Despite the advent of evidence-based medicine, many research methods have become 'standard' even though there are legitimate scientific reasons to question the conclusions reached by such methods. We first illustrate prominent examples of inappropriate (yet regimented) research methods that are in widespread use. Second, as a way to improve the situation, we suggest a model of research that relies on standardized statistical analyses that individual researchers must consider as a default, but are free to challenge when they can marshal sufficient scientific evidence to demonstrate that the challenge is warranted. Third, we characterize the current system as analogous to 'unnatural selection' in the biological world and argue that our proposed model of research will enable 'natural' to replace 'unnatural' selection in the choice of research methodologies. Given the pervasiveness of inappropriate research methods, we believe that there are strong scientific and ethical reasons to create such a system, that, if properly designed, will both facilitate creativity and ensure methodological rigor while protecting the public at large from the threats posed by poor medical treatment decisions resulting from flawed research methodology. C1 [Berger, Vance W.] Univ Maryland, NCI, Baltimore, MD 21201 USA. [Matthews, J. Rosser] Georgetown Univ, Washington, DC USA. [Grosch, Eric N.] United Urgent Care Clin, Ft Myers, FL USA. RP Berger, VW (reprint author), Univ Maryland, NCI, Baltimore, MD 21201 USA. EM vb78c@nih.gov OI Matthews, J Rosser/0000-0002-8304-2948 NR 21 TC 6 Z9 6 U1 0 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 EI 1477-0334 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD JUN PY 2008 VL 17 IS 3 BP 231 EP 242 DI 10.1177/0962280207080639 PG 12 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 320OL UT WOS:000257244300002 PM 17925317 ER PT J AU Baker, SG Kramer, BS AF Baker, Stuart G. Kramer, Barnett S. TI Randomized trials for the real world: making as few and as reasonable assumptions as possible SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID DESIGN AB The strength of the randomized trial to yield conclusions not dependent on assumptions applies only in an ideal setting. In the real world various complications such as loss-to-follow-up, missing outcomes, noncompliance and nonrandom selection into a trial force a reliance on assumptions. To handle real world complications, it is desirable to make as few and as reasonable assumptions as possible. This article reviews four techniques for using a few reasonable assumptions to design or analyse randomized trials in the presence of specific real world complications: 1) a double sampling design for survival data to avoid strong assumptions about informative censoring, 2) sensitivity analysis for partially missing binary outcomes that uses the randomization to reduce the number of parameters specified by the investigator, 3) an estimate of the effect of treatment received in the presence of all-or-none compliance that requires reasonable assumptions, and 4) statistics for binary outcomes that avoid some assumptions for generalizing results to a target population. C1 [Baker, Stuart G.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb.l.6i@nih.gov NR 19 TC 3 Z9 3 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD JUN PY 2008 VL 17 IS 3 BP 243 EP 252 DI 10.1177/0962280207080640 PG 10 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 320OL UT WOS:000257244300003 PM 17925312 ER PT J AU Hwang, M Gorivodsky, M Kim, M Westphal, H Geum, D AF Hwang, Minyoung Gorivodsky, Marat Kim, Minjung Westphal, Heiner Geum, Dongho TI The neuronal differentiation potential of Ldb1-null mutant embryonic stem cells is dependent on extrinsic influences SO STEM CELLS LA English DT Article DE Ldb1; embryonic stem cells; neuronal differentiation; embryoid body; five-stage method; adherent monolayer culture method ID ANTERIOR PRIMITIVE ENDODERM; MOUSE EMBRYO; HOMEODOMAIN PROTEINS; AXIS FORMATION; LIM; BINDING; DICKKOPF-1; INTERACTOR; INHIBITOR; INDUCTION AB LIM-domain binding protein 1 (Ldb1) is a multiadaptor protein that mediates the action of transcription factors, including LIM-homeodomain proteins. To elucidate the functional role of Ldb1 in the neuronal differentiation of embryonic stem (ES) cells, we have generated Ldb1-null mutant (Ldb1(-/-)) ES cells and examined neuronal differentiation potentials in vitro using two different neuronal differentiation protocols. When subjected to a five-stage protocol that recapitulates in vivo conditions of neuronal differentiation, wild-type ES cells differentiated into a wide spectrum of neuronal cell types. However, Ldb1(-/-) ES cells did not differentiate into neuronal cells; instead, they differentiated into sarcomeric alpha-actinin-positive muscle cells. In contrast, when an adherent monolayer culture procedure (which is based on the default mechanism of neural induction and eliminates environmental influences) was applied, both wild-type and Ldb1(-/-) ES cells differentiated into MAP2-positive mature neurons. Comparison of the results obtained when two different neuronal differentiation protocols were used suggests that Ldb1(-/-) ES cells have an innate potential to differentiate into neuronal cells, but this potential can be inhibited by environmental influences. C1 [Gorivodsky, Marat; Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. [Hwang, Minyoung; Geum, Dongho] Korea Univ, Grad Sch Med, Seoul, South Korea. [Kim, Minjung] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Westphal, H (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. EM hw@helix.nih.gov; geumd@korea.ac.kr NR 28 TC 8 Z9 8 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2008 VL 26 IS 6 BP 1490 EP 1495 DI 10.1634/stemcells.2007-1099 PG 6 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 315VF UT WOS:000256907600012 PM 18388304 ER PT J AU Vazin, T Chen, J Lee, CT Amable, R Freed, WJ AF Vazin, Tandis Chen, Jia Lee, Chun-Ting Amable, Rose Freed, William J. TI Assessment of stromal-derived inducing activity in the generation of dopaminergic neurons from human embryonic stem cells SO STEM CELLS LA English DT Article DE human embryonic stem cells; dopaminergic; PA6 cells; stromal-derived inducing activity; differentiation ID HEPATOCYTE GROWTH-FACTOR; IN-VITRO; NEUROTROPHIC FACTOR; PROGENITOR CELLS; ES CELLS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; DIFFERENTIATION; MIDBRAIN; INDUCTION AB Producing dopaminergic (DA) neurons is a major goal of human embryonic stem cell (hESC) research. DA neurons can be differentiated from hESC by coculture with the mouse PA6 stromal cell line; this differentiation-inducing effect is termed stromal-derived inducing activity (SDIA). The molecular and biochemical nature of SDIA is, however, unknown. Various studies have suggested that SDIA involves either a fixation-resistant component located on the PA6 cell surface or factors secreted into the medium by PA6 cells. To address this question, hESC were cocultured with PA6 cells for 12 days and then further differentiated with sonic hedgehog homolog, fibroblast growth factor-8, and glial cell line-derived neurotrophic factor. After 18 days, 34% of cells were tyrosine hydroxylase (TH)+. When PA6 cells were fixed or irradiated, the number of TH+ cells was decreased by threefold, whereas mitomycin-c treatment of feeder cells decreased the number of TH+ cells by 32%. The neural-inducing effect of PA6 cells, as monitored by beta-III-tubulin expression, was minimally affected by mitomycin-c treatment or fixation but was decreased 50% by irradiation. Medium conditioned by PA6 cells was ineffective in differentiating TH+ cells when used alone. Conditioned medium combined with heparin and/or fixed PA6 cells produced TH+ cell differentiation, although less effectively than PA6 cell coculture. Thus, PA6 cell surface activity is required for neural differentiation of hESC, but secreted factors are required for the specific DA neuron-inducing effect. C1 [Vazin, Tandis; Chen, Jia; Lee, Chun-Ting; Amable, Rose; Freed, William J.] NIDA, Dev & Plast Sect, Cellular Neurobiol Res Bran, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Vazin, Tandis] AlbaNova Univ Ctr, Royal Inst Technol, Dept Biotechnol, Stockholm, Sweden. RP Vazin, T (reprint author), NIDA, Dev & Plast Sect, Cellular Neurobiol Res Bran, Intramural Res Program,NIH,Dept Hlth & Human Serv, 333 Cassell Dr,Triad Bldg,Room 3303, Baltimore, MD 21224 USA. EM vazint@mail.nih.gov FU Intramural NIH HHS [Z01 DA000472-04] NR 49 TC 46 Z9 53 U1 2 U2 6 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2008 VL 26 IS 6 BP 1517 EP 1525 DI 10.1634/stemcells.2008-0039 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 315VF UT WOS:000256907600015 PM 18388303 ER PT J AU Hedlund, E Pruszak, J Lardaro, T Ludwig, W Vinuela, A Kim, KS Isacson, O AF Hedlund, Eva Pruszak, Jan Lardaro, Thomas Ludwig, Wesley Vinuela, Angel Kim, Kwang-Soo Isacson, Ole TI Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease SO STEM CELLS LA English DT Article DE Pitx3; transplantation; Parkinson's disease; stage-specific embryonic antigen-1; mouse embryonic stem cells ID TRANSCRIPTION FACTOR PITX3; SUBSTANTIA-NIGRA; RAT MODEL; DEVELOPMENTAL DEFECTS; MONOCLONAL-ANTIBODY; TUMOR-FORMATION; FLOW-CYTOMETRY; ANTIGEN SSEA-1; MUTANT MICE; GENE PITX3 AB Both fetal ventral mesencephalic (VM) and embryonic stem (ES) cell-derived dopamine neurons have been used successfully to correct behavioral responses in animal models of Parkinson's disease. However, grafts derived from fetal VM cells or from ES cells contain multiple cell types, and the majority of these cells are not dopamine neurons. Isolation of ES cell-derived dopamine neurons and subsequent transplantation would both elucidate the capacity of these neurons to provide functional input and also further explore an efficient and safer use of ES cells for the treatment of Parkinson's disease. Toward this goal, we used a Pitx3-enhanced green fluorescent protein (Pitx3-eGFP) knock-in mouse blastocyst-derived embryonic stem (mES) cell line and fluorescence-activated cell sorting (FACS) to select and purify midbrain dopamine neurons. Initially, the dopaminergic marker profile of intact Pitx3-eGFP mES cultures was evaluated after differentiation in vitro. eGFP expression overlapped closely with that of Pitx3, Nurr1, Engrailed-1, Lmx1a, tyrosine hydroxylase (TH), L-aromatic amino acid decarboxylase (AADC), and vesicular monoamine transporter 2 (VMAT2), demonstrating that these cells were of a midbrain dopamine neuron character. Furthermore, postmitotic Pitx3-eGFP(+) dopamine neurons, which constituted 2%-5% of all live cells in the culture after dissociation, could be highly enriched to >90% purity by FACS, and these isolated neurons were viable, extended neurites, and maintained a dopaminergic profile in vitro. Transplantation to 6-hydroxydopamine-lesioned rats showed that an enriched dopaminergic population could survive and restore both amphetamine- and apomorphine-induced functions, and the grafts contained large numbers of midbrain dopamine neurons, which innervated the host striatum. C1 [Hedlund, Eva; Pruszak, Jan; Ludwig, Wesley; Vinuela, Angel; Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Ctr Neuroregenerat Res, Belmont, MA 02478 USA. [Lardaro, Thomas; Kim, Kwang-Soo] Harvard Univ, Sch Med, McLean Hosp, Mol Neurobiol Lab, Belmont, MA 02478 USA. [Hedlund, Eva; Pruszak, Jan; Lardaro, Thomas; Ludwig, Wesley; Vinuela, Angel; Kim, Kwang-Soo; Isacson, Ole] Harvard Univ, Sch Med, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. RP Isacson, O (reprint author), Harvard Univ, Sch Med, McLean Hosp, Ctr Neuroregenerat Res, 115 Mill St, Belmont, MA 02478 USA. EM eva.hedlund@licr.ki.se; isacson@hms.harvard.edu RI Pruszak, Jan/G-6972-2015; OI Pruszak, Jan/0000-0003-4297-4009; Hedlund, Eva/0000-0001-6347-0075 FU NINDS NIH HHS [P50 NS039793, P50 NS039793-08, P50 NS39793]; PHS HHS [48866] NR 57 TC 84 Z9 85 U1 2 U2 8 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2008 VL 26 IS 6 BP 1526 EP 1536 DI 10.1634/stemcells.2007-0996 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 315VF UT WOS:000256907600016 PM 18388307 ER PT J AU Raghunandan, R Ruiz-Hidalgo, M Jia, Y Ettinger, R Rudikoff, E Riggins, P Farnsworth, R Tesfaye, A Laborda, J Bauer, SR AF Raghunandan, Ramadevi Ruiz-Hidalgo, Maria Jia, Yifeng Ettinger, Rachael Rudikoff, Eva Riggins, Patrick Farnsworth, Richard Tesfaye, Abeba Laborda, Jorge Bauer, Steven R. TI Dlk1 influences differentiation and function of B lymphocytes SO STEM CELLS AND DEVELOPMENT LA English DT Article ID BONE-MARROW CULTURES; ADIPOCYTE DIFFERENTIATION; CELL-DIFFERENTIATION; STROMAL CELLS; PROTEIN DLK; DELTA-LIKE; EXPRESSION; GROWTH; LYMPHOPOIESIS; ANTIGEN AB The Dlk1 (delta-like-1) gene is a member of the epidermal growth factor (EGF)-like homeotic gene family. It influences cell-cell interactions between stromal cells and pro-B cells in vitro. To define the in vivo role of the dlk protein in B cell development, we established a Dlk1(-/-) mouse model. In spleens of Dlk1(-/-) mice, transitional B cell numbers were increased and the ratio between transitional B cell subsets was altered. Numbers of follicular B cells decreased, while the number of marginal zone B cells and the size of the marginal zone were increased. Loss of dlk resulted in increased immunoglobulin G1 (IgG(1)) and IgG(3) in preimmune sera. Furthermore, there was an exaggerated primary T-dependent antigen-specific humoral immune response. In bone marrow, the lack of dlk led to increased numbers of the earliest B lineage cells in young mice without affecting numbers of later B lineage cells. In vitro experiments showed that lack of dlk on either stromal cells or pro-B cells caused changes in differentiation and proliferation of pro-B cells, suggesting that lack of dlk leads to changes in cell-cell interactions in the bone marrow microenvironment. These results show that dlk expression is essential for normal B cell development. C1 [Raghunandan, Ramadevi; Jia, Yifeng; Rudikoff, Eva; Riggins, Patrick; Farnsworth, Richard; Tesfaye, Abeba; Bauer, Steven R.] US FDA, Ctr Biol Evaluat & Res, Cellular & Tissue Therapies Branch, Div Cellular & Gene Therapies, Bethesda, MD 20892 USA. [Ruiz-Hidalgo, Maria; Laborda, Jorge] Univ Castilla La Mancha, Biochem & Mol Biol Branch, Med Sch Reg Ctr Biomed Invest CRIB, Albacete, Spain. [Ettinger, Rachael] NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Bauer, SR (reprint author), FDA Ctr Biol Evaluat & Res, Cell & Tissue Therapy Branch, Div Cellular & Gene Therapies, Off Cellular Tissue & Gene Therapies, NIH Bldg 29B Room 2NN10,HFM-740,1401 Rockville Pi, Rockville, MD 20852 USA. EM Steven.Bauer@fda.hhs.gov RI Bauer, Steven/G-5559-2012; Laborda, Jorge/L-5726-2014; Ruiz-Hidalgo, Maria/L-1956-2014; OI Laborda, Jorge/0000-0002-9210-838X; Bauer, Steven/0000-0003-2831-846X FU Intramural NIH HHS NR 50 TC 46 Z9 47 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUN PY 2008 VL 17 IS 3 BP 495 EP 507 DI 10.1089/scd.2007.0102 PG 13 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 318TL UT WOS:000257115600011 PM 18513163 ER PT J AU Larsson, SC Mannisto, S Virtanen, MJ Kontto, J Albanes, D Virtamo, J AF Larsson, Susanna C. Mannisto, Satu Virtanen, Mikko J. Kontto, Jukka Albanes, Demetrius Virtamo, Jarmo TI Coffee and tea consumption and risk of stroke subtypes in male smokers SO STROKE LA English DT Article DE cerebral infarction; coffee; cohort study; epidemiology; stroke; tea ID C-REACTIVE PROTEIN; IMPAIRED GLUCOSE-TOLERANCE; CARDIOVASCULAR-DISEASE; CONTROLLED-TRIAL; ISCHEMIC-STROKE; GREEN TEA; INSULIN SENSITIVITY; WOMEN; MEN; MORTALITY AB Background and Purpose-Coffee and tea consumption could potentially reduce the risk of stroke because these beverages have antioxidant properties, and coffee may improve insulin sensitivity. We examined the associations of coffee and tea consumption with risk of stroke subtypes. Methods-We used prospective data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort study of 26 556 male Finnish smokers aged 50 to 69 years without a history of stroke at baseline. Coffee and tea consumption was assessed at baseline using a validated food-frequency questionnaire. During a mean follow-up of 13.6 years, from 1985 through December 2004, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained from national registries. Results-After adjustment for age and cardiovascular risk factors, both consumption of coffee and tea was statistically significantly inversely associated with the risk of cerebral infarction but not intracerebral or subarachnoid hemorrhage. The multivariate relative risk of cerebral infarction for men in the highest category of coffee consumption (>= 8 cups/d) was 0.77 (95% CI, 0.66 to 0.90; P for trend < 0.001) compared with those in the lowest category (< 2 cups/d). The corresponding relative risk comparing men in the highest category of tea consumption (>= 2 cups/d) with those in the lowest category (nondrinkers) was 0.79 (95% CI, 0.68 to 0.92; P for trend = 0.002). Conclusions-These results suggest that high consumption of coffee and tea may reduce the risk of cerebral infarction among men, independent of known cardiovascular risk factors. C1 [Larsson, Susanna C.] Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden. [Mannisto, Satu; Virtanen, Mikko J.; Kontto, Jukka; Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. [Albanes, Demetrius] NCI, NIH, Bethesda, MD 20892 USA. RP Larsson, SC (reprint author), Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Box 210, SE-17177 Stockholm, Sweden. EM susanna.larsson@ki.se RI Albanes, Demetrius/B-9749-2015; Larsson, Susanna/F-6065-2015; OI Larsson, Susanna/0000-0003-0118-0341; Mannisto, Satu/0000-0002-8668-3046; Kontto, Jukka/0000-0003-3899-9852 FU CCR NIH HHS [N01-RC-37004, N01-RC-45035]; NCI NIH HHS [N01-CN-45165] NR 44 TC 48 Z9 50 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2008 VL 39 IS 6 BP 1681 EP 1687 DI 10.1161/STROKEAHA.107.504183 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 305FG UT WOS:000256162600011 PM 18369170 ER PT J AU Celnik, P Webster, B Glasser, DM Cohen, LG AF Celnik, Pablo Webster, Brian Glasser, Davis M. Cohen, Leonardo G. TI Effects of action observation on physical training after stroke SO STROKE LA English DT Article DE stroke; action observation; mirror neurons system; rehabilitation ID MIRROR-NEURON SYSTEM; USE-DEPENDENT PLASTICITY; VENTRAL PREMOTOR CORTEX; PRIMARY MOTOR CORTEX; MEMORY; FACILITATION; STIMULATION; MECHANISMS; RECOVERY; OUTPUTS AB Background and Purpose-In healthy humans, observation of another individual performing a motor training task (action observation [AO]) facilitates, in the observer, the effects of physical training (PT) on motor memory formation. It is not known whether this facilitatory process, of potential value for neurorehabilitation, occurs after stroke. Methods-Eight chronic stroke patients completed this crossover- randomized investigation. A transcranial magnetic stimulation protocol that tests formation of motor memories was used to determine the effects of PT alone and in combination with AO in 2 different forms: congruent (PT + AO(congruent)) and incongruent (PT + AO(incongruent)) to the practiced task. Results-The magnitude of motor memory formation was larger with PT + AO(congruent) than with PT alone or PT + AO(incongruent). This effect was associated with a differential corticomotor excitability change in the muscles acting as agonist and antagonist of the trained/observed movements. Conclusions-These results indicate that congruent AO in association with physical training can enhance the effects of motor training after stroke. C1 [Celnik, Pablo] Johns Hopkins Univ Hosp, Dept Phys Med & Rehabil, Baltimore, MD 21287 USA. [Celnik, Pablo] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Celnik, Pablo; Webster, Brian; Glasser, Davis M.; Cohen, Leonardo G.] NINDS, Human Cort Physiol Sec, Bethesda, MD 20892 USA. [Celnik, Pablo; Webster, Brian; Glasser, Davis M.; Cohen, Leonardo G.] NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. RP Celnik, P (reprint author), Johns Hopkins Univ Hosp, Dept Phys Med & Rehabil, 600 N Wolfe St, Baltimore, MD 21287 USA. EM pcelnik@jhmi.edu FU Intramural NIH HHS; NICHD NIH HHS [5K12HD001097, K12 HD001097, R01 HD053793, R01HD053793-01A1] NR 30 TC 91 Z9 96 U1 1 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2008 VL 39 IS 6 BP 1814 EP 1820 DI 10.1161/STROKEAHA.107.508184 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 305FG UT WOS:000256162600032 PM 18403746 ER PT J AU Ovbiagele, B Drogan, O Koroshetz, WJ Fayad, P Saver, JL AF Ovbiagele, Bruce Drogan, Oksana Koroshetz, Walter J. Fayad, Pierre Saver, Jeffrey L. TI Outpatient practice patterns after stroke hospitalization among neurologists SO STROKE LA English DT Article DE adherence; ischemic stroke; neurologists; practice patterns ID TRANSIENT ISCHEMIC ATTACK; PREVENTION; GUIDELINES; ADHERENCE; PROGRAM; POPULATION; INITIATION; STATIN; RATES; RISK AB Background and Purpose-Care after stroke hospitalization can provide several opportunities to optimize vascular risk reduction. However, not much is known about poststroke practice patterns among neurologists. Such knowledge may help direct specific efforts to improve the impact of practicing neurologists on clinical outcomes after stroke. Methods-A survey soliciting information on processes of care in the outpatient setting after recent hospitalization for ischemic stroke or transient ischemic attack was mailed to a random sample of 833 US and Canadian neurologist members of the American Academy of Neurology. Results-A total of 475 (57%) responses were received. Practice demographics of survey responders and nonresponders were largely similar. Fourteen percent of respondents identified themselves as vascular neurologists. Overall, respondents reported frequently checking for medication adherence and counseling patients on lifestyle modification. However, neurologists reported screening more frequently for diabetes, hypertension, and dyslipidemia than actually treating these conditions (all P < 0.0001) Vascular neurologists were more likely than general neurologists to screen for hypertension (97% versus 86%, P = 0.016), dyslipidemia (94% versus 68%, P < 0.001), diabetes (89% versus 62%, P < 0.001), and sleep apnea (94% versus 79%, P = 0.007) as well as to treat hypertension (71% versus 45%, P < 0.001), dyslipidemia (82% versus 50%, P < 0.001), diabetes (45% versus 21%, P < 0.001), and current smoking (77% versus 59%, P = 0.005). Neurologists with mostly government-insured and uninsured patients were significantly more likely to engage in vascular risk reduction treatment than neurologists with mostly commercially insured patients. Conclusions-Self-reported rates of screening and treatment of major vascular risk factors by most neurologists after stroke hospitalization are substantial but not universal. Bridging knowledge gaps or adopting a systematic management approach in coordination with primary care physicians could help optimize poststroke care. C1 [Ovbiagele, Bruce; Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Med Ctr, Los Angeles, CA 90095 USA. [Ovbiagele, Bruce; Saver, Jeffrey L.] Univ Calif Los Angeles, Med Ctr, Stroke Ctr, Los Angeles, CA 90095 USA. [Drogan, Oksana] Amer Acad Neurol, St Paul, MN USA. [Koroshetz, Walter J.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Fayad, Pierre] Univ Nebraska Med Ctr, Dept Neurol Sci, Omaha, NE USA. RP Ovbiagele, B (reprint author), Univ Calif Los Angeles, Dept Neurol, Med Ctr, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM Ovibes@mednet.ucla.edu OI Saver, Jeffrey/0000-0001-9141-2251 NR 19 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2008 VL 39 IS 6 BP 1850 EP 1854 DI 10.1161/STROKEAHA.107.504860 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 305FG UT WOS:000256162600037 PM 18388342 ER PT J AU Powell, AC Stratakis, CA Patronas, NJ Steinberg, SM Batista, D Alexander, HR Pingpank, JE Keil, M Bartlett, DL Libutti, SK AF Powell, Anathea C. Stratakis, Constantine A. Patronas, Nicholas J. Steinberg, Seth M. Batista, Dalia Alexander, H. Richard Pingpank, James E. Keil, Meg Bartlett, David L. Libutti, Steven K. TI Operative management of Cushing Syndrome secondary to micronodular adrenal hyperplasia SO SURGERY LA English DT Article ID NODULAR ADRENOCORTICAL-DISEASE; CARNEY COMPLEX; DIAGNOSIS; MUTATIONS; INTERLEUKIN-6; DEXAMETHASONE; EXPRESSION; PDE11A; TUMORS AB Background. We reviewed our experience with micronodular adrenal hyperplasia (MAH), its pigmented variant primary pigmented nodular adrenocortical disease (PPNAD), and the association with Carney's complex (CNC) to better characterize these disorders. Methods. This retrospective study analyzes clinical data and operative reports of 34 patients identified with MAH and/or PPNAD who underwent resection between 1969 and 2006 at the Clinical Research Center, an inpatient research hospital at the National Institutes of Health. Symptoms and anthropometric and biochemical data were used to evaluate effect of resection. Results. Fifteen patients (44%) presented as adults and 19 (56%) as children. Twenty-five patients (74%) presented with noncyclic Cushing syndrome and 9 patients (26%) presented with cyclic Cushing syndrome. Thirty-one patients underwent bilateral resection; this was curative biochemically in 30 patients. Fourteen operations were performed laparoscopically (41%), and 20 were performed as open resections (59%). There was 1 postoperative complication in the laparoscopic group (7%) and 6 complications in the open group (30%; P = .20). Follow-up was available for 25 patients (74%). Statistically significant improvements in anthropometrics were observed for both adults and children. The most frequent manifestation of CNC requiring additional operation was cardiac myxoma, which was associated strongly with an atypical (cyclic) presentation of Cushing syndrome (P = .009). Conclusion. Cushing syndrome due to AIAH and PPNAD may be cured by bilateral adrenal resection. All patients should be screened for manifestations of CNC at the time of adrenal diagnosis with particular attention to cardiac disease. C1 [Powell, Anathea C.; Alexander, H. Richard; Pingpank, James E.; Bartlett, David L.; Libutti, Steven K.] NICHHD, Tumor Angiogenesis Sect, Surg Branch, NCI,NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.; Batista, Dalia] NICHHD, Sect Endocrinol Genet, Dev Endocrinol Branch, NCI,NIH, Bethesda, MD 20892 USA. [Stratakis, Constantine A.; Batista, Dalia; Keil, Meg] NICHHD, Pediat Endocrinol Program, NCI, NIH, Bethesda, MD 20892 USA. [Patronas, Nicholas J.] Warren F Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD USA. [Steinberg, Seth M.] NCI, Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Batista, Dalia] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Batista, Dalia] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Libutti, SK (reprint author), NCI, Tumor Angiogenesis Sect, Ctr Canc Res, 10 Ctr Dr 4W-5940, Bethesda, MD 20892 USA. EM libuttis@mail.nih.gov FU Intramural NIH HHS [NIH0012762233]; NICHD NIH HHS [Z01 HD000642, Z01HD000642-04] NR 23 TC 21 Z9 25 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUN PY 2008 VL 143 IS 6 BP 750 EP 758 DI 10.1016/j.surg.2008.03.022 PG 9 WC Surgery SC Surgery GA 315DU UT WOS:000256858900007 PM 18549891 ER PT J AU Kaushal, A Citrin, D AF Kaushal, Aradhana Citrin, Deborah TI The role of radiation therapy in the management of sarcomas SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article ID SOFT-TISSUE SARCOMA; ISOLATED LIMB PERFUSION; NECROSIS-FACTOR-ALPHA; ELECTRON-BEAM RADIOTHERAPY; RETROPERITONEAL SARCOMA; POSTOPERATIVE RADIOTHERAPY; ADJUVANT CHEMOTHERAPY; PROGNOSTIC FACTORS; RANDOMIZED TRIAL; NEOADJUVANT CHEMOTHERAPY AB Sarcomas represent a heterogeneous, challenging, and rare group of tumors that present many management challenges. In this article, the authors concentrate on the radiotherapeutic management of sarcomas occurring in the most common locations: the extremities, the trunk, and the retroperitoneum. An overview of the current radiotherapeutic management of soft tissue sarcoma is presented in addition to a discussion of how surgical management may affect radiotherapeutic management. Finally, the authors describe current controversies surrounding the appropriate management of sarcomas with radiotherapy and describe ongoing studies and future areas of research. C1 [Citrin, Deborah] NCI, Sect Imaging & Mol Therapeut, Radiat Oncol Branch, Natl Canc Ctr, Bethesda, MD 20892 USA. RP Citrin, D (reprint author), NCI, Sect Imaging & Mol Therapeut, Radiat Oncol Branch, Natl Canc Ctr, Bldg 10,Hatfield CRC,B2-3500,10 Ctr Dr, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 51 TC 33 Z9 35 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 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD JUN PY 2008 VL 88 IS 3 BP 629 EP + DI 10.1016/j.suc.2008.03.005 PG 19 WC Surgery SC Surgery GA 320DN UT WOS:000257214000012 PM 18514703 ER PT J AU Li, Y AF Li, Yan TI Generalized regression estimators of a finite population total using the Box-Cox technique SO SURVEY METHODOLOGY LA English DT Article DE generalized regression (GREG) estimator; Box-Cox technique; pseudo-maximum likelihood (PML) ID IMPORT DEMAND EQUATION; FUNCTIONAL FORM; COMPLEX SURVEYS; MODEL; TRANSFORMATION; VARIANCE AB A new generalized regression estimator of a finite population total based on the Box-Cox transformation technique and its variance estimator are proposed under a general unequal probability sampling design. By being design consistent, the proposed estimator maintains the robustness property of the GREG estimator even if the underlying model fails. Furthermore, the Box-Cox technique automatically finds a reasonable transformation for the dependent variable using the data. The robustness and efficiency of the new estimator are evaluated analytically and via Monte Carlo simulation studies. C1 Univ Maryland, Coll Pk Biostat Branch, Div Canc Epidemiol & Genet, Natl Canc Inst,NIH, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Univ Maryland, Coll Pk Biostat Branch, Div Canc Epidemiol & Genet, Natl Canc Inst,NIH, DHHS Execut Plaza S Room 8014,6120 Execut Blvd,MS, Bethesda, MD 20892 USA. EM lisherry@mail.nih.gov NR 47 TC 1 Z9 1 U1 0 U2 6 PU STATISTICS CANADA PI OTTAWA PA 100 TUNNEYS PASTURE DRIVEWAY, OTTAWA, ONTARIO K1A 0T6, CANADA SN 0714-0045 J9 SURV METHODOL JI Surv. Methodol. PD JUN PY 2008 VL 34 IS 1 BP 79 EP 89 PG 11 WC Social Sciences, Mathematical Methods; Statistics & Probability SC Mathematical Methods In Social Sciences; Mathematics GA 342AK UT WOS:000258756800008 ER PT J AU Cropley, VL Innis, RB Nathan, PJ Brown, AK Sangare, JL Lerner, A Ryu, YH Sprague, KE Pike, VW Fujita, M AF Cropley, Vanessa L. Innis, Robert B. Nathan, Pradeep J. Brown, Amira K. Sangare, Janet L. Lerner, Alicja Ryu, Yong Hoon Sprague, Kelly E. Pike, Victor W. Fujita, Masahiro TI Small effect of dopamine release and no effect of dopamine depletion on [F-18]fallypride binding in healthy humans SO SYNAPSE LA English DT Article DE D-2 radioligand; D-amphetamine; alpha-methyl-para-tyrosine; phasic; tonic; PET ID POSITRON-EMISSION-TOMOGRAPHY; BASE-LINE OCCUPANCY; ORAL D-AMPHETAMINE; RECEPTOR OCCUPANCY; NONHUMAN-PRIMATES; IN-VIVO; EXTRASTRIATAL REGIONS; ENDOGENOUS DOPAMINE; COGNITIVE FUNCTION; F-18 FALLYPRIDE AB Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [F-18]fallypride in healthy subjects to assess (1) the reproducibility of [F-18]fallypride and (2) both D-amphetamine-induced and (X-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [F-18]fallypride binding in striatal and extrastriatal areas. Subjects underwent [F-18]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BPND) of [F-18]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BPND was computed and correlated with change in cognition and mood. Test-retest variability of [F-18]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BPND by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BPND and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [F-18]fallypride BPND in both striatum and extrastriatal regions. These findings indicate that [F-18]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans. C1 [Cropley, Vanessa L.; Innis, Robert B.; Brown, Amira K.; Sangare, Janet L.; Lerner, Alicja; Ryu, Yong Hoon; Sprague, Kelly E.; Pike, Victor W.; Fujita, Masahiro] NIMH, NIH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Cropley, Vanessa L.] Swinburne Univ Technol, Brain Sci Inst, Hawthorn, Vic 3122, Australia. [Nathan, Pradeep J.] Monash Univ, Sch Psychol Psychiat & Psychol Med, Clayton, Vic 3168, Australia. [Ryu, Yong Hoon] Yonsei Univ, Coll Med, Dept Nucl Med, Seoul, South Korea. RP Fujita, M (reprint author), NIMH, NIH, Mol Imaging Branch, Bldg 31,Rm B2-B37,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. EM fujitam@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [Z01-MH-002852-03] NR 47 TC 69 Z9 70 U1 0 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUN PY 2008 VL 62 IS 6 BP 399 EP 408 DI 10.1002/syn.20506 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 296YC UT WOS:000255580800001 PM 18361438 ER PT J AU Kolbrich, EA Goodwin, RS Gorelick, DA Hayes, RJ Stein, EA Huestis, MA AF Kolbrich, Erin A. Goodwin, Robert S. Gorelick, David A. Hayes, Robert J. Stein, Elliot A. Huestis, Marilyn A. TI Plasma pharmacokinetics of 3.4-methylenedioxymethamphetamine after controlled oral administration to young adults SO THERAPEUTIC DRUG MONITORING LA English DT Article DE MDMA; plasma; pharmacokinetics; ecstasy; metabolites; nonlinear ID MDMA ECSTASY; 3,4-METHYLENEDIOXYMETHAMPHETAMINE ECSTASY; GAS-CHROMATOGRAPHY; PSYCHOMOTOR PERFORMANCE; HUMAN PHARMACOLOGY; MASS-SPECTROMETRY; HUMANS; METABOLITES; CYP2D6; URINE AB This study examines the plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylene-dioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) in young adults for up to 143 hours after drug administration. Seventeen female and male participants (black, white, and Hispanic) received placebo, low (1.0 mg/kg), and high (1.6 mg/kg) oral MDMA doses (comparable to recreational doses) in a double-blind, randomized, balanced, within-subject design while residing on a closed research unit. Doses were separated by 1 week or more. A fully validated two-dimensional gas chromatography/mass spectrometry method simultaneously quantified MDMA, HMMA, MDA, and HMA. Calibration curves were MDA, 1 to 100 ng/mL; HMA, 2.5 to 100 ng/mL; and MDMA and HMMA, 2.5 to 400 ng/mL. Mean standard deviation maximum plasma concentrations (C-max) of 162.9 +/- 39.8 and 171.9 +/- 79.5 ng/mL were observed for MDMA and HMMA, respectively, after low-dose MDMA. After the high dose, mean MDMA C-max significantly increased to 291.8 +/- 76.5 ng/mL, whereas mean HMMA C-max was unchanged at 173.5 +/- 66.3 ng/mL. High intersubject variability in C-max was observed. Mean MDA C-max were 8.4 +/- 2.1 (low) and 13.8 +/- 3.8 (high) ng/mL. HMA C-max were 3.5 +/- 0.4 and 3.9 +/- 0.9 ng/mL after the low and high doses, respectively. AUC(infinity) displayed similar trends to C-max demonstrating nonlinear pharmacokinetics. Times of last plasma detection were generally HMA < MDA < MDMA < HMMA. Mean half-lives (t(1/2)) of MDMA, MDA, and HMMA were approximately 7 to 8 hours, 10.5 to 12.5 hours, and 11.5 to 13.5 hours, respectively. HMA t(1/2) showed high variability. Mean MDMA volume of distribution was constant for low and high doses; clearance was significantly higher after the low dose. This study presents MDMA plasma pharmacokinetic data for the first time from blacks and females as well as measurement of HMMA and HMA concentrations after low and high MDMA doses and more frequent and extended plasma sampling than in prior studies. C1 [Kolbrich, Erin A.; Goodwin, Robert S.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Gorelick, David A.] Natl Inst Drug Abuse, Off Sci Director, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Hayes, Robert J.; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Chem & Drug Metab Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000468-04] NR 58 TC 57 Z9 58 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD JUN PY 2008 VL 30 IS 3 BP 320 EP 332 DI 10.1097/FTD.0b013e3181684fa0 PG 13 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 312BW UT WOS:000256645100009 PM 18520604 ER PT J AU Paleari, L Cesario, A Granone, P D'Angelillo, RM Russo, P AF Paleari, L. Cesario, A. Granone, P. D'Angelillo, R. Maria Russo, P. TI Early detection of cancer: lessons from lung cancer CT screening SO THORAX LA English DT Letter ID COMPUTED-TOMOGRAPHY; IDENTIFICATION; SURVIVAL C1 [Paleari, L.] Natl Canc Inst, Lung Canc Unit, Genoa, Italy. [Cesario, A.; Granone, P.] Catholic Univ, Thorac Surg Unit, I-00167 Rome, Italy. [Cesario, A.; Russo, P.] IRCCS San Raffaele, Rome, Italy. [D'Angelillo, R. Maria] Radiotherapy Unit, Rome, Italy. RP Cesario, A (reprint author), Catholic Univ, Surg Pathol Unit, Largo A Gemelli 2, I-00167 Rome, Italy. EM alfcesario@rm.unicatt.it RI CESARIO, Alfredo/O-4215-2015; OI CESARIO, Alfredo/0000-0003-4687-0709; D'Angelillo, Rolando M./0000-0003-3636-6429 NR 8 TC 2 Z9 2 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD JUN PY 2008 VL 63 IS 6 BP 566 EP 566 DI 10.1136/thx.2007.086330 PG 1 WC Respiratory System SC Respiratory System GA 307AJ UT WOS:000256289600020 PM 18511643 ER PT J AU Robbins, J AF Robbins, Jacob TI Dr. Joseph Edward ("Ed") Rall 1920-2008 - In memoriam SO THYROID LA English DT Biographical-Item C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Robbins, J (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUN PY 2008 VL 18 IS 6 BP 677 EP 678 DI 10.1089/thy.2008.0136 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 327WS UT WOS:000257759800021 PM 18578626 ER PT J AU Berman, RF Pessah, IN Mouton, PR Mav, D Harry, GJ AF Berman, Robert F. Pessah, Issac N. Mouton, Peter R. Mav, Deepak Harry, G. Jean TI Modeling neonatal thimerosal exposure in mice SO TOXICOLOGICAL SCIENCES LA English DT Letter C1 [Berman, Robert F.] Univ Calif Davis, Dept Neurol Surg, Davis, CA 95616 USA. [Berman, Robert F.] Univ Calif Davis, Ctr Childrens Environm Hlth, Davis, CA 95616 USA. [Pessah, Issac N.] Univ Calif Davis, Ctr Childrens Environm Hlth, Davis, CA 95616 USA. [Pessah, Issac N.] Univ Calif Davis, Dept Mol Biosci, Davis, CA 95616 USA. [Mouton, Peter R.] Stereol Res Ctr, Chester, MD 21619 USA. [Mav, Deepak] Constella Grp LLC, Durham, NC 27713 USA. [Harry, G. Jean] NIH, Neurotoxicol Grp, Neurobiol Lab, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Berman, RF (reprint author), Univ Calif Davis, Dept Neurol Surg, Davis, CA 95616 USA. NR 1 TC 0 Z9 0 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUN PY 2008 VL 103 IS 2 BP 416 EP 416 DI 10.1093/toxsci/kfn051 PG 1 WC Toxicology SC Toxicology GA 299MX UT WOS:000255760800021 ER PT J AU Cho, MH Niles, A Huang, RL Inglese, J Austin, CP Riss, T Xia, MH AF Cho, Ming-Hsuang Niles, Andrew Huang, Ruili Inglese, James Austin, Christopher P. Riss, Terry Xia, Menghang TI A bioluminescent cytotoxicity assay for assessment of membrane integrity using a proteolytic biomarker SO TOXICOLOGY IN VITRO LA English DT Article DE 1536-well; NTP 1408 compound library; membrane integrity; cytotoxicity assay; protease release assay; qHTS Renal mesangial cells; HEK293 cells ID INVITRO; CELLS AB Measurement of cell membrane integrity has been widely used to assess chemical cytotoxity. Several assays are available for determining cell membrane integrity including differential labeling techniques using neutral red and trypan blue dyes or fluorescent compounds such as propidium iodide. Other common methods for assessing cytotoxicity are enzymatic "release" assays which measure the extra-cellular activities of lactate clehydrogenase (LDH), adenylate kinase (AK), or glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in culture medium. However, all these assays suffer from several practical limitations, including multiple reagent additions, scalability, low sensitivity, poor linearity, or requisite washes and medium exchanges. We have developed a new cytotoxicity assay which measures the activity of released intracellular proteases as a result of cell membrane impairment. It allows for a homogenous, one-step addition assay with a luminescent readout. We have optimized and miniaturized this assay into a 1536-well format, and validated it by screening a library of known compounds from the National Toxicology Program (NTP) using HEK 293 and human renal mesangial cells by quantitative high-throughput screening (qHTS). Several known and novel membrane disrupters were identified from the library, which indicates that the assay is robust and suitable for large scale library screening. This cytotoxicity assay, combined with the qHTS platform, allowed us to quickly and efficiently evaluate compound toxicities related to cell membrane integrity. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Cho, Ming-Hsuang; Huang, Ruili; Inglese, James; Austin, Christopher P.; Xia, Menghang] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Niles, Andrew; Riss, Terry] Promega Corp, Res & Dev, Madison, WI USA. RP Xia, MH (reprint author), NIH, Chem Genom Ctr, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov FU Intramural NIH HHS [Z01 HG200319-04, Z99 HG999999] NR 23 TC 30 Z9 32 U1 1 U2 9 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 JUN PY 2008 VL 22 IS 4 BP 1099 EP 1106 DI 10.1016/j.tiv.2008.02.013 PG 8 WC Toxicology SC Toxicology GA 303YJ UT WOS:000256076900034 PM 18400464 ER PT J AU Oyler, GA Kuo, CL Sepulveda, J Tsai, YC Kincaid, CR Tzipori, S Shoemaker, CB AF Oyler, George A. Kuo, C. L. Sepulveda, J. Tsai, Y. C. Kincaid, C. R. Tzipori, S. Shoemaker, Charles B. TI Therapeutics which accelerate degradation BoNT/A LC within neurons SO TOXICON LA English DT Meeting Abstract CT 6th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins CY JUN 12-15, 2008 CL Baveno, ITALY DE persistence; ubiquitin; camelid antibody C1 [Oyler, George A.] Synaptic Res, Baltimore, MD USA. [Tsai, Y. C.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 1 PY 2008 VL 51 SU 1 MA 49 BP 17 EP 17 DI 10.1016/j.toxicon.2008.04.051 PG 1 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 319VJ UT WOS:000257192200050 ER PT J AU Hallett, M AF Hallett, Mark TI Focal hand dystonia SO TOXICON LA English DT Meeting Abstract CT 6th International Conference on Basic and Therapeutic Aspects of Botulinum and Tetanus Toxins CY JUN 12-15, 2008 CL Baveno, ITALY DE focal hand dystonia; therapy; technique C1 [Hallett, Mark] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD JUN 1 PY 2008 VL 51 SU 1 MA 85 BP 28 EP 29 DI 10.1016/j.toxicon.2008.04.087 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 319VJ UT WOS:000257192200086 ER PT J AU Masilamani, M Narayanan, S Prieto, M Borrego, F Coligan, JE AF Masilamani, Madhan Narayanan, Sriram Prieto, Martha Borrego, Francisco Coligan, John E. TI Uncommon endocytic and trafficking pathway of the natural killer cell CD94/NKG2A inhibitory receptor SO TRAFFIC LA English DT Article DE cD94/NKG2A; endocytosis; inhibitory receptor; natural killer cells; trafficking ID CLATHRIN-MEDIATED ENDOCYTOSIS; MAMMALIAN-CELLS; NK CELLS; IMMUNOLOGICAL SYNAPSE; ACTIN CYTOSKELETON; RECYCLING PATHWAY; MEMBRANE DOMAINS; GTPASE ACTIVITY; DOWN-REGULATION; COATED PITS AB The CD94/NKG2A inhibitory receptor, expressed by natural killer and T cells, is constantly exposed to its HLA-E ligand expressed by surrounding cells. Ligand exposure often induces receptor downregulation. For CD94/NKG2A, this could potentiate activation receptor(s) induced responses to normal bystander cells. We investigated CD94/NKG2A endocytosis and found that it occurs by an amiloride-sensitive, Rac1-dependent macropinocytic-like process; however, it does not require clathrin, dynamin, ADP ribosylation factor-6, phosphoinositide-3 kinase or the actin cytoskeleton. Once endocytosed, CD94/NKG2A traffics to early endosomal antigen 1(+), Rab5(+) early endosomes. It does appear in Rab4(+) early/sorting endosome, but, in the time period examined, fails to reach Rab11(+) recycling or Rab7(+) late endosomes or lysosome-associated membrane protein-1(+) lysosomes. These results indicate that CD94/NKG2A utilizes a previously undescribed endocytic mechanism coupled with an abbreviated trafficking pattern, perhaps to insure surface expression. C1 [Masilamani, Madhan; Narayanan, Sriram; Prieto, Martha; Borrego, Francisco; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov OI Narayanan, Sriram/0000-0002-6484-2800; Masilamani, Madhan/0000-0001-8181-8848 FU Intramural NIH HHS NR 77 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD JUN PY 2008 VL 9 IS 6 BP 1019 EP 1034 DI 10.1111/j.1600-0854.2008.00738.x PG 16 WC Cell Biology SC Cell Biology GA 298CQ UT WOS:000255664400012 PM 18363778 ER PT J AU Fadeyi, E Adams, S Peterson, B Hackett, J Byrne, P Klein, HG Marincola, FM Leitman, SF Stroncek, DF AF Fadeyi, Emmanuel Adams, Sharon Peterson, Brett Hackett, Julia Byrne, Phyllis Klein, Harvey G. Marincola, Francesco M. Leitman, Susan F. Stroncek, David F. TI Analysis of a high-throughput HLA antibody screening assay for use with platelet donors SO TRANSFUSION LA English DT Article ID ACUTE LUNG INJURY; SSOP-LUMINEX METHOD; FLOW-CYTOMETRY; TRANSFUSION; NEUTROPHILS; SPECTRUM; TRALI AB BACKGROUND: Passive infusion of HLA antibodies has been implicated in transfusion reactions. A rapid, inexpensive method of screening blood donors for HLA antibodies might reduce the incidence of reactions. A high-throughput microbead-flow analyzer HLA antibody detection technique was compared with an enzyme-linked immunosorbent assay (ELISA) method. STUDY DESIGN AND METHODS: Ninety-six apheresis platelet (PLT) donors were tested for antibodies to Class I and II HLA antigens with mixed-antigen microbead-flow analyzer and ELISAs. For both assays, samples reactive in the mixed-antigen assay were tested with a panel-reactive antibody (PRA) assay. Samples reactive in both the mixed-antigen and the PRA assays were considered positive. RESULTS: In the mixed-antigen microbead assay, 46 (48%) samples were reactive to Class I antigens and 20 (21%) to Class II. Further testing in the microbead PRA assay revealed that 34 (35%) had antibodies to Class I antigens, 18 (19%) to Class II, and 42 (44%) to either Class I or Class II. Class I antibodies were present in 56 percent of females and 36 percent of males. In the mixed-antigen ELISA, 4 samples were reactive with Class I antigens, 4 with Class II antigens, and 5 with Class I or Class II. All 5 reactive samples were also reactive in the ELISA PRA assay and were from females. CONCLUSION: The microbead assay was more sensitive than the ELISA and detected antibodies in a large proportion of donors. Samples reactive in the mixed-antigen microbead assay should be confirmed by a second assay before concluding that antibodies are present. C1 [Fadeyi, Emmanuel; Adams, Sharon; Peterson, Brett; Hackett, Julia; Byrne, Phyllis; Klein, Harvey G.; Marincola, Francesco M.; Leitman, Susan F.; Stroncek, David F.] NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711,10 Ctr Dr,MSC 1184, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [Z01 CL002095-11] NR 14 TC 24 Z9 27 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUN PY 2008 VL 48 IS 6 BP 1174 EP 1179 DI 10.1111/j.1537-2995.2008.01684.x PG 6 WC Hematology SC Hematology GA 309GH UT WOS:000256448200021 PM 18422853 ER PT J AU O'Brien, SJ Johnson, W Driscoll, C Pontius, J Pecon-Slattery, J Menotti-Raymond, M AF O'Brien, Stephen J. Johnson, Warren Driscoll, Carlos Pontius, Joan Pecon-Slattery, Jill Menotti-Raymond, Marilyn TI State of cat genomics SO TRENDS IN GENETICS LA English DT Review ID MAJOR HISTOCOMPATIBILITY COMPLEX; CLASS-II REGION; DOMESTIC CAT; FELIS-CATUS; NUCLEAR GENOME; GENETIC INDIVIDUALIZATION; PLEISTOCENE EXTINCTIONS; MAMMALIAN EVOLUTION; LOCI; MAP AB Our knowledge of cat family biology was recently expanded to include a genomics perspective with the completion of a draft whole genome sequence of an Abyssinian cat. The utility of the new genome information has been demonstrated by applications ranging from disease gene discovery and comparative genomics to species conservation. Patterns of genomic organization among cats and inbred domestic cat breeds have illuminated our view of domestication, revealing linkage disequilibrium tracks consequent of breed formation, defining chromosome exchanges that punctuated major lineages of mammals and suggesting ancestral continental migration events that led to 37 modern species of Felidae. We review these recent advances here. As the genome resources develop, the cat is poised to make a major contribution to many areas in genetics and biology. C1 [O'Brien, Stephen J.; Johnson, Warren; Driscoll, Carlos; Pecon-Slattery, Jill; Menotti-Raymond, Marilyn] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Pecon-Slattery, Jill] NCI, SAIC Frederick Inc, Basic Res Program, Lab Genom Divers, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov RI Johnson, Warren/D-4149-2016; OI Johnson, Warren/0000-0002-5954-186X; Driscoll, Carlos/0000-0003-2392-505X FU NCI NIH HHS [N01-CO-12400] NR 104 TC 41 Z9 45 U1 4 U2 45 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JUN PY 2008 VL 24 IS 6 BP 268 EP 279 DI 10.1016/j.tig.2008.03.004 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 313OP UT WOS:000256750200005 PM 18471926 ER PT J AU Wang, E Worschech, A Marincola, FM AF Wang, Ena Worschech, Andrea Marincola, Francesco M. TI The immunologic constant of rejection SO TRENDS IN IMMUNOLOGY LA English DT Review ID C VIRUS-INFECTION; T-CELLS; ALLOGRAFT-REJECTION; GENE-EXPRESSION; MELANOMA PATIENTS; PERIPHERAL-BLOOD; NORMAL TISSUE; B-LYMPHOCYTE; TUMOR; CANCER AB The complexity underlying a pathologic process does not necessarily require a complex explanation. The biology determining allograft or cancer rejection, autoimmunity or tissue damage during pathogen infections is complex; however, common patterns are emerging that lead to a common final outcome. For instance, tissue destruction occurs with resolution of the pathogenic process (cancer, infection) or tissue damage and organ failure (autoimmunity, allograft rejection). Observations in humans based on transcriptional profiling converge into what we call an 'immunologic constant of rejection' that characterizes such occurrences. This constant includes the coordinate activation of interferon-stimulated genes (ISGs) and immune effector functions (IEFs). Understanding this final effector pathway may suggest novel strategies for the induction or inhibition of tissue-specific destruction with therapeutic intent in cancer and other immune pathologies. C1 [Wang, Ena; Worschech, Andrea; Marincola, Francesco M.] NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Worschech, Andrea; Marincola, Francesco M.] Genelux Corp, San Diego, CA 92109 USA. [Worschech, Andrea] Wuerzburg Univ, Dept Biochem, D-97074 Wurzburg, Germany. RP Marincola, FM (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Fmarincola@mail.cc.nih.gov RI Worschech, Andrea/I-3919-2012 OI Worschech, Andrea/0000-0002-4303-8653 NR 74 TC 75 Z9 76 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUN PY 2008 VL 29 IS 6 BP 256 EP 262 DI 10.1016/j.it.2008.03.002 PG 7 WC Immunology SC Immunology GA 317EQ UT WOS:000257003000002 PM 18457994 ER PT J AU Francischetti, IMB AF Francischetti, Ivo M. B. TI Does activation of the blood coagulation cascade have a role in malaria pathogenesis? SO TRENDS IN PARASITOLOGY LA English DT Review ID PLASMODIUM-FALCIPARUM MALARIA; DISSEMINATED INTRAVASCULAR COAGULATION; EXPERIMENTAL CEREBRAL MALARIA; NITRIC-OXIDE BIOAVAILABILITY; TUMOR-NECROSIS-FACTOR; TISSUE FACTOR; INFECTED ERYTHROCYTES; ENDOTHELIAL-CELLS; MALAWIAN CHILDREN; AFRICAN CHILDREN AB Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor in the brain endothelium of patients who have died from cerebral malaria casts new light on our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells support the assembly of multimolecular coagulation complexes. Tissue factor expression by the endothelium and amplification of the coagulation cascade by parasitized red blood cells and/or activated platelets (particularly at sequestration sites) have crucial roles in mounting and sustaining a coagulation-inflammation cycle which contributes to organ dysfunction and coma in falciparum malaria. C1 NIAID, Vector Biol Sect, Lab Malaria & Vector Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Francischetti, IMB (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ifrancischetti@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999] NR 56 TC 38 Z9 38 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD JUN PY 2008 VL 24 IS 6 BP 258 EP 263 DI 10.1016/j.pt.2008.03.009 PG 6 WC Parasitology SC Parasitology GA 313NP UT WOS:000256747600006 PM 18467176 ER PT J AU Pflug, R Nelson, R Huber, S Reitsamer, H AF Pflug, Renate Nelson, Ralph Huber, Sonja Reitsamer, Herbert TI Modulation of horizontal cell function by dopaminergic ligands in mammalian retina SO VISION RESEARCH LA English DT Article DE rabbit; intracellular recording; flicker responses; dopamine ID INDUCED FLICKER ENHANCEMENT; LIGHT-STIMULATED RELEASE; RABBIT RETINA; RAT RETINA; CONE PHOTORECEPTORS; GLUTAMATE RECEPTORS; GANGLION-CELLS; FISH RETINA; CAT RETINA; LOCALIZATION AB Light responses of rabbit horizontal cell somata (HC) to flickering light stimuli recorded with sharp electrodes consist of a distinctive flicker component superimposed on a sustained hyperpolarisation. Activation of dopamine D1/D5 receptors depolarises HC dark membrane potential and suppresses the flicker component of responses to photopic stimuli without affecting the sustained hyperpolarising response component. Waveforms of responses to scotopic stimuli are preserved. Similar response modulation was observed in depolarising cells of the inner retina, suggesting that activation of D1/D5 receptors of HC causes modification of cone signal transmission to higher order neurons. The impact of dopamine D1/D5 receptor activation on the function of HC in the light stimulated retina is discussed. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Pflug, Renate; Huber, Sonja; Reitsamer, Herbert] Med Univ Vienna, Dept Physiol, Ctr Physiol & Pathophysiol, A-1090 Vienna, Austria. [Nelson, Ralph] NIH, NINDS, Neural Circuitry Unit, Rockville, MD 20892 USA. [Reitsamer, Herbert] Paracelsus Univ, Dept Ophthalmol & Optometry, Salzburg, Austria. RP Pflug, R (reprint author), Med Univ Vienna, Dept Physiol, Ctr Physiol & Pathophysiol, Schwarzpanierstr 17, A-1090 Vienna, Austria. EM renate.pflug@meduniwien.ac.at FU Intramural NIH HHS [Z01 NS002631-25] NR 52 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN PY 2008 VL 48 IS 12 BP 1383 EP 1390 DI 10.1016/j.visres.2008.03.004 PG 8 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 312BY UT WOS:000256645300003 PM 18440579 ER PT J AU Falanga, V Brem, H Ennis, WJ Wolcott, R Gould, LJ Ayello, EA AF Falanga, Vincent Brem, Harold Ennis, William J. Wolcott, Randall Gould, Lisa J. Ayello, Elizabeth A. TI Maintenance debridement in the treatment of difficult-to-heal chronic wounds - Recommendations of an expert panel SO WOUNDS-A COMPENDIUM OF CLINICAL RESEARCH AND PRACTICE LA English DT Article ID QUALITY-OF-LIFE; VENOUS LEG ULCERS; BED PREPARATION; TISSUE INHIBITOR; PRESSURE ULCERS; DIABETIC FOOT; GUIDELINES; EXPRESSION; BIOFILMS; FIBROBLASTS AB Introduction: Maintenance debridement has been proposed as a therapeutic intervention to address the problem of chronic wounds characterized by an adequate wound bed but absent or slow healing. A panel of experts convened to address the rationale and method of maintenance debridement. Purpose: The goals of the panel were to summarize the scientific rationale for maintenance debridement, discuss the biochemical and cellular abnormalities in the wound bed, and provide a working algorithm for how maintenance debridement should be used. Methods: A multidisciplinary panel of wound healing and wound care experts comprising the fields of nursing, dermatology, internal medicine, and surgery was assembled to address maintenance debridement from different points of view and offer a unified approach. Findings: The chronic wound contains a number of microbial, biochemical, and cellular features and abnormalities that prevent or slow its progression to healing despite a seemingly adequate wound bed. Under these circumstances, maintenance debridement is proposed as a way to remove tissues that are colonized with an excessive bacterial burden and diminish what can be described as a biochemical and cellular burden that impairs healing. A working clinical algorithm is proposed. Conclusion: Maintenance debridement is a proactive way to "jumpstart" the wound and keep it in a healing mode, even when traditional debridement may not appear necessary because of a seemingly "healthy" wound bed. C1 Boston Univ, Dept Dermatol & Biochem, Boston, MA 02215 USA. NYU, Sch Med, Div Wound Healing & Regenerat Med, Dept Surg, New York, NY USA. Univ Illinois, Chicago, IL USA. SW Reg Wound Care Ctr, Lubbock, TX USA. James A Haley Vet Hosp, Dept Surg, Tampa, FL 33612 USA. Excelsior Coll Sch Nursing, Albany, NY USA. RP Falanga, V (reprint author), NIH, Roger Williams Canc Med Ctr, Ctr Biomed Res Excellence, Dept Dermatol, 50 Maude St, Providence, RI 02908 USA. EM vfalanga@bu.edu NR 51 TC 1 Z9 1 U1 1 U2 3 PU H M P COMMUNICATIONS PI MALVERN PA 83 GENERAL WARREN BLVD, STE 100, MALVERN, PA 19355 USA SN 1044-7946 J9 WOUNDS JI Wounds-Compend. Clin. Res. Pract. PD JUN PY 2008 SU S BP 2 EP 13 PG 12 WC Dermatology; Surgery SC Dermatology; Surgery GA 329RT UT WOS:000257889000001 ER PT J AU Hasumi, H Baba, M Hong, SB Hasumi, Y Huang, Y Yao, M Valera, VA Linehan, WM Schmidt, LS AF Hasumi, Hisashi Baba, Masaya Hong, Seung-Beom Hasumi, Yukiko Huang, Ying Yao, Masahiro Valera, Vladimir A. Linehan, W. Marston Schmidt, Laura S. TI Identification and characterization of a novel folliculin-interacting protein FNIP2 SO GENE LA English DT Article DE BHD; FLCN; AMPK; FNIP1; renal cell carcinoma (RCC); tumor suppressor ID HOGG-DUBE-SYNDROME; DIFFERENTIATION-RELATED PROTEIN; CELL RENAL-CARCINOMA; BHD GENE; TUMORS; EXPRESSION; MUTATIONS; FAMILIES AB Birt-Hogg-Dube' syndrome characterized by increased risk for renal neoplasia is caused by germline mutations in the BHD/FLCN gene encoding a novel tumor suppressor protein, folliculin(FLCN), which interacts with FNIP1 and 51-AMP-activated protein kinase(AMPK). Here we report the identification and characterization of a novel FNIP1 homolog FNIP2 that also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. These data taken together with our previous results that demonstrated FNIP1 binding to the C-terminus of FLCN suggest that FLCN tumor suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 through its C-terminus. Furthermore, we demonstrate that FNIP1 and FNIP2 are able to form homo- or heteromeric multimers suggesting that they may function independently or cooperatively with FLCN. Differential expression of FNIP1 and FNIP2 transcripts in some normal tissues may indicate tissue specificity for these homologs. Interestingly FNIP1 and FNIP2 were oppositely expressed in human clear cell renal cell carcinoma (RCC), and coordinately expressed in chromophobe RCC and oncocytoma, suggesting their differential function in different histologic variants of RCC. Published by Elsevier B.V. C1 [Schmidt, Laura S.] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hasumi, Hisashi; Baba, Masaya; Hong, Seung-Beom; Hasumi, Yukiko; Valera, Vladimir A.; Linehan, W. Marston; Schmidt, Laura S.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. [Huang, Ying; Yao, Masahiro] Yokohama City Univ, Grad Sch Med, Dept Urol & Mol Genet, Yokohama, Kanagawa 232, Japan. RP Schmidt, LS (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Bldg 560,Rm 12-69, Frederick, MD 21702 USA. EM schmidtl@ncifcrf.gov RI Baba, Masaya/L-7490-2013 OI Baba, Masaya/0000-0002-5308-6683 FU Intramural NIH HHS [Z01 SC006659-25, Z99 CA999999]; NCI NIH HHS [N01 CO012400, N01-CO-12400, N01CO12400] NR 19 TC 84 Z9 90 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 31 PY 2008 VL 415 IS 1-2 BP 60 EP 67 DI 10.1016/j.gene.2008.02.022 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 304YN UT WOS:000256145100007 PM 18403135 ER PT J AU Petibone, DM Morris, SM Hotchkiss, CE Mattison, DR Tucker, JD AF Petibone, D. M. Morris, S. M. Hotchkiss, C. E. Mattison, D. R. Tucker, J. D. TI Technique for culturing Macaca mulatta peripheral blood lymphocytes for fluorescence in situ hybridization of whole chromosome paints SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Macaca mulatta; whole chromosome painting; chromosome translocations; baseline; methods ID DOSE RECONSTRUCTION; IONIZING-RADIATION; NONHUMAN-PRIMATES; RHESUS-MONKEYS; ABERRATIONS; FREQUENCY; TRANSLOCATIONS; FASCICULARIS; PERSISTENCE; CLONING AB The rhesus monkey (Macaca mulatto) has long been an important model in biomedical and behavioral research. The biomedical importance of M. mulatto is due to its 93% genetic similarity with humans and its complex social behavior. The recent sequencing of the M. mulatto genome has enhanced its role in biological research. However, the use of the macaque as an experimental model in cytogenetic assays has been problematic due to difficulties in obtaining large numbers of well-spread cells in metaphase without the use of extremely toxic mitogens such as staphylococcal enterotoxin A (SEA). Here we describe a technique for culturing and producing sufficient numbers of cells in metaphase using the common mitogens phytohemagglutinin (PHA), concanavalin A (ConA), and T-cell growth factor (TCGF) which act synergistically to induce M. mulatto T-lymphocyte division. Using this method we have obtained a mitotic index in 48 h cultures of 12.0 +/- 2.2 metaphase cells/100cells (n =5 animals). Fluorescence in situ hybridization with whole chromosome painting of M. mulatto cells was performed with human whole-chromosome probes that labeled the following chromosomes for human (M. mulatto): 1(1), 2q(12), 2p(13), 4(5) pairs in red, and 3(2), 5(6) and 6(4) pairs in green. In humans this probe combination simultaneously paints 3 chromosome pairs in red and 3 in green, whereas in M. mulatto 4 chromosome pairs are labeled in red and 3 pairs are labeled in green. Using this method we show a baseline frequency of 0.026 translocations per 100 whole-genome cell equivalents in peripheral blood lymphocytes obtained from unexposed adolescent non-human primates. This method will add to the usefulness of M. mulatto as an animal model in biomedical research. (C) 2008 Elsevier B.V. All rights reserved. C1 [Petibone, D. M.; Tucker, J. D.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Morris, S. M.] US FDA, Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, Jefferson, AR 72079 USA. [Hotchkiss, C. E.] Bionetics Corp, Jefferson, AR 72079 USA. [Mattison, D. R.] NIH, HHS, Bethesda, MD 20892 USA. RP Tucker, JD (reprint author), Wayne State Univ, Dept Biol Sci, 1370 Biol Sci Bldg,5047 Gullen Mall, Detroit, MI 48202 USA. EM jtucker@biology.biosci.wayne.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 28 TC 2 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 31 PY 2008 VL 653 IS 1-2 BP 76 EP 81 DI 10.1016/j.mrgentox.2008.03.012 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 326DQ UT WOS:000257638700011 PM 18499509 ER PT J AU Ha, VL Bharti, S Inoue, H Vass, WC Campa, F Nie, ZZ de Gramont, A Ward, Y Randazzo, PA AF Ha, Vi Luan Bharti, Sanita Inoue, Hiroki Vass, William C. Campa, Fanny Nie, Zhongzhen de Gramont, Armand Ward, Yvona Randazzo, Paul A. TI ASAP3 is a focal adhesion-associated Arf GAP that functions in cell migration and invasion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GTPASE-ACTIVATING-PROTEIN; ADP-RIBOSYLATION FACTOR; ACTIN CYTOSKELETON; PLASMA-MEMBRANE; TUMOR INVASION; RHO GTPASES; PODOSOMES; COMPLEX; ARAP3; SRC AB ASAP3, an Arf GTPase-activating protein previously called DDEFL1 and ACAP4, has been implicated in the pathogenesis of hepatocellular carcinoma. We have examined in vitro and in vivo functions of ASAP3 and compared it to the related Arf GAP ASAP1 that has also been implicated in oncogenesis. ASAP3 was biochemically similar to ASAP1: the pleckstrin homology domain affected function of the catalytic domain by more than 100-fold; catalysis was stimulated by phosphatidylinositol 4,5-bisphosphate; and Arf1, Arf5, and Arf6 were used as substrates in vitro. Like ASAP1, ASAP3 associated with focal adhesions and circular dorsal ruffles. Different than ASAP1, ASAP3 did not localize to invadopodia or podosomes. Cells, derived from a mammary carcinoma and from a glioblastoma, with reduced ASAP3 expression had fewer actin stress fiber, reduced levels of phosphomyosin, and migrated more slowly than control cells. Reducing ASAP3 expression also slowed invasion of mammary carcinoma cells. In contrast, reduction of ASAP I expression had no effect on migration or invasion. We propose that ASAP3 functions nonredundantly with ASAP1. to control cell movement and may have a role in cancer cell invasion. In comparing ASAP1. and ASAP3, we also found that invadopodia are dispensable for the invasive behavior of cells derived from a mammary carcinoma. C1 [Ha, Vi Luan; Bharti, Sanita; Inoue, Hiroki; Campa, Fanny; Nie, Zhongzhen; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Vass, William C.] NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. [Ward, Yvona] NCI, Canc Cell Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. [de Gramont, Armand] NIDDK, NIH, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), Bldg 37,Rm 2042, Bethesda, MD 20892 USA. EM Randazzo@helix.nih.gov FU Intramural NIH HHS NR 62 TC 21 Z9 22 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 30 PY 2008 VL 283 IS 22 BP 14915 EP 14926 DI 10.1074/jbc.M709717200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 306EV UT WOS:000256232000003 PM 18400762 ER PT J AU Li, Y Suggs, C Wright, JT Yuan, ZA Aragon, M Fong, H Simmons, D Daly, B Golub, EE Harrison, G Kulkarni, AB Gibson, CW AF Li, Yong Suggs, Cynthia Wright, J. Timothy Yuan, Zhi-an Aragon, Melissa Fong, Hanson Simmons, Darrin Daly, Bill Golub, Ellis E. Harrison, Gerald Kulkarni, Ashok B. Gibson, Carolyn W. TI Partial rescue of the amelogenin null dental enamel phenotype SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACETYL-D-GLUCOSAMINE; MATRIX PROTEINS; GENE-EXPRESSION; TRANSGENIC MICE; IMPERFECTA; ODONTOBLASTS; MUTATION; BIOLOGY; EXON-8; BINDS AB The amelogenins are the most abundant secreted proteins in developing dental enamel. Enamel from amelogenin (Amelx) null mice is hypoplastic and disorganized, similar to that observed in X-linked forms of the human enamel defect amelogenesis imperfecta resulting from amelogenin gene mutations. Both transgenic strains that express the most abundant amelogenin (TgM180) have relatively normal enamel, but strains of mice that express a mutated amelogenin (TgP70T), which leads to amelogenesis imperfecta in humans, have heterogeneous enamel structures. When Amelx null (KO) mice were mated with transgenic mice that produce M180 (TgM180), the resultant TgM180KO offspring showed evidence of rescue in' enamel thickness, mineral density, and volume in molar teeth. Rescue was not observed in the molars from the TgP70TKO mice. It was concluded that a single amelogenin protein was able to significantly rescue the KO phenotype and that one amino acid change abrogated this function during development. C1 [Li, Yong; Yuan, Zhi-an; Aragon, Melissa; Gibson, Carolyn W.] Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, Philadelphia, PA 19104 USA. [Golub, Ellis E.; Harrison, Gerald] Univ Penn, Sch Dent Med, Dept Biochem, Philadelphia, PA 19104 USA. [Suggs, Cynthia; Simmons, Darrin; Daly, Bill] Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC 27599 USA. [Fong, Hanson] Univ Washington, Dept Mat Sci & Engn, Seattle, WA 98195 USA. [Kulkarni, Ashok B.] NIDCR, Funct Genom Sect, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Gibson, CW (reprint author), Univ Penn, Sch Dent Med, Dept Anat & Cell Biol, 240 S 40th St, Philadelphia, PA 19104 USA. EM gibson@biochem.dental.upenn.edu FU NIDCR NIH HHS [DE 011089] NR 54 TC 20 Z9 20 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 30 PY 2008 VL 283 IS 22 BP 15056 EP 15062 DI 10.1074/jbc.M707992200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 306EV UT WOS:000256232000019 PM 18390542 ER PT J AU LaCasse, RA Striebel, JF Favara, C Kercher, L Chesebro, B AF LaCasse, Rachel A. Striebel, James F. Favara, Cynthia Kercher, Lisa Chesebro, Bruce TI Role of Erk1/2 activation in prion disease pathogenesis: Absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE prion; knock-out mouse; neurodegeneration; chemokine; scrapie; transmissible spongiform encephalopathies ID CREUTZFELDT-JAKOB-DISEASE; CENTRAL-NERVOUS-SYSTEM; SCRAPIE-INFECTED MICE; NECROSIS-FACTOR-ALPHA; ALZHEIMERS-DISEASE; PROTEIN-KINASES; SPONGIFORM ENCEPHALOPATHIES; CHEMOKINE RECEPTORS; SIGNAL-TRANSDUCTION; GENE-EXPRESSION AB Prion diseases are neurodegenerative infections with gliosis and vacuolation. The mechanisms of degeneration remain unclear, but chemokines may be important. In current experiments CCR1 knock-out (KO) mice succumbed more rapidly to scrapie infection than WT controls. Infected KO mice had upregulation of CCL3, a CCR1 ligand, and CCR5, a receptor with specificity for CCL3. Both infected KO and WT mice had upregulation of CCR5-mediated signaling involving activation of Erk1/2 in astrocytes; however, activation was earlier in KO mice suggesting a role in pathogenesis. In both mouse strains activation of the Erk1/2 pathway may lead to astrocyte dysfunction resulting in neurodegeneration. Published by Elsevier B.V. C1 [LaCasse, Rachel A.; Striebel, James F.; Favara, Cynthia; Kercher, Lisa; Chesebro, Bruce] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bchesebro@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000937-04] NR 46 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAY 30 PY 2008 VL 196 IS 1-2 BP 16 EP 26 DI 10.1016/j.jneuroim.2008.02.009 PG 11 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 320UY UT WOS:000257261700002 PM 18396336 ER PT J AU Pomeroy, IM Jordan, EK Frank, JA Matthews, PM Esiri, MM AF Pomeroy, Ian M. Jordan, Elaine K. Frank, Joseph A. Matthews, Paul M. Esiri, Margaret M. TI Diffuse cortical atrophy in a marmoset model of multiple sclerosis SO NEUROSCIENCE LETTERS LA English DT Article DE multiple sclerosis; experimental autoimmune; encephalomyelitis; marmoset; callithrix jacchus; cortical atrophy; cortical lesions ID ALZHEIMERS-DISEASE; WHITE-MATTER; AUTOIMMUNE ENCEPHALOMYELITIS; CEREBRAL-CORTEX; LESION LOAD; DISABILITY; DEMYELINATION; PATHOLOGY; INJURY AB Marmoset experimental autoimmune encephalomyelitis (EAE) has previously been shown to replicate the essential features of both white matter and grey matter lesions of MS. This study set out to investigate whether cortical atrophy occurs in marmoset EAE and whether cortical thinning is related to the presence of focal, demyelinated cortical lesions. Seventeen leucocortical lesions and 13 subpial lesions were identified in 6 EAE cases. Cortical thickness surrounding these lesions was recorded and compared with matched cortical areas from five control animals. We found a diffuse 13-21 % loss of cortical thickness in all areas of EAE cortex compared with control animals but there was no additional loss seen in demyelinated versus myelinated EAE cortex. These findings could not be accounted for by effects of age, sex and disease duration. We conclude that localised cortical demyelination is not responsible for the major part of the atrophy observed and that cortical thinning is largely due to more diffuse or more remote factors. Marmoset EAE is an invaluable tool which can be used to further investigate the cause and the substrate of cortical loss in demyelinating diseases. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Pomeroy, Ian M.; Matthews, Paul M.; Esiri, Margaret M.] Univ Oxford, Dept Clin Neurol, Oxford, England. [Jordan, Elaine K.; Frank, Joseph A.] NIH, Lab Expt Radiol Res, Bethesda, MD USA. RP Pomeroy, IM (reprint author), Royal Hallamshire Hosp, Dept Neurol, Sheffield S10 2RX, S Yorkshire, England. EM ian.pomeroy@nhs.net OI Matthews, Paul M/0000-0002-1619-8328 FU Intramural NIH HHS [Z01 CL090005-12]; Multiple Sclerosis Society [688] NR 21 TC 24 Z9 24 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 30 PY 2008 VL 437 IS 2 BP 121 EP 124 DI 10.1016/j.neulet.2008.03.069 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 307PN UT WOS:000256330900011 PM 18440142 ER PT J AU Rowland, LM Shadmehr, R Kravitz, D Holcomb, HH AF Rowland, Laura M. Shadmehr, Reza Kravitz, Dwight Holcomb, Henry H. TI Sequential neural changes during motor learning in schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE PET; visuomotor; arm reaching; neural plasticity; rCBF; motor learning ID LONG-TERM POTENTIATION; PREFRONTAL CORTEX; SENSORIMOTOR CORTEX; BRAIN ACTIVATION; BASAL-GANGLIA; INTRAVENOUS (H2O)-O-15; CORTICAL CONNECTIONS; REACHING MOVEMENTS; NEURONAL-ACTIVITY; SKILL AB Positron emission tomography (PET) was used to investigate differences in neural plasticity associated with learning a unique motor task in patients with schizophrenia and healthy volunteers. Working with a robotic manipulandum, subjects learned reaching movements in a force field. Visual cues were provided to guide the reaching movements. PET rCBF measures were acquired while participants learned the motor skill over successive runs. The groups did not differ in behavioral performance but did differ in their rCBF activity patterns. Healthy volunteers displayed blood flow increases in primary motor cortex and supplementary motor area with motor learning. The patients with schizophrenia displayed an increase in the primary visual cortex with motor learning. Changes in these regions were positively correlated with changes in each group's motor accuracy, respectively. This is the first study to employ a unique arm-reaching motor learning test to assess neural plasticity during multiple phases of motor learning in patients with schizophrenia. The patients may have an inability to rapidly tune motor cortical neural populations to a preferred direction. The visual system, however, appears to be highly compensated in schizophrenia and the inability to rapidly modulate the motor cortex may be substantially corrected by the schizophrenic group's visuomotor adaptations. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Rowland, Laura M.; Holcomb, Henry H.] Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Rowland, Laura M.; Holcomb, Henry H.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Shadmehr, Reza] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Kravitz, Dwight] NIMH, Bethesda, MD 20892 USA. [Holcomb, Henry H.] Johns Hopkins Med Inst, Dept Psychiat, Baltimore, MD 21205 USA. RP Holcomb, HH (reprint author), Maryland Psychiat Res Ctr, POB 21247, Baltimore, MD 21228 USA. EM hholcomb@mprc.umaryland.edu RI Kravitz, Dwight/B-8430-2012 FU NIMH NIH HHS [K01 MH077230-03, K01 MH077230]; NINDS NIH HHS [R01 NS037422-01A1, R01 NS037422] NR 84 TC 6 Z9 6 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAY 30 PY 2008 VL 163 IS 1 BP 1 EP 12 DI 10.1016/j.pscychresns.2007.10.006 PG 12 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 311AQ UT WOS:000256572700001 PM 18407471 ER PT J AU Dickstein, DP van der Veen, JW Knopf, L Towbin, KE Pine, DS Leibenluft, E AF Dickstein, Daniel P. van der Veen, Jan Willem Knopf, Lisa Towbin, Kenneth E. Pine, Daniel S. Leibenluft, Ellen TI Proton magnetic resonance spectroscopy in youth with severe mood dysregulation SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE magnetic resonance spectroscopy; irritable mood; child; adolescent ID PEDIATRIC BIPOLAR DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PHOSPHOINOSITOL CYCLE ACTIVITY; N-ACETYL-ASPARTATE; MAJOR DEPRESSION; SODIUM VALPROATE; IN-VIVO; LITHIUM TREATMENT; MR SPECTROSCOPY; RATING-SCALE AB Increasing numbers of youth are presenting for psychiatric evaluation with markedly irritable mood plus "hyperarousal" symptoms. Diagnostically homeless in current nosology, the syndrome (as well as its underlying neurobiology) is little understood. To address this problem, we conducted an exploratory proton magnetic resonance spectroscopy (MRS) study in a large sample of youth with chronic, functionally disabling irritability accompanied by hyperarousal, a clinical syndrome known as "severe mood dysregulation" (SMD), which may represent a broad phenotype of pediatric bipolar disorder. Medication-free SMD youth (N = 36) and controls (N=48) underwent 1.5 Tesla MRS in four regions of interest. The following three neurometabolites, relative to creatine (Cr), were quantified with LCModel Software: (a) myo-inositol (mI), a marker of intra-cellular second messengers linked to the neurobiology of bipolar disorder; (b) glutamate/glutaminc (GLX), a marker of the major excitatory neurotransmitter glutamate; and (c) N-acetyl aspartate (NAA), a marker of neuronal energetics. SMD subjects had significantly lower temporal mI/Cr versus controls. However, this difference did not survive correction for multiple comparisons. Given studies implicating mI in lithium's action in BD adults and youth, further work is necessary to determine potential therapeutic implications of our present finding and how SMD youth differ pathophysiologically from those with strictly defined BD. Published by Elsevier Ireland Ltd. C1 [Dickstein, Daniel P.; Knopf, Lisa; Towbin, Kenneth E.; Leibenluft, Ellen] NIMH, Div Intramural Res Programs, Unit Bipolar Spectrum Disorders, Bethesda, MD 20892 USA. [Knopf, Lisa; Towbin, Kenneth E.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Div Intramural Res Programs, Emot & Dev Branch, Bethesda, MD 20892 USA. [Dickstein, Daniel P.] EP Bradley Hosp, E Providence, RI USA. [Dickstein, Daniel P.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Dickstein, DP (reprint author), Bradley Hasbro Childrens Res Ctr, 1 Hoppin St,Coro W Rm 2-056, Providence, RI 02903 USA. EM Daniel_Dickstein@Brown.edu RI Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 FU Intramural NIH HHS [Z99 MH999999]; NIMH NIH HHS [K22 MH74945] NR 51 TC 11 Z9 12 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAY 30 PY 2008 VL 163 IS 1 BP 30 EP 39 DI 10.1016/j.pscychresns.2007.11.006 PG 10 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 311AQ UT WOS:000256572700004 PM 18403184 ER PT J AU Shi, HF Bencze, KZ Stemmler, TL Philpott, CC AF Shi, Haifeng Bencze, Krisztina Z. Stemmler, Timothy L. Philpott, Caroline C. TI A cytosolic iron chaperone that delivers iron to ferritin SO SCIENCE LA English DT Article ID COPPER CHAPERONE; PROTEIN; BINDING; MECHANISMS; FRATAXIN; DISEASE AB Ferritins are the main iron storage proteins found in animals, plants, and bacteria. The capacity to store iron in ferritin is essential for life in mammals, but the mechanism by which cytosolic iron is delivered to ferritin is unknown. Human ferritins expressed in yeast contain little iron. Human poly (rC)- binding protein 1 ( PCBP1) increased the amount of iron loaded into ferritin when expressed in yeast. PCBP1 bound to ferritin in vivo and bound iron and facilitated iron loading into ferritin in vitro. Depletion of PCBP1 in human cells inhibited ferritin iron loading and increased cytosolic iron pools. Thus, PCBP1 can function as a cytosolic iron chaperone in the delivery of iron to ferritin. C1 [Shi, Haifeng; Philpott, Caroline C.] NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Bencze, Krisztina Z.; Stemmler, Timothy L.] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. RP Philpott, CC (reprint author), NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU Intramural NIH HHS [Z01 DK054510-03]; NIDDK NIH HHS [R01 DK068139, R01 DK068139-01A1] NR 19 TC 184 Z9 195 U1 3 U2 25 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 30 PY 2008 VL 320 IS 5880 BP 1207 EP 1210 DI 10.1126/science.1157643 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 306FF UT WOS:000256233000036 PM 18511687 ER PT J AU Zhang, Y Turanov, AA Hatfield, DL Gladyshev, VN AF Zhang, Yan Turanov, Anton A. Hatfield, Dolph L. Gladyshev, Vadim N. TI In silico identification of genes involved in selenium metabolism: evidence for a third selenium utilization trait SO BMC GENOMICS LA English DT Article ID ESCHERICHIA-COLI; SELENOCYSTEINE INCORPORATION; SELENOPROTEIN SYNTHESIS; XANTHINE DEHYDROGENASE; EUBACTERIUM-BARKERI; MOLYBDENUM ENZYMES; MECHANISM; EVOLUTION; INSERTION; BIOSYNTHESIS AB Background: Selenium (Se) is a trace element that occurs in proteins in the form of selenocysteine (Sec) and in tRNAs in the form of selenouridine (SeU). Selenophosphate synthetase (SelD) is required for both utilization traits. However, previous research also revealed SelDs in two organisms lacking Sec and SeU, suggesting a possible additional use of Se that is dependent on SelD. Results: In this study, we conducted comparative genomics and phylogenetic analyses to characterize genes involved in Se utilization. Candidate genes identified included SelA/SelB and YbbB that define Sec and SeU pathways, respectively, and NADH oxidoreductase that is predicted to generate a SelD substrate. In addition, among 227 organisms containing SelD, 10 prokaryotes were identified that lacked SelA/SelB and YbbB. Investigation of selD neighboring genes in these organisms revealed a SirA-like protein and two hypothetical proteins HP1 and HP2 that were strongly linked to a novel Se utilization. With these new signature proteins, 32 bacteria and archaea were found that utilized these proteins, likely as part of the new Se utilization trait. Metabolic labeling of one organism containing an orphan SelD, Enterococcus faecalis, with (75)Se revealed a protein containing labile Se species that could be released by treatment with reducing agents, suggesting non-Sec utilization of Se in this organism. Conclusion: These studies suggest the occurrence of a third Se utilization trait in bacteria and archaea. C1 [Zhang, Yan; Turanov, Anton A.; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Zhang, Yan; Turanov, Anton A.; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Hatfield, Dolph L.] NCI, Lab Canc Prevent, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. EM yzhang@genomics.unl.edu; turanov@genomics.unl.edu; hatfield@mail.nci.nih.gov; vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013 FU NIGMS NIH HHS [R01 GM061603] NR 38 TC 18 Z9 19 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 29 PY 2008 VL 9 AR 251 DI 10.1186/1471-2164-9-251 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 316AA UT WOS:000256920100001 PM 18510720 ER PT J AU Shulman-Peleg, A Shatsky, M Nussinov, R Wolfson, HJ AF Shulman-Peleg, Alexandra Shatsky, Maxim Nussinov, Ruth Wolfson, Haim J. TI Prediction of interacting single-stranded RNA bases by protein-binding patterns SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein-RNA interactions; nucleotide and dinucleotide binding sites; physicochemical binding patterns; multiple binding site alignment; RNA aptamer drug design ID MULTIPLE SEQUENCE ALIGNMENT; STRUCTURAL BASIS; FAMILIES DATABASE; NUCLEIC-ACIDS; U1A PROTEIN; INDUCED FIT; RECOGNITION; SITES; COMPLEX; CLASSIFICATION AB Prediction of protein-RNA interactions at the atomic level of detail is crucial for our ability to understand and interfere with processes such as gene expression and regulation. Here, we investigate protein binding pockets that accommodate extruded nucleotides not involved in RNA base pairing. We observed that most of the protein-interacting nucleotides are part of a consecutive fragment of at least two nucleotides whose rings have significant interactions with the protein. Many of these share the same protein binding cavity and more than 30% of such pairs are pi-stacked. Since these local geometries cannot be inferred from the nucleotide identities, we present a novel framework for their prediction from the properties of protein binding sites. First, we present a classification of known RNA nucleotide and dinucleotide protein binding sites and identify the common types of shared 3-D physicochemical binding patterns. These are recognized by a new classification methodology that is based on spatial multiple alignment. The shared patterns reveal novel similarities between dinucleotide binding sites of proteins with different overall sequences, folds and functions. Given a protein structure, we use these patterns for the prediction of its RNA dinucleotide binding sites. Based on the binding modes of these nucleotides, we further predict an RNA fragment that interacts with those protein binding sites. With these knowledge-based predictions, we construct an RNA fragment that can have a previously unknown sequence and structure. In addition, we provide a drug design application in which the database of all known small-molecule binding sites is searched for regions similar to nucleotide and dinucleotide binding patterns, suggesting new fragments and scaffolds that can target them. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Shulman-Peleg, Alexandra; Wolfson, Haim J.] Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. [Shatsky, Maxim] Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA USA. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Shulman-Peleg, A (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM shulmana@post.tau.ac.il; wolfson@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01 CO012400, N01-CO-12400, N01CO12400]; NIAID NIH HHS [1UC1AI067231, UC1 AI067231] NR 67 TC 29 Z9 30 U1 1 U2 15 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 29 PY 2008 VL 379 IS 2 BP 299 EP 316 DI 10.1016/j.jmb.2008.03.043 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 307ON UT WOS:000256328300009 PM 18452949 ER PT J AU Pan, YP Nussinov, R AF Pan, Yongping Nussinov, Ruth TI P53-induced DNA bending: The interplay between p53-ONA and p53-p53 interactions SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; P53 CORE DOMAIN; MOLECULAR-DYNAMICS SIMULATIONS; BINDING DOMAIN; TRANSCRIPTION-FACTOR; COOPERATIVE BINDING; HELICOIDAL ANALYSIS; RESPONSE ELEMENT; STRUCTURAL BASIS; RECOGNITION AB Specific p53 binding-induced DNA bending and its underlying responsible forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome; however, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half-site, different DNA bending extents were observed. The analysis showed that the dimer-dimer interactions in p53 were similar for the complexes; on the other hand, the specific interactions between the p53 and DNA, including the interactions of Arg280, Lys 120, and Arg248 with the DNA, varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory, whereas those for the CTAG sequence were partially dissociated in part of the trajectory, which affected the stability of the nearby Arg280-Gua base interactions. Thus, DNA bending depends*on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which is in turn related to the DNA sequence and DNA flexibility. C1 [Pan, Yongping; Nussinov, Ruth] NCI, Ctr Canc Res, Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU Intramural NIH HHS [Z01 BC010441-06]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 53 TC 22 Z9 22 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 29 PY 2008 VL 112 IS 21 BP 6716 EP 6724 DI 10.1021/jp800680w PG 9 WC Chemistry, Physical SC Chemistry GA 303QK UT WOS:000256055400024 PM 18461991 ER PT J AU Golestaneh, N Fan, JG Zelenka, P Chepelinsky, AB AF Golestaneh, Nady Fan, Jianguo Zelenka, Peggy Chepelinsky, Ana B. TI PKC putative phosphorylation site Ser(235) is required for MIP/AQP0 translocation to the plasma membrane SO MOLECULAR VISION LA English DT Article; Proceedings Paper CT 16th International Congress of Eye Research CY SEP, 2004 CL Sydney, AUSTRALIA SP Int Soc Eye Res ID MAJOR INTRINSIC PROTEIN; LENS EPITHELIAL-CELLS; AUTOSOMAL-DOMINANT CATARACT; KINASE-C-GAMMA; AQUAPORIN WATER PERMEABILITY; TRANS-GOLGI NETWORK; GAP-JUNCTIONS; ER RETENTION; MIP; MUTATION AB Purpose: To investigate the functional significance of MIP/AQP0 phosphorylation at serine(235). Methods: MIP/AQP0 expression and cellular localization was studied in rat lens epithelia explants induced to differentiate by FGF-2. MIP wild type (WT) and MIP (S235A) mutant expression plasmids were constructed and transiently expressed in RKI3 cells. Subcellular localization of endogenous MIP in differentiating lens epithelia explants or of transfected MIP expression vectors in RK13 cells was analyzed by immunofluorescence confocal microscopy. Results: MIP/AQP0 expressed in lens epithelia explants induced to differentiate by FGF-2 localizes to the plasma membrane of elongating cells. However, MIP/AQP0 translocation to the plasma membrane was prevented by inhibiting PKC activity with Go6976, resulting in retention in the cytoplasmic compartment. This effect was specific to MIP/AQP0; localization of AQP1 to the cell membrane was not affected by Go6976. When the consensus PKC phosphorylation site at MIP Ser(235) was mutated to alanine and transiently expressed in transfected RK13 cells, the mutant MIP was retained in the cytoplasmic compartment in contrast to WT MIP that localized to the plasma membrane of the transfected RK13 cells. Colocalization studies indicated that the mutant MIP was retained in the trans-Golgi network. Conclusions: Our results indicate that serine(235) is required for proper intracellular transport of MIP/AQP0 from the trans-Golgi network to the plasma membrane. A PKC dependent phosphorylation event involving MIP at serine(235) is most likely involved in this process. C1 [Golestaneh, Nady; Fan, Jianguo; Zelenka, Peggy; Chepelinsky, Ana B.] NEI, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Chepelinsky, AB (reprint author), NEI, Lab Mol & Dev Biol, NIH, Bldg 31,Room 6A32,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM abc@helix.nih.gov NR 71 TC 11 Z9 14 U1 0 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAY 29 PY 2008 VL 14 IS 120 BP 1006 EP 1014 PG 9 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 327SW UT WOS:000257749800001 PM 18523655 ER PT J AU Swanson, JM Volkow, ND AF Swanson, James M. Volkow, Nora D. TI Increasing use of stimulants warns of potential abuse SO NATURE LA English DT Letter C1 [Swanson, James M.] Univ Calif Irvine, Dept Pediat, Child Dev Ctr, Irvine, CA 92612 USA. [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Swanson, JM (reprint author), Univ Calif Irvine, Dept Pediat, Child Dev Ctr, 19722 MacArthur Blvd, Irvine, CA 92612 USA. FU Intramural NIH HHS [Z99 DA999999] NR 2 TC 29 Z9 29 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 29 PY 2008 VL 453 IS 7195 BP 586 EP 586 DI 10.1038/453586a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 305NN UT WOS:000256185200014 PM 18509418 ER PT J AU Rambaut, A Pybus, OG Nelson, MI Viboud, C Taubenberger, JK Holmes, EC AF Rambaut, Andrew Pybus, Oliver G. Nelson, Martha I. Viboud, Cecile Taubenberger, Jeffery K. Holmes, Edward C. TI The genomic and epidemiological dynamics of human influenza A virus SO NATURE LA English DT Article ID PHYLOGENETIC ANALYSIS; MEMBRANE ASSOCIATION; GENETIC EVOLUTION; MATRIX PROTEIN; M(2) PROTEIN; H3N2 VIRUSES; HEMAGGLUTININ; REASSORTMENT; H1N1; GLYCOPROTEINS AB The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome- scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/ H3N2 and A/ H1N1 subtypes co- circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/ H3N2 and A/ H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/ H1N1, indicative of weaker antigenic drift. These results suggest a sink - source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions. C1 [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh EH9 3JT, Midlothian, Scotland. [Pybus, Oliver G.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Nelson, Martha I.; Holmes, Edward C.] Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab, University Pk, PA 16802 USA. [Viboud, Cecile; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Rambaut, A (reprint author), Univ Edinburgh, Inst Evolutionary Biol, Ashworth Labs, Edinburgh EH9 3JT, Midlothian, Scotland. EM a.rambaut@ed.ac.uk; ech15@psu.edu RI pybus, oliver/B-2640-2012; OI Pybus, Oliver/0000-0002-8797-2667; Rambaut, Andrew/0000-0003-4337-3707; Holmes, Edward/0000-0001-9596-3552 FU Intramural NIH HHS [Z01 AI000996-01] NR 49 TC 434 Z9 452 U1 6 U2 72 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 29 PY 2008 VL 453 IS 7195 BP 615 EP U2 DI 10.1038/nature06945 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 305NN UT WOS:000256185200035 PM 18418375 ER PT J AU Ershler, WB Ferrucci, L Longo, DL AF Ershler, William B. Ferrucci, Luigi Longo, Dan L. TI Hutchinson-Gilford progeria syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID GENDER; AGE C1 [Ershler, William B.; Ferrucci, Luigi; Longo, Dan L.] NIA, Baltimore, MD 21225 USA. RP Ershler, WB (reprint author), NIA, Baltimore, MD 21225 USA. FU Intramural NIH HHS [ZIA AG000015-56] NR 4 TC 6 Z9 6 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 29 PY 2008 VL 358 IS 22 BP 2409 EP 2410 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 307GF UT WOS:000256306700024 PM 18509130 ER PT J AU Merideth, MA Collins, FS Gahl, WA AF Merideth, Melissa A. Collins, Francis S. Gahl, William A. TI Hutchinson-Gilford progeria syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MISREGULATION; DEFECTS C1 [Merideth, Melissa A.; Collins, Francis S.; Gahl, William A.] NHGRI, Bethesda, MD 20892 USA. RP Merideth, MA (reprint author), NHGRI, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov NR 5 TC 1 Z9 1 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 29 PY 2008 VL 358 IS 22 BP 2410 EP 2411 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 307GF UT WOS:000256306700026 ER PT J AU Caddick, SEK Harrison, CJ Stavridou, I Mitchell, JL Hemmings, AM Brearley, CA AF Caddick, Samuel E. K. Harrison, Christopher J. Stavridou, Ioanna Mitchell, Jennifer L. Hemmings, Andrew M. Brearley, Charles A. TI A Solanum tuberosum inositol phosphate kinase (StITPK1) displaying inositol phosphate-inositol phosphate and inositol phosphate-ADP phosphotransferase activities SO FEBS LETTERS LA English DT Article DE ATP-grasp fold; inositol polyphosphate kinase; phosphotransferase; Solanum tuberosum ID 1,3,4-TRISPHOSPHATE 5/6-KINASE; 1,3,4,5,6-PENTAKISPHOSPHATE 2-KINASE; ARABIDOPSIS; PURIFICATION; METABOLISM; SEEDS AB We describe a multifunctional inositol polyphosphate kinase/phosphotransferase from Solanum tuberosum, StITPK alpha (GenBank accession: EF362784), hereafter called StITPK1. StITPK1 displays inositol 3,4,5,6-tetrakisphosphate 1-kinase activity: K-m = 27 mu M, and V-max = 19 nmol min(-1) mg(-1). The enzyme displays inositol 1,3,4,5,6-pentakisphosphate 1-phosphatase activity in the absence of a nucleotide acceptor and inositol 1,3,4,5,6-pentakisphosphate-ADP phosphotransferase activity in the presence of physiological concentrations of ADP. Additionally, StITPK1 shows inositol phosphate-inositol phosphate phosphotransferase activity. Homology modelling provides a structural rationale of the catalytic abilities of StITPK1. Inter-substrate transfer of phosphate groups between inositol phosphates is an evolutionarily conserved function of enzymes of this class. (C) 2008 Federation of European Biochemical Societies. All rights reserved. C1 [Caddick, Samuel E. K.; Harrison, Christopher J.; Stavridou, Ioanna; Hemmings, Andrew M.; Brearley, Charles A.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, England. [Hemmings, Andrew M.] Univ E Anglia, Sch Chem Sci & Pharm, Norwich NR4 7TJ, Norfolk, England. [Mitchell, Jennifer L.] Lab Signal Transduct, Inositide Signaling Grp, Res Triangle Pk, NC 27709 USA. [Mitchell, Jennifer L.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Brearley, CA (reprint author), Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, England. EM c.brearley@uea.ac.uk RI HEMMINGS, ANDREW/E-5517-2011; OI Brearley, Charles/0000-0001-6179-9109 FU Biotechnology and Biological Sciences Research Council [BB/C514090/01, BB/C514090/1] NR 20 TC 9 Z9 9 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAY 28 PY 2008 VL 582 IS 12 BP 1731 EP 1737 DI 10.1016/j.febslet.2008.04.034 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 332VG UT WOS:000258110600017 PM 18442482 ER PT J AU Zhang, D Hu, XM Wei, SJ Liu, J Gao, HM Qian, L Wilson, B Liu, GT Hong, JS AF Zhang, Dan Hu, Xiaoming Wei, Sung-Jen Liu, Jie Gao, Huiming Qian, Li Wilson, Belinda Liu, Gengtao Hong, Jau-Shyong TI Squamosamide derivative FLZ protects dopaminergic neurons against inflammation-mediated neurodegeneration through the inhibition of NADPH oxidase activity SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; PARKINSONS-DISEASE; SIGNAL-TRANSDUCTION; MICROGLIAL ACTIVATION; ANNONA-GLABRA; SH-SY5Y CELLS; NITRIC-OXIDE; COMPOUND FLZ; SUPEROXIDE; DEGENERATION AB Background: Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD) through over-activation of microglia, which consequently causes the excessive production of proinflammatory and neurotoxic factors, and impacts surrounding neurons and eventually induces neurodegeneration. Hence, prevention of microglial over-activation has been shown to be a prime target for the development of therapeutic agents for inflammation-mediated neurodegenerative diseases. Methods: For in vitro studies, mesencephalic neuron-glia cultures and reconstituted cultures were used to investigate the molecular mechanism by which FLZ, a squamosamide derivative, mediates anti-inflammatory and neuroprotective effects in both lipopolysaccharide-(LPS)-and 1-methyl-4-phenylpyridinium-(MPP+)-mediated models of PD. For in vivo studies, a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-(MPTP-) induced PD mouse model was used. Results: FLZ showed potent efficacy in protecting dopaminergic (DA) neurons against LPS-induced neurotoxicity, as shown in rat and mouse primary mesencephalic neuronal-glial cultures by DA uptake and tyrosine hydroxylase (TH) immunohistochemical results. The neuroprotective effect of FLZ was attributed to a reduction in LPS-induced microglial production of proinflammatory factors such as superoxide, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E-2 (PGE(2)). Mechanistic studies revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of NADPH oxidase (PHOX), the key microglial superoxide-producing enzyme. A critical role for PHOX in FLZ-elicited neuroprotection was further supported by the findings that 1) FLZ's protective effect was reduced in cultures from PHOX-/- mice, and 2) FLZ inhibited LPS-induced translocation of the cytosolic subunit of p47(PHOX) to the membrane and thus inhibited the activation of PHOX. The neuroprotective effect of FLZ demonstrated in primary neuronal-glial cultures was further substantiated by an in vivo study, which showed that FLZ significantly protected against MPTP-induced DA neuronal loss, microglial activation and behavioral changes. C1 [Zhang, Dan; Hu, Xiaoming; Gao, Huiming; Qian, Li; Wilson, Belinda; Hong, Jau-Shyong] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. [Wei, Sung-Jen] NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Liu, Jie] NIEHS, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Qian, Li] Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. [Liu, Gengtao] Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, Beijing 100050, Peoples R China. [Liu, Gengtao] Peking Union Med Coll, Beijing 100050, Peoples R China. RP Hong, JS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. EM zhangd2@niehs.nih.gov; hux2@niehs.nih.gov; wei2@niehs.nih.gov; liu6@niehs.nih.gov; gao2@niehs.nih.gov; qianl2@niehs.nih.gov; wilson3@niehs.nih.gov; liugt@imm.ac.cn; hong3@niehs.nih.gov RI gao, huiming/C-8454-2012 FU Intramural NIH HHS NR 39 TC 21 Z9 26 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 28 PY 2008 VL 5 AR 21 DI 10.1186/1742-2094-5-21 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 313AY UT WOS:000256714700001 PM 18507839 ER PT J AU Perez, MA Cohen, LG AF Perez, Monica A. Cohen, Leonardo G. TI Mechanisms underlying functional changes in the primary motor cortex ipsilateral to an active hand SO JOURNAL OF NEUROSCIENCE LA English DT Article DE primary motor cortex; interhemispheric inhibition; transcallosal pathways; intracortical inhibition; transcranial magnetic stimulation; force ID TRANSCRANIAL MAGNETIC STIMULATION; DORSAL INTEROSSEOUS MUSCLE; INTERHEMISPHERIC INHIBITION; VOLUNTARY CONTRACTION; FINGER MOVEMENTS; TRANSCALLOSAL INHIBITION; INTRACORTICAL INHIBITION; DIFFERENT COMPLEXITIES; VOLITIONAL INHIBITION; BRAIN-STIMULATION AB Performance of a unimanual hand motor task results in functional changes in both primary motor cortices (M1(ipsilateral) and M1(contralateral)). The neuronal mechanisms controlling the corticospinal output originated in M1(ipsilateral) and the resting hand during a unimanual task remain unclear. Here, we assessed functional changes within M1(ipsilateral) and in interhemispheric inhibition (IHI) associated with parametric increases in unimanual force. We measured motor-evoked potential (MEP) recruitment curves (RCs) and shortinterval intracortical inhibition (SICI) in M1(ipsilateral), IHI from M1(contralateral) to M1(ipsilateral), and the influence of IHI over SICI using transcranial magnetic stimulation at rest and during 10, 30, and 70% of maximal right wrist flexion force. EMG from the left resting flexor carpi radialis (FCR) muscle was comparable across conditions. Left FCR MEP RCs increased, and SICI decreased with increasing right wrist force. Activity-dependent (rest and 10, 30, and 70%) left FCR maximal MEP size correlated with absolute changes in SICI. IHI decreased with increasing force at matched conditioned MEP amplitudes. IHI and SICI were inversely correlated at increasing forces. In the presence of IHI, SICI decreased at rest and 70% force. In summary, we found activity-dependent changes in (1) SICI in M1(ipsilateral), (2) IHI from M1(contralateral) to M1(ipsilateral), and (3) the influence of IHI over SICI in the left resting hand during force generation by the right hand. Our findings indicate that interactions between GABAergic intracortical circuits mediating SICI and interhemispheric glutamatergic projections between M1s contribute to control activity-dependent changes in corticospinal output to a resting hand during force generation by the opposite hand. C1 NINDS, NIH, Human Cort Physiol Sect, Bethesda, MD 20892 USA. NINDS, NIH, Stroke Neurorehabil Clin, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, NIH, Human Cort Physiol Sect, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002978-09] NR 71 TC 130 Z9 131 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 28 PY 2008 VL 28 IS 22 BP 5631 EP 5640 DI 10.1523/JNEUROSCI.0093-08.2008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 306HL UT WOS:000256238800003 PM 18509024 ER PT J AU Sekine, Y Ouchi, Y Sugihara, G Takei, N Yoshikawa, E Nakamura, K Iwata, Y Tsuchiya, KJ Suda, S Suzuki, K Kawai, M Takebayashi, K Yamamoto, S Matsuzaki, H Ueki, T Mori, N Gold, MS Cadet, JL AF Sekine, Yoshimoto Ouchi, Yasuomi Sugihara, Genichi Takei, Nori Yoshikawa, Etsuji Nakamura, Kazuhiko Iwata, Yasuhide Tsuchiya, Kenji J. Suda, Shiro Suzuki, Katsuaki Kawai, Masayoshi Takebayashi, Kiyokazu Yamamoto, Shigeyuki Matsuzaki, Hideo Ueki, Takatoshi Mori, Norio Gold, Mark S. Cadet, Jean L. TI Methamphetamine causes microglial activation in the brains of human abusers SO JOURNAL OF NEUROSCIENCE LA English DT Article DE methamphetamine; addiction; neurotoxicity; microglia; positron emission tomography; human ID INDUCED NEURONAL APOPTOSIS; INDUCED NEUROTOXICITY; IN-VIVO; PSYCHIATRIC-SYMPTOMS; DOPAMINE TRANSPORTERS; DECISION-MAKING; NULL MUTATION; MOUSE-BRAIN; STRIATUM; DEATH AB Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [C-11](R)-(1-[ 2-chlorophenyl]-N-methyl-N-[ 1-methylpropyl]-3-isoquinoline carboxamide) ([C-11](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [C-11](R)-PK11195 in brain regions with dopaminergic and/ or serotonergic innervation. The mean levels of [C-11](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (> 250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence. C1 [Sekine, Yoshimoto; Cadet, Jean L.] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH,Dept Hlth Human Serv, Baltimore, MD 21224 USA. [Sekine, Yoshimoto; Nakamura, Kazuhiko; Iwata, Yasuhide; Suda, Shiro; Suzuki, Katsuaki; Kawai, Masayoshi; Takebayashi, Kiyokazu; Mori, Norio] Hamamatsu Univ Sch Med, Dept Psychiat & Neurol, Hamamatsu, Shizuoka 4313192, Japan. [Ueki, Takatoshi] Hamamatsu Univ Sch Med, Dept Anat & Neurosci, Hamamatsu, Shizuoka 4313192, Japan. [Ouchi, Yasuomi] Hamamatsu Univ Sch Med, Mol Imaging Frontier Res Ctr, Hamamatsu, Shizuoka 4313192, Japan. [Sugihara, Genichi; Takei, Nori; Tsuchiya, Kenji J.; Yamamoto, Shigeyuki; Mori, Norio] Osaka Hamamatsu Joint Res Ctr Child Mental Dev, Hamamatsu Ctr, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. [Yoshikawa, Etsuji] Hamamatsu Photon KK, Cent Res Lab, Hamakita Ku, Shizuoka 4348601, Japan. [Matsuzaki, Hideo] Osaka Hamamatsu Joint Res Ctr Child Mental Dev, Osaka Ctr, Suita, Osaka 5650871, Japan. [Gold, Mark S.] Univ Florida, Coll Med, Div Foods Addit, Dept Psychiat, Gainesville, FL 32610 USA. RP Sekine, Y (reprint author), NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH,Dept Hlth Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ouchi@hama-med.ac.jp; jcadet@intra.nida.nih.gov OI Tsuchiya, Kenji/0000-0002-1314-4199 FU Intramural NIH HHS [Z01 DA000494-01] NR 48 TC 142 Z9 143 U1 0 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 28 PY 2008 VL 28 IS 22 BP 5756 EP 5761 DI 10.1523/JNEUROSCI.1179-08.2008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 306HL UT WOS:000256238800016 PM 18509037 ER PT J AU Keck, GE Kraft, MB Truong, AP Li, W Sanchez, CC Kedei, N Lewin, NE Blumberg, PM AF Keck, Gary E. Kraft, Matthew B. Truong, Anh P. Li, Wei Sanchez, Carina C. Kedei, Noerni Lewin, Nancy E. Blumberg, Peter M. TI Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: Bryostatin look-alikes that mimic phorbol ester function SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CELL-CYCLE; RING AB Highly potent bryostatin analogues which contain the complete bryostatin core structure have been synthesized using a pyran annulation approach as a key strategic element. The A ring pyran was assembled using a pyran annulation reaction between a C(1)-C(8) hydroxy allylsilane and an aldehyde comprising C(9)-C(13). This pyran was transformed to a new hydroxy allyisilane and then coupled with a preformed C ring aldehyde subunit in a second pyran annulation, with concomitant formation of the B ring. This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay. C1 [Keck, Gary E.; Kraft, Matthew B.; Truong, Anh P.; Li, Wei; Sanchez, Carina C.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Kedei, Noerni; Lewin, Nancy E.; Blumberg, Peter M.] NCI, Natl Inst Hlth, Ctr Canc Res, LCBG, Bethesda, MD 20892 USA. RP Keck, GE (reprint author), Univ Utah, Dept Chem, 315 S 1400 E,RM 2020, Salt Lake City, UT 84112 USA. FU Intramural NIH HHS; NIGMS NIH HHS [GM28961, R01 GM028961, R01 GM028961-18, R01 GM028961-19, R01 GM028961-20, R01 GM028961-21, R01 GM028961-22, R01 GM028961-23, R01 GM028961-24, R01 GM028961-25A1, R01 GM028961-26] NR 20 TC 68 Z9 68 U1 3 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 28 PY 2008 VL 130 IS 21 BP 6660 EP + DI 10.1021/ja8022169 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 305DO UT WOS:000256158200004 PM 18452293 ER PT J AU Cronin-Fenton, DP Mooney, MM Clegg, LX Harlan, LC AF Cronin-Fenton, Deirdre P. Mooney, Margaret M. Clegg, Limin X. Harlan, Linda C. TI Treatment and survival in a population-based sample of patients diagnosed with gastroesophageal adenocarcinoma SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE adenocarcinoma; esophageal adenocarcinoma; gastroesophageal; gastric adenocarcinoma; survival; chemotherapy; radiotherapy ID ADVANCED ESOPHAGEAL CANCER; PHASE-II TRIAL; GASTRIC-CANCER; COLORECTAL-CANCER; SOCIOECONOMIC-STATUS; RANDOMIZED-TRIAL; ADJUVANT THERAPY; CO-MORBIDITY; CARCINOMA; SURGERY AB AIM: To examine the extent of use of specific therapies in clinical practice, and their relationship to therapies validated in clinical trials. METHODS: The US National Cancer Institutes' Patterns of Care study was used to examine therapies and survival of patients diagnosed in 2001 with histologically-confirmed gastroesophageal adenocarcinoma (n = 1356). The study re-abstracted data and verified therapy with treating physicians for a population-based stratified random sample. RESULTS: Approximately 62% of patients had stomach adenocarcinoma (SAC), while 22% had gastric-cardia adenocarcinoma (GCA), and 16% lower esophageal adenocarcinoma (EAC). Stage IV/ unstaged esophageal cancer patients were most likely and stage I-III stomach cancer patients least likely to receive chemotherapy as all or part of their therapy; gastric-cardia patients received chemotherapy at a rate between these two. In multivariable analysis by anatomic site, patients 70 years and older were significantly less likely than younger patients to receive chemotherapy alone or chemoradiation for all three anatomic sites. Among esophageal and stomach cancer patients, receipt of chemotherapy was associated with lower mortality; but no association was found among gastric-cardia patients. CONCLUSION: This study highlights the relatively low use of clinical trials-validated anti-cancer therapies in community practice. Use of chemotherapy-based treatment was associated with lower mortality, dependent on anatomic site. Findings suggest that physicians treat lower esophageal and SAC as two distinct entities, while gastric-cardia patients receive a mix of the treatment strategies employed for the two other sites. (C) 2008 The WIG Press. All rights reserved. C1 [Harlan, Linda C.] NCI, Appl Res Program, DCCPS, Bethesda, MD 20892 USA. [Cronin-Fenton, Deirdre P.; Clegg, Limin X.] NCI, Surveillance Res Program, DCCPS, Bethesda, MD 20892 USA. [Cronin-Fenton, Deirdre P.] Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8200 Aarhus, Denmark. [Mooney, Margaret M.] NCI, DCTD, CTEP, Bethesda, MD 20892 USA. [Clegg, Limin X.] Dept Vet Affairs, Off Healthcare Inspect, Off Inspector Gen, Washington, DC 20420 USA. RP Harlan, LC (reprint author), NCI, Appl Res Program, DCCPS, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM lh50w@nih.gov FU NCI NIH HHS [N01PC35136, N01PC35141, N02 PC015105, N01PC35143, N01PC35138, N01PC35135, N01PC35137, N01PC35133, N01PC35142, N01PC35145, N01PC35139] NR 47 TC 9 Z9 9 U1 0 U2 0 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 28 PY 2008 VL 14 IS 20 BP 3165 EP 3173 DI 10.3748/wjg.14.3165 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 308CC UT WOS:000256364900007 PM 18506920 ER PT J AU Nasrollahzadeh, D Kamangar, F Aghcheli, K Sotoudeh, M Islami, F Abnet, CC Shakeri, R Pourshams, A Marjani, HA Nouraie, M Khatibian, M Semnani, S Ye, W Boffetta, P Dawsey, SM Malekzadeh, R AF Nasrollahzadeh, D. Kamangar, F. Aghcheli, K. Sotoudeh, M. Islami, F. Abnet, C. C. Shakeri, R. Pourshams, A. Marjani, H. A. Nouraie, M. Khatibian, M. Semnani, S. Ye, W. Boffetta, P. Dawsey, S. M. Malekzadeh, R. TI Opium, tobacco, and alcohol use in relation to oesophageal squamous cell carcinoma in a high-risk area of Iran SO BRITISH JOURNAL OF CANCER LA English DT Article DE oesophageal cancer; Iran; opium; tobacco; alcohol ID NORTHEASTERN IRAN; GOLESTAN COHORT; GASTRIC CANCERS; MUTAGENS; RELIABILITY; POPULATION; PYROLYSIS; VALIDITY; SMOKERS AB The very high incidence of oesophageal squamous cell carcinoma (ESCC) in Golestan Province in northeastern Iran was suggested by studies in the 1970s as partly due to opium use, which is not uncommon in this area, but based on limited numbers. From December 2003 to June 2007, we administered a validated structured questionnaire to 300 ESCC cases and 571 controls, matched on neighbourhood of residence, age (+/- 2 years), and sex. We used conditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. Compared with those who used neither tobacco nor opium, risk of ESCC was increased in those who used tobacco only (OR, 95% CI: 1.70, 1.05-2.73), in those who used opium only (2.12, 1.21-3.74), and in those who used both tobacco and opium (2.35, 1.50-3.67). All forms of tobacco use (cigarettes, hookah, and nass) were associated with higher ESCC risk. Similarly, use of both crude opium and other forms of opium were associated with higher risk. Alcohol consumption was seen in only 2% of the cases and 2% of the controls, and was not associated with ESCC risk. C1 [Nasrollahzadeh, D.; Aghcheli, K.; Sotoudeh, M.; Islami, F.; Shakeri, R.; Pourshams, A.; Marjani, H. A.; Nouraie, M.; Khatibian, M.; Malekzadeh, R.] Univ Tehran, Med Sci, Shriati Hosp, Digest Dis Res Ctr, Tehran 14117, Iran. [Nasrollahzadeh, D.; Ye, W.] Karolinska Inst, Stockholm, Sweden. [Kamangar, F.; Abnet, C. C.; Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Islami, F.; Boffetta, P.] Int Agcy Res Canc, F-69372 Lyon, France. [Semnani, S.] Gorgan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. RP Malekzadeh, R (reprint author), Univ Tehran, Med Sci, Shriati Hosp, Digest Dis Res Ctr, Kargar St, Tehran 14117, Iran. EM kamangaf@mail.nih.gov; malek@ams.ac.ir RI Ye, Weimin/A-5939-2008; Abnet, Christian/C-4111-2015; Semnani, Shahryar/N-2270-2016; OI Abnet, Christian/0000-0002-3008-7843; Semnani, Shahryar/0000-0002-8768-6142; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 FU Intramural NIH HHS NR 26 TC 115 Z9 115 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 27 PY 2008 VL 98 IS 11 BP 1857 EP 1863 DI 10.1038/sj.bjc.6604369 PG 7 WC Oncology SC Oncology GA 307GY UT WOS:000256308600023 PM 18475303 ER PT J AU Tsuge, H Nagahama, M Oda, M Iwamoto, S Utsunomiya, H Marquez, VE Katunuma, N Nishizawa, M Sakurai, J AF Tsuge, Hideaki Nagahama, Masahiro Oda, Masataka Iwamoto, Shinobu Utsunomiya, Hiroko Marquez, Victor E. Katunuma, Nobuhiko Nishizawa, Mugio Sakurai, Jun TI Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens L-toxin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE complex; crystal structure; protein recognition ID SITE-DIRECTED MUTAGENESIS; CRYSTAL-STRUCTURE; IOTA-TOXIN; BOTULINUM-C2 TOXIN; ADENYLATE-CYCLASE; DIPHTHERIA-TOXIN; CHOLERA-TOXIN; COMPLEX; RIBOSYLTRANSFERASE; MECHANISM AB The ADP-ribosylating toxins (ADPRTs) produced by pathogenic bacteria modify intracellular protein and affect eukaryotic cell function. Actin-specific ADPRTs (including Clostridium perfringens L-toxin and Clostridium botulinun C2 toxin) ADP-ribosylate G-actin at Arg-177, leading to disorganization of the cytoskeleton and cell death. Although the structures of many actin-specific ADPRTs are available, the mechanisms underlying actin recognition and selective ADP-ribosylation of Arg-177 remain unknown. Here we report the crystal structure of actin-la in complex with the nonhydrolyzable NAD analog beta TAD at 2.8 angstrom resolution. The structure indicates that la recognizes actin via five loops around NAD: loop I (Tyr-60-Tyr-62 in the N domain), loop II (active-site loop), loop III, loop IV (PN loop), and loop V (ADP-ribosylating turn-turn loop). We used site-directed mutagenesis to confirm that loop I on the N domain and loop II are essential for the ADP-ribosyltransferase activity. Furthermore, we revealed that Glu-378 on the EXE loop is in close proximity to Arg-177 in actin, and we proposed that the ADP-ribosylation of Arg-177 proceeds by an SN1 reaction via first an oxocarbenium ion intermediate and second a cationic intermediate by alleviating the strained conformation of the first oxocarbenium ion. Our results suggest a common reaction mechanism for ADPRTs. Moreover, the structure might be of use in rational drug design to block toxin-substrate recognition. C1 [Tsuge, Hideaki; Utsunomiya, Hiroko; Katunuma, Nobuhiko] Tokushima Bunri Univ, Inst Hlth Sci, Tokushima 7708514, Japan. [Nagahama, Masahiro; Oda, Masataka; Iwamoto, Shinobu; Nishizawa, Mugio; Sakurai, Jun] Tokushima Bunri Univ, Fac Pharmaceut Sci, Tokushima 7708514, Japan. [Tsuge, Hideaki] Univ Tokushima, Inst Enzyme Res, Tokushima 7708503, Japan. [Tsuge, Hideaki] Harima Inst, RIKEN, Spring Ctr 8, Struct Biophys Lab, Sayo, Hyogo 6795148, Japan. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Tsuge, H (reprint author), Tokushima Bunri Univ, Inst Hlth Sci, 180 Yamashiro Cho, Tokushima 7708514, Japan. EM tsuge@tokushima.bunri-u.ac.jp; sakurai@ph.bunri-u.ac.jp OI Tsuge, Hideaki/0000-0003-0166-9163 FU Intramural NIH HHS NR 38 TC 48 Z9 48 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2008 VL 105 IS 21 BP 7399 EP 7404 DI 10.1073/pnas.0801215105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 308HC UT WOS:000256378100013 PM 18490658 ER PT J AU Gireesh, ED Plenz, D AF Gireesh, Elakkat D. Plenz, Dietmar TI Neuronal avalanches organize as nested theta- and beta/gamma-oscillations during development of cortical layer 2/3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dopamine; in vivo; multielectrode array; organotypic culture; rat ID DEVELOPMENT IN-VITRO; SOMATOSENSORY CORTEX; GAMMA-OSCILLATIONS; CEREBRAL-CORTEX; VISUAL-CORTEX; FREQUENCY OSCILLATIONS; ELECTRICAL-ACTIVITY; DEVELOPING NETWORKS; PREFRONTAL CORTEX; SLICE CULTURES AB Maturation of the cerebral cortex involves the spontaneous emergence of distinct patterns of neuronal synchronization, which regulate neuronal differentiation, synapse formation, and serve as a substrate for information processing. The intrinsic activity patterns that characterize the maturation of cortical layer 2/3 are poorly understood. By using microelectrode array recordings in vivo and in vitro, we show that this development is marked by the emergence of nested theta- and beta/gamma-oscillations that require NMDA- and GABA(A)-mediated synaptic transmission. The oscillations organized as neuronal avalanches, i.e.,they were synchronized across cortical sites forming diverse and millisecond-precise spatiotemporal patterns that distributed in sizes according to a power law with a slope of -1.5. The correspondence between nested oscillations and neuronal avalanches required activation of the dopamine D(1) receptor. We suggest that the repetitive formation of neuronal avalanches provides an intrinsic template for the selective fin king of external inputs to developing superficial layers. C1 [Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Porter Neurosci Res Ctr, Room 3A-100,35 Convent Dr, Bethesda, MD 20892 USA. EM plenzd@mail.nih.gov FU Intramural NIH HHS NR 47 TC 127 Z9 127 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 27 PY 2008 VL 105 IS 21 BP 7576 EP 7581 DI 10.1073/pnas.0800537105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 308HC UT WOS:000256378100044 PM 18499802 ER PT J AU Morcock, DR Thomas, JA Sowder, RC Henderson, LE Crise, BJ Gorelick, RJ AF Morcock, David R. Thomas, James A. Sowder, Raymond C., II Henderson, Louis E. Crise, Bruce J. Gorelick, Robert J. TI HIV-1 inactivation by 4-vinylpyridine is enhanced by dissociating Zn2+ from nucleocapsid protein SO VIROLOGY LA English DT Article DE HIV-1; nucleocapsid; zinc finger; reverse transcription; provirus; sulfhydryl reagents ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACID-CHAPERONE ACTIVITY; MURINE LEUKEMIA-VIRUS; FUSION INHIBITOR T-20; ZINC-FINGER; REVERSE TRANSCRIPTION; IN-VITRO; ENVELOPE GLYCOPROTEINS; SECONDARY STRUCTURE; VIRAL REPLICATION AB Selective inactivation of critical cysteine residues in human immunodeficiency virus type one (HIV-1) was observed after treatment with 4-vinylpyridine (4-VP), with and without the membrane-permeable metal chelator N,N,N',N'-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN). Chromatographic analysis showed that cysteines contained within nucleocapsid zinc fingers, in the context of whole virus or purified protein, were essentially unreactive, but became reactive when a chelator was included. Virus treated with 4-VP showed only a modest decrease in infectivity; after TPEN addition, nearly complete inactivation of HIV-1 occurred. Similarly, quantitation of viral DNA products from 4-VP-treated virus infections showed no significant effects on reverse transcription, but did show a 14-fold reduction in proviruses; when TPEN was added, a 10(5)-fold decrease in late reverse transcription products was observed and no proviruses were detected. Since 4-VP effectiveness was greatly enhanced by TPEN, this strongly suggests that modification of nucleocapsid zinc fingers is necessary and sufficient for HIV-1 inactivation by sulfhydryl reagents. Published by Elsevier Inc. C1 [Morcock, David R.; Thomas, James A.; Sowder, Raymond C., II; Henderson, Louis E.; Crise, Bruce J.; Gorelick, Robert J.] NCI, SAIC Frederick Inc, Basic Res Program, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Gorelick, RJ (reprint author), NCI, SAIC Frederick Inc, Basic Res Program, AIDS Vaccine Program, 4th Floor,POB B, Frederick, MD 21702 USA. EM gorelick@ncifcrf.gov OI Thomas, James/0000-0002-2509-490X FU NCI NIH HHS [N01 CO012400, N01-CO-12400, N01CO12400] NR 73 TC 15 Z9 15 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2008 VL 375 IS 1 BP 148 EP 158 DI 10.1016/j.virol.2008.01.045 PG 11 WC Virology SC Virology GA 301MY UT WOS:000255901500014 PM 18304600 ER PT J AU Wang, RX Soll, L Dugan, V Runstadler, J Happ, G Slemons, RD Taubenberger, JK AF Wang, Ruixue Soll, Lindsey Dugan, Vivien Runstadler, Jonathan Happ, George Slemons, Richard D. Taubenberger, Jeffery K. TI Examining the hemagglutinin subtype diversity among wild duck-origin influenza A viruses using ethanol-fixed cloacal swabs and a novel RT-PCR method SO VIROLOGY LA English DT Article DE influenza A virus; hemagglutinin; subtype; RT-PCR; surveillance ID REAL-TIME PCR; NORTH-AMERICA; GENES; BIRDS; SURVEILLANCE; ASSAY; SET AB This study presents an interconnected approach for circumventing two inherent limitations associated with studies defining the natural history of influenza A viruses in wild birds. The first limiting factor is the ability to maintain a cold chain from specimen collection to the laboratory when study sites are in more remote locations. The second limiting factor is the ability to identify all influenza A virus HA subtypes present in an original sample. We report a novel method for molecular subtyping of avian influenza A virus hemagglutinin genes using degenerate primers designed to amplify all known hemagglutinin subtypes. It was shown previously that templates larger than 200 by were not consistently amplifiable from ethanol-fixed cloacal swabs. For this study, new primer sets were designed within these constraints. This method was used to perform subtyping RT-PCR on 191 influenza RNA-positive ethanol-fixed cloacal swabs obtained from 880 wild ducks in central Alaska in 2005. Seven different co-circulating hemagglutinin subtypes were identified in this study set, including H1; H3, H4, H5, H6, H8, and H12. In addition, 16% of original cloacal samples showed evidence of mixed infection, with samples yielding from two-to-five different hemagglutinin subtypes. This study further demonstrates the complex ecobiology of avian influenza A viruses in wild birds. (c) 2008 Elsevier Inc. All rights reserved. C1 [Wang, Ruixue; Soll, Lindsey; Dugan, Vivien; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Runstadler, Jonathan; Happ, George] Univ Alaska, Inst Arctic Biol, Fairbanks, AK 99775 USA. [Slemons, Richard D.] Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43210 USA. RP Taubenberger, JK (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,Rm 3E19A2,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000996-01] NR 28 TC 37 Z9 40 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 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2008 VL 375 IS 1 BP 182 EP 189 DI 10.1016/j.virol.2008.01.041 PG 8 WC Virology SC Virology GA 301MY UT WOS:000255901500017 PM 18308356 ER PT J AU Minang, JT Trivett, MT Coren, LV Barsov, EV Piatak, M Chertov, O Chertova, E Ott, DE Ohlen, C AF Minang, Jacob T. Trivett, Matthew T. Coren, Lori V. Barsov, Eugene V. Piatak, Michael, Jr. Chertov, Oleg Chertova, Elena Ott, David E. Ohlen, Claes TI The Mamu B*17-restricted SIV NefIW9 to TW9 mutation abrogates correct epitope processing and presentation without loss of replicative fitness SO VIROLOGY LA English DT Article DE AIDS; CD8(+)T-cell clones; immune escape; nef; SIV ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; RHESUS-MONKEYS; HIV-1 NEF; IN-VIVO; ESCAPE MUTATIONS; TYPE-1 INFECTION; VIRAL ESCAPE; INDUCED CD4; CELLS AB CD8(+) cytotoxic T lymphocytes (CTL) play an important role in controlling virus replication in HIV- and SIV-infected humans and monkeys, respectively. Three well-studied SfV CTL determinants are the two Mamu A*01-restricted epitopes Gag CM9 and Tat SL8, and the Marrur B*17-restricted epitope Nef IW9. Point mutations leading to amino acid replacements in these epitopes have been reported to mediate SIV escape from CTL control. We found that synthetic peptides containing mutations in SIV Gag CN19 and Tat SL8 were no longer recognized by the respective CTL. On the other hand, the described I-to-T replacement at the N-terminal amino acid residue of the SIV Nef IW9 epitope only moderately affected CTL recognition of the variant peptide, TW9. In an attempt to dissect the mechanism of escape of the Nef TW9 mutation, we investigated the effect of this mutation on CTL recognition of CD4(+)T cells infected with an engineered SIV,,,,,239 that contained the TW9 mutation in Nef. Although, the wild type and mutant virus both infected and efficiently replicated in rhesus macaque CD4+T cells, the TW9 mutant virus failed to induce IFN-gamma expression in an SIV Nef IW9-specific CTL clone. Thus, unlike escape from Gag CM9- or Tat SL8-speefic CTL control presumably by loss of epitope binding, these results point to a defect at the level of processing and/or presentation of the variant TW9 epitope with resultant loss of triggering of the cognate TCR on CTL generated against the wild type peptide. Our data highlight the value of functional assays using virus-infected target cells as opposed to peptide-pulsed APC when assessing relevant escape mutations in CTL epitopes. Published by Elsevier Inc. C1 [Minang, Jacob T.; Trivett, Matthew T.; Coren, Lori V.; Barsov, Eugene V.; Piatak, Michael, Jr.; Chertova, Elena; Ott, David E.; Ohlen, Claes] NCI Frederick, SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Chertov, Oleg] NCI Frederick, SAIC Frederick Inc, Res Technol Program, Frederick, MD 21702 USA. RP Ohlen, C (reprint author), NCI Frederick, SAIC Frederick Inc, AIDS & Canc Virus Program, POB B, Frederick, MD 21702 USA. EM cohlen@ncifcrf.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01-CO-124000] NR 44 TC 9 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2008 VL 375 IS 1 BP 307 EP 314 DI 10.1016/j.virol.2008.02.005 PG 8 WC Virology SC Virology GA 301MY UT WOS:000255901500029 PM 18328525 ER PT J AU Li, GW Zhang, P Wang, JP Gregg, EW Yang, WY Gong, QH Li, H Li, HL Jiang, YY An, YL Shuai, Y Zhang, B Zhang, JL Thompson, TJ Gerzoff, RB Roglic, G Hu, YH Bennett, PH AF Li, Guangwei Zhang, Ping Wang, Jinping Gregg, Edward W. Yang, Wenying Gong, Qiuhong Li, Hui Li, Hongliang Jiang, Yayun An, Yali Shuai, Ying Zhang, Bo Zhang, Jingling Thompson, Theodore J. Gerzoff, Robert B. Roglic, Gojka Hu, Yinghua Bennett, Peter H. TI The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study SO LANCET LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; MORTALITY; RISK; REDUCTION; METFORMIN; EXERCISE; MELLITUS; PROGRAM; PEOPLE; NIDDM AB Background Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of active intervention, and whether such interventions reduce the risk of cardiovascular disease (CVD) and mortality, is unclear. We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes, diabetes-related macrovascular and microvascular complications, and mortality. Methods In 1986, 577 adults with impaired glucose tolerance from 33 clinics in China were randomly assigned to either the control group or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention took place over 6 years until 1992. In 2006, study participants were followed-up to assess the long-term effect of the interventions. The primary outcomes were diabetes incidence, CVD incidence and mortality, and all-cause mortality. Findings Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio [HRR] 0 . 49; 95% CI 0 . 33-0-73) during the active intervention period and a 43% lower incidence (0 . 57; 0 . 41-0 . 81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first CVD events (HRR 0 . 98; 95% CI 0 . 71-1.37), CVD mortality (0 . 83; 0.48-1.40), and all-cause mortality (0 - 96; 0 . 65-1.41), but our study had limited statistical power to detect differences for these outcomes. Interpretation Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention. However, whether lifestyle intervention also leads to reduced CVD and mortality remains unclear. Funding Centers for Disease Control and Prevention, WHO, the China-Japan Friendship Hospital, and Da Qing First Hospital. C1 [Zhang, Ping; Gregg, Edward W.; Thompson, Theodore J.; Gerzoff, Robert B.] Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA 30341 USA. [Li, Guangwei; Yang, Wenying; Gong, Qiuhong; Li, Hongliang; An, Yali; Shuai, Ying; Zhang, Bo] China Japan Friendship Hosp, Dept Endocrinol, Beijing 100029, Peoples R China. [Wang, Jinping; Li, Hui; Jiang, Yayun; Zhang, Jingling; Hu, Yinghua] Da Qing First Hosp, Dept Cardiol, Da Qing, Peoples R China. [Roglic, Gojka] WHO, Dept Chron Dis & Hlth Promot, CH-1211 Geneva, Switzerland. [Bennett, Peter H.] NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Zhang, P (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA 30341 USA. EM guangwei_li@medmail.com.cn; pzhang@cdc.gov FU PHS HHS [U58/CCU424123-01-02] NR 24 TC 566 Z9 640 U1 10 U2 82 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAY 24 PY 2008 VL 371 IS 9626 BP 1783 EP 1789 DI 10.1016/S0140-6736(08)60766-7 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 304IO UT WOS:000256103400033 PM 18502303 ER PT J AU Carleton, KL Spady, TC Streelman, JT Kidd, MR McFarland, WN Loew, ER AF Carleton, Karen L. Spady, Tyrone C. Streelman, J. Todd Kidd, Michael R. McFarland, William N. Loew, Ellis R. TI Visual sensitivities tuned by heterochronic shifts in opsin gene expression SO BMC BIOLOGY LA English DT Article ID TUNING SPECTRAL SENSITIVITY; AFRICAN CICHLID FISHES; JUVENILE YELLOW PERCH; LAKE MALAWI CICHLIDS; COLOR-VISION; HAPLOCHROMIS-BURTONI; MOLECULAR EVOLUTION; ADAPTIVE EVOLUTION; MESSENGER-RNA; DEVELOPMENTAL-CHANGES AB Background: Cichlid fishes have radiated into hundreds of species in the Great Lakes of Africa. Brightly colored males display on leks and vie to be chosen by females as mates. Strong discrimination by females causes differential male mating success, rapid evolution of male color patterns and, possibly, speciation. In addition to differences in color pattern, Lake Malawi cichlids also show some of the largest known shifts in visual sensitivity among closely related species. These shifts result from modulated expression of seven cone opsin genes. However, the mechanisms for this modulated expression are unknown. Results: In this work, we ask whether these differences might result from changes in developmental patterning of cone opsin genes. To test this, we compared the developmental pattern of cone opsin gene expression of the Nile tilapia, Oreochromis niloticus, with that of several cichlid species from Lake Malawi. In tilapia, quantitative polymerase chain reaction showed that opsin gene expression changes dynamically from a larval gene set through a juvenile set to a final adult set. In contrast, Lake Malawi species showed one of two developmental patterns. In some species, the expressed gene set changes slowly, either retaining the larval pattern or progressing only from larval to juvenile gene sets ( neoteny). In the other species, the same genes are expressed in both larvae and adults but correspond to the tilapia adult genes ( direct development). Conclusion: Differences in visual sensitivities among species of Lake Malawi cichlids arise through heterochronic shifts relative to the ontogenetic pattern of the tilapia outgroup. Heterochrony has previously been shown to be a powerful mechanism for change in morphological evolution. We found that altering developmental expression patterns is also an important mechanism for altering sensory systems. These resulting sensory shifts will have major impacts on visual communication and could help drive cichlid speciation. C1 [Carleton, Karen L.] Univ Maryland, Dept Biol, College Pk, MD 20742 USA. [Spady, Tyrone C.] NHGRI, NIH, Bethesda, MD 20892 USA. [Streelman, J. Todd] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Kidd, Michael R.] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [McFarland, William N.] Univ Washington, Friday Harbor Labs, Friday Harbor, WA 98250 USA. [Loew, Ellis R.] Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. RP Carleton, KL (reprint author), Univ Maryland, Dept Biol, College Pk, MD 20742 USA. EM kcarleto@umd.edu; spadyty@mail.nih.gov; js585@mail.gatech.edu; mrkidd@mail.utexas.edu; mcfarla@u.washington.edu; erl1@cornell.edu NR 77 TC 63 Z9 63 U1 4 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD MAY 23 PY 2008 VL 6 AR 22 DI 10.1186/1741-7007-6-22 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 314ZY UT WOS:000256848900001 PM 18500997 ER PT J AU Levine, SJ AF Levine, Stewart J. TI Molecular mechanisms of soluble cytokine receptor generation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ALPHA-CONVERTING-ENZYME; NECROSIS-FACTOR-ALPHA; EXOSOME-LIKE VESICLES; BINDING-PROTEIN; MESSENGER-RNA; GROWTH-FACTOR; TRANSMEMBRANE CHEMOKINES; INTERLEUKIN-6 RECEPTOR; CELLULAR CHOLESTEROL; PROTEOLYTIC ACTIVITY AB Soluble cytokine receptors play key roles in regulating cytokine-mediated biological events by binding and modulating the activity of target ligands in either an antagonistic or agonistic fashion. This Minireview will provide an overview of the molecular mechanisms mediating the generation of soluble cytokine receptors, which include sheddase-mediated proteolytic cleavage of cell-surface receptors, generation of soluble receptors by alternative gene splicing, transcription and translation of cytokine-binding genes, and extracellular release of membrane-bound receptors within vesicles such as exosomes. C1 NHLBI, NIH, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, NIH, Pulm & Vasc Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Intramural NIH HHS NR 71 TC 56 Z9 59 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14177 EP 14181 DI 10.1074/jbc.R700052200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400002 PM 18385130 ER PT J AU Younes, A Lyashkov, AE Graham, D Sheydina, A Volkova, MV Mitsak, M Vinogradova, TM Lukyanenko, YO Li, Y Ruknudin, AM Boheler, KR van Eyk, J Lakatta, EG AF Younes, Antoine Lyashkov, Alexey E. Graham, David Sheydina, Anna Volkova, Maria V. Mitsak, Megan Vinogradova, Tatiana M. Lukyanenko, Yevgeniya O. Li, Yue Ruknudin, Abdul M. Boheler, Kenneth R. van Eyk, Jennifer Lakatta, Edward G. TI Ca2+-stimulated basal adenylyl cyclase activity localization in membrane lipid microdomains of cardiac sinoatrial nodal pacemaker cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHODIESTERASE ACTIVITY; DIASTOLIC DEPOLARIZATION; RYANODINE RECEPTOR; TRANSGENIC MICE; SIGNALING COMPONENTS; DIRECTED EXPRESSION; PLASMA-MEMBRANE; CA2+ RELEASES; BEATING RATE; CYCLIC-AMP AB Spontaneous, rhythmic subsarcolemmal local Ca2+ releases driven by cAMP- mediated, protein kinase A (PKA)- dependent phosphorylation are crucial for normal pacemaker function of sinoatrial nodal cells (SANC). Because local Ca2+ releases occur beneath the cell surface membrane, near to where adenylyl cyclases (ACs) reside, we hypothesized that the dual Ca2+ and cAMP/ PKA regulatory components of automaticity are coupled via Ca2+ activation of AC activity within membrane microdomains. Here we show by quantitative reverse transcriptase PCR that SANC express Ca2+-activated AC isoforms 1 and 8, in addition to AC type 2, 5, and 6 transcripts. Immunolabeling of cell fractions, isolated by sucrose gradient ultracentrifugation, confirmed that ACs localize to membrane lipid microdomains. AC activity within these lipid microdomains is activated by Ca2+ over the entire physiological Ca2+ range. In intact SANC, the high basal AC activity produces a high level of cAMP that is further elevated by phosphodiesterase inhibition. cAMP and cAMP- mediated PKA- dependent activation of ion channels and Ca2+ cycling proteins drive sarcoplasmic reticulum Ca2+ releases, which, in turn, activate ACs. This feed forward "fail safe" system, kept in check by a high basal phosphodiesterase activity, is central to the generation of normal rhythmic, spontaneous action potentials by pacemaker cells. C1 [Younes, Antoine; Lyashkov, Alexey E.; Sheydina, Anna; Volkova, Maria V.; Vinogradova, Tatiana M.; Lukyanenko, Yevgeniya O.; Li, Yue; Ruknudin, Abdul M.; Boheler, Kenneth R.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Graham, David; Mitsak, Megan; van Eyk, Jennifer] Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lakattae@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [P01 HL077180, P01 HL077180-020001, P01 HL077180-040001, P01 HL077180-010001, P01 HL077180-030001] NR 45 TC 47 Z9 48 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14461 EP 14468 DI 10.1074/jbc.M707540200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400033 PM 18356168 ER PT J AU Kim, SJ Son, TG Park, HR Park, M Kim, MS Kim, HS Chung, HY Mattson, MP Lee, J AF Kim, So Jung Son, Tae Gen Park, Hee Ra Park, Mikyung Kim, Min-Sun Kim, Hyung Sik Chung, Hae Young Mattson, Mark P. Lee, Jaewon TI Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRAUMATIC BRAIN-INJURY; RAT DENTATE GYRUS; STEM-CELLS; DIETARY RESTRICTION; SIGNALING PATHWAYS; ENRICHED ENVIRONMENT; NEUROTROPHIC FACTORS; OXIDATIVE DAMAGE; HEME OXYGENASE-1; IN-VITRO AB Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair. C1 [Kim, So Jung; Park, Hee Ra; Park, Mikyung; Kim, Min-Sun; Kim, Hyung Sik; Chung, Hae Young; Lee, Jaewon] Pusan Natl Univ, Dept Pharm, Coll Pharm, Pusan 609735, South Korea. [Kim, So Jung; Park, Hee Ra; Park, Mikyung; Kim, Min-Sun; Kim, Hyung Sik; Chung, Hae Young; Lee, Jaewon] Pusan Natl Univ, Res Inst Drug Dev, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. [Son, Tae Gen; Mattson, Mark P.] NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Lee, J (reprint author), Pusan Natl Univ, Dept Pharm, Coll Pharm, Pusan 609735, South Korea. EM neuron@pusan.ac.kr RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 NR 60 TC 133 Z9 139 U1 2 U2 15 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14497 EP 14505 DI 10.1074/jbc.M708373200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400037 PM 18362141 ER PT J AU Pavlicek, J Coon, SL Ganguly, S Weller, JL Hassan, SA Sackett, DL Klein, DC AF Pavlicek, Jiri Coon, Steven L. Ganguly, Surajit Weller, Joan L. Hassan, Sergio A. Sackett, Dan L. Klein, David C. TI Evidence that proline focuses movement of the floppy loop of arylalkylamine N-acetyltransferase (EC 2.3.1.87) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SCREENED COULOMB POTENTIALS; MELATONIN RHYTHM ENZYME; PINEAL-GLAND; ANGSTROM RESOLUTION; CATALYTIC MECHANISM; MOLECULAR-DYNAMICS; PROTEIN; SUPERFAMILY; BACKBONE AB Arylalkylamine N-acetyltransferase (AANAT) catalyzes the N-acetylation of serotonin, the penultimate step in the synthesis of melatonin. Pineal AANAT activity increases at night in all vertebrates, resulting in increased melatonin production. This increases circulating levels of melatonin, thereby providing a hormonal signal of darkness. Kinetic and structural analysis of AANAT has determined that one element is floppy. This element, termed Loop 1, is one of three loops that comprise the arylalkylamine binding pocket. During the course of chordate evolution, Loop 1 acquired the tripeptide CPL, and the enzyme became highly active. Here we focused on the functional importance of the CPL tripeptide and found that activity was markedly reduced when it was absent. Moreover, increasing the local flexibility of this tripeptide region by P64G and P64A mutations had the counterintuitive effect of reducing activity and reducing the overall movement of Loop 1, as estimated from Langevin dynamics simulations. Binding studies indicate that these mutations increased the off-rate constant of a model substrate without altering the dissociation constant. The structural kink and local rigidity imposed by Pro-64 may enhance activity by favoring configurations of Loop 1 that facilitate catalysis and do not become immobilized by intramolecular interactions. C1 [Pavlicek, Jiri; Coon, Steven L.; Ganguly, Surajit; Weller, Joan L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Sackett, Dan L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Cell Biophys, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Hassan, Sergio A.] NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov RI Pavlicek, Jiri/G-9927-2014 FU Intramural NIH HHS [Z01 CT000265-11] NR 36 TC 12 Z9 13 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14552 EP 14558 DI 10.1074/jbc.M800593200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400043 PM 18362150 ER PT J AU Gomez-Quiroz, LE Factor, VM Kaposi-Novak, P Coulouarn, C Conner, EA Thorgeirsson, SS AF Gomez-Quiroz, Luis E. Factor, Valentina M. Kaposi-Novak, Pal Coulouarn, Cedric Conner, Elizabeth A. Thorgeirsson, Snorri S. TI Hepatocyte-specific c-Met deletion disrupts redox homeostasis and sensitizes to Fas-mediated apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FETAL-RAT HEPATOCYTES; NF-KAPPA-B; GROWTH-FACTOR; OXIDATIVE STRESS; REACTIVE OXYGEN; SIGNALING PATHWAY; CELL-DEATH; ACTIVATION; EXPRESSION; PROTECTS AB The hepatocyte growth factor and its receptor c-Met direct a pleiotropic signal transduction pathway that controls cell survival. We previously demonstrated that mice lacking c-Met (Met-KO) in hepatocytes were hypersensitive to Fas-induced liver injury. In this study, we used primary hepatocytes isolated from Met-KO and control (Cre-Ctrl) mice to address more directly the protective effects of c-Met signaling. Loss of c-Met function increased sensitivity to Fas-mediated apoptosis. Hepatocyte growth factor suppressed apoptosis in Cre-Ctrl but not Met-KO hepatocytes concurrently with up-regulation of NF-kappa B and major antiapoptotic proteins Bcl-2 and Bcl-xL. Intriguingly, Met-KO hepatocytes exhibited intrinsic activation of NF-kappa B as well as Bcl-2 and Bcl-xL. Furthermore, unchallenged Met-KO cells displayed oxidative stress as evidenced by overproduction of reactive oxygen species, which was associated with greater NADPH and Rac1 activities, was blocked by the known NADPH oxidase inhibitors, and was paralleled by increased lipid peroxidation and reduced glutathione (GSH) content. N-Acetylcysteine, an antioxidant and GSH precursor, significantly reduced Jo2-induced cell death. Conversely, the GSH-depleting agent buthionine sulfoximine completely abolished the protective effects of N-acetylcysteine in Met-KO hepatocytes. In conclusion, genetic inactivation of c-Met in mouse hepatocytes caused defects in redox regulation, which may account for the increased sensitivity to Fas-induced apoptosis and adaptive up-regulation of NF-kappa B survival signaling. These data provide evidence that intact c-Met signaling is a critical factor in the protection against excessive generation of endogenous reactive oxygen species. C1 [Gomez-Quiroz, Luis E.; Factor, Valentina M.; Kaposi-Novak, Pal; Coulouarn, Cedric; Conner, Elizabeth A.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), 37 Convent Dr,Bldg 37,Rm 4146A, Bethesda, MD 20892 USA. EM snorri_s_thorgeirsson@nih.gov RI Gomez-Quiroz, Luis/L-8415-2013; Coulouarn, Cedric/E-5472-2011; OI Gomez-Quiroz, Luis Enrique/0000-0002-5704-5985 FU Intramural NIH HHS [Z99 CA999999] NR 46 TC 40 Z9 40 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14581 EP 14589 DI 10.1074/jbc.M707733200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400046 PM 18348981 ER PT J AU Walseng, E Bakke, O Roche, PA AF Walseng, Even Bakke, Oddmund Roche, Paul A. TI Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC CLASS-II; HLA-DR MOLECULES; INVARIANT CHAIN COMPLEXES; DENDRITIC CELL MATURATION; ANTIGEN PRESENTATION; PLASMA-MEMBRANE; SURFACE EXPRESSION; LIPID RAFTS; INTRACELLULAR-TRANSPORT; TARGETING SIGNALS AB Major histocompatibility complex (MHC) class II molecules (MHC-II) function by binding antigenic peptides and displaying these peptides on the surface of antigen presenting cells (APCs) for recognition by peptide-MHC-II (pMHC-II)-specific CD4 T cells. It is known that cell surface MHC-II can internalize, exchange antigenic peptides in endosomes, and rapidly recycle back to the plasma membrane; however, the molecular machinery and trafficking pathways utilized by internalizing/recycling MHC-II have not been identified. We now demonstrate that unlike newly synthesized invariant chain-associated MHC-II, mature cell surface pMHC-II complexes internalize following clathrin-, AP-2-, and dynamin-independent endocytosis pathways. Immunofluorescence microscopy of MHC-II expressing HeLa-CIITA cells, human B cells, and human DCs revealed that pMHC enters Arf6(+) Rab35(+) EHD1(+) tubular endosomes following endocytosis. These data contrast the internalization pathways followed by newly synthesized and peptide-loaded MHC-II molecules and demonstrates that cell surface pMHC-II internalize and rapidly recycle from early endocytic compartments in tubular endosomes. C1 [Walseng, Even; Roche, Paul A.] NCI, Expt Immunol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Walseng, Even; Bakke, Oddmund] Univ Oslo, Dept Mol Biosci, Ctr Immune Regulat, N-0316 Oslo, Norway. [Bakke, Oddmund] Univ Bergen, Gade Inst, N-5021 Bergen, Norway. RP Roche, PA (reprint author), Bldg 10 Rm 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov OI Bakke, Oddmund/0000-0003-4843-7626 FU Intramural NIH HHS NR 63 TC 77 Z9 78 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14717 EP 14727 DI 10.1074/jbc.M801070200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400060 PM 18378669 ER PT J AU Frederick, ED Ramos, SBV Blackshear, PJ AF Frederick, Elizabeth D. Ramos, Silvia B. V. Blackshear, Perry J. TI A unique C-terminal repeat domain maintains the cytosolic localization of the placenta-specific tristetraprolin family member ZFP36L3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ZINC-FINGER PROTEINS; NUCLEAR EXPORT SIGNAL; PRIMARY RESPONSE GENE; AU-RICH ELEMENTS; MESSENGER-RNA; TRANSCRIPTION FACTOR; NUCLEOTIDE-SEQUENCE; TIS11 FAMILY; MECHANISMS; BINDING AB Members of the tristetraprolin family of CCCH tandem zinc finger proteins bind to AU-rich elements in certain cellular mRNAs, leading to their deadenylation and destabilization. Studies in knock-out mice demonstrated roles for three of the family members, tristetraprolin, ZFP36L1, and ZFP36L2, in inflammation, chorioallantoic fusion, and early embryonic development, respectively. However, little is known about a recently discovered placenta-specific tristetraprolin family member, ZFP36L3. Tristetraprolin, ZFP36L1, and ZFP36L2 have been shown to shuttle between the nucleus and cytoplasm, using typical hydrophobic amino acid-rich nuclear export sequences, and nuclear localization sequences located within the tandem zinc finger domain. In contrast, we previously showed that green fluorescent protein-labeled ZFP36L3, expressed in HEK293 cells, remained cytosolic, even in the presence of the nuclear export blocker leptomycin B. We show here that the conserved tandem zinc finger domain contains an active nuclear localization signal. However, the sequence corresponding to the nuclear export signal in the other family members was nonfunctional, and thus did not contribute to the cytosolic localization. The unique C-terminal repeat domain could override the activity of the nuclear localization sequence, preventing the import of ZFP36L3 into the nucleus. Immunostaining of mouse placenta demonstrated that ZFP36L3 was located only in the cytoplasm of trophoblast cells. Thus, in contrast to the other mammalian members of this protein family, ZFP36L3 is a "full-time" cytosolic protein, rather than a nucleocytoplasmic shuttling protein. The significance of this difference in subcellular localization to the physiology of placental trophoblast cells, where ZFP36L3 is selectively expressed, remains to be determined. C1 [Frederick, Elizabeth D.; Ramos, Silvia B. V.; Blackshear, Perry J.] NIEHS, Res Triangle Pk, NC 27709 USA. [Frederick, Elizabeth D.; Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, A2-05 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090080-10] NR 33 TC 16 Z9 17 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 23 PY 2008 VL 283 IS 21 BP 14792 EP 14800 DI 10.1074/jbc.M801234200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302BL UT WOS:000255941400067 PM 18367448 ER PT J AU Berquist, BR McNeill, DR Wilson, DM AF Berquist, Brian R. McNeill, Daniel R. Wilson, David M., III TI Characterization of abasic endonuclease activity of human Ape1 on alternative substrates, as well as effects of ATP and sequence context on AP site incision SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ape1; DNA repair; polymerase stalling; class switch recombination; RNA cleavage ID BASE EXCISION-REPAIR; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; IMMUNOGLOBULIN GENE DIVERSIFICATION; CLASS-SWITCH RECOMBINATION; DNA-REPAIR; MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; HOMOLOGOUS RECOMBINATION; TRANSLESION SYNTHESIS; EXONUCLEASE ACTIVITY AB Human Ape1 is a multifunctional protein with a major role in initiating repair of apurinic/apyrimidinic (AP) sites in DNA by catalyzing hydrolytic incision of the phosphodiester backbone immediately adjacent to the damage. Besides in double-stranded DNA, Ape1 has been shown to cleave at AP sites in single-stranded regions of a number of biologically relevant DNA conformations and in structured single-stranded DNA. Extension of these studies has revealed a more expansive repertoire of model substrates on which Ape1 exerts AP endonuclease activity. In particular, Ape1 possesses the ability to cleave at AP sites located in (i) the DNA strand of a DNA/RNA hybrid, (ii) "pseudo-triplex" bubble substrates designed to mimic stalled replication or transcription intermediates, and (iii) configurations that emulate R-loop structures that arise during class switch recombination. Moreover, Ape1 was found to cleave AP-site-containing single-stranded RNA, suggesting a novel "cleansing" function that may contribute to the elimination of detrimental cellular AP-RNA molecules. Finally, sequence context immediately surrounding an abasic site in duplex DNA was found to have a less than threefold effect on the incision efficiency of Ape1, and ATP was found to exert complex effects on the endonuclease capacity of Ape1 on double-stranded substrates. The results suggest that in addition to abasic sites in conventional duplex genomic DNA, Ape1 has the ability to incise at AP sites in DNA conformations formed during DNA replication, transcription, and class switch recombination, and that Ape1 can endonucleolytically destroy damaged RNA. Published by Elsevier Ltd. C1 [Berquist, Brian R.; McNeill, Daniel R.; Wilson, David M., III] NIA, Unit Struct & Funct Base Excis Repair, Lab Mol Gerontol, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Unit Struct & Funct Base Excis Repair, Lab Mol Gerontol, Natl Inst Hlth, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000743-06] NR 50 TC 53 Z9 55 U1 2 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 23 PY 2008 VL 379 IS 1 BP 17 EP 27 DI 10.1016/j.jmb.2008.03.053 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 312AW UT WOS:000256642500003 PM 18439621 ER PT J AU Gorski, SA Snyder, SK John, S Grummt, I Misteli, T AF Gorski, Stanislaw A. Snyder, Sara K. John, Sam Grummt, Ingrid Misteli, Tom TI Modulation of RNA polymerase assembly dynamics in transcriptional regulation SO MOLECULAR CELL LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; FACTOR TIF-IA; IN-VIVO; RIBOSOMAL-RNA; LIVING CELLS; FLUORESCENCE RECOVERY; GENE-TRANSCRIPTION; RDNA TRANSCRIPTION; II TRANSCRIPTION; FACTOR UBF AB The interaction of transcription factors with target genes is highly dynamic. Whether the dynamic nature of these interactions is merely an intrinsic property of transcription factors or serves a regulatory role is unknown. Here we have used single-cell fluorescence imaging combined with computational modeling and chromatin immunoprecipitation to analyze transcription complex dynamics in gene regulation during the cell cycle in living cells. We demonstrate a link between the dynamics of RNA polymerase I (RNA Pol I) assembly and transcriptional output. We show that transcriptional upregulation is accompanied by prolonged retention of RNA Pol I components at the promoter, resulting in longer promoter dwell time, and an increase in the steady-state population of assembling polymerase. As a consequence, polymerase assembly efficiency and, ultimately, the rate of entry into processive elongation are elevated. Our results show that regulation of rDNA transcription in vivo occurs via modulation of the efficiency of transcription complex subunit capture and assembly. C1 [Gorski, Stanislaw A.; Snyder, Sara K.; John, Sam; Misteli, Tom] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Grummt, Ingrid] German Canc Res Ctr, Div Mol Biol Cell 2, D-69120 Heidelberg, Germany. RP Misteli, T (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS [Z01 BC010309-09] NR 45 TC 53 Z9 53 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 23 PY 2008 VL 30 IS 4 BP 486 EP 497 DI 10.1016/j.molcel.2008.04.021 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 306SA UT WOS:000256266900009 PM 18498750 ER PT J AU Costanzi, S AF Costanzi, Stefano TI On the applicability of GPCR homology models to computer-aided drug discovery: A comparison between in silico and crystal structures of the beta(2)-adrenergic receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED-RECEPTORS; A(2A) ADENOSINE RECEPTOR; 2ND EXTRACELLULAR LOOP; BETA-2-ADRENERGIC RECEPTOR; ADRENERGIC-RECEPTOR; LIGAND RECOGNITION; HORMONE-RECEPTOR; P2Y(1) RECEPTOR; BINDING-SITE; TSH RECEPTOR AB The publication of the crystal structure of the beta(2)-adrenergic receptor (beta(2)-AR) proved that G protein-coupled receptors (GPCRs) share a structurally conserved rhodopsin-like 7TM core. Here, to probe to which extent realistic GPCR structures can be recreated through modeling, carazolol was docked at two rhodopsin-based homology models of the human beta(2)-AR. The first featured a rhodopsin-like second extracellular loop, which interfered with ligand docking and with the orientation of several residues in the binding pocket. The second featured a second extracellular loop built completely de novo, which afforded a more accurate model of the binding pocket and a better docking of the ligand. Furthermore, incorporating available biochemical and computational data to the model by correcting the conformation of a single residue lining the binding pocket -Phe290(6.52)-, resulted in significantly improved docking poses. These results support the applicability of GPCR modeling to the design of site-directed mutagenesis experiments and to drug discovery. C1 NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDKD, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS [Z01 DK013025-01] NR 63 TC 107 Z9 107 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 22 PY 2008 VL 51 IS 10 BP 2907 EP 2914 DI 10.1021/jim800044k PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 301OU UT WOS:000255906300007 PM 18442228 ER PT J AU Maguire, AM Simonelli, F Pierce, EA Pugh, EN Mingozzi, F Bennicelli, J Banfi, S Marshall, KA Testa, F Surace, EM Rossi, S Lyubarsky, A Arruda, VR Konkle, B Stone, E Sun, JW Jacobs, J Dell'Osso, L Hertle, R Ma, JX Redmond, TM Zhu, XS Hauck, B Zelenaia, O Shindler, KS Maguire, MG Wright, JF Volpe, NJ McDonnell, JW Auricchio, A High, KA Bennett, J AF Maguire, Albert M. Simonelli, Francesca Pierce, Eric A. Pugh, Edward N., Jr. Mingozzi, Federico Bennicelli, Jeannette Banfi, Sandro Marshall, Kathleen A. Testa, Francesco Surace, Enrico M. Rossi, Settimio Lyubarsky, Arkady Arruda, Valder R. Konkle, Barbara Stone, Edwin Sun, Junwei Jacobs, Jonathan Dell'Osso, Lou Hertle, Richard Ma, Jian-xing Redmond, T. Michael Zhu, Xiaosong Hauck, Bernd Zelenaia, Olga Shindler, Kenneth S. Maguire, Maureen G. Wright, J. Fraser Volpe, Nicholas J. McDonnell, Jennifer Wellman Auricchio, Alberto High, Katherine A. Bennett, Jean TI Safety and efficacy of gene transfer for Leber's congenital amaurosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RETINITIS-PIGMENTOSA; LIGHT REFLEX; VISUAL CYCLE; CHILDHOOD BLINDNESS; RPE65 MUTATIONS; CANINE MODEL; THERAPY; ISOMEROHYDROLASE; DYSTROPHY; VISION AB Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hPPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA. C1 [Maguire, Albert M.; Pierce, Eric A.; Pugh, Edward N., Jr.; Bennicelli, Jeannette; Lyubarsky, Arkady; Shindler, Kenneth S.; Maguire, Maureen G.; Volpe, Nicholas J.; Bennett, Jean] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Maguire, Albert M.; Mingozzi, Federico; Marshall, Kathleen A.; Arruda, Valder R.; Sun, Junwei; Zhu, Xiaosong; Hauck, Bernd; Zelenaia, Olga; Wright, J. Fraser; McDonnell, Jennifer Wellman; High, Katherine A.; Bennett, Jean] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA. [Maguire, Albert M.; Pierce, Eric A.; Bennicelli, Jeannette; Lyubarsky, Arkady; Arruda, Valder R.; Konkle, Barbara; Shindler, Kenneth S.; Maguire, Maureen G.; Wright, J. Fraser; Volpe, Nicholas J.; High, Katherine A.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Simonelli, Francesca; Testa, Francesco; Rossi, Settimio] Univ Naples 2, Naples, Italy. [Simonelli, Francesca; Banfi, Sandro; Surace, Enrico M.; Auricchio, Alberto] Telethon Inst Genet & Med, Naples, Italy. [Auricchio, Alberto] Univ Naples Federico 2, Naples, Italy. [Stone, Edwin] Univ Iowa, Carver Ctr, Coll Med, Iowa City, IA USA. [Jacobs, Jonathan; Dell'Osso, Lou] Vet Affairs Med Ctr, Cleveland, OH USA. [Hertle, Richard] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Ma, Jian-xing] Univ Oklahoma, Oklahoma City, OK USA. [Redmond, T. Michael] NEI, Bethesda, MD 20892 USA. [Surace, Enrico M.; High, Katherine A.] Howard Hughes Med Inst, Coconut Grove, FL 33133 USA. RP Bennett, J (reprint author), FM Kirby Ctr Mol Ophthalmol, Stellar Chance Labs 309C, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM jebennet@mail.med.upenn.edu RI Shindler, Kenneth/D-2095-2009; Testa, Francesco/J-3185-2012; Rossi, Settimio/J-4922-2012; OI Simonelli, Francesca/0000-0001-8520-6769; Testa, Francesco/0000-0002-1482-1577; Surace, Enrico Maria/0000-0002-2975-942X; Pierce, Eric/0000-0002-2354-4102; BANFI, Sandro/0000-0002-6541-8833; AURICCHIO, Alberto/0000-0002-0832-2472; Redmond, T. Michael/0000-0002-1813-5291 FU Howard Hughes Medical Institute; NCRR NIH HHS [UL1 RR024134]; NEI NIH HHS [R01 EY010820-11, EY-10820, R01 EY010820, R01 EY010820-12, R01 EY010820-13]; Telethon [GGP07180, TGM06B01] NR 25 TC 1051 Z9 1099 U1 13 U2 81 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 22 PY 2008 VL 358 IS 21 BP 2240 EP 2248 DI 10.1056/NEJMoa0802315 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 303EK UT WOS:000256023600006 PM 18441370 ER PT J AU Van Duyne, R Easley, R Wu, WL Berro, R Pedati, C Klase, Z Kehn-Hall, K Flynn, EK Symer, DE Kashanchi, F AF Van Duyne, Rachel Easley, Rebecca Wu, Weilin Berro, Reem Pedati, Caitlin Klase, Zachary Kehn-Hall, Kylene Flynn, Elizabeth K. Symer, David E. Kashanchi, Fatah TI Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR SO RETROVIROLOGY LA English DT Article ID VIRUS TYPE-1 TAT; HP1 CHROMO DOMAIN; HISTONE H3; IN-VITRO; ACTIVATED TRANSCRIPTION; EPIGENETIC CONTROL; EUCHROMATIC GENES; P-TEFB; PROTEIN; BINDING AB Background: The rate of transcription of the HIV-1 viral genome is mediated by the interaction of the viral protein Tat with the LTR and other transcriptional machinery. These specific interactions can be affected by the state of post-translational modifications on Tat. Previously, we have shown that Tat can be phosphorylated and acetylated in vivo resulting in an increase in the rate of transcription. In the present study, we investigated whether Tat could be methylated on lysine residues, specifically on lysine 50 and 51, and whether this modification resulted in a decrease of viral transcription from the LTR. Results: We analyzed the association of Tat with histone methyltransferases of the SUV39-family of SET domain containing proteins in vitro. Tat was found to associate with both SETDB1 and SETDB2, two enzymes which exhibit methyltransferase activity. siRNA against SETDB1 transfected into cell systems with both transient and integrated LTR reporter genes resulted in an increase in transcription of the HIV-LTR in the presence of suboptimal levels of Tat. In vitro methylation assays with Tat peptides containing point mutations at lysines 50 and 51 showed an increased incorporation of methyl groups on lysine 51, however, both residues indicated susceptibility for methylation. Conclusion: The association of Tat with histone methyltransferases and the ability for Tat to be methylated suggests an interesting mechanism of transcriptional regulation through the recruitment of chromatin remodeling proteins to the HIV-1 promoter. C1 [Van Duyne, Rachel; Easley, Rebecca; Wu, Weilin; Berro, Reem; Pedati, Caitlin; Klase, Zachary; Kehn-Hall, Kylene; Kashanchi, Fatah] George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Flynn, Elizabeth K.; Symer, David E.] NCI, Basic Res Lab, Canc Res Ctr, Ft Detrick, MD 21702 USA. [Symer, David E.] NCI, Biochem & Mol Biol Lab, Canc Res Ctr, Ft Detrick, MD 21702 USA. [Kashanchi, Fatah] WM Keck Inst Prot Technol & Applicat, Washington, DC 20037 USA. RP Kashanchi, F (reprint author), George Washington Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20037 USA. EM bcmrvv@gwumc.edu; bcmrle@gwumc.edu; bcmwxw@gwumc.edu; ramroom@gmail.com; bcmcsp@gwumc.edu; bcmzak@gwumc.edu; bcmkwk@gwumc.edu; flynn@ncifcrf.gov; symerd@mail.nih.gov; bcmfxk@gwumc.edu RI Symer, David/E-4173-2011; Kehn-Hall, Kylene/I-5752-2013 FU Intramural NIH HHS [NIH0011255384, Z01 BC010631-04]; NIAID NIH HHS [AI071903-01, R21 AI071903] NR 72 TC 47 Z9 48 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAY 22 PY 2008 VL 5 AR 40 DI 10.1186/1742-4690-5-40 PG 13 WC Virology SC Virology GA 309RY UT WOS:000256479100001 PM 18498648 ER PT J AU Kapustin, Y Souvorov, A Tatusova, T Lipman, D AF Kapustin, Yuri Souvorov, Alexander Tatusova, Tatiana Lipman, David TI Splign: algorithms for computing spliced alignments with identification of paralogs SO BIOLOGY DIRECT LA English DT Article ID MESSENGER-RNA; DNA-SEQUENCES; GENOMIC DNA; PROGRAM; TOOL AB Background: The computation of accurate alignments of cDNA sequences against a genome is at the foundation of modern genome annotation pipelines. Several factors such as presence of paralogs, small exons, non-consensus splice signals, sequencing errors and polymorphic sites pose recognized difficulties to existing spliced alignment algorithms. Results: We describe a set of algorithms behind a tool called Splign for computing cDNA-to-Genome alignments. The algorithms include a high-performance preliminary alignment, a compartment identification based on a formally defined model of adjacent duplicated regions, and a refined sequence alignment. In a series of tests, Splign has produced more accurate results than other tools commonly used to compute spliced alignments, in a reasonable amount of time. Conclusion: Splign's ability to deal with various issues complicating the spliced alignment problem makes it a helpful tool in eukaryotic genome annotation processes and alternative splicing studies. Its performance is enough to align the largest currently available pools of cDNA data such as the human EST set on a moderate-sized computing cluster in a matter of hours. The duplications identification (compartmentization) algorithm can be used independently in other areas such as the study of pseudogenes. Reviewers: This article was reviewed by: Steven Salzberg, Arcady Mushegian and Andrey Mironov (nominated by Mikhail Gelfand). C1 [Kapustin, Yuri; Souvorov, Alexander; Tatusova, Tatiana; Lipman, David] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. RP Kapustin, Y (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20814 USA. EM kapustin@ncbi.nlm.nih.gov; souvorov@ncbi.nlm.nih.gov; tatiana@ncbi.nlm.nih.gov; lipman@ncbi.nlm.nih.gov NR 15 TC 89 Z9 94 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 21 PY 2008 VL 3 AR 20 DI 10.1186/1745-6150-3-20 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 319IV UT WOS:000257158200001 PM 18495041 ER PT J AU Natanson, C Kern, SJ Lurie, P Banks, SM Wolfe, SM AF Natanson, Charles Kern, Steven J. Lurie, Peter Banks, Steven M. Wolfe, Sidney M. TI Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death - A meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID POLYMERIZED BOVINE HEMOGLOBIN; ABDOMINAL AORTIC-ANEURYSM; NITRIC-OXIDE; OXYGEN CARRIER; PREOPERATIVE HEMODILUTION; ENDOTHELIAL-CELLS; HEMORRHAGIC-SHOCK; RANDOMIZED-TRIAL; CARDIAC-SURGERY; BLINDED TRIAL AB Context Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit. Objective To assess the safety of HBBSs in surgical, stroke, and trauma patients. Data Sources PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases. Study Selection Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review. Data Extraction Data on death and myocardial infarction (MI) as outcome variables. Results Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I-2 = 0%, P >= .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication. Conclusion Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI. C1 [Natanson, Charles; Kern, Steven J.; Banks, Steven M.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Lurie, Peter; Wolfe, Sidney M.] Hlth Res Grp, Washington, DC USA. RP Natanson, C (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cnatanson@cc.nih.gov NR 48 TC 285 Z9 292 U1 5 U2 37 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 21 PY 2008 VL 299 IS 19 BP 2304 EP 2312 DI 10.1001/jama.299.19.jrv80007 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 302QN UT WOS:000255984500025 PM 18443023 ER PT J AU Wang, XY Zhao, M Ghitza, UE Li, YQ Lu, L AF Wang, Xiao-Yi Zhao, Mei Ghitza, Udi E. Li, Yan-Qin Lu, Lin TI Stress impairs reconsolidation of drug memory via glucocorticoid receptors in the basolateral amygdala SO JOURNAL OF NEUROSCIENCE LA English DT Article DE memory; stress; morphine; corticosterone; reconsolidation; amygdala ID CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED PLACE PREFERENCE; COCAINE-SEEKING; INDUCED RELAPSE; PROTEIN-SYNTHESIS; HEROIN-SEEKING; DISRUPTING RECONSOLIDATION; MOLECULAR-MECHANISMS; DECLARATIVE MEMORY; NEURAL MECHANISMS AB Relapse to drug taking induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Previous studies indicate that drug seeking can be inhibited by disrupting the reconsolidation of a drug-related memory. Stress plays an important role in modulating different stages of memory including reconsolidation, but its role in the reconsolidation of a drug-related memory has not been investigated. Here, we examined the effects of stress and corticosterone on reconsolidation of a drug-related memory using a conditioned place preference (CPP) procedure. We also determined the role of glucocorticoid receptors (GRs) in the basolateral amygdala (BLA) in modulating the effects of stress on reconsolidation of this memory. We found that rats acquired morphine CPP after conditioning, and that this CPP was inhibited by stress given immediately after re-exposure to a previously morphine-paired chamber ( a reconsolidation procedure). The disruptive effect of stress on reconsolidation of morphine related memory was prevented by inhibition of corticosterone synthesis with metyrapone or BLA, but not central amygdala (CeA), injections of the glucocorticoid (GR) antagonist RU38486 [( 11,17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one]. Finally, the effect of stress on drug related memory reconsolidation was mimicked by systemic injections of corticosterone or injections of RU28362 [11,17-dihydroxy- 6-methyl-17-(1-propynyl) androsta-1,4,6-triene-3-one] ( a GR agonist) into BLA, but not the CeA. These results show that stress blocks reconsolidation of a drug-related memory, and this effect is mediated by activation of GRs in the BLA. C1 [Wang, Xiao-Yi; Zhao, Mei; Li, Yan-Qin; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Dept Neuropharmacol, Beijing 100083, Peoples R China. [Ghitza, Udi E.] NIDA, NIH, Behav Neurosci Branch, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, Dept Neuropharmacol, 38 Xue Yuan Rd,Haidian Dist, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn NR 86 TC 77 Z9 83 U1 1 U2 15 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 21 PY 2008 VL 28 IS 21 BP 5602 EP 5610 DI 10.1523/JNEUROSCI.0750-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 303UK UT WOS:000256066200022 PM 18495894 ER PT J AU Woodcock, HL Brooks, BR Pastor, RW AF Woodcock, H. Lee Brooks, Bernard R. Pastor, Richard W. TI Pathways and populations: Stereoelectronic insights into the exocyclic torsion of 5-(hydroxymethyl)tetrahydropyran SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID HYDROXYMETHYL GROUP CONFORMATION; NEUTRON FIBER DIFFRACTION; HYDROGEN-BONDING SYSTEM; ALPHA-D-GLUCOPYRANOSE; BETA-D-GLUCOPYRANOSE; SYNCHROTRON X-RAY; AB-INITIO; CRYSTAL-STRUCTURE; AQUEOUS-SOLUTION; FORCE-FIELD AB High level ab initio computations in vacuum and with the IEFPCM implicit solvent model are carried out on 5-(hydroxymethyl)tetrahydropyran to investigate the effects of water on the exocyclic torsional surface. Rotamer populations evaluated from the omega(C-C-C-O), theta(C-C-C-O) solvent surface agree almost quantitatively with experimental values for the closely related methyl 4-deoxy-alpha-D-xylohexopyranoside. Potentials of mean force obtained from the two surfaces show substantial solvent stabilization of the TG (omega = 180 +/- 60 degrees) rotamer and the barriers at omega = 120 and 240 degrees but solvent destabilization at the cis barrier (omega = 0 degrees). Natural bond orbital analyses indicate that energetics of these effects are largely explained by overstabilization of the vacuum GT (omega = 60 +/- 160 degrees) and GG (omega = 300 +/- 60 degrees) rotamers. Solvent stabilization of 0 conformations provides entropic stabilization. C1 [Woodcock, H. Lee; Brooks, Bernard R.; Pastor, Richard W.] NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. RP Woodcock, HL (reprint author), NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. EM hlwood@nih.gov RI Woodc, Henry/D-9275-2011; OI Woodcock, Henry/0000-0003-3539-273X FU Intramural NIH HHS [Z01 HL000340-03] NR 29 TC 6 Z9 6 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 21 PY 2008 VL 130 IS 20 BP 6345 EP + DI 10.1021/ja077633z PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 300VU UT WOS:000255854100022 PM 18444612 ER PT J AU Connor, HD Sturgeon, BE Mottley, C Sipe, HJ Mason, RP AF Connor, Henry D. Sturgeon, Bradley E. Mottley, Carolyn Sipe, Herbert J., Jr. Mason, Ronald P. TI L-tryptophan radical cation electron spin resonance studies: Connecting solution-derived hyperfine coupling constants with protein spectral interpretations SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROSTAGLANDIN-H SYNTHASE; NUCLEAR DOUBLE-RESONANCE; CYTOCHROME-C-OXIDASE; HIGH-FIELD EPR; RIBONUCLEOTIDE REDUCTASE; TYROSYL RADICALS; HYDROGEN-PEROXIDE; PHOTOGENERATED TRYPTOPHAN; VERSATILE PEROXIDASE; ENDOR SPECTROSCOPY AB Fast-flow electron spin resonance (ESR) spectroscopy has been used to detect a free radical formed from the reaction of L-tryptophan with Ce4+ in an acidic aqueous environment. Computer simulations of the ESR spectra from L-tryptophan and several isotopically modified forms strongly support the conclusion that the L-tryptophan radical cation has been detected by ESR for the first time. The hyperfine coupling constants (HFCs) determined,from the well-resolved isotropic ESR spectra support experimental and computational efforts to understand L-tryptophan's role in protein catalysis of oxidation-reduction processes. L-Tryptophan HFCs facilitated the simulation of fast-flow ESR spectra of free radicals from two related compounds, tryptamine and 3-methylindole, Analysis of these three compounds' beta-methylene hydrogen HFC data along with equivalent L-tyrosine data has led to a new computational method that can distinguish between these two amino acid free radicals in proteins without dependence on isotope labeling, electron-nuclear double resonance, or high-field ESR. This approach also produces geometric parameters (dihedral angles for the beta-methylene hydrogens) that should facilitate protein site assignment of observed L-tryptophan radicals as has been done for L-tyrosine radicals. C1 [Connor, Henry D.; Sturgeon, Bradley E.; Mottley, Carolyn; Sipe, Herbert J., Jr.; Mason, Ronald P.] NIEHS, Lab Pharmacol & Chem, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), Kentucky Wesleyan Coll, Dept Chem, Owensboro, KY 42301 USA. EM mason4@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050139-13] NR 39 TC 18 Z9 18 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD MAY 21 PY 2008 VL 130 IS 20 BP 6381 EP 6387 DI 10.1021/ja0780277 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 300VU UT WOS:000255854100028 PM 18433127 ER PT J AU Llovet, JM Di Bisceglie, AM Bruix, J Kramer, BS Lencioni, R Zhu, AX Sherman, M Schwartz, M Lotze, M Talwalkar, J Gores, GJ AF Llovet, Josep M. Di Bisceglie, Adrian M. Bruix, Jordi Kramer, Barnett S. Lencioni, Riccardo Zhu, Andrew X. Sherman, Morris Schwartz, Myron Lotze, Michael Talwalkar, Jayant Gores, Gregory J. CA Panel Experts HCC-Design Clinical TI Design and endpoints of clinical trials in hepatocellular carcinoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID RANDOMIZED CONTROLLED TRIAL; METASTATIC BREAST-CANCER; CELL LUNG-CANCER; QUALITY-OF-LIFE; PROSPECTIVE VALIDATION; LIVER-TRANSPLANTATION; MAGNETIC-RESONANCE; PROGNOSTIC-FACTOR; DRUG DEVELOPMENT; NATURAL-HISTORY AB The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC. C1 [Llovet, Josep M.; Bruix, Jordi] Hosp Clin Barcelona, Inst Biomed Invest August Pi Sunyer, CIBERehd, Translat Res Lab,Barcelona Clin Liver Canc Grp,Li, E-08036 Barcelona, Catalonia, Spain. [Llovet, Josep M.; Schwartz, Myron] Mt Sinai Sch Med, Div Liver Dis, Mt Sinai Liver Canc Program, New York, NY USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, St Louis, MO 63103 USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Lencioni, Riccardo] Univ Pisa, Dept Oncol, Div Radiol, I-56100 Pisa, Italy. [Zhu, Andrew X.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA. [Sherman, Morris] Univ Toronto, Dept Med, Toronto, ON, Canada. [Lotze, Michael] Univ Pittsburgh, Dept Surg & Bioengn, Pittsburgh, PA USA. [Talwalkar, Jayant; Gores, Gregory J.] Mayo Clin, Ctr Digest Dis, Rochester, MN USA. RP Llovet, JM (reprint author), Hosp Clin Barcelona, Inst Biomed Invest August Pi Sunyer, CIBERehd, Translat Res Lab,Barcelona Clin Liver Canc Grp,Li, Villarroel 170, E-08036 Barcelona, Catalonia, Spain. EM jmllovet@clinic.ub.es RI Llovet, Josep M /D-4340-2014; OI Llovet, Josep M /0000-0003-0547-2667; Bruix, Jordi/0000-0002-9826-0753 FU NCI NIH HHS [P01 CA 101944-01]; NCRR NIH HHS [RR 024151]; NIDDK NIH HHS [1R01DK076986-01, K24 DK 60498-01] NR 60 TC 910 Z9 953 U1 11 U2 81 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 21 PY 2008 VL 100 IS 10 BP 698 EP 711 DI 10.1093/jnci/djn134 PG 14 WC Oncology SC Oncology GA 305IT UT WOS:000256172400007 PM 18477802 ER PT J AU Pfeiffer, RM Mitani, A Matsuno, RK Anderson, WF AF Pfeiffer, Ruth M. Mitani, Aya Matsuno, Rayna K. Anderson, William F. TI Racial differences in breast cancer trends in the united states (2000-2004) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID SUBTYPE C1 [Pfeiffer, Ruth M.; Matsuno, Rayna K.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. RP Pfeiffer, RM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM pfeiffer@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 NR 7 TC 17 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 21 PY 2008 VL 100 IS 10 BP 751 EP 752 DI 10.1093/jnci/djn112 PG 2 WC Oncology SC Oncology GA 305IT UT WOS:000256172400013 PM 18477805 ER PT J AU Wang, SM Duyn, JH AF Wang, Shumin Duyn, Jeff H. TI Time-domain finite-difference/finite-element hybrid simulations of radio frequency coils in magnetic resonance imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MAXWELLS EQUATIONS; RADIOFREQUENCY COIL; BOUNDARY; STABILITY; BODY; MRI AB A hybrid method that combines the finite- difference time-domain (FDTD) method and the finite-element time-domain (FETD) method is presented for simulating radio-frequency (RF) coils in magnetic resonance imaging. This method applies a high-fidelity FETD method to RF coils, while the human body is modeled with a low-cost FDTD method. Since the FDTD and the FETD methods are applied simultaneously, the dynamic interaction between RF coils and the human body is fully accounted for. In order to simplify the treatment of the highly irregular FDTD/FETD interface, composite elements are proposed. Two examples are provided to demonstrate the validity and effectiveness of the hybrid method in high-field receive-and-transmit coil design. This approach is also applicable to general bio-electromagnetic simulations. C1 [Wang, Shumin; Duyn, Jeff H.] Natl Inst Neurol Disorders & Stroke, NIH, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Wang, SM (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Lab Funct & Mol Imaging, 10 Ctr Dr 10-B1D728, Bethesda, MD 20892 USA. EM james.wang@ieee.org RI Duyn, Jozef/F-2483-2010 FU Intramural NIH HHS NR 26 TC 10 Z9 10 U1 1 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAY 21 PY 2008 VL 53 IS 10 BP 2677 EP 2692 DI 10.1088/0031-9155/53/10/016 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 307UB UT WOS:000256342700016 PM 18445873 ER PT J AU Jiang, LQ Wang, MY Zhang, J Monticone, RE Telljohann, R Spinetti, G Pintus, G Lakatta, EG AF Jiang, Liqun Wang, Mingyi Zhang, Jing Monticone, Robert E. Telljohann, Richard Spinetti, Gaia Pintus, Gianfranco Lakatta, Edward G. TI Increased Aortic Calpain-1 Activity Mediates Age-Associated Angiotensin II Signaling of Vascular Smooth Muscle Cells SO PLOS ONE LA English DT Article AB Background: Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. Methodology/Principal Findings: The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001. Conclusions/Significance: Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis. C1 [Jiang, Liqun; Wang, Mingyi; Zhang, Jing; Monticone, Robert E.; Telljohann, Richard; Spinetti, Gaia; Pintus, Gianfranco; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Jiang, LQ (reprint author), NIA, Cardiovasc Sci Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. EM mingyiw@grc.nia.nih.gov OI Spinetti, Gaia/0000-0001-7996-6809 FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 56 TC 40 Z9 42 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 21 PY 2008 VL 3 IS 5 AR e2231 DI 10.1371/journal.pone.0002231 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 391UK UT WOS:000262258700039 PM 18493299 ER PT J AU Nakashima, A Maruki, Y Imamura, Y Kondo, C Kawamata, T Kawanishi, I Takata, H Matsuura, A Lee, KS Kikkawa, U Ohsumi, Y Yonezawa, K Kamada, Y AF Nakashima, Akio Maruki, Yoshiko Imamura, Yuko Kondo, Chika Kawamata, Tomoko Kawanishi, Ippei Takata, Hideki Matsuura, Akira Lee, Kyung S. Kikkawa, Ushio Ohsumi, Yoshinori Yonezawa, Kazuyoshi Kamada, Yoshiaki TI The Yeast Tor Signaling Pathway Is Involved in G2/M Transition via Polo-Kinase SO PLOS ONE LA English DT Article AB The target of rapamycin (Tor) protein plays central roles in cell growth. Rapamycin inhibits cell growth and promotes cell cycle arrest at G1 (G0). However, little is known about whether Tor is involved in other stages of the cell division cycle. Here we report that the rapamycin-sensitive Tor complex 1 (TORC1) is involved in G2/M transition in S. cerevisiae. Strains carrying a temperature-sensitive allele of KOG1 (kog1-105) encoding an essential component of TORC1, as well as yeast cell treated with rapamycin show mitotic delay with prolonged G2. Overexpression of Cdc5, the yeast polo-like kinase, rescues the growth defect of kog1-105, and in turn, Cdc5 activity is attenuated in kog1-105 cells. The TORC1-Type2A phosphatase pathway mediates nucleocytoplasmic transport of Cdc5, which is prerequisite for its proper localization and function. The C-terminal polo-box domain of Cdc5 has an inhibitory role in nuclear translocation. Taken together, our results indicate a novel function of Tor in the regulation of cell cycle and proliferation. C1 [Nakashima, Akio; Maruki, Yoshiko; Kawanishi, Ippei; Kikkawa, Ushio; Ohsumi, Yoshinori; Yonezawa, Kazuyoshi] Kobe Univ, Biosignal Res Ctr, Kobe, Hyogo, Japan. [Nakashima, Akio; Yonezawa, Kazuyoshi; Kamada, Yoshiaki] Japan Sci & Technol Agcy, CREST, Kawaguchi, Japan. [Imamura, Yuko; Kondo, Chika; Kawamata, Tomoko; Kamada, Yoshiaki] Natl Inst Basic Biol, Div Mol Cell Biol, Okazaki, Aichi, Japan. [Takata, Hideki; Matsuura, Akira] Natl Inst Longevity Sci, Dept Geriat Res, Obu Aichi, Japan. [Lee, Kyung S.] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res, Lab Metabolism, Bethesda, MD USA. RP Nakashima, A (reprint author), Kobe Univ, Biosignal Res Ctr, Kobe, Hyogo, Japan. EM yoshikam@nibb.ac.jp RI Kawamata-HORIE, Tomoko/B-1699-2017; OI Kawamata-HORIE, Tomoko/0000-0002-3990-1194; Kamada, Yoshiaki/0000-0001-7395-660X; Matsuura, Akira/0000-0002-2300-7227 NR 51 TC 33 Z9 33 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 21 PY 2008 VL 3 IS 5 AR e2223 DI 10.1371/journal.pone.0002223 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 391UK UT WOS:000262258700031 PM 18493323 ER PT J AU Cirino, CM Leitman, SF Williams, E Fedorko, D Palmore, TN Klion, A Ockenhouse, C Fitzhugh, C Tisdale, JF Hsieh, MM AF Cirino, Christopher M. Leitman, Susan F. Williams, Esther Fedorko, Daniel Palmore, Tara N. Klion, Amy Ockenhouse, Christian Fitzhugh, Courtney Tisdale, John F. Hsieh, Matthew M. TI Transfusion-associated babesiosis with an atypical time course after nonmyeloablative transplantation for sickle cell disease SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Cirino, Christopher M.] St Vincent Hlth Ctr, Erie, PA 16544 USA. [Leitman, Susan F.; Williams, Esther; Fedorko, Daniel] NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. [Palmore, Tara N.; Klion, Amy] NIAID, NIH, Bethesda, MD 20892 USA. [Ockenhouse, Christian] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Fitzhugh, Courtney; Tisdale, John F.; Hsieh, Matthew M.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Cirino, CM (reprint author), St Vincent Hlth Ctr, Erie, PA 16544 USA. OI Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS [Z99 CL999999] NR 6 TC 10 Z9 10 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 20 PY 2008 VL 148 IS 10 BP 794 EP 795 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 308EX UT WOS:000256372200015 PM 18490697 ER PT J AU Chmelar, J Anderson, JM Mu, JB Jochim, RC Valenzuela, JG Kopecky, J AF Chmelar, Jindrich Anderson, Jennifer M. Mu, Jianbing Jochim, Ryan C. Valenzuela, Jesus G. Kopecky, Jan TI Insight into the sialome of the castor bean tick, Ixodes ricinus SO BMC GENOMICS LA English DT Article ID HISTAMINE-BINDING PROTEINS; SALIVARY-GLAND EXTRACT; PATHWAY INHIBITOR TFPI; HOST IMMUNE-RESPONSE; ORNITHODOROS-MOUBATA; LYME-DISEASE; MOLECULAR-CLONING; 3-DIMENSIONAL STRUCTURE; DERMACENTOR-VARIABILIS; SCAPULARIS AB Background: In recent years, there have been several sialome projects revealing transcripts expressed in the salivary glands of ticks, which are important vectors of several human diseases. Here, we focused on the sialome of the European vector of Lyme disease, Ixodes ricinus. Results: In the attempt to describe expressed genes and their dynamics throughout the feeding period, we constructed cDNA libraries from four different feeding stages of Ixodes ricinus females: unfed, 24 hours after attachment, four ( partially fed) and seven days ( fully engorged) after attachment. Approximately 600 randomly selected clones from each cDNA library were sequenced and analyzed. From a total 2304 sequenced clones, 1881 sequences forming 1274 clusters underwent subsequent functional analysis using customized bioinformatics software. Clusters were sorted according to their predicted function and quantitative comparison among the four libraries was made. We found several groups of over-expressed genes associated with feeding that posses a secretion signal and may be involved in tick attachment, feeding or evading the host immune system. Many transcripts clustered into families of related genes with stage-specific expression. Comparison to Ixodes scapularis and I. pacificus transcripts was made. Conclusion: In addition to a large number of homologues of the known transcripts, we obtained several novel predicted protein sequences. Our work contributes to the growing list of proteins associated with tick feeding and sheds more light on the dynamics of the gene expression during tick feeding. Additionally, our results corroborate previous evidence of gene duplication in the evolution of ticks. C1 [Anderson, Jennifer M.; Mu, Jianbing; Jochim, Ryan C.; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Chmelar, Jindrich; Kopecky, Jan] Acad Sci Czech Republic, Ctr Biol, Ceske Budejovice, Czech Republic. [Chmelar, Jindrich] Univ S Bohemia, Fac Sci, Ceske Budejovice, Czech Republic. RP Chmelar, J (reprint author), Univ S Bohemia, Fac Sci, Ceske Budejovice, Czech Republic. EM chmelar@paru.cas.cz; jenanderson@niaid.nih.gov; jmu@niaid.nih.gov; rjochim@niaid.nih.gov; jvalenzuela@niaid.nih.gov; jan@paru.cas.cz RI Jochim, Ryan/C-6756-2013; Kopecky, Jan/G-9347-2014 FU Intramural NIH HHS NR 84 TC 47 Z9 47 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 20 PY 2008 VL 9 AR 233 DI 10.1186/1471-2164-9-233 PG 21 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 308OR UT WOS:000256400400001 PM 18489795 ER PT J AU Chami, HA Devereux, RB Gottdiener, JS Mehra, R Roman, MJ Benjamin, EJ Gottlieb, DJ AF Chami, Hassan A. Devereux, Richard B. Gottdiener, John S. Mehra, Reena Roman, Mary J. Benjamin, Emelia J. Gottlieb, Daniel J. TI Left ventricular morphology and Systolic function in sleep-disordered breathing - The sleep heart health study SO CIRCULATION LA English DT Article DE sleep; hypertrophy; epidemiology; ventricular function, left ID POSITIVE AIRWAY PRESSURE; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; APNEA SYNDROME; SYSTEMIC HYPERTENSION; CARDIAC STRUCTURE; AMERICAN-INDIANS; HYPERTROPHY; MASS; HEMODYNAMICS AB Background-Whether sleep-disordered breathing (SDB) is a risk factor for left ventricular (LV) hypertrophy and dysfunction is controversial. We assessed the relation of SDB to LV morphology and systolic function in a community-based sample of middle-aged and older adults. Methods and Results-The present study was a cross-sectional observational study of 2058 Sleep Heart Health Study participants (mean age 65 +/- 12 years; 58% women; 44% ethnic minorities) who had technically adequate echocardiograms. A polysomnographically derived apnea-hypopnea index (AHI) and hypoxemia index (percent of sleep time with oxyhemoglobin saturation <90%) were used to quantify SDB severity. LV mass index was significantly associated with both AHI and hypoxemia index after adjustment for age, sex, ethnicity, study site, body mass index, current and prior smoking, alcohol consumption, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and prevalent myocardial infarction. Adjusted LV mass index was 41.3 (SD 9.90) g/m(2.7) in participants with AHI < 5 (n=957) and 44.1 (SD 9.90) g/m(2.7) in participants with AHI >= 30 (n=84) events per hour. Compared with participants with AHI < 5, those with AHI >= 30 had an adjusted odds ratio of 1.78 (95% confidence interval 1.14 to 2.79) for LV hypertrophy. A higher AHI and higher hypoxemia index were also associated with larger LV diastolic dimension and lower LV ejection fraction, with a trend toward lower LV fractional shortening. LV wall thickness was significantly associated with the hypoxemia index but not with AHI. Left atrial diameter was not associated with either SDB measure. Conclusions-In a community-based cohort, SDB is associated with echocardiographic evidence of increased LV mass and reduced LV systolic function. C1 [Chami, Hassan A.; Benjamin, Emelia J.; Gottlieb, Daniel J.] Boston Univ, Sch Med, Ctr Pulm, Dept Med, Boston, MA 02118 USA. [Chami, Hassan A.; Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Devereux, Richard B.; Roman, Mary J.] Weill Cornell Med Coll, New York, NY USA. [Gottdiener, John S.] Univ Maryland Hosp, Baltimore, MD 21201 USA. [Mehra, Reena] Univ Hosp Cleveland, Case Med Sch, Cleveland, OH 44106 USA. [Benjamin, Emelia J.] Natl Heart Lung Blood Inst Framingham Heart Study, Framingham, MA USA. RP Chami, HA (reprint author), Boston Univ, Sch Med, Ctr Pulm, Dept Med, 715 Albany St,R-304, Boston, MA 02118 USA. EM hchami@bu.edu OI Mehra, Reena/0000-0002-6222-2675; Chami, Hassan/0000-0002-9239-2528; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [U01 HL080295, 2U01-HL53941, HL-30605, HL-41642, HL-41652, HL-41654, HL-47540, HL-65521, HL080124, N01 HC015103, N01 HC025195, N01 HC035129, N01 HC045133, N01 HC075150, N01 HC085079, N01-HC-25195, N01-HC-5222, N01-HC-75150, N01-HC85079, N01-HC85080, N01-HC85081, N01-HC85082, N01-HC85083, N01-HC85084, N01-HC85085, N01-HC85086, N01HC25195, N01HC75150, N01HC85079, N01HC85086, P01 HL047540, R01 HL075078, R01 HL080124, R01 HL080124-05, U01 HL-080295, U01 HL041642, U01 HL041642-19, U01 HL041652, U01 HL041652-20, U01 HL041654, U01 HL041654-20, U01 HL053916, U01 HL053916-14, U01 HL053931, U01 HL053931-10, U01 HL053934, U01 HL053934-14, U01 HL053937, U01 HL053937-14, U01 HL053938, U01 HL053938-14, U01 HL053940-05, U01 HL053941, U01 HL053941-09, U01 HL053941-14, U01 HL063429, U01 HL063429-09, U01 HL063463, U01 HL063463-09, U01 HL064360, U01 HL064360-09, U01 HL065521, U01 HL065521-08, U01 HL080295-05, U01HL53916, U01HL53931, U01HL53934, U01HL53937, U01HL53938, U01HL53940, U01HL53941, U01HL63429, U01HL63463, U01HL64360]; NINDS NIH HHS [6R01-NS-17950, R01 NS017950, R01 NS017950-28] NR 46 TC 69 Z9 72 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 20 PY 2008 VL 117 IS 20 BP 2599 EP 2607 DI 10.1161/CIRCULATIONAHA.107.717892 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 303PQ UT WOS:000256053200007 PM 18458174 ER PT J AU Moens, AL Takimoto, E Tocchetti, CG Chakir, K Bedja, D Cormaci, G Ketner, EA Majmudar, M Gabrielson, K Halushka, MK Mitchell, JB Biswal, S Channon, KM Wolin, MS Alp, NJ Paolocci, N Champion, HC Kass, DA AF Moens, An L. Takimoto, Eiki Tocchetti, Carlo G. Chakir, Khalid Bedja, Djahida Cormaci, Gianfranco Ketner, Elizabeth A. Majmudar, Maulik Gabrielson, Kathleen Halushka, Marc K. Mitchell, James B. Biswal, Shyam Channon, Keith M. Wolin, Michael S. Alp, Nicholas J. Paolocci, Nazareno Champion, Hunter C. Kass, David A. TI Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin - Efficacy of recoupling nitric oxide synthase as a therapeutic strategy SO CIRCULATION LA English DT Article DE antioxidants; heart failure; hypertrophy; nitric oxide synthase; reactive oxygen species; remodeling; therapeutics ID CYCLOHYDROLASE-I OVEREXPRESSION; PRESERVED EJECTION FRACTION; KINASE TYPE-I; HEART-FAILURE; CARDIOVASCULAR-DISEASE; SIGNALING PATHWAYS; OXIDATIVE STRESS; ANGIOTENSIN-II; MICE; SUPPLEMENTATION AB Background-Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction. Methods and Results-C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (-46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts. Conclusions-NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder. C1 [Moens, An L.; Takimoto, Eiki; Tocchetti, Carlo G.; Chakir, Khalid; Bedja, Djahida; Cormaci, Gianfranco; Ketner, Elizabeth A.; Majmudar, Maulik; Gabrielson, Kathleen; Paolocci, Nazareno; Champion, Hunter C.; Kass, David A.] Johns Hopkins Med Inst, Div Cardiol, Dept Med, Baltimore, MD 21205 USA. [Halushka, Marc K.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Biswal, Shyam] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Wolin, Michael S.] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Channon, Keith M.; Alp, Nicholas J.] Univ Oxford, Dept Cardiovasc Med, Oxford, England. RP Kass, DA (reprint author), Johns Hopkins Med Inst, Div Cardiol, Dept Med, Ross Res Bldg,Room 858,720 Rutland Ave, Baltimore, MD 21205 USA. EM dkass@jhmi.edu OI tocchetti, carlo gabriele/0000-0001-5983-688X; Halushka, Marc/0000-0002-7112-7389; Paolocci, Nazareno/0000-0001-7011-997X FU British Heart Foundation [RG/07/003/23133]; NHLBI NIH HHS [HL43023, R01 HL081205-03, P01 HL059408-09, HL31069, R01 HL081205, R01 HL047511-07, P01 HL059408, R01 HL031069, R01 HL031069-23, HL66331, P01 HL043023-170002, R01 HL066331-07, R01 HL066331, HL081205, R01 HL047511, R37 HL031069, P01 HL043023, HL-47511, HL-59408]; NIA NIH HHS [R01 AG018324, AG-18324, R01 AG018324-04]; NIEHS NIH HHS [P30 ES 03819, P30 ES003819, P30 ES003819-12] NR 40 TC 154 Z9 157 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 20 PY 2008 VL 117 IS 20 BP 2626 EP 2636 DI 10.1161/CIRCULATIONAHA.107.737031 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 303PQ UT WOS:000256053200010 PM 18474817 ER PT J AU Cutler, JA Davis, BR AF Cutler, Jeffrey A. Davis, Barry R. TI Thiazide-type diuretics and beta-adrenergic blockers as first-line drug treatments for hypertension SO CIRCULATION LA English DT Editorial Material ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; ISOLATED SYSTOLIC HYPERTENSION; HIGH BLOOD-PRESSURE; VENTRICULAR EJECTION FRACTIONS; CONVERTING-ENZYME-INHIBITOR; JOINT NATIONAL COMMITTEE; CALCIUM-CHANNEL BLOCKER; CARDIOVASCULAR EVENTS; RANDOMIZED-TRIAL C1 [Davis, Barry R.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Cutler, Jeffrey A.] NHLBI, Bethesda, MD 20892 USA. RP Davis, BR (reprint author), Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, 1200 Herman Pressler St,Suite E801, Houston, TX 77030 USA. EM Barry.R.Davis@uth.tmc.edu FU NHLBI NIH HHS [N01 HC035130] NR 59 TC 39 Z9 41 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAY 20 PY 2008 VL 117 IS 20 BP 2691 EP 2704 DI 10.1161/CIRCULATIONAHA.107.709931 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 303PQ UT WOS:000256053200017 PM 18490537 ER PT J AU Sloand, EM Wu, CO Greenberg, P Young, N Barrett, J AF Sloand, Elaine M. Wu, Colin O. Greenberg, Peter Young, Neal Barrett, John TI Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTERNATIONAL WORKING GROUP; ANTITHYMOCYTE GLOBULIN; ANTILYMPHOCYTE GLOBULIN; CELL TRANSPLANTATION; LEUKEMIA; ANEMIA; HYPOCELLULARITY; EFFICACY; CRITERIA; MODEL AB Purpose Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosuppressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group. Patients and Methods One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combination or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care. Results Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P = .001 and P = .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival. Conclusion IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease. C1 [Sloand, Elaine M.] NHLBI, Div Intramural Res, Hematol Branch, Bethesda, MD 20892 USA. Stanford Univ, Ctr Canc, Div Hematol, Stanford, CA 94305 USA. RP Sloand, EM (reprint author), NHLBI, Div Intramural Res, Hematol Branch, 9000 Rockville Pike,Bldg 10,CRC 5230, Bethesda, MD 20892 USA. EM sloande@nhlbi.nih.gov NR 35 TC 140 Z9 150 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 BP 2505 EP 2511 DI 10.1200/JCO.2007.11.9214 PG 7 WC Oncology SC Oncology GA 302LR UT WOS:000255970300018 PM 18413642 ER PT J AU Keating, NL Landrum, MB Klabunde, CN Fletcher, RH Rogers, SO Doucette, WR Tisnado, D Clauser, S Kahn, KL AF Keating, Nancy L. Landrum, Mary Beth Klabunde, Carrie N. Fletcher, Robert H. Rogers, Selwyn O. Doucette, William R. Tisnado, Diana Clauser, Steven Kahn, Katherine L. TI Adjuvant chemotherapy for stage III colon cancer: Do physicians agree about the importance of patient age and comorbidity? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POPULATION-BASED COHORT; COLORECTAL-CANCER; ELDERLY-PATIENTS; POOLED ANALYSIS; FLUOROURACIL; THERAPY; CARE; EFFICACY; QUALITY; TRIALS AB Purpose We surveyed cancer physicians to understand how patients' age and comorbidity influence adjuvant chemotherapy recommendations and whether physician or practice characteristics also affect these recommendations. Methods National survey of surgeons and medical oncologists caring for patients with colorectal cancer regarding whether they would recommend adjuvant chemotherapy for hypothetical patients with stage III colon cancer who varied by age ( 55 v 80 years) and comorbid illness ( none, moderate, severe congestive heart failure [ CHF]). Repeated measures logistic regression was used to assess the influence of patient, physician, and practice characteristics on chemotherapy recommendations. Results Of 1,096 physicians, nearly all recommended chemotherapy for patients who were 55 years old with no comorbidity (99.0%), 55-years old with moderate CHF (88.6%), or 80 years old with no comorbidity (92.6%); many fewer recommended chemotherapy for 55-year-old patients with severe CHF (24.9%) or 80-year-old patients with moderate (47.2%) or severe (9.0%) CHF (P < .001). Younger physicians (P < .001) were more likely than others to recommend adjuvant chemotherapy overall, although physician factors explained little of the variability in recommendations. Conclusion Physicians agree with guidelines recommending adjuvant chemotherapy for young, healthy patients with stage III colon cancer but differ widely on recommendations for patients who are older and sicker. Few physician or practice characteristics were associated with recommendations. For older and sicker patients, the individual physicians seen may have a substantial impact on the likelihood of receiving chemotherapy. Understanding better the sources of variation not explained by patients' clinical characteristics may allow improved tailoring of therapy to patients most likely to benefit. C1 [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Iowa, Div Clin & Adm Pharm, Iowa City, IA USA. RAND Corp, Santa Monica, CA USA. Univ Calif Los Angeles, Div Gen Internal Med, Los Angeles, CA USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU NCI NIH HHS [U01 CA01013, U01 CA093324, U01 CA093329, U01 CA093332, U01 CA093326, U01 CA093344, U01 CA093348]; PHS HHS [U01 CDA093344] NR 32 TC 60 Z9 60 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 BP 2532 EP 2537 DI 10.1200/JCO.2007.15.9434 PG 6 WC Oncology SC Oncology GA 302LR UT WOS:000255970300022 PM 18487570 ER PT J AU Allegra, CJ Yothers, G O'Connell, MJ Sharif, S Wolmark, N AF Allegra, C. J. Yothers, G. O'Connell, M. J. Sharif, S. Wolmark, N. TI Initial safety report of NSABP C-08, a randomized phase III study of modified 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Florida, Gainesville, FL USA. Univ Pittsburgh, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 4006 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401381 ER PT J AU Aplenc, R Strauss, LC Shusterman, S Ingle, AM Agrawal, S Sun, J Wright, JJ Blaney, SM Adamson, PC AF Aplenc, R. Strauss, L. C. Shusterman, S. Ingle, A. M. Agrawal, S. Sun, J. Wright, J. J. Blaney, S. M. Adamson, P. C. TI Pediatric phase I trial and pharmacokinetic (PK) study of dasatinib: A report from the Children's Oncology Group Phase I Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Bristol Myers Squibb Co, Princeton, NJ USA. Childrens Hosp Boston, Boston, MA USA. Childrens Oncol Grp, Arcadia, CA USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Texas Childrens Canc Ctr, Houston, TX USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3591 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401005 ER PT J AU Aragon-Ching, JB Jain, L Draper, D Gulley, JL Arlen, PM Wright, JJ Jones, E Chen, CC Figg, WD Dahut, WL AF Aragon-Ching, J. B. Jain, L. Draper, D. Gulley, J. L. Arlen, P. M. Wright, J. J. Jones, E. Chen, C. C. Figg, W. D. Dahut, W. L. TI Updated analysis of a phase II study using sorafenib (S) for metastatic castrate-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Aragon-Ching, J. B.; Jain, L.; Draper, D.; Gulley, J. L.; Arlen, P. M.; Wright, J. J.; Jones, E.; Chen, C. C.; Figg, W. D.; Dahut, W. L.] NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 16026 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402005 ER PT J AU Arons, E Suntum, T Sunshine, J Orthwein, A Margulies, I Stetler-Stevenson, M Kreitman, RJ AF Arons, E. Suntum, T. Sunshine, J. Orthwein, A. Margulies, I. Stetler-Stevenson, M. Kreitman, R. J. TI Molecular distinctions between variant and classic hairy cell leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Arons, E.; Suntum, T.; Sunshine, J.; Orthwein, A.; Margulies, I.; Stetler-Stevenson, M.; Kreitman, R. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 18002 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402607 ER PT J AU Badros, AZ Philip, S Niesvizk, R Goloubeva, O Harris, C Zweibel, J Wright, JJ Burger, A Baer, MR Egorin, MJ Grant, S AF Badros, A. Z. Philip, S. Niesvizk, R. Goloubeva, O. Harris, C. Zweibel, J. Wright, J. J. Burger, A. Baer, M. R. Egorin, M. J. Grant, S. TI Phase I trial of vorinostat plus bortezomib (bort) in relapsed/refractory multiple myeloma (mm) patients (pts) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Maryland, Baltimore, MD 21201 USA. Cornell Univ, New York, NY 10021 USA. NCI, Canc Therapy & Evaluat Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8548 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403162 ER PT J AU Besse, B Smit, EF Felip, E Siena, S Blackhall, F Barlesi, F Giaccone, G AF Besse, B. Smit, E. F. Felip, E. Siena, S. Blackhall, F. Barlesi, F. Giaccone, G. TI A phase II study of first-line erlotinib in patients (pts) with stage IIIB/IV non-small-cell lung cancer (NSCLC) including dose escalation to toxicity in current and former smokers (C/FS) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Inst Gustave Roussy, Villejuif, France. Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. Vall dHebron Univ Hosp, Barcelona, Spain. Osped Niguarda Ca Granda, Milan, Italy. Christie Hosp NHS Trust, Manchester M20 4BX, Lancs, England. Assistance Publ Hop Marseille, Marseille, France. NCI, Bethesda, MD 20892 USA. RI Blackhall, Fiona/N-2186-2015 OI Blackhall, Fiona/0000-0001-8716-3395 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8111 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402869 ER PT J AU Biagi, JJ Oza, AM Grimshaw, R Ellard, SL Lee, U Sederias, J Ivy, SP Eisenhauer, EA AF Biagi, J. J. Oza, A. M. Grimshaw, R. Ellard, S. L. Lee, U. Sederias, J. Ivy, S. P. Eisenhauer, E. A. TI A phase II study of sunitinib (SU11248) in patients (pts) with recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma - NCIC CTG IND 185 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Canc Ctr SE Ontario, Kingston, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. British Columbia Canc Ctr So Interior, Kelowna, BC, Canada. Fraser Valley Ctr, British Columbia Canc Ctr, Surrey, BC, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NCI, Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5522 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402031 ER PT J AU Bianchini, G Zhao, Y Zambetti, M Pusztai, L Mariani, G Carcangiu, ML Valagussa, P Gianni, L Simon, R AF Bianchini, G. Zhao, Y. Zambetti, M. Pusztai, L. Mariani, G. Carcangiu, M. L. Valagussa, P. Gianni, L. Simon, R. TI Cross-platform performance of genes predictive of pathologic response to doxorubicin-paclitaxel containing regimens SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Fdn IRCCS Ist Nazl Tumori, Milan, Italy. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11061 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403937 ER PT J AU Bradley, DA Daignault, S Ryan, C DiPaola, RP Smith, DC Mathew, P Gross, M Chen, AP Keller, ET Hussain, MH AF Bradley, D. A. Daignault, S. Ryan, C. DiPaola, R. P. Smith, D. C. Mathew, P. Gross, M. Chen, A. P. Keller, E. T. Hussain, M. H. TI Cilengitide in asymptomatic metastatic androgen independent prostate cancer (AIPC) patients (pts): A randomized phase II trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor, MI 48109 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Canc Inst New Jersey, New Brunswick, NJ USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RI Keller, Evan/M-1446-2016 OI Keller, Evan/0000-0002-7592-7535 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5144 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401753 ER PT J AU Cella, D Lai, J Garcia, SF Reeve, BB Weinfurt, KP George, J Stone, A AF Cella, D. Lai, J. Garcia, S. F. Reeve, B. B. Weinfurt, K. P. George, J. Stone, A. TI The patient reported outcomes measurement information system-Cancer (PROMIS-Ca): Cancer-specific application of a generic fatigue measure SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Evanston NW Healthcare, Evanston, IL USA. NCI, Bethesda, MD 20892 USA. Duke Univ, Durham, NC USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6537 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402513 ER PT J AU Chigurupati, S Son, TG Hyun, DH Lathia, JD Arumugam, TV Mattson, MP AF Chigurupati, S. Son, T. G. Hyun, D. H. Lathia, J. D. Arumugam, T. V. Mattson, M. P. TI Lifelong running reduces oxidative stress and degenerative changes in the testes of mice SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NIA, Baltimore, MD 21224 USA. Texas Tech Univ Hlth Sci, Sch Pharm, Amarillo, TX USA. RI Arumugam, Thiruma/B-4898-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14693 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400935 ER PT J AU Chintala, L Kurzrock, R Fu, S Naing, A Wheler, JJ Moulder, SL Newman, R Gagel, R Sebti, S Wright, JJ Hong, DS AF Chintala, L. Kurzrock, R. Fu, S. Naing, A. Wheler, J. J. Moulder, S. L. Newman, R. Gagel, R. Sebti, S. Wright, J. J. Hong, D. S. TI Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancer (NCI protocol 7156) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. NCI, Washington, DC USA. NR 0 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3593 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401047 ER PT J AU Choong, NW Cohen, EE Kozloff, MF Taber, D Wade, JL Hu, S Ivy, SP Nichols, K Dekker, A Vokes, EE AF Choong, N. W. Cohen, E. E. Kozloff, M. F. Taber, D. Wade, J. L., III Hu, S. Ivy, S. P. Nichols, K. Dekker, A. Vokes, E. E. TI Phase II trial of sunitinib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Chicago, Chicago, IL 60637 USA. Ingalls Mem Hosp, Harvey, IL USA. Michiana Hematol Oncol, South Bend, IN USA. Canc Care Specialists Cent Illinois, Decatur, IL USA. David C Pratt Canc Ctr, St Louis, MO USA. NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6064 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402283 ER PT J AU Cohen, EE Needles, BM Cullen, KJ Wong, SJ Wade, JL Ivy, SP Villaflor, VM Seiwert, TY Nichols, K Vokes, EE AF Cohen, E. E. Needles, B. M. Cullen, K. J. Wong, S. J. Wade, J. L., III Ivy, S. P. Villaflor, V. M. Seiwert, T. Y. Nichols, K. Vokes, E. E. TI Phase 2 study of sunitinib in refractory thyroid cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Chicago, IL 60637 USA. St Johns Mercy Med Ctr, St Louis, MO 63141 USA. Univ Maryland, Baltimore, MD 21201 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Decatur Mem Hosp, Decatur, IL USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 64 Z9 67 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6025 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402286 ER PT J AU Cole, DE Balis, FM Grant, N White, T Dunleavy, K Janik, JE Whalen, L Goodspeed, W Wilson, WH AF Cole, D. E. Balis, F. M. Grant, N. White, T. Dunleavy, K. Janik, J. E. Whalen, L. Goodspeed, W. Wilson, W. H. TI Pharmacokinetics (pk) and tolerance of infusional vincristine (vcr) for aggressive lymphomas indicate dose reductions for excretory organ dysfunction are not necessary SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Cole, D. E.; Balis, F. M.; Grant, N.; White, T.; Dunleavy, K.; Janik, J. E.; Whalen, L.; Goodspeed, W.; Wilson, W. H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2550 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400684 ER PT J AU Cronin, WM Cecchini, RS Wickerham, DL Vogel, VG Costantino, JP Wolmark, N AF Cronin, W. M. Cecchini, R. S. Wickerham, D. L. Vogel, V. G. Costantino, J. P. Wolmark, N. TI Factors associated with participant adherence in the NSABP Study of Tamoxifen and Raloxifene (STAR) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NSABP Biostat Ctr, Pittsburgh, PA USA. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6518 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402417 ER PT J AU De Groot, JF Wen, PY Lamborn, K Chang, S Cloughesy, TF Chen, AP DeAngelis, LM Mehta, MP Gilbert, MR Yung, WK Prados, MD AF De Groot, J. F. Wen, P. Y. Lamborn, K. Chang, S. Cloughesy, T. F. Chen, A. P. DeAngelis, L. M. Mehta, M. P. Gilbert, M. R. Yung, W. K. Prados, M. D. TI Phase II single arm trial of aflibercept in patients with recurrent temozolomide-resistant glioblastoma: NABTC 0601 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif Los Angeles, San Francisco, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. NCI, Rockville, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Wisconsin Hosp, Madison, WI USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 NR 0 TC 25 Z9 25 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2020 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400518 ER PT J AU Decensi, A Robertson, C Guerrieri-Gonzaga, A Serrano, D Cazzaniga, M Gulisano, M Johansson, H Cassano, E Moroni, S Johnson, K Bonanni, B AF Decensi, A. Robertson, C. Guerrieri-Gonzaga, A. Serrano, D. Cazzaniga, M. Gulisano, M. Johansson, H. Cassano, E. Moroni, S. Johnson, K. Bonanni, B. TI A randomized double-blind 2x2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention of high-risk premenopausal women SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Div Canc Prevent & Genet, Milan, Italy. Univ Strathclyde, Glasgow, Lanark, Scotland. Osped S Bortolo, Vicenza, Italy. Div Breast Diagnost, Milan, Italy. Div Gynaecol Surg, Milan, Italy. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 1503 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400411 ER PT J AU Dookeran, KA Wang, Y Gao, X Ferrer, K Sekosan, M Lukaszczyk, B Radeke, EK McCaskill-Stevens, W Zaren, HA Gehlert, S AF Dookeran, K. A. Wang, Y. Gao, X. Ferrer, K. Sekosan, M. Lukaszczyk, B. Radeke, E. K. McCaskill-Stevens, W. Zaren, H. A. Gehlert, S. TI p53 as an additional marker to the intrinsic subtype classification as a method to further stratify breast cancer survival in African American (AA) women SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Canc Fdn Minority Underserved Populat, Chicago, IL USA. MBCCOP Stroger Hosp, Chicago, IL USA. NCI, Bethesda, MD 20892 USA. Univ Chicago, Chicago, IL 60637 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 22007 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457404100 ER PT J AU Dowlati, A Mekhail, T O'Brien, T Rutherford, K Snell, M Ness, A Ma, P Ivy, SP Halmos, B AF Dowlati, A. Mekhail, T. O'Brien, T. Rutherford, K. Snell, M. Ness, A. Ma, P. Ivy, S. P. Halmos, B. TI Phase II trial of becatecarin (rebeccamycin analogue) in relapsed sensitive small cell lung cancer (SCLC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Unvivers Hosp Ireland Canc Ctr, Cleveland, OH USA. Clevleland Clin, Taussig Canc Ctr, Cleveland, OH USA. MetroHlth Med Ctr, Cleveland, OH USA. NCI, Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 19060 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402946 ER PT J AU DuBois, SG Shusterman, S Ingle, AM Baruchel, S Stempak, D Sun, J Ivy, SP Glade-Bender, J Blaney, SM AF DuBois, S. G. Shusterman, S. Ingle, A. M. Baruchel, S. Stempak, D. Sun, J. Ivy, S. P. Glade-Bender, J. Blaney, S. M. CA PC Adamson Childrens Oncology Grp TI A pediatric phase I trial and pharmacokinetic (PK) study of sunitinib: A Children's Oncology Group Phase I Consortium study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif San Francisco, Sch Med, San Francisco, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Oncol Grp, Arcadia, CA USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Childrens Oncol Grp, Omaha, NE USA. NCI, Bethesda, MD 20892 USA. Columbia Univ, New York, NY USA. Texas Childrens Canc Ctr, Houston, TX USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3561 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400796 ER PT J AU Duchnowska, R Jassem, J Thorat, MA Morimiya, A Sledge, GW Li, L Biernat, W Szczylik, C Steeg, PS Badve, SS AF Duchnowska, R. Jassem, J. Thorat, M. A. Morimiya, A. Sledge, G. W. Li, L. Biernat, W. Szczylik, C. Steeg, P. S. Badve, S. S. TI Gene expression analysis for prediction of early brain metastasis (BM) in HER2-positive (HER2+) breast cancer patients (pts) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mil Inst Med, Warsaw, Poland. Med Univ, Gdansk, Poland. Indiana Univ, Indianapolis, IN 46204 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 1019 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400304 ER PT J AU Figg, WD Aragon-Ching, JB Steinberg, SM Gulley, JL Arlen, PM Sartor, O Petrylak, DP Higano, CS Hussain, MH Dahut, WL AF Figg, W. D. Aragon-Ching, J. B. Steinberg, S. M. Gulley, J. L. Arlen, P. M. Sartor, O. Petrylak, D. P. Higano, C. S. Hussain, M. H. Dahut, W. L. TI Randomized phase III trial of thalidomide (Th) or placebo (P) for non-metastatic PSA recurrent prostate cancer (PCa) treated with intermittent therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Tulane Med Sch, New Orleans, LA USA. Columbia Univ, New York Presbyterian Hosp, New York, NY USA. Univ Washington, Seattle, WA 98195 USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5016 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401928 ER PT J AU Fine, HA Puduvalli, VK Chamberlain, MC Carpentier, AF Cher, L Mason, WP van den Bent, MJ Hong, S Thornton, D Wick, W AF Fine, H. A. Puduvalli, V. K. Chamberlain, M. C. Carpentier, A. F. Cher, L. Mason, W. P. van den Bent, M. J. Hong, S. Thornton, D. Wick, W. TI Enzastaurin (ENZ) versus lomustine (CCNU) in the treatment of recurrent, intracranial glioblastoma multiforme (GBM): A phase III study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Washington, Seattle, WA 98195 USA. Hop La Pitie Salpetriere, Paris, France. Austin Hlth, Heidelberg, Vic, Australia. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Dr Daniel Den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Tubingen, Tubingen, Germany. RI Puduvalli, Vinay/A-2411-2016 NR 0 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2005 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400496 ER PT J AU Fojo, AT Stein, WD Yang, J Bates, SE AF Fojo, A. T. Stein, W. D. Yang, J. Bates, S. E. TI Effect of bevacizumab (Bev) on the growth rate constants of renal carcinoma (RCC) tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Fojo, A. T.; Stein, W. D.; Yang, J.; Bates, S. E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11044 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403959 ER PT J AU Giaccone, G Smit, EF van Groeningen, C Hogedoorn, PC AF Giaccone, G. Smit, E. F. van Groeningen, C. Hogedoorn, P. C. TI Phase II study of imatinib in patients with WHO B3 and C thymomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. Leiden Univ, Med Ctr, Leiden, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14665 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401058 ER PT J AU Gold, B Kirchhoff, T Stefanov, S Lautenberger, J Olshen, AB Kosarin, K Dean, M Boyd, J Norton, L Offit, K AF Gold, B. Kirchhoff, T. Stefanov, S. Lautenberger, J. Olshen, A. B. Kosarin, K. Dean, M. Boyd, J. Norton, L. Offit, K. CA Ashkenazi Breast Canc Working Grp TI Identification of a new breast cacner risk locus in a genome-wide association study of Ashkenazi Jews SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Frederick, MD 21701 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Mem Hlth Univ Med Ctr, Savannah, GA 31404 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11005 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457404034 ER PT J AU Grossman, SA Ye, X Chamberlain, MC Mikkelsen, T Batchelor, TT Desideri, S Piantadosi, S Fine, HA AF Grossman, S. A. Ye, X. Chamberlain, M. C. Mikkelsen, T. Batchelor, T. T. Desideri, S. Piantadosi, S. Fine, H. A. TI Phase II trial of talampanel in conjunction with standard radiation (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Comprehens Canc Ctr, Baltimore, MD USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2014 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400525 ER PT J AU Gunderson, LL Jessup, JM Sargent, DJ Greene, FL Stewart, A AF Gunderson, L. L. Jessup, J. M. Sargent, D. J. Greene, F. L. Stewart, A. CA AJCC 7th Ed'n Hindgut Taskforce HT TI TN categorization for rectal and colon cancers based on national survival outcome data SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Scottsdale, AZ USA. NCI, Rockville, MD USA. Mayo Clin, Rochester, MN USA. Carolinas Med Ctr, Charlotte, NC 28203 USA. Amer Coll Surg, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 4020 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401657 ER PT J AU Gutierrez, M Kummar, S Allen, D Turkbey, B Choyke, P Wright, JJ Kurkjian, C Giaccone, G Doroshow, JH Murgo, AJ AF Gutierrez, M. Kummar, S. Allen, D. Turkbey, B. Choyke, P. Wright, J. J. Kurkjian, C. Giaccone, G. Doroshow, J. H. Murgo, A. J. TI A phase II study of multikinase inhibitor sorafenib in patients with relapsed non-small cell lung cancer (NSCLC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Gutierrez, M.; Kummar, S.; Allen, D.; Turkbey, B.; Choyke, P.; Wright, J. J.; Kurkjian, C.; Giaccone, G.; Doroshow, J. H.; Murgo, A. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 19084 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402788 ER PT J AU Haggstrom, D Arora, N Oakley-Girvan, I AF Haggstrom, D. Arora, N. Oakley-Girvan, I. TI Primary and subspecialty care models of follow-up care delivery among colorectal cancer survivors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Indiana Univ, VA HSR&D Indianapolis COE, Indianapolis, IN 46204 USA. NCI, Bethesda, MD 20892 USA. No Calif Canc Ctr, Fremont, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6540 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402475 ER PT J AU Hammers, HJ Verheul, H Wilky, B Salumbides, B Holleran, J Egorin, MJ Lodge, M Wahl, RL Zwiebel, JA Carducci, MA Pili, R AF Hammers, H. J. Verheul, H. Wilky, B. Salumbides, B. Holleran, J. Egorin, M. J. Lodge, M. Wahl, R. L. Zwiebel, J. A. Carducci, M. A. Pili, R. TI Phase I safety and pharmacokinetic/pharmacodynamic results of the histone deacetylase inhibitor vorinostat in combination with bevacizumab in patients with kidney cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 16094 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401879 ER PT J AU Harris, BA Berger, AM Mitchell, S Steinberg, SM Baker, KL Handel, DL Bolle, J Bush, EG Avila, DN Pavletic, SZ AF Harris, B. A. Berger, A. M. Mitchell, S. Steinberg, S. M. Baker, K. L. Handel, D. L. Bolle, J. Bush, E. G. Avila, D. N. Pavletic, S. Z. TI Spiritual well-being in long-term survivors with chronic graft versus host disease after hematopoietic stem cell transplant SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Harris, B. A.; Berger, A. M.; Mitchell, S.; Steinberg, S. M.; Baker, K. L.; Handel, D. L.; Bolle, J.; Bush, E. G.; Avila, D. N.; Pavletic, S. Z.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 3 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 18017 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402647 ER PT J AU Henderson, TO Rajaraman, P Stovall, M Smith, S Mertens, A Meadows, A Neglia, JP Inskip, P Whitton, J Robison, LL Diller, L AF Henderson, T. O. Rajaraman, P. Stovall, M. Smith, S. Mertens, A. Meadows, A. Neglia, J. P. Inskip, P. Whitton, J. Robison, L. L. Diller, L. TI New primary sarcomas in survivors of childhood cancer: A detailed analysis of the effects of treatment: a report from the Childhood Cancer Survivor Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Emory Univ, Atlanta, GA 30322 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Minnesota, Minneapolis, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10007 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403539 ER PT J AU Henry, LR Prindiville, SA Swain, SM Cordes, R Soballe, PW AF Henry, L. R. Prindiville, S. A. Swain, S. M. Cordes, R. Soballe, P. W. TI The influence of a gene expression profile on breast cancer decisions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Naval Med Ctr, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. Washington Canc Inst, Washington, DC USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11546 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400215 ER PT J AU Hirschfeld, S AF Hirschfeld, S. TI Resource expectations for pediatric studies: Correlation of study type and patient number for FDA labeling SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Hirschfeld, S.] NICHD, NIH, Bethesda, MD USA. RI Hirschfeld, Steven/E-2987-2016 OI Hirschfeld, Steven/0000-0003-0627-7249 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6632 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402492 ER PT J AU Hirte, HW Vidal, L Fleming, GF Sugimoto, AK Morgan, RJ Biagi, JJ Wang, L McGill, S Ivy, SP Oza, AM AF Hirte, H. W. Vidal, L. Fleming, G. F. Sugimoto, A. K. Morgan, R. J. Biagi, J. J. Wang, L. McGill, S. Ivy, S. P. Oza, A. M. TI A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, Chicago and California consortia trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Juravinski Canc Ctr, Hamilton, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. London Hlth Sci Ctr, London, ON, Canada. City Hope Med Ctr, Duarte, CA USA. Canc Ctr SE Ontario, Kingston, ON, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 19 Z9 19 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5521 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402029 ER PT J AU Huang, H Menefee, ME Edgerly, M Kotz, H Poruchynsky, M Stein, WD Bates, SE Fojo, AT AF Huang, H. Menefee, M. E. Edgerly, M. Kotz, H. Poruchynsky, M. Stein, W. D. Bates, S. E. Fojo, A. T. TI Ixabepilone (BMS-247550) and metastatic renal cell carcinoma (mRCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Mayo Clin, Jacksonville, FL 32224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5053 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401847 ER PT J AU Irwin, ML Smith, A Aiello, E Cronin, K McTiernan, A Bernstein, L Baumgartner, R Gilliland, F Ballard-Barbash, R AF Irwin, M. L. Smith, A. Aiello, E. Cronin, K. McTiernan, A. Bernstein, L. Baumgartner, R. Gilliland, F. Ballard-Barbash, R. TI Post-diagnosis mammographic density and risk of death in breast cancer survivors: The Health, Eating, Activity, and Lifestyle (HEAL) study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Yale Univ, New Haven, CT USA. NCI, Bethesda, MD 20892 USA. Grp Hlth Cooperat Puget Sound, Seattle, WA 98121 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Univ Louisville, Louisville, KY 40292 USA. Univ So Calif, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 22095 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457404109 ER PT J AU Jackman, DM Sequist, LV Cioffredi, L Ruiz, MG Janne, PA Giaccone, G Miller, VA Johnson, BE AF Jackman, D. M. Sequist, L. V. Cioffredi, L. Ruiz, M. Gallegos Janne, P. A. Giaccone, G. Miller, V. A. Johnson, B. E. TI Impact of EGFR and KRAS genotype on outcomes in a clinical trial registry of NSCLC patients initially treated with erlotinib or gefitinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Vrije Univ Amsterdam, Amsterdam, Netherlands. NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 4 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8035 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402885 ER PT J AU Jacobs, S Fox, B Krailo, MD Hartley, G Navid, F Wexler, L Blaney, SM Frank, B Adamson, PC Widemann, BC AF Jacobs, S. Fox, B. Krailo, M. D. Hartley, G. Navid, F. Wexler, L. Blaney, S. M. Frank, B. Adamson, P. C. Widemann, B. C. TI Phase II trial of ixabepilone (BMS-247550) in children and young adults with refractory solid tumors: A report from the Children's Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Oncol Grp, Arcadia, CA USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Texas Childrens Canc Ctr, Houston, TX USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10026 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403585 ER PT J AU Jain, L Aragon-Ching, JB Arlen, PM Gully, JL Venitz, J Wright, JJ Dahut, WL Figg, WD AF Jain, L. Aragon-Ching, J. B. Arlen, P. M. Gully, J. L. Venitz, J. Wright, J. J. Dahut, W. L. Figg, W. D. TI Exploratory covariate analysis for phase II clinical trial of sorafenib (S) in metastatic castrate-resistant prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Richmond, VA USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14690 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400900 ER PT J AU Jo, S Juhasz, A Zhang, K Ruel, C Wilczynski, SP Yun, Y Ellenhorn, JD Paz, B Vora, N Shibata, S AF Jo, S. Juhasz, A. Zhang, K. Ruel, C. Wilczynski, S. P. Yun, Y. Ellenhorn, J. D. Paz, B. Vora, N. Shibata, S. TI Human papillomavirus (HPV) infection as a prognostic factor in patients with oropharyngeal squamous cell carcinoma treated in a prospective phase II clinical trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 City Hope Natl Med Ctr, Duarte, CA 91010 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6035 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402262 ER PT J AU Julian, TB Land, SR Wang, Y Vicini, F Arthur, D Mamounas, EP Costantino, JP Wolmark, N AF Julian, T. B. Land, S. R. Wang, Y. Vicini, F. Arthur, D. Mamounas, E. P. Costantino, J. P. Wolmark, N. TI Is boost therapy necessary in the treatment of DCIS? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NSABP, Operat & Biostat Ctr, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Pittsburgh, PA USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Virginia Commonwealth Univ, Med Ctr, Massey Canc Ctr, Richmond, VA USA. Aultman Canc Ctr, Canton, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 537 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400120 ER PT J AU Kadan-Lottick, NS Brouwers, P Kaleita, TA Breiger, D Stork, LC Bostrom, BC Neglia, JP AF Kadan-Lottick, N. S. Brouwers, P. Kaleita, T. A. Breiger, D. Stork, L. C. Bostrom, B. C. Neglia, J. P. TI Comparison of neurobehavioral outcomes in survivors of childhood acute lymphoblastic leukemia (ALL) previously randomized to intrathecal methotrexate vs. intrathecal methotrexate/hydrocortisone/cytarabine SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Yale Univ, Sch Med, New Haven, CT USA. NIH, Rockville, MD USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Washington, Sch Med, Seattle, WA USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Childrens Hosp & Clin, Minneapolis, MN USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10033 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403397 ER PT J AU Kamangar, F Ren, J Abnet, CC Taylor, PR Dawsey, SM Qiao, Y AF Kamangar, F. Ren, J. Abnet, C. C. Taylor, P. R. Dawsey, S. M. Qiao, Y. TI Serum pepsinogens and gastrin-17 and gastric and esophageal cancers: A long-term prospective study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Beijing 100730, Peoples R China. RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 4561 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401614 ER PT J AU Karakunnel, JJ Gulley, JL Arlen, PM Mulquin, M Wright, JJ Turkbey, IB Choyke, P Ahlers, CM Figg, WD Dahut, WL AF Karakunnel, J. J. Gulley, J. L. Arlen, P. M. Mulquin, M. Wright, J. J. Turkbey, I. B. Choyke, P. Ahlers, C. M. Figg, W. D. Dahut, W. L. TI Phase II trial of cediranib (AZD2171) in docetaxel-resistant, castrate-resistant prostate cancer (CRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Karakunnel, J. J.; Gulley, J. L.; Arlen, P. M.; Mulquin, M.; Wright, J. J.; Turkbey, I. B.; Choyke, P.; Ahlers, C. M.; Figg, W. D.; Dahut, W. L.] NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5136 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401896 ER PT J AU Karmely, M Rubinstein, DB Pichinuk, E Ziv, R Benhar, I Feng, N Wreschner, DH AF Karmely, M. Rubinstein, D. B. Pichinuk, E. Ziv, R. Benhar, I. Feng, N. Wreschner, D. H. TI Inhibiting MUC1 a/b chain interaction mediates cytotoxicity of cells expressing MUC1: The MUC1 dyad oncoprotein as a functional target SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Tel Aviv Univ, Ramat Aviv, Israel. NCI, Bethesda, MD 20892 USA. Arius Res, Toronto, ON, Canada. Biomodifying Inc, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14000 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400738 ER PT J AU Kies, MS Gibson, MK Kim, SW Savvides, P Blumenschein, GR Worden, F Chen, H Grandis, JR Argiris, AE AF Kies, M. S. Gibson, M. K. Kim, S. W. Savvides, P. Blumenschein, G. R., Jr. Worden, F. Chen, H. Grandis, J. R. Argiris, A. E. TI Cetuximab (C) and bevacizumab (B) in patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN): An interim analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Pittsburgh, Pittsburgh, PA USA. Case Western Univ, Cleveland, OH 44106 USA. Univ Michigan, Ann Arbor, MI 48109 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 6072 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402219 ER PT J AU Kreitman, RJ Wilson, WH Stetler-Stevenson, M Noel, P FitzGerald, DJ Pastan, I AF Kreitman, R. J. Wilson, W. H. Stetler-Stevenson, M. Noel, P. FitzGerald, D. J. Pastan, I. TI Pharmacokinetics of recombinant immunotoxin BL22 during phase II testing in chemo-resistant hairy cell leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Kreitman, R. J.; Wilson, W. H.; Stetler-Stevenson, M.; Noel, P.; FitzGerald, D. J.; Pastan, I.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3001 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400752 ER PT J AU Laheru, DA Cohen, SJ Phillips, M Armstrong, DK Brahmer, J Jaffee, EM Weil, S Pastan, I Hassan, R AF Laheru, D. A. Cohen, S. J. Phillips, M. Armstrong, D. K. Brahmer, J. Jaffee, E. M. Weil, S. Pastan, I. Hassan, R. TI A phase I study of MORab-009, a monoclonal antibody against mesothelin, in mesothelioma, pancreatic and ovarian cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Morphotek, Exton, PA USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3578 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400819 ER PT J AU Land, SR Kopec, JA Lee, M Haile, SR Ritter, MW Krag, D Anderson, SJ Ganz, PA Wolmark, N AF Land, S. R. Kopec, J. A. Lee, M. Haile, S. R. Ritter, M. W. Krag, D. Anderson, S. J. Ganz, P. A. Wolmark, N. TI Quality of life in breast cancer patients receiving sentinel-node (SN) biopsy alone or with axillary dissection (AD): Results from NSABP Protocol B-32 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Pittsburgh, Grad Sch Publ Hlth, NSABP, Pittsburgh, PA USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Vermont, Burlington, VT USA. Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. Allegheny Gen Hosp, NSABP, Pittsburgh, PA 15212 USA. RI Haile, Sarah/C-2330-2011 OI Haile, Sarah/0000-0002-4704-6570 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 9533 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403619 ER PT J AU Mackall, C Baird, K Love, C Wayne, A Fry, T AF Mackall, C. Baird, K. Love, C. Wayne, A. Fry, T. TI Prolonged survival in patients with ultra high-risk pediatric sarcomas following reduced intensity allogeneic peripheral blood stem cell transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 21000 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403734 ER PT J AU Mackay, H Hirte, HW Covens, A MacAlpine, K Wang, L Tsao, MS Pan, J Zwiebel, JA Oza, AM AF Mackay, H. Hirte, H. W. Covens, A. MacAlpine, K. Wang, L. Tsao, M. S. Pan, J. Zwiebel, J. A. Oza, A. M. TI A phase II trial of the histone deacetylase inhibitor belinostat (PXD101) in patients with platinum resistant epithelial ovarian tumors and micropapillary/borderline (LMP) ovarian tumors. A PMH phase II consortium trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada. Princess Margaret Hosp Phase II Consortium, Toronto, ON, Canada. Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5518 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402047 ER PT J AU Madan, RA Gulley, JL Dahut, WL Tsang, KY Steinberg, SM Schlom, J Arlen, PM AF Madan, R. A. Gulley, J. L. Dahut, W. L. Tsang, K. Y. Steinberg, S. M. Schlom, J. Arlen, P. M. TI Overall survival (OS) analysis of a phase II study using a pox viral-based vaccine, PSA-TRICOM, in the treatment of metastatic, castrate-resistant prostate cancer (mCRPC): Implications for clinical trial design SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Madan, R. A.; Gulley, J. L.; Dahut, W. L.; Tsang, K. Y.; Steinberg, S. M.; Schlom, J.; Arlen, P. M.] NCI, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3005 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400748 ER PT J AU Maki, RG Keohan, ML Undevia, SD Livingston, M Cooney, MM Elias, A Saulle, MF Wright, JJ D'Adamo, DR Schuetze, SM AF Maki, R. G. Keohan, M. L. Undevia, S. D. Livingston, M. Cooney, M. M. Elias, A. Saulle, M. F. Wright, J. J. D'Adamo, D. R. Schuetze, S. M. CA Sorafenib Sarcoma Study Grp TI Updated results of a phase II study of oral multi-kinase inhibitor sorafenib in sarcomas, CTEP study #7060 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Chicago Hosp, Chicago, IL 60637 USA. Carolinas HealthCare, Charlotte, NC USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10531 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403856 ER PT J AU Matulonis, UA Berlin, ST Krasner, CN Tyburski, K Lee, J Roche, M Ivy, SP Lenahan, C King, M Penson, RT AF Matulonis, U. A. Berlin, S. T. Krasner, C. N. Tyburski, K. Lee, J. Roche, M. Ivy, S. P. Lenahan, C. King, M. Penson, R. T. TI Cediranib (AZD2171) is an active agent in recurrent epithelial ovarian cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 5 Z9 5 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5501 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402056 ER PT J AU Mayer, M Steeg, PS Schiff, H AF Mayer, M. Steeg, P. S. Schiff, H. TI BrainMetsBC.org: Evaluation of a new resource for breast cancer patients with brain metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 AdvancedBC Org, New York, NY USA. NCI, Bethesda, MD 20892 USA. SHARE Self Help Women Breast Ovarian Canc, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 20711 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403369 ER PT J AU McGregor, LM Spunt, SL Santana, VM Stewart, CF Ward, DA Wu, J Watkins, A Ivy, SP Furman, WL Fouladi, M AF McGregor, L. M. Spunt, S. L. Santana, V. M. Stewart, C. F. Ward, D. A. Wu, J. Watkins, A. Ivy, S. P. Furman, W. L. Fouladi, M. TI A phase I study of oxaliplatin and etoposide in pediatric patients with refractory solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 St Jude Childrens Res Hosp, Memphis, TN 38105 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10024 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403307 ER PT J AU Meany, HJ Fox, E Aikin, A Whitcomb, P Murphy, RF Widemann, BC Balis, FM AF Meany, H. J. Fox, E. Aikin, A. Whitcomb, P. Murphy, R. F. Widemann, B. C. Balis, F. M. TI Pediatric phase I trial design using a pharmacodynamic marker as the primary endpoint SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Childrens Natl Med Ctr, Washington, DC 20010 USA. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 10027 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403574 ER PT J AU Meerasahib, A Donohue, TB Childs, RW AF Meerasahib, A. Donohue, T. B. Childs, R. W. TI Successful re-initiation of calcineurin inhibitors in patients with posterior reversible encephalopathy syndrome (PRES) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Washington Hosp Ctr, Washington, DC 20010 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 18014 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402650 ER PT J AU Menefee, ME Huang, H Edgerly, M Kotz, H Merino, M Balis, FM Chen, CC Robey, R Bates, SE Fojo, AT AF Menefee, M. E. Huang, H. Edgerly, M. Kotz, H. Merino, M. Balis, F. M. Chen, C. C. Robey, R. Bates, S. E. Fojo, A. T. TI Y Effects of the P-glycoprotein (Pgp) antagonist tariquidar (XR-9576; TQD) on Pgp function as well as the toxicity and efficacy of combined chemotherapy in patients with metastatic adrenocortical cancer (mACC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mayo Clin, Jacksonville, FL 32224 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2543 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400644 ER PT J AU Min, CJ Liebes, LF Escalon, J Hamilton, A Yee, H Buckley, MT Wright, JJ Osman, I Polsky, D Pavlick, AC AF Min, C. J. Liebes, L. F. Escalon, J. Hamilton, A. Yee, H. Buckley, M. T. Wright, J. J. Osman, I. Polsky, D. Pavlick, A. C. TI Phase II trial of sorafenib (S [BAY 43-9006]) in metastatic melanoma (MM) including detection of BRAF with mutant specific-PCR (MS-PCR) and altered proliferation pathways-final outcome analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NYU, Med Ctr, New York, NY 10016 USA. Sydney Canc Ctr, Sydney, NSW, Australia. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 9072 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403276 ER PT J AU Mobarek, DA Ascensao, JL Stroncek, D Bennett, M Adams, S Kvanli, M Schechter, GP AF Mobarek, D. A. Ascensao, J. L. Stroncek, D. Bennett, M. Adams, S. Kvanli, M. Schechter, G. P. TI Comparison of JAK2(V617F) prevalence in African American and caucasian patients with myeloproliferative disease (MPD) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 George Washington Univ, Washington, DC USA. NIH, Bethesda, MD 20892 USA. VA Med Ctr, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 18001 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402558 ER PT J AU Mohebtash, M Madan, RA Gulley, JL Jones, J Pazdur, M Rauckhorst, M Schlom, J Arlen, PM AF Mohebtash, M. Madan, R. A. Gulley, J. L. Jones, J. Pazdur, M. Rauckhorst, M. Schlom, J. Arlen, P. M. TI PANVAC vaccine alone or with docetaxel for patients with metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Mohebtash, M.; Madan, R. A.; Gulley, J. L.; Jones, J.; Pazdur, M.; Rauckhorst, M.; Schlom, J.; Arlen, P. M.] NCI, NIH, Bethesda, MD 20892 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3035 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400749 ER PT J AU Morris, JC Shapiro, GI Tan, AR Lawrence, DP Olencki, TE Dezube, BJ Hsu, FJ Reiss, M Berzofsky, JA AF Morris, J. C. Shapiro, G. I. Tan, A. R. Lawrence, D. P. Olencki, T. E. Dezube, B. J. Hsu, F. J. Reiss, M. Berzofsky, J. A. TI Phase I/II study of GC1008: A human anti-transforming growth factor-beta (TGF beta) monoclonal antibody (MAb) in patients with advanced malignant melanoma (MM) or renal cell carcinoma (RCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Canc Inst New Jersey, New Brunswick, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Ohio State Univ, Columbus, OH 43210 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Genzyme Corp, Cambridge, MA USA. NR 0 TC 28 Z9 30 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 9028 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403243 ER PT J AU Ning, YM Arlen, PM Gulley, JL Stein, WD Fojo, AT Latham, L Wright, JJ Parnes, H Figg, WD Dahut, WL AF Ning, Y. M. Arlen, P. M. Gulley, J. L. Stein, W. D. Fojo, A. T. Latham, L. Wright, J. J. Parnes, H. Figg, W. D. Dahut, W. L. TI Phase II trial of thalidomide (T), bevacizumab (Bv), and docetaxel (Doc) in patients (pts) with metastatic castration-refractory prostate cancer (mCRPC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 US FDA, Silver Spring, MD USA. NCI, Bethesda, MD 20892 USA. Med Oncol Branch, Bethesda, MD USA. Canc Therapy Evaluat Program, Rockville, MD USA. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5000 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401900 ER PT J AU O'Mahony, D Aleman, K Bernstein, WB Wyvill, K Whitby, D Tosato, G Jaffe, ES Pittaluga, S Little, RF Yarchoan, R AF O'Mahony, D. Aleman, K. Bernstein, W. B. Wyvill, K. Whitby, D. Tosato, G. Jaffe, E. S. Pittaluga, S. Little, R. F. Yarchoan, R. TI Preliminary results of a clinical trial using chemo-immunotherapy in Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. Div Canc Epidemiol & Genet, Bethesda, MD USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Pathol Lab, Bethesda, MD USA. NIH, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 19534 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403140 ER PT J AU O'Reilly, EM Niedzwiecki, D Hollis, DR Bekaii-Saab, TS Pluard, T Duffy, A Overcash, F Ivy, SP Goldberg, RM AF O'Reilly, E. M. Niedzwiecki, D. Hollis, D. R. Bekaii-Saab, T. S. Pluard, T. Duffy, A. Overcash, F. Ivy, S. P. Goldberg, R. M. TI A phase II trial of sunitinib (S) in previously-treated pancreas adenocarcinoma (PAC), CALGB 80603 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Duke Univ, Med Ctr, Durham, NC USA. Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. Washington State Univ, Sch Med, St Peters, MO USA. Canc & Leukemia Grp B, Chicago, IL USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. Univ N Carolina, Chapel Hill, NC USA. RI Bekaii-Saab, Tanios/E-2733-2011; Goldberg , Richard/M-1311-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 4515 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401150 ER PT J AU Oken, MM Church, TR Inampudi, S Oancea, SC Watt, GD Plunkett, M Marquez, G AF Oken, M. M. Church, T. R. Inampudi, S. Oancea, S. C. Watt, G. D. Plunkett, M. Marquez, G. CA Minnesota PLCO Program NCI TI Sensitivity of computer-aided diagnosis among participants at one center in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Minnesota, Minneapolis, MN USA. Consulting Radiologists, Minneapolis, MN USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 1546 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400449 ER PT J AU Oza, AM Elit, L Provencher, D Biagi, JJ Panasci, L Sederias, J Dancey, JE Tsao, S Eisenhauer, EA AF Oza, A. M. Elit, L. Provencher, D. Biagi, J. J. Panasci, L. Sederias, J. Dancey, J. E. Tsao, S. Eisenhauer, E. A. TI A phase II study of temsirolimus (CCI-779) in patients with metastatic and/or locally advanced recurrent endometrial cancer previously treated with chemotherapy: NCIC CTG IND 160b SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Toronto, Princess Margaret Hosp, NCIC Clin Trials Grp, Toronto, ON, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. Ctr Hosp Univ Montreal, Montreal, PQ, Canada. Canc Ctr SE Ontario Kingston, Kingston, ON, Canada. McGill Univ, Montreal, PQ, Canada. NCIC Clin Trials Grp, Kingston, ON, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 16 Z9 16 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5516 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402124 ER PT J AU Ozbun, L Vathipadiekal, V Radonovich, ME Pise-Masison, C Saxena, D Hauschka, PV Mok, SC Birrer, MJ AF Ozbun, L. Vathipadiekal, V. Radonovich, M. E. Pise-Masison, C. Saxena, D. Hauschka, P. V. Mok, S. C. Birrer, M. J. TI Cancer stem cell gene signature of ovarian tumor side populations SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5546 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402050 ER PT J AU Pastan, I Wilson, WH Stetler-Stevenson, M Noel, P Fitzgerald, J Kreitman, RJ AF Pastan, I. Wilson, W. H. Stetler-Stevenson, M. Noel, P. Fitzgerald, J. Kreitman, R. J. TI Early phase I results of recombinant immunotoxin HA22 in patients with B-cell leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Pastan, I.; Wilson, W. H.; Stetler-Stevenson, M.; Noel, P.; Fitzgerald, J.; Kreitman, R. J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3039 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400714 ER PT J AU Piekarz, R Luchenko, V Draper, D Wright, JJ Figg, WD Fojo, AT Bates, SE AF Piekarz, R. Luchenko, V. Draper, D. Wright, J. J. Figg, W. D. Fojo, A. T. Bates, S. E. TI Phase I trial of romidepsin, a histone deacetylase inhibitor, given on days one, three and five in patients with thyroid and other advanced cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Piekarz, R.; Luchenko, V.; Draper, D.; Wright, J. J.; Figg, W. D.; Fojo, A. T.; Bates, S. E.] NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3571 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401054 ER PT J AU Portera, CC Dancey, JE AF Portera, C. C. Dancey, J. E. TI Evaluation of phase II clinical trials of small molecule targeted inhibitors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Portera, C. C.; Dancey, J. E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14686 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400897 ER PT J AU Puzanov, I Lee, W Berlin, JD Calcutt, MW Hachey, DL Vermeulen, WL Spanswick, VJ Hartley, JA Chen, AP Rothenberg, ML AF Puzanov, I. Lee, W. Berlin, J. D. Calcutt, M. W. Hachey, D. L. Vermeulen, W. L. Spanswick, V. J. Hartley, J. A. Chen, A. P. Rothenberg, M. L. TI Final results of phase I and pharmacokinetic trial of SJG-136 administered on a daily x 3 schedule SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Vanderbilt Ingram Canc Ctr, Nashville, TN USA. UCL, London, England. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2504 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400663 ER PT J AU Ramalingam, SS Mack, PC Vokes, EE Longmate, J Govindan, R Koczywas, M Ivy, SP Belani, CP Gandara, DR AF Ramalingam, S. S. Mack, P. C. Vokes, E. E. Longmate, J. Govindan, R. Koczywas, M. Ivy, S. P. Belani, C. P. Gandara, D. R. TI Cediranib (AZD2171) for the treatment of recurrent small cell lung cancer (SCLC): A California Consortium phase II study (NCI # 7097) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Emory Univ, Atlanta, GA 30322 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Univ Chicago, Chicago, IL 60637 USA. City Hope Canc Ctr, Duarte, CA USA. Washington Univ, St Louis, MO USA. NCI, Rockville, MD USA. Penn State Canc Inst, Hershey, PA USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8078 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402818 ER PT J AU Roberts, A Gandhi, L O'Connor, OA Rudin, CM Khaira, D Xiong, H Chiu, Y Greco, R Krivoshik, AP Wilson, WH AF Roberts, A. Gandhi, L. O'Connor, O. A. Rudin, C. M. Khaira, D. Xiong, H. Chiu, Y. Greco, R. Krivoshik, A. P. Wilson, W. H. TI Reduction in platelet counts as a mechanistic biomarker and guide for adaptive dose-escalation in phase I studies of the Bcl-2 family inhibitor ABT-263 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Royal Melbourne Hosp, Melbourne, Vic, Australia. Dana Farber Canc Inst, Boston, MA 02115 USA. Columbia Univ, Med Ctr, New York, NY USA. Johns Hopkins Univ, Baltimore, MD USA. Dedicated Phase I, Phoenix, AZ USA. Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3542 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401070 ER PT J AU Schubert, J Young, NS Luzzatto, L Brodsky, RA Socie, G Rother, RP Rollins, SA Hillmen, P AF Schubert, J. Young, N. S. Luzzatto, L. Brodsky, R. A. Socie, G. Rother, R. P. Rollins, S. A. Hillmen, P. TI Lack of correlation of eculizumab therapy in paroxysmal nocturnal hemoglobinuria (PNH) patients with myeloproliferative disorders, myelodysplastic syndromes, acute leukemias or aplastic anemia with long-term treatment SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Saarland, Sch Med, D-6650 Homburg, Saar, Germany. NHLBI, Bethesda, MD 20892 USA. Ist Toscano Tumori, Florence, Italy. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Hosp St Louis, Paris, France. INSERM, Paris, France. Alex Pharmaceut, Cheshire, CT USA. St James Inst Oncol, Leeds, W Yorkshire, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 7092 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402601 ER PT J AU Sharifi, N Hamada, A Sissung, T Danesi, R Venzon, D Baum, C Gulley, JL Price, DK Dahut, WL Figg, WD AF Sharifi, N. Hamada, A. Sissung, T. Danesi, R. Venzon, D. Baum, C. Gulley, J. L. Price, D. K. Dahut, W. L. Figg, W. D. TI A polymorphism in a transporter of testosterone as a determinant of androgen independence in prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Pisa, Pisa, Italy. RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5066 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401712 ER PT J AU Sharma, K Janik, JE Torres-Cabala, CA Lee, CC O'Mahony, D Morris, JC AF Sharma, K. Janik, J. E. Torres-Cabala, C. A. Lee, C. C. O'Mahony, D. Morris, J. C. TI Breast involvement in patients with HTLV-1-associated adult T-cell leukemia/lymphoma (ATL) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Sharma, K.; Janik, J. E.; Torres-Cabala, C. A.; Lee, C. C.; O'Mahony, D.; Morris, J. C.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 14009 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400703 ER PT J AU Shreeve, SM Palmieri, D Johnson, MM Aldape, KD Davis, S Meltzer, PS Davis, GL Hoffmann, CM Steinberg, SM Steeg, PS AF Shreeve, S. M. Palmieri, D. Johnson, M. M. Aldape, K. D. Davis, S. Meltzer, P. S. Davis, G. L. Hoffmann, C. M. Steinberg, S. M. Steeg, P. S. TI Correlation of hexokinase-2 expression with overall survival and potential as a therapeutic target in the treatment of breast cancer brain metastases SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Sigma Aldrich, St Louis, MO USA. RI Palmieri, Diane/B-4258-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 1005 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400281 ER PT J AU Shusterman, S London, WB Gillies, SD Hank, JA Voss, S Seeger, RC Hecht, T Reisfeld, RA Maris, JM Sondel, PM AF Shusterman, S. London, W. B. Gillies, S. D. Hank, J. A. Voss, S. Seeger, R. C. Hecht, T. Reisfeld, R. A. Maris, J. M. Sondel, P. M. TI Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children's Oncology Group (COG) phase II study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Ctr Data, Childrens Oncol Grp, Gainesville, FL USA. EMD Lexigen Res Ctr, Billerica, MA USA. Univ Wisconsin, Madison, WI USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. NCI, Frederick, MD 21701 USA. Scripps Res Inst, La Jolla, CA 92037 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3002 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400698 ER PT J AU Silverman, LR Verma, A Odchimar-Reissig, R Cozza, A Najfeld, V Licht, JD Zwiebel, JA AF Silverman, L. R. Verma, A. Odchimar-Reissig, R. Cozza, A. Najfeld, V. Licht, J. D. Zwiebel, J. A. TI A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Initial results of the phase I trial: A New York Cancer Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mt Sinai Sch Med, New York, NY USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Northwestern Univ, Sch Med, Chicago, IL USA. NCI, Rockville, MD USA. NR 0 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 7000 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402594 ER PT J AU Simon, R Bianchini, G Zambetti, M Govi, S Mariani, G Carcangiu, ML Valagussa, P Gianni, L AF Simon, R. Bianchini, G. Zambetti, M. Govi, S. Mariani, G. Carcangiu, M. L. Valagussa, P. Gianni, L. TI Outcome prediction in estrogen-receptor positive, chemotherapy- and tamoxifen-treated patients with locally advanced breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Fdn IRCCS, Ist Tumori Milano, Milan, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11104 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457404094 ER PT J AU Smith, SM Pro, B Cisneros, A Smith, S Stiff, P Lester, E Modi, S Dancey, JE Vokes, EE van Besien, K AF Smith, S. M. Pro, B. Cisneros, A. Smith, S. Stiff, P. Lester, E. Modi, S. Dancey, J. E. Vokes, E. E. van Besien, K. TI Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Chicago, IL 60637 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Loyola Univ, Sch Med, Maywood, IL 60153 USA. Oncol Care Associates, St Joseph, MI USA. Joliet Oncol Hematol Associates, Joliet, IL USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8514 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403047 ER PT J AU Sosman, JA Flaherty, KT Atkins, MB McDermott, DF Rothenberg, ML Vermeulen, WL Harlacker, K Hsu, A Wright, JJ Puzanov, I AF Sosman, J. A. Flaherty, K. T. Atkins, M. B. McDermott, D. F. Rothenberg, M. L. Vermeulen, W. L. Harlacker, K. Hsu, A. Wright, J. J. Puzanov, I. TI Updated results of phase I trial of sorafenib (S) and bevacizumab (B) in patients with metastatic renal cell cancer (mRCC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Vanderbilt Univ, Med Ctr, Nashville, TN USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5011 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402006 ER PT J AU Speakman, J Reeves, D AF Speakman, J. Reeves, D. TI Improving cancer care and research through the reuse of standardized electronic data SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Speakman, J.; Reeves, D.] NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 17556 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402440 ER PT J AU Sridhar, SS Mackenzie, MJ Hotte, SJ Mukherjee, SD Kollmannsberger, C Haider, MA Chen, EX Wang, L Srinivasan, R Ivy, SP Moore, MJ AF Sridhar, S. S. Mackenzie, M. J. Hotte, S. J. Mukherjee, S. D. Kollmannsberger, C. Haider, M. A. Chen, E. X. Wang, L. Srinivasan, R. Ivy, S. P. Moore, M. J. TI Activity of cediranib (AZD2171) in patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the PMH Consortium SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. London Reg Canc Ctr, London, ON N6A 4L6, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. BC Canc Agcy, Vancouver, BC, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5047 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401719 ER PT J AU Srinivasan, R Choueiri, TK Vaishampayan, U Rosenberg, JE Stein, MN Logan, T Bukowski, RM Mueller, T Keer, HN Linehan, WM AF Srinivasan, R. Choueiri, T. K. Vaishampayan, U. Rosenberg, J. E. Stein, M. N. Logan, T. Bukowski, R. M. Mueller, T. Keer, H. N. Linehan, W. M. TI A phase II study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Karmanos Canc Insitute, Detroit, MI USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Canc Inst New Jersey, New Brunswick, NJ USA. Indiana Univ, Indianapolis, IN USA. Cleveland Clin, Cleveland, OH 44106 USA. Exelixis, San Francisco, CA USA. NR 0 TC 18 Z9 18 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5103 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457402011 ER PT J AU Tang, P Cohen, SJ Bjarnason, GA Kollmannsberger, C Virik, K MacKenzie, MJ Brown, J Wang, L Chen, AP Moore, MJ AF Tang, P. Cohen, S. J. Bjarnason, G. A. Kollmannsberger, C. Virik, K. MacKenzie, M. J. Brown, J. Wang, L. Chen, A. P. Moore, M. J. TI Phase II trial of aflibercept (VEGF Trap) in previously treated patients with metastatic colorectal cancer (MCRC): A PMH phase II consortium trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Princess Margaret Phase II Consortium, Toronto, ON, Canada. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. NR 0 TC 13 Z9 14 U1 1 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 4027 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401521 ER PT J AU Tannir, NM Zurita, AJ Heymach, JV Tran, HT Pagliaro, LC Corn, P Aparicio, AM Ashe, R Wright, JJ Jonasch, E AF Tannir, N. M. Zurita, A. J. Heymach, J. V. Tran, H. T. Pagliaro, L. C. Corn, P. Aparicio, A. M. Ashe, R. Wright, J. J. Jonasch, E. TI A randomized phase II trial of sorafenib versus sorafenib plus low-dose interferon-alfa: Clinical results and biomarker analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 5093 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401713 ER PT J AU Theoret, MR Cohen, CJ Dudley, ME Morgan, RA Rosenberg, SA AF Theoret, M. R. Cohen, C. J. Dudley, M. E. Morgan, R. A. Rosenberg, S. A. TI In vitro and in vivo studies of human lymphocytes genetically engineered to express T cell receptors that recognize a p53 antigenic epitope SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Theoret, M. R.; Cohen, C. J.; Dudley, M. E.; Morgan, R. A.; Rosenberg, S. A.] NCI, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3032 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400734 ER PT J AU Tomasello, L Sertoli, MR Rubagotti, A Guglielmini, P Tacchini, L Bedognetti, D Ricci, F Sanguineti, S Cassata, A Boccardo, F AF Tomasello, L. Sertoli, M. R. Rubagotti, A. Guglielmini, P. Tacchini, L. Bedognetti, D. Ricci, F. Sanguineti, S. Cassata, A. Boccardo, F. TI Combination of sorafenib and weekly gemcitabine in patients (pts) with metastatic renal cell Cancer (MRCC): A phase II study, preliminary results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Natl Canc Inst, Genoa, Italy. Univ Genoa, Genoa, Italy. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 16011 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401763 ER PT J AU Townsley, C Oza, AM Tang, P Siu, LL Pond, GR Sarveswaran, P Webster, S Zwiebel, JA Chen, EX AF Townsley, C. Oza, A. M. Tang, P. Siu, L. L. Pond, G. R. Sarveswaran, P. Webster, S. Zwiebel, J. A. Chen, E. X. TI Expanded phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11096 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403975 ER PT J AU van den Bent, MJ Wick, W Liepa, AM Puduvalli, VK Carpentier, AF Cher, L Mason, WP Taphoorn, MJ Hong, S Fine, HA AF van den Bent, M. J. Wick, W. Liepa, A. M. Puduvalli, V. K. Carpentier, A. F. Cher, L. Mason, W. P. Taphoorn, M. J. Hong, S. Fine, H. A. TI Time to deterioration in dimensions of health-related quality of life (HRQL) for patients with recurrent glioblastoma multiforme (GBM): Results from the randomized, phase III trial of enzastaurin (ENZ) versus lomustine (CCNU) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dr Daniel Den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Univ Tubingen, Tubingen, Germany. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Hop La Pitie Salpetriere, Paris, France. Austin Hlth, Heidelberg, Vic, Australia. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Med Ctr Haaglanden, The Hague, Netherlands. NIH, Bethesda, MD 20892 USA. RI Puduvalli, Vinay/A-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 2040 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457400559 ER PT J AU Voortman, J Pham, TV Knol, JC Giaccone, G Jimenez, CR AF Voortman, J. Pham, T. V. Knol, J. C. Giaccone, G. Jimenez, C. R. TI Time-course MALDI-TOF-MS serum peptide profiling of non-small cell lung cancer patients treated with bortezomib, cisplatin and gemcitabine SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8007 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403023 ER PT J AU Wilson, WH Czuczman, MS LaCasce, AS Gerecitano, JF Leonard, JP Dunleavy, K Krivoshik, AP Xiong, H Chiu, Y O'Connor, OA AF Wilson, W. H. Czuczman, M. S. LaCasce, A. S. Gerecitano, J. F. Leonard, J. P. Dunleavy, K. Krivoshik, A. P. Xiong, H. Chiu, Y. O'Connor, O. A. TI A phase 1 study evaluating the safety, pharmacokinetics, and efficacy of ABT-263 in subjects with refractory or relapsed lymphoid malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Weill Cornell Med Coll, New York, NY USA. Abbott Labs, Abbott Pk, IL 60064 USA. Columbia Univ, Med Ctr, New York, NY USA. NR 0 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 8511 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403039 ER PT J AU Wolmark, N Wieand, S Kuebler, PJ Colangelo, L O'Connell, MJ Yothers, G AF Wolmark, N. Wieand, S. Kuebler, P. J. Colangelo, L. O'Connell, M. J. Yothers, G. TI A phase III trial comparing FULV to FULV plus oxaliplatin in stage II or III carcinoma of the colon: Survival results of NSABP Protocol C-07 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. NSABP, Pittsburgh, PA USA. CCOP, Columbus, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA LBA4005 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401154 ER PT J AU Yang, J AF Yang, J. CA NIH-P01 Grant Breast Canc Res Grp TI Effect of ERK on tumorigenesis and on inhibition of FOXO3a via MDM2-mediated degradation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NIH P01 Grant Breast Canc Res Grp, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 11101 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457403961 ER PT J AU Yang, SX Kummar, S Rubinstein, L Gutierrez, M Murgo, AJ Parchment, RE Nguyen, D Chen, AP Tomaszewski, JE Doroshow, JH AF Yang, S. X. Kummar, S. Rubinstein, L. Gutierrez, M. Murgo, A. J. Parchment, R. E. Nguyen, D. Chen, A. P. Tomaszewski, J. E. Doroshow, J. H. CA NCI Phase 0 Working Grp TI Phase 0 pharmacodynamic study of poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with refractory solid tumors and lymphomas: Immunohistochemistry results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. SAIC Inc, Frederick, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 20 PY 2008 VL 26 IS 15 SU S MA 3580 PG 1 WC Oncology SC Oncology GA V25CZ UT WOS:000208457401017 ER PT J AU Caughey, B Baron, GS AF Caughey, Byron Baron, Gerald S. TI Are cheetahs on the run from prion-like amyloidosis? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ACINONYX-JUBATUS; PROTEIN; DISEASE; GENE C1 [Caughey, Byron; Baron, Gerald S.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59894 USA. RP Caughey, B (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59894 USA. EM bcaughey@nih.gov; gbaron@nih.gov FU Intramural NIH HHS NR 14 TC 3 Z9 3 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 20 PY 2008 VL 105 IS 20 BP 7113 EP 7114 DI 10.1073/pnas.0803438105 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 305FJ UT WOS:000256162900003 PM 18487456 ER PT J AU Aid, S Langenbach, R Bosetti, F AF Aid, Saba Langenbach, Robert Bosetti, Francesca TI Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2 SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NEURONAL OXIDATIVE DAMAGE; ALZHEIMERS-DISEASE; INDUCIBLE CYCLOOXYGENASE; INFLAMMATORY RESPONSE; GENE-EXPRESSION; INNATE IMMUNITY; MOUSE-BRAIN; PHOSPHOLIPASE A(2); INDUCED SEIZURE AB Background: Cyclooxygenases (COX)-1 and -2 are key mediators of the inflammatory response in the central nervous system. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. However, the specific roles of COX-1 and COX-2 in modulating a neuroinflammatory response are unclear. Recently, we demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS). Methods: In this study, we investigated the role of COX-2 in the neuroinflammatory response to intracerebroventricular-injected LPS (5 mu g), a model of direct activation of innate immunity, using COX-2 deficient (COX-2(-/-)) and wild type (COX-2(+/+))mice, as well as COX-2(+/+) mice pretreated for 6 weeks with celecoxib, a COX-2 selective inhibitor. Results: Twenty-four hours after LPS injection, COX-2(-/-) mice showed increased neuronal damage, glial cell activation, mRNA and protein expression of markers of inflammation and oxidative stress, such as cytokines, chemokines, iNOS and NADPH oxidase. Brain protein levels of IL-1 beta, NADPH oxidase subunit p67(phox), and phosphorylated-signal transducer and activator of transcription 3 (STAT3) were higher in COX-2(-/-) and in celecoxib-treated mice, compared to COX-2(+/+) mice. The increased neuroinflammatory response in COX-2(-/-) mice was likely mediated by the upregulation of STAT3 and suppressor of cytokine signaling 3 (SOCS3). Conclusion: These results show that inhibiting COX-2 activity can exacerbate the inflammatory response to LPS, possibly by increasing glial cells activation and upregulating the STAT3 and SOCS3 pathways in the brain. C1 [Aid, Saba; Bosetti, Francesca] NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. [Langenbach, Robert] Natl Inst Environm Hlth, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Bosetti, F (reprint author), NIA, NIH, Brain Physiol & Metab Sect, 9000 Mem Dr,Bldg 9 Room 1S126, Bethesda, MD 20892 USA. EM aidsab@mail.nih.gov; langenb1@niehs.nih.gov; frances@mail.nih.gov FU Intramural NIH HHS NR 68 TC 69 Z9 72 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAY 19 PY 2008 VL 5 AR 17 DI 10.1186/1742-2094-5-17 PG 14 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 313AV UT WOS:000256714400002 PM 18489773 ER PT J AU Dumitrescu, CE Collins, MT AF Dumitrescu, Claudia E. Collins, Michael T. TI McCune-Albright syndrome SO ORPHANET JOURNAL OF RARE DISEASES LA English DT Review ID POLYOSTOTIC FIBROUS DYSPLASIA; GROWTH-HORMONE EXCESS; STIMULATORY G-PROTEIN; ACTIVATING MUTATIONS; PRECOCIOUS PUBERTY; SECONDARY HYPERPARATHYROIDISM; THYROID ABNORMALITIES; PAMIDRONATE TREATMENT; HYPOVITAMINOSIS-D; NATURAL-HISTORY AB McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of bone (FD), cafe-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome, and renal phosphate wasting. Cafe-au-lait spots usually appear in the neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal involvement is seen in approximately 50% of the patients with MAS. The disease results from somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, G(s) alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however, should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is dictated by the tissues affected, and the extent to which they are affected. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS. C1 [Dumitrescu, Claudia E.; Collins, Michael T.] Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Dumitrescu, CE (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. EM mosteanuc@nidcr.nih.gov; mc247k@nih.gov NR 70 TC 95 Z9 103 U1 5 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1172 J9 ORPHANET J RARE DIS JI Orphanet J. Rare Dis. PD MAY 19 PY 2008 VL 3 AR 12 DI 10.1186/1750-1172-3-12 PG 12 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 336OT UT WOS:000258375200001 PM 18489744 ER PT J AU Nsubuga, MM Biggar, RJ Combs, S Marshall, V Mbisa, G Kambugu, F Mehta, M Biryahwaho, B Rabkin, CS Whitby, D Mbulaiteye, SM AF Nsubuga, Martin M. Biggar, Robert J. Combs, Susan Marshall, Vickie Mbisa, Georgina Kambugu, Fred Mehta, Meghna Biryahwaho, Benon Rabkin, Charles S. Whitby, Denise Mbulaiteye, Sam M. TI Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions SO CANCER LETTERS LA English DT Article DE Africa; epidemiology; immunosuppression ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; HERPESVIRUS VIREMIA; LYTIC REPLICATION; PERIPHERAL-BLOOD; QUANTIFICATION; POPULATION; INFECTION; SEQUENCES; HYPOXIA AB Introduction: Human herpesvirus 8 (HHV8) is necessary for Kaposi sarcoma (KS) to develop, but whether peripheral blood viral load is a marker of KS burden (total number of KS lesions), KS progression (the rate of eruption of new KS lesions), or both is unclear. We investigated these relationships in persons with AIDS. Methods: Newly diagnosed patients with AIDS-related KS attending Mulago Hospital, in Kampala, Uganda, were assessed for KS burden and progression by questionnaire and medical examination. Venous blood samples were taken for HHV8 load measurements by PCR. Associations were examined with odds ratio (OR) and 95% confidence intervals (CI) from logistic regression models and with t-tests. Results: Among 74 patients (59% men), median age was 34.5 years (interquartile range [IQR], 28.5-41). HHV8 DNA was detected in 93% and quantified in 77% patients. Median virus load was 3.8 logs(10)/10(6) peripheral blood cells (IQR 3.4-5.0) and was higher in men than women (4.4 vs. 3.8 logs; p = 0.04), in patients with faster (>20 lesions per year) than slower rate of KS lesion eruption (4.5 vs. 3.6 logs; p < 0.001). and higher, but not significantly, among patients with more (>median 20 KS lesions) than fewer KS lesions (4.4 vs. 4.0 logs; p = 0.16). HHV8 load was unrelated to CD4 lymphocyte count (p = 0.23). Conclusions: We show significant association of HHV8 load in peripheral blood with rate of eruption of KS lesions, but not with total lesion count. Our results suggest that viral load increases concurrently with development of new KS lesions. Published by Elsevier Ireland Ltd. C1 [Biggar, Robert J.; Combs, Susan; Rabkin, Charles S.; Mbulaiteye, Sam M.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Nsubuga, Martin M.; Kambugu, Fred; Mehta, Meghna] Makerere Univ, Sch Med, Kampala, Uganda. State Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. [Marshall, Vickie; Mbisa, Georgina; Whitby, Denise] NCI, Viral Oncol Sect, AIDS Vaccine Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Biryahwaho, Benon] Uganda Virus Res Inst, Entebbe, Uganda. RP Mbulaiteye, SM (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 7080, Bethesda, MD 20892 USA. EM mbulaits@mail.nih.gov FU Intramural NIH HHS [Z01 CP010150-08, Z01 CP010176-07, Z99 CA999999]; NCI NIH HHS [N01CO12400] NR 25 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAY 18 PY 2008 VL 263 IS 2 BP 182 EP 188 DI 10.1016/j.canlet.2007.12.025 PG 7 WC Oncology SC Oncology GA 300FU UT WOS:000255810500004 PM 18234418 ER PT J AU Espinoza, F Silverman, D Kogevinas, M Creus, A Fernandez, F Garcia-Closas, M Tardon, A Garcia-Closas, R Serra, C Carrato, A Rothman, N Dosemeci, M Malats, N Marcos, R AF Espinoza, Felicidad Silverman, Debra Kogevinas, Manolis Creus, Amadeu Fernandez, Francisco Garcia-Closas, Montserrat Tardon, Adonina Garcia-Closas, Reina Serra, Consol Carrato, Alfredo Rothman, Nathaniel Dosemeci, Mustafa Malats, Nuria Marcos, Ricard TI Micronuclei assessment in the urothelial cells of women using hair dyes and its modulation by genetic polymorphisms SO CANCER LETTERS LA English DT Article DE hair dyes; urothelial cells; micronucleus test; genotoxicity; NAT1; NAT2; GSTM1 ID BLADDER-CANCER RISK; CHROMOSOMAL-ABERRATIONS; PERIPHERAL LYMPHOCYTES; PARA-PHENYLENEDIAMINE; EXFOLIATED CELLS; FANCONI-ANEMIA; PERSONAL USE; DAMAGE; ASSAY; GENOTOXICITY AB Increases in the frequency of micronuclei (MN) in exposed cells can be used as a measure of genotoxicity. Hair dyes contain chemicals that are eliminated by urine and could be genotoxic to urothelial cells. To address this question, we evaluated whether hair dye use is associated with an increase in the frequency of MN in urothelial cells, and whether this association is modified by NAT1 (N-acetyltransferase 1), NAT2 (N-acetyltransferase 2) and GSTM1 (glutathione-S-transferase M1) genotypes. We included 92 women participating as controls in a bladder cancer case-control study in Spain. Of those, 72 had adequate number of cells to be included in the MN analysis. There were no significant differences in the mean MN frequency in women using hair dyes in the last month (9.88 MN/1000 cells), in comparison with the MN in unexposed women (9.50 MN/1000 cells). No statistically significant differences in MN frequency were observed by type of hair dye or color of the hair dye. Comparison of subjects in the highest quartile of MN frequency (>= 12 MN/1000 cells) and those in the lowest quartile (<= 4 MN/1000 cells) suggested an association between hair dye use and elevated MN frequency (OR 14.2 (95% CI 0.81-247.8; P = 0.069)). None of the polymorphisms examined significantly modified association between hair dye use and frequency of MN. Findings of an increased frequency of MN in urothelial cells of hair dye users suggest a possible genotoxic effect of hair dye compounds and need confirmation in larger studies. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Espinoza, Felicidad; Creus, Amadeu; Marcos, Ricard] Univ Autonoma Barcelona, Dept Genet & Microbiol, Grp Mutagenesi, Bellaterra 08193, Spain. [Silverman, Debra; Garcia-Closas, Montserrat; Rothman, Nathaniel; Dosemeci, Mustafa] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kogevinas, Manolis; Fernandez, Francisco; Malats, Nuria] Municipal Inst Med Res, Ctr Res Environm Epidemiol, Barcelona, Spain. [Kogevinas, Manolis] Univ Crete, Sch Med, Iraklion, Greece. [Tardon, Adonina] Univ Oviedo, Oviedo, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Tenerife, Spain. [Serra, Consol] Consorci Hosp Parc Tauli, Sabadell, Spain. [Carrato, Alfredo] Hosp Gen Univ Elche, Elche, Spain. RP Marcos, R (reprint author), Univ Autonoma Barcelona, Dept Genet & Microbiol, Grp Mutagenesi, Edifici Cn, Bellaterra 08193, Spain. EM Ricard.Marcos@uab.es RI Garcia-Closas, Montserrat /F-3871-2015; Kogevinas, Manolis/C-3918-2017; Creus, Amadeu/A-7778-2013; Serra, C/E-6879-2014 OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Marcos, Ricard/0000-0001-7891-357X; Creus, Amadeu/0000-0003-0848-9448; Serra, C/0000-0001-8337-8356 FU Intramural NIH HHS; NCI NIH HHS [N02-CP-11015] NR 51 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAY 18 PY 2008 VL 263 IS 2 BP 259 EP 266 DI 10.1016/j.canlet.2008.01.010 PG 8 WC Oncology SC Oncology GA 300FU UT WOS:000255810500013 PM 18262724 ER PT J AU Polavarapu, N Marino-Ramirez, L Landsman, D McDonald, JF Jordan, IK AF Polavarapu, Nalini Marino-Ramirez, Leonardo Landsman, David McDonald, John F. Jordan, I. King TI Evolutionary rates and patterns for human transcription factor binding sites derived from repetitive DNA SO BMC GENOMICS LA English DT Article ID TRANSPOSABLE ELEMENTS; HUMAN GENOME; REGULATORY SEQUENCES; GENE-REGULATION; REPEAT; RECRUITMENT; FRAGMENTS; INSERTION; SELECTION; PROMOTER AB Background: The majority of human non-protein-coding DNA is made up of repetitive sequences, mainly transposable elements (TEs). It is becoming increasingly apparent that many of these repetitive DNA sequence elements encode gene regulatory functions. This fact has important evolutionary implications, since repetitive DNA is the most dynamic part of the genome. We set out to assess the evolutionary rate and pattern of experimentally characterized human transcription factor binding sites (TFBS) that are derived from repetitive versus non-repetitive DNA to test whether repeat-derived TFBS are in fact rapidly evolving. We also evaluated the position-specific patterns of variation among TFBS to look for signs of functional constraint on TFBS derived from repetitive and non-repetitive DNA. Results: We found numerous experimentally characterized TFBS in the human genome, 7-10% of all mapped sites, which are derived from repetitive DNA sequences including simple sequence repeats (SSRs) and TEs. TE-derived TFBS sequences are far less conserved between species than TFBS derived from SSRs and non-repetitive DNA. Despite their rapid evolution, several lines of evidence indicate that TE-derived TFBS are functionally constrained. First of all, ancient TE families, such as MIR and L2, are enriched for TFBS relative to younger families like Alu and LI. Secondly, functionally important positions in TE-derived TFBS, specifically those residues thought to physically interact with their cognate protein binding factors (TF), are more evolutionarily conserved than adjacent TFBS positions. Finally, TE-derived TFBS show position-specific patterns of sequence variation that are highly distinct from random patterns and similar to the variation seen for non-repeat derived sequences of the same TFBS. Conclusion: The abundance of experimentally characterized human TFBS that are derived from repetitive DNA speaks to the substantial regulatory effects that this class of sequence has on the human genome. The unique evolutionary properties of repeat-derived TFBS are perhaps even more intriguing. TE-derived TFBS in particular, while clearly functionally constrained, evolve extremely rapidly relative to non-repeat derived sites. Such rapidly evolving TFBS are likely to confer species-specific regulatory phenotypes, i.e. divergent expression patterns, on the human evolutionary lineage. This result has practical implications with respect to the widespread use of evolutionary conservation as a surrogate for functionally relevant non-coding DNA. Most TE-derived TFBS would be missed using the kinds of sequence conservation-based screens, such as phylogenetic footprinting, that are used to help characterize non-coding DNA. Thus, the very TFBS that are most likely to yield human-specific characteristics will be neglected by the comparative genomic techniques that are currently de rigeur for the identification of novel regulatory sites. C1 [Polavarapu, Nalini; McDonald, John F.; Jordan, I. King] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Marino-Ramirez, Leonardo; Landsman, David] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Jordan, IK (reprint author), Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. EM nalini@gatech.edu; marino@ncbi.nlm.nih.gov; landsman@ncbi.nlm.nih.gov; john.mcdonald@biology.gatech.edu; king.jordan@biology.gatech.edu RI Landsman, David/C-5923-2009; Marino-Ramirez, Leonardo/I-5759-2013; OI Marino-Ramirez, Leonardo/0000-0002-5716-8512; Landsman, David/0000-0002-9819-6675 FU Intramural NIH HHS [Z99 LM999999] NR 40 TC 33 Z9 34 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 17 PY 2008 VL 9 AR 226 DI 10.1186/1471-2164-9-226 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 308OO UT WOS:000256400100001 PM 18485226 ER PT J AU Wu, YT Tan, HL Huang, Q Kim, YS Pan, N Ong, WY Liu, ZG Ong, CN Shen, HM AF Wu, You-Tong Tan, Hui-Ling Huang, Qing Kim, You-Sun Pan, Ning Ong, Wei-Yi Liu, Zheng-Gang Ong, Choon-Nam Shen, Han-Ming TI Autophagy plays a protective role during zVAD-induced necrotic cell death SO AUTOPHAGY LA English DT Article DE zVAD; autophagy; necrosis; cathepsin; L929 cells ID MAMMALIAN-CELLS; DNA-DAMAGE; APOPTOSIS; NECROSIS; DEGRADATION; SURVIVAL; CALPAIN; PROTEIN; STRESS; TUMORIGENESIS AB The aim of this study is to examine the role of autophagy in cell death by using a well-established system in which zVAD, a pan-caspase inhibitor, induces necrotic cell death in L929 murine fibrosarcoma cells. First, we observed the presence of autophagic hallmarks, including an increased number of autophagosomes and the accumulation of LC3-II in zVAD-treated L929 cells. Since the presence of such autophagic hallmarks could be the result of either increased flux of autophagy or blockage of autophagosome maturation (lysosomal fusion and degradation), we next tested the effect of rapamycin, a specific inhibitor for mTOR, and chloroquine, a lysosomal enzyme inhibitor, on zVAD-induced cell death. To our surprise, rapamycin, known to be an autophagy inducer, blocked zVAD-induced cell death, whereas chloroquine greatly sensitized zVAD-induced cell death in L929 cells. Moreover, similar results with rapamycin and chloroquine were also observed in U937 cells when challenged with zVAD. Consistently, induction of autophagy by serum starvation offered significant protection against zVAD-induced cell death, whereas knockdown of Atg5, Atg7 or Beclin I markedly sensitized zVAD-induced cell death in L929 cells. More importantly, Atg genes knockdown completely abolished the protective effect of serum starvation on zVAD-induced cell death. Finally, we demonstrated that zVAD was able to inhibit lysosomal enzyme cathepsin B activity, and subsequently blocked autophagosome maturation. Taken together, in contrast to the previous conception that zVAD induces autophagic cell death, here we provide compelling evidence suggesting that autophagy serves as a cell survival mechanism and suppression of autophagy via inhibition of lysosomal function contributes to zVAD-induced necrotic cell death. C1 [Wu, You-Tong; Tan, Hui-Ling; Huang, Qing; Ong, Choon-Nam; Shen, Han-Ming] Natl Univ Singapore, Dept Community Occupat & Family Med, Yong Loo Lin Sch Med, Singapore 117597, Singapore. [Pan, Ning; Ong, Wei-Yi] Natl Canc Inst, NIH, Baltimore, MD USA. [Kim, You-Sun; Liu, Zheng-Gang] Natl Univ Singapore, Dept Anat, Yong Loo Lin Sch Med, Singapore 117597, Singapore. RP Shen, HM (reprint author), Natl Univ Singapore, Dept Community Occupat & Family Med, Yong Loo Lin Sch Med, Singapore 117597, Singapore. EM cofshm@nus.edu.sg RI SHEN, Han-Ming/B-5942-2011; Ong, Choon Nam/E-8638-2010 OI SHEN, Han-Ming/0000-0001-7369-5227; NR 49 TC 111 Z9 118 U1 2 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD MAY 16 PY 2008 VL 4 IS 4 BP 457 EP 466 PG 10 WC Cell Biology SC Cell Biology GA 301NX UT WOS:000255904000010 PM 18253089 ER PT J AU Gould, TD O'Donnell, KC Picchini, AM Dow, ER Chen, G Manji, HK AF Gould, Todd D. O'Donnell, Kelley C. Picchini, Alyssa M. Dow, Eliot R. Chen, Guang Manji, Husseini K. TI Generation and behavioral characterization of beta-catenin forebrain-specific conditional knock-out mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE depression; bipolar disorder; mood; Wnt pathway; glycogen synthase kinase; behavior; mice ID GLYCOGEN-SYNTHASE KINASE-3; TAIL-SUSPENSION TEST; DEPRESSION-LIKE BEHAVIOR; FORCED SWIM TEST; MOUSE-BRAIN; SYNAPSIN-I; LITHIUM; STRAINS; EXPRESSION; SIGNAL AB The canonical Wnt pathway and beta-catenin have been implicated in the pathophysiology of mood disorders. We generated forebrain-specific CRE-mediated conditional P-catenin knock-out mice to begin exploring the behavioral implications of decreased Wnt pathway signaling in the central nervous system. In situ hybridization revealed a progressive knock-out of P-catenin that began between 2 and 4 weeks of age, and by 12 weeks resulted in considerably decreased P-catenin expression in regions of the forebrain, including the frontal cortex, hippocampus, and striatum. A significant decrease in protein levels of P-catenin in these brain regions was observed by Western blot. Behavioral characterization of these mice in several tests (including the forced swim test, tail suspension test (TST), learned helplessness, response and sensitization to stimulants, and light/dark box among other tests) revealed relatively circumscribed alterations. In the TST, knock-out mice spent significantly less time struggling (a depression-like phenotype). However, knock-out mice did not differ from their wild-type littermates in the other behavioral tests of mood-related or anxiety-related behaviors. These results suggest that a 60-70% beta-catenin reduction in circumscribed brain regions is only capable of inducing subtle behavioral changes. Alternatively, regulating P-catenin may modulate drug effects rather than being a model of mood disorder pathophysiology per se. (c) 2007 Elsevier B.V. All rights reserved. C1 [Gould, Todd D.; O'Donnell, Kelley C.; Picchini, Alyssa M.; Dow, Eliot R.; Chen, Guang; Manji, Husseini K.] NIMH, Lab Mol Pathophysiol & Expt Therapeut, Natl Inst Hlth, Bethesda, MD USA. RP Gould, TD (reprint author), Univ Maryland, Sch Med, Mood & Anxiety Disorders Program, Dept Psychiat, 701 W Pratt St,Suite 388, Baltimore, MD 21201 USA. EM tgould@psych.umaryland.edu RI Chen, Guang/A-2570-2017 FU Intramural NIH HHS [Z01 MH002841-04] NR 41 TC 43 Z9 43 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 16 PY 2008 VL 189 IS 1 BP 117 EP 125 DI 10.1016/j.bbr.2007.12.028 PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 289PG UT WOS:000255065800013 PM 18299155 ER PT J AU Minor, RK Villarreal, J McGraw, M Percival, SS Ingram, DK de Cabo, R AF Minor, Robin K. Villarreal, Julissa McGraw, Michael Percival, Susan S. Ingram, Donald K. de Cabo, Rafael TI Calorie restriction alters physical performance but not cognition in two models of altered neuroendocrine signaling SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE behavior; calorie restriction; cognition; hypothalamus; learning; monosodium glutamate (MSG); neuroendocrine system; neuropeptide Y (NPY) ID NEONATAL MONOSODIUM GLUTAMATE; ADMINISTERED NEUROPEPTIDE-Y; CHRONIC FOOD RESTRICTION; ARCUATE NUCLEUS; DIETARY RESTRICTION; NEURODEGENERATIVE DISORDERS; MOLECULAR-MECHANISMS; MOTOR-PERFORMANCE; TRANSGENIC RATS; INDUCED OBESITY AB A major neuroendocrinological effect of calorie restriction (CR) is induction of neuropeptide Y (NPY) in the arcuate nucleus (ARC). Aside from its appetite-stimulating effects, NPY is thought to be involved in the modulation of behavioral processes including anxiety and learning and memory. In the present study physical fitness, anxiety, and learning/memory-related tasks were assessed in mice lacking NPY or a functional ARC after dietary manipulation by CR. Physical fitness was improved by CR when measured by inclined screen and rotarod, and this diet effect was not affected by NPY or ARC status. As has been observed previously, the NPY knockout mice displayed heightened anxiety in an open field. This phenotype was not fully recapitulated in the ARC-lesioned model. CR affected neither total locomotor activity in the open field nor thigmotaxic behavior in these models. Neither NPY nor CR had a significant effect on Morris water maze performance; however, ARC-damaged mice were unable to learn the task, and this deficit was not corrected by CR. We conclude that despite established effects of CR on ARC signaling, our results suggest a mechanistic separation between the two where behavior is concerned. Published by Elsevier B.V. C1 [Minor, Robin K.; Villarreal, Julissa; McGraw, Michael; Ingram, Donald K.; de Cabo, Rafael] NIA, NIH, Intramural Res Program, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Minor, Robin K.; Percival, Susan S.] Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP de Cabo, R (reprint author), NIA, NIH, Intramural Res Program, Lab Expt Gerontol, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS NR 61 TC 16 Z9 16 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAY 16 PY 2008 VL 189 IS 1 BP 202 EP 211 DI 10.1016/j.bbr.2007.12.030 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 289PG UT WOS:000255065800022 PM 18291538 ER PT J AU Osabe, M Sugatani, J Takemura, A Yamazaki, Y Ikari, A Kitamura, N Negishi, M Miwa, M AF Osabe, Makoto Sugatani, Junko Takemura, Akiko Yamazaki, Yasuhiro Ikari, Akira Kitamura, Naomi Negishi, Masahiko Miwa, Masao TI Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE CAR; CDK4; MDM2; cell proliferation; HGF; UGT1A1 ID HEPATOCYTE GROWTH-FACTOR; NUCLEAR RECEPTOR; UGT1A1 GENE; CYCLE; MDM2; P53 AB Constitutive androstane receptor (CAR) is a transcription factor to regulate the expression of several genes related to drug-metabolism. Here, we demonstrate that CAR protein accumulates during G1 in human SW480 and HepG2 cells. After the G1/S phase transition, CAR protein levels decreased, and CAR was hardly detected in cells by the late M phase. CAR expression in both cell lines was suppressed by RNA interference-mediated suppression of CDK4. Depletion of CAR by RNA interference in both cells and by hepatocyte growth factor treatment in HepG2 cells resulted in decreased MDM2 expression that led to p21 upregulation and repression of HepG2 cell growth. Thus, our results demonstrate that CAR expression is an early G1 event regulated by CDK4 that contributes to MDM2 expression; these findings suggest that CAR may influence the expression of genes involved in not only the metabolism of endogenous and exogenous substances but also in the cell proliferation. (C) 2008 Elsevier Inc. All rights reserved. C1 [Osabe, Makoto; Sugatani, Junko; Takemura, Akiko; Yamazaki, Yasuhiro; Ikari, Akira; Miwa, Masao] Univ Shizuoka, Sch Pharmaceut Sci, Dept Pharmacobiochem, Suruga Ku, Shizuoka 4228526, Japan. [Sugatani, Junko] Univ Shizuoka, Sch Pharmaceut Sci, Global COE Program, Shizuoka 4228526, Japan. [Kitamura, Naomi] Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biol Sci, Yokohama, Kanagawa 227, Japan. [Negishi, Masahiko] Natl Inst Environm Hlth Sci, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC USA. RP Sugatani, J (reprint author), Univ Shizuoka, Sch Pharmaceut Sci, Dept Pharmacobiochem, Suruga Ku, 52-1 Yada, Shizuoka 4228526, Japan. EM sugatani@u-shizuoka-ken.ac.jp NR 15 TC 15 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 16 PY 2008 VL 369 IS 4 BP 1027 EP 1033 DI 10.1016/j.bbrc.2008.02.140 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 286RW UT WOS:000254864700008 PM 18331826 ER PT J AU Shen, JS Edwards, NJ Bin Hong, Y Murray, GJ AF Shen, Jin-Song Edwards, Nancy J. Bin Hong, Young Murray, Gary J. TI Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE pharmacological chaperone; Gaucher disease; lysosomal storage disorders; glucocerebrosidase; molecular chaperone; molecular mechanisms of pharmacological action; enzyme replacement therapy ID ACID BETA-GLUCOSIDASE; MANNOSE-TERMINAL GLUCOCEREBROSIDASE; ENZYME REPLACEMENT; CHAPERONES INCREASE; GAUCHER-DISEASE; ACTIVE-SITE; INHIBITORS; FIBROBLASTS; THERAPY; SLOW AB Intravenous enzyme replacement therapy (ERT) with purified glucocerebrosidase (GLA) leads to significant improvement of the clinical manifestations in patients with Type 1 Gaucher disease. However, the high doses required, slow response and inability to recover most of the infused enzyme in the target tissues may be attributed to losses occurring during transit en route to the lysosome. Preincubation of GLA with isofagomine (IFG), a slow-binding inhibitor, significantly increased stability of the enzyme to heat, neutral pH and denaturing agents in vitro. Preincubation of GLA with isofagomine prior to uptake by cultured cells results in increased intracellular enzyme activity accompanied by an increase in enzyme protein suggesting that reduced denaturation of GLA in the presence of isofagomine leads to a decrease in the degradation of the enzyme after internalization. Preincubation of GLA with slow-binding inhibitors before infusion may improve the effectiveness of ERT for Gaucher disease. Published by Elsevier Inc. C1 [Shen, Jin-Song; Edwards, Nancy J.; Bin Hong, Young; Murray, Gary J.] Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Murray, GJ (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D04,9000 Rockville Pike, Bethesda, MD 20892 USA. EM murrayg@mail.nih.gov FU Intramural NIH HHS [Z01 NS002982-09] NR 23 TC 37 Z9 37 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 16 PY 2008 VL 369 IS 4 BP 1071 EP 1075 DI 10.1016/j.bbrc.2008.02.125 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 286RW UT WOS:000254864700016 PM 18328804 ER PT J AU Zaslavsky, L Bao, Y Tatusova, TA AF Zaslavsky, Leonid Bao, Yiming Tatusova, Tatiana A. TI Visualization of large influenza virus sequence datasets using adaptively aggregated trees with sampling-based subscale representation SO BMC BIOINFORMATICS LA English DT Article ID EVOLUTION; TIME AB Background: With the amount of influenza genome sequence data growing rapidly, researchers need machine assistance in selecting datasets and exploring the data. Enhanced visualization tools are required to represent results of the exploratory analysis on the web in an easy-to-comprehend form and to facilitate convenient information retrieval. Results: We developed an approach to visualize large phylogenetic trees in an aggregated form with a special representation of subscale details. The initial aggregated tree representation is built with a level of resolution automatically selected to fit into the available screen space, with terminal groups selected based on sequence similarity. The default aggregated representation can be refined by users interactively. Structure and data variability within terminal groups are displayed using small trees that have the same vertical size as the text annotation of the group. These subscale representations are calculated using systematic sampling from the corresponding terminal group. The aggregated tree containing terminal groups can be annotated using aggregation of structured metadata, such as seasonal distribution, geographic locations, etc. Availability: The algorithms are implemented in JavaScript within the NCBI Influenza Virus Resource [1]. C1 [Zaslavsky, Leonid; Bao, Yiming; Tatusova, Tatiana A.] Natl Lib Med, Ctr Informat Biol, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Zaslavsky, L (reprint author), Natl Lib Med, Ctr Informat Biol, Natl Inst Hlth, Bethesda, MD 20894 USA. EM zaslavsk@ncbi.nlm.nih.gov; bao@ncbi.nlm.nih.gov; tatiana@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 25 TC 17 Z9 17 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 16 PY 2008 VL 9 AR 237 DI 10.1186/1471-2105-9-237 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 314SK UT WOS:000256828900001 PM 18485197 ER PT J AU Huzil, JT Chik, JK Slysz, GW Freedman, H Tuszynski, J Taylor, RE Sackett, DL Schriemer, DC AF Huzil, J. Torin Chik, John K. Slysz, Gordon W. Freedman, Holly Tuszynski, Jack Taylor, Richard E. Sackett, Dan L. Schriemer, David C. TI A unique mode of microtubule stabilization induced by peloruside A SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE microtubules; peloruside A; mass spectrometry; hydrogen-deuterium exchange; simulations ID EXCHANGE MASS-SPECTROMETRY; RESISTANT CELL-LINES; BETA-TUBULIN; TAXOID SITE; AUTOMATED DOCKING; CREMOPHOR-EL; EPOTHILONE-A; LAULIMALIDE; PACLITAXEL; AGENTS AB Microtubules are significant therapeutic targets for the treatment of cancer, where suppression of microtubule dynamicity by drugs such as paclitaxel forms the basis of clinical efficacy. Peloruside A, a macrolide isolated from New Zealand marine sponge Mycale hentscheli, is a microtubule-stabilizing agent that synergizes with taxoid drugs through a unique site and is an attractive lead compound in the development of combination therapies. We report here unique allosteric properties of microtubule stabilization via peloruside A and present a structural model of the peloruside-binding site. Using a strategy involving comparative hydrogen-deuterium exchange mass spectrometry of different microtubule-stabilizing agents, we suggest that taxoid-site ligands epothilone A and docetaxel stabilize microtubules primarily through improved longitudinal interactions centered on the interdimer interface, with no observable contributions from lateral interactions between protofilaments. The mode by which peloruside A achieves microtubule stabilization also involves the interdimer interface, but includes contributions from the alpha/beta-tubulin intradimer interface and protofilament contacts, both in the form of destabilizations. Using data-directed molecular docking simulations, we propose that peloruside A binds within a pocket on the exterior of beta-tubulin at a previously unknown ligand site, rather than on a-tubulin as suggested in earlier studies. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Chik, John K.; Slysz, Gordon W.; Schriemer, David C.] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Huzil, J. Torin; Freedman, Holly; Tuszynski, Jack] Cross Canc Inst, Div Expt Oncol E, Edmonton, AB T6G 1Z2, Canada. [Taylor, Richard E.] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Taylor, Richard E.] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA. [Sackett, Dan L.] NICHHD, NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RP Schriemer, DC (reprint author), Univ Calgary, Fac Med, Dept Biochem & Mol Biol, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM dschriem@ucalgary.ca FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM077683, R01 GM077683-06, R01 GM077683-07] NR 50 TC 92 Z9 94 U1 0 U2 15 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 16 PY 2008 VL 378 IS 5 BP 1016 EP 1030 DI 10.1016/j.jmb.2008.03.026 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 305IO UT WOS:000256171900005 PM 18405918 ER PT J AU Adams, BJ Carr, JG Ozonoff, A Lauer, MS Balady, GJ AF Adams, Brian J. Carr, John G. Ozonoff, Al Lauer, Michael S. Balady, Gary J. TI Effect of exercise training in supervised cardiac rehabilitation programs on prognostic variables from the exercise tolerance test SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HEART-RATE RECOVERY; CORONARY-ARTERY DISEASE; IMPAIRED CHRONOTROPIC RESPONSE; TREADMILL EXERCISE; PULMONARY REHABILITATION; MYOCARDIAL-INFARCTION; AMERICAN ASSOCIATION; MORTALITY; PREDICTOR; SCORE AB Meta-analyses showed that exercise training decreased mortality in patients after myocardial infarction, but no single adequately powered trial has shown this benefit. The purpose of this study was to evaluate the effect of cardiac rehabilitative exercise training on prognostic variables derived from the exercise tolerance test and whether these changes had an effect on predicted cardiovascular and all-cause mortality using externally validated risk scores. Two hundred ten consecutive patients who completed a 12-week cardiac rehabilitation program were analyzed. Peak MET level, heart rate recovery, chronotropic index, Duke prognostic score, and Cleveland Clinic Foundation risk score obtained at program entry and exit were compared. All prognostic variables and risk score-derived predicted 5-year mortality rates improved significantly after cardiac rehabilitation. Exercise capacity increased by 32% (6.6 +/- 2.7 to 8.7 +/- 2.9 METS; p <0.0001), heart rate recovery increased by 20% (15 +/- 9 to 18 +/- 10 beats/min; p <0.0001), and chronotropic index increased by 11% (56 +/- 22% to 62 +/- 22%; p <0.0001). Duke prognostic score 5-year predicted cardiovascular mortality rate decreased by 33% (6 +/- 4% to 4 +/- 2%; p <0.0001), and Cleveland Clinic Foundation risk score 5-year predicted total mortality rate decreased by 40% (5 +/- 7% to 3 +/- 5%; p <0.0001). These improvements remained significant in high-risk subgroups. When controlled for age, gender, diabetes, MET level achieved, ejection fraction, and beta-blocker use, changes remained significant (p <0.0001) for each outcome measure. In conclusion, exercise training in supervised cardiac rehabilitation programs significantly improved exercise capacity, measures of chronotropic dynamics, and prognostic risk scores. These differences translate into a decrease in predicted mortality. (C) 2008 Elsevier Inc. All rights reserved. C1 [Adams, Brian J.; Carr, John G.; Ozonoff, Al; Balady, Gary J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect,Boston Med Ctr, Boston, MA 02118 USA. [Lauer, Michael S.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Lauer, Michael S.] NHLBI, Div Prevent & Popoulat Sci, Bethesda, MD 20892 USA. RP Balady, GJ (reprint author), Boston Univ, Sch Med, Dept Med, Cardiol Sect,Boston Med Ctr, Boston, MA 02118 USA. EM gary.balady@bmc.org RI Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Ozonoff, Al/0000-0003-4233-5899 NR 28 TC 23 Z9 24 U1 0 U2 8 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2008 VL 101 IS 10 BP 1403 EP 1407 DI 10.1016/j.amjcard.2008.01.016 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 302LO UT WOS:000255970000006 PM 18471449 ER PT J AU Johansen, AMW Lie, RT Wilcox, AJ Andersen, LF Drevon, CA AF Johansen, Anne Marte W. Lie, Rolv T. Wilcox, Allen J. Andersen, Lene F. Drevon, Christian A. TI Maternal dietary intake of vitamin A and risk of orofacial clefts: A population-based case-control study in Norway SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; cleft lip; cleft palate; diet; Norway; pregnancy; vitamin A ID FOOD FREQUENCY QUESTIONNAIRE; BIRTH-DEFECTS; SUPPLEMENTS; ANOMALIES; EXPOSURE; RETINOL; PALATE; WOMEN; WATER; LIP AB A population-based case-control study was carried out in Norway between 1996 and 2001. The aim was to evaluate the association between maternal intake of vitamin A from diet and supplements and risk of having a baby with an orofacial cleft. Data on maternal dietary intake were available from 535 cases (188 with cleft palate only and 347 with cleft lip with or without cleft palate) and 693 controls. The adjusted odds ratio for isolated cleft palate only was 0.47 (95% confidence interval: 0.24, 0.94) when comparing the fourth and first quartiles of maternal intake of total vitamin A. In contrast, there was no appreciable association of total vitamin A with isolated cleft lip with or without cleft palate. An intake of vitamin A above the 95th percentile was associated with a lower estimated risk of all isolated clefts compared with the 40th-60th percentile (adjusted odds ratio = 0.48, 95% confidence interval: 0.20, 1.14). Maternal intake of vitamin A is associated with reduced risk of cleft palate only, and there is no evidence of increased risk of clefts among women in our study with the highest 5% of vitamin A intake. C1 [Johansen, Anne Marte W.; Andersen, Lene F.; Drevon, Christian A.] Univ Oslo, Dept Nutr, Inst Basic Med Sci, Fac Med, N-0316 Oslo, Norway. [Lie, Rolv T.] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Epidemiol & Med Stat, Bergen, Norway. [Wilcox, Allen J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Durham, NC USA. RP Johansen, AMW (reprint author), Univ Oslo, Dept Nutr, Inst Basic Med Sci, Fac Med, POB 1046, N-0316 Oslo, Norway. EM a.m.w.johansen@medisin.uio.no RI Drevon, Christian /F-6012-2010; OI Wilcox, Allen/0000-0002-3376-1311 NR 26 TC 17 Z9 19 U1 0 U2 2 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 MAY 15 PY 2008 VL 167 IS 10 BP 1164 EP 1170 DI 10.1093/aje/kwn035 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 299LC UT WOS:000255756100004 PM 18343877 ER PT J AU Prentice, RL Chlebowski, RT Stefanick, ML Manson, JE Pettinger, M Hendrix, SL Hubbell, FA Kooperberg, C Kuller, LH Lane, DS McTiernan, A O'Sullivan, MJ Rossouw, JE Anderson, GL AF Prentice, Ross L. Chlebowski, Rowan T. Stefanick, Marcia L. Manson, JoAnn E. Pettinger, Mary Hendrix, Susan L. Hubbell, F. Allan Kooperberg, Charles Kuller, Lewis H. Lane, Dorothy S. McTiernan, Anne O'Sullivan, Mary Jo Rossouw, Jacques E. Anderson, Garnet L. TI Estrogen plus progestin therapy and breast cancer in recently postmenopausal women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; clinical trials as topic; cohort studies; estrogens; hormone replacement therapy; postmenopause; progestins ID INITIATIVE RANDOMIZED-TRIAL; HORMONE-REPLACEMENT THERAPY; MAMMOGRAPHIC DENSITY; CLINICAL-TRIAL; CARDIOVASCULAR-DISEASE; RISK; CELLS; HYSTERECTOMY; RELIABILITY; BENEFITS AB The Women's Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy ("gap time") in the Women's Health Initiative trial and in a corresponding subset of the Women's Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993-1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use. C1 [Prentice, Ross L.; Pettinger, Mary; Kooperberg, Charles; McTiernan, Anne; Anderson, Garnet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Chlebowski, Rowan T.] Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Los Angeles, CA 90024 USA. [Stefanick, Marcia L.] Stanford Univ, Stanford Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Hendrix, Susan L.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Hubbell, F. Allan] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Kuller, Lewis H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Lane, Dorothy S.] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [O'Sullivan, Mary Jo] Univ Miami, Dept Obstet & Gynecol, Miami, FL 33152 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM rprentic@fhcrc.org FU NCI NIH HHS [P01 CA053996, CA53996]; WHI NIH HHS [N01 WH022110, N01 WH022110-024] NR 29 TC 89 Z9 89 U1 1 U2 1 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 MAY 15 PY 2008 VL 167 IS 10 BP 1207 EP 1216 DI 10.1093/aje/kwn044 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 299LC UT WOS:000255756100009 PM 18372396 ER PT J AU Montgomery, MP Kamel, F Saldana, TM Alavanja, CR Sandler, DP AF Montgomery, M. P. Kamel, F. Saldana, T. M. Alavanja, C. R. Sandler, D. P. TI Incident diabetes and pesticide exposure among licensed pesticide applicators: Agricultural Health Study, 1993-2003 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE agrochemicals; diabetes mellitus; environmental exposure; hydrocarbons; chlorinated; insecticides; pesticides; phosphoric acid esters ID PERSISTENT ORGANIC POLLUTANTS; OPERATION RANCH HAND; SERUM CONCENTRATIONS; CHLORDANE TOXICITY; NATIONAL-HEALTH; INSULIN; DIOXIN; VETERANS; ASSOCIATION; DICHLORVOS AB Exposure to certain environmental toxicants may be associated with increased risk of developing diabetes. The authors' aim was to investigate the relation between lifetime exposure to specific agricultural pesticides and diabetes incidence among pesticide applicators. The study included 33,457 licensed applicators, predominantly non-Hispanic White males, enrolled in the Agricultural Health Study. Incident diabetes was self-reported in a 5-year follow-up interview (1999-2003), giving 1,176 diabetics and 30,611 nondiabetics for analysis. Lifetime exposure to pesticides and covariate information were reported by participants at enrollment (1993-1997). Using logistic regression, the authors considered two primary measures of pesticide exposure: ever use and cumulative lifetime days of use. They found seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor, and cyanazine) for which the odds of diabetes incidence increased with both ever use and cumulative days of use. Applicators who had used the organochlorine insecticides aldrin, chlordane, and heptachlor more than 100 lifetime days had 51%, 63%, and 94% increased odds of diabetes, respectively. The observed association of organochlorine and organophosphate insecticides with diabetes is consistent with results from previous human and animal studies. Long-term exposure from handling certain pesticides, in particular, organochlorine and organophosphate insecticides, may be associated with increased risk of diabetes. C1 [Montgomery, M. P.; Kamel, F.; Sandler, D. P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Saldana, T. M.] Social & Sci Syst, Durham, NC USA. [Alavanja, C. R.] NCI, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. RP Sandler, DP (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sandler@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS [Z01 ES049030-11] NR 29 TC 83 Z9 86 U1 1 U2 10 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 MAY 15 PY 2008 VL 167 IS 10 BP 1235 EP 1246 DI 10.1093/aje/kwn028 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 299LC UT WOS:000255756100012 PM 18343878 ER PT J AU Neuhouser, ML Tinker, L Shaw, PA Schoeller, D Bingham, SA Van Horn, L Beresford, SAA Caan, B Thomson, C Satterfield, S Kuller, L Heiss, G Smit, E Sarto, G Ockene, J Stefanick, ML Assaf, A Runswick, S Prentice, RL AF Neuhouser, Marian L. Tinker, Lesley Shaw, Pamela A. Schoeller, Dale Bingham, Sheila A. Van Horn, Linda Beresford, Shirley A. A. Caan, Bette Thomson, Cynthia Satterfield, Suzanne Kuller, Lew Heiss, Gerardo Smit, Ellen Sarto, Gloria Ockene, Judith Stefanick, Marcia L. Assaf, Annlouise Runswick, Shirley Prentice, Ross L. TI Use of recovery biomarkers to calibrate nutrient consumption self-reports in the Women's Health Initiative SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); biological markers; diet; energy intake; epidemiologic methods; measurement error; nutrition assessment; proteins ID DIETARY MODIFICATION TRIAL; DOUBLY LABELED WATER; FOOD-FREQUENCY QUESTIONNAIRE; MEASUREMENT ERROR; ENERGY-EXPENDITURE; NUTRITIONAL EPIDEMIOLOGY; BIOCHEMICAL MARKERS; URINE COLLECTIONS; BREAST-CANCER; FAT AB Underreporting of energy consumption by self-report is well-recognized, but previous studies using recovery biomarkers have not been sufficiently large to establish whether participant characteristics predict misreporting. In 2004-2005, 544 participants in the Women's Health Initiative Dietary Modification Trial completed a doubly labeled water protocol (energy biomarker), 24-hour urine collection (protein biomarker), and self-reports of diet (assessed by food frequency questionnaire (FFQ)), exercise, and lifestyle habits; 111 women repeated all procedures after 6 months. Using linear regression, the authors estimated associations of participant characteristics with misreporting, defined as the extent to which the log ratio (self-reported FFQ/nutritional biomarker) was less than zero. Intervention women in the trial underreported energy intake by 32% (vs. 27% in the comparison arm) and protein intake by 15% (vs. 10%). Younger women had more underreporting of energy (p = 0.02) and protein (p = 0.001), while increasing body mass index predicted increased underreporting of energy and overreporting of percentage of energy derived from protein (p = 0.001 and p = 0.004, respectively). Blacks and Hispanics underreported more than did Caucasians. Correlations of initial measures with repeat measures (n = 111) were 0.72, 0.70, 0.46, and 0.64 for biomarker energy, FFQ energy, biomarker protein, and FFQ protein, respectively. Recovery biomarker data were used in regression equations to calibrate self-reports; the potential application of these equations to disease risk modeling is presented. The authors confirm the existence of systematic bias in dietary self-reports and provide methods of correcting for measurement error. C1 [Neuhouser, Marian L.; Tinker, Lesley; Beresford, Shirley A. A.; Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Schoeller, Dale] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Bingham, Sheila A.; Runswick, Shirley] Univ Cambridge, Med Res Council Dunn Human Nutr Unit, Cambridge, England. [Van Horn, Linda] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Beresford, Shirley A. A.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Caan, Bette] Kaiser Permanente, Div Res, Oakland, CA USA. [Thomson, Cynthia] Univ Arizona, Coll Agr & Life Sci, Dept Nutr Sci, Tucson, AZ USA. [Thomson, Cynthia] Univ Arizona, Arizona Canc Ctr, Div Prevent & Control, Tucson, AZ USA. [Satterfield, Suzanne] Univ Tennessee, Hlth Sci Ctr, Coll Med, Dept Prevent Med, Memphis, TN USA. [Kuller, Lew] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Heiss, Gerardo] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Smit, Ellen] Portland State Univ, Coll Urban & Publ Affairs, Sch Community Hlth, Portland, OR 97207 USA. [Sarto, Gloria] Univ Wisconsin, Sch Med, Dept Obstet & Gynecol, Madison, WI USA. [Ockene, Judith] Univ Massachusetts, Med Ctr, Dept Med, Worcester, MA USA. [Stefanick, Marcia L.] Stanford Univ, Stanford Prevent Res Ctr, Palo Alto, CA 94304 USA. [Assaf, Annlouise] Pfizer Inc, New York, NY USA. RP Neuhouser, ML (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 110 Fairview Ave N,M4B402, Seattle, WA 98109 USA. EM mneuhous@fhcrc.org FU Medical Research Council [MC_U105630924]; NCI NIH HHS [R01 CA119171]; WHI NIH HHS [N01 WH042116, N01 WH032100, N01 WH032105, N01 WH042112, N01WH22110] NR 49 TC 148 Z9 148 U1 1 U2 11 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 MAY 15 PY 2008 VL 167 IS 10 BP 1247 EP 1259 DI 10.1093/aje/kwn026 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 299LC UT WOS:000255756100013 PM 18344516 ER PT J AU Rom, WN Pinkerton, KE Martin, WJ Forastiere, F AF Rom, William N. Pinkerton, Kent E. Martin, William J. Forastiere, Francesco TI Global warming: A challenge to all American Thoracic Society members SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID OBSTRUCTIVE PULMONARY-DISEASE; CLIMATE-CHANGE; MORTALITY; HEALTH; TEMPERATURE; CHINA C1 [Rom, William N.] NYU, Sch Med, New York, NY 10016 USA. [Pinkerton, Kent E.] Univ Calif Davis, Ctr Hlth & Environm, Davis, CA 95616 USA. [Martin, William J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Forastiere, Francesco] Rome E Hlth Author, Rome, Italy. RP Rom, WN (reprint author), NYU, Sch Med, New York, NY 10016 USA. RI Forastiere, Francesco/J-9067-2016 OI Forastiere, Francesco/0000-0002-9162-5684 NR 17 TC 2 Z9 2 U1 2 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2008 VL 177 IS 10 BP 1053 EP 1054 DI 10.1164/rccm.200801-052ED PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 303NA UT WOS:000256046000001 PM 18460457 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cara, CL Cruz-Lopez, O Preti, D Tolomeo, M Grimaudo, S Di Cristina, A Zonta, N Balzarini, J Brancale, A Sarkar, T Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cara, Carlota Lopez Cruz-Lopez, Olga Preti, Delia Tolomeo, Manlio Grimaudo, Stefania Di Cristina, Antonella Zonta, Nicola Balzarini, Jan Brancale, Andrea Sarkar, Taradas Hamel, Ernest TI Design, synthesis, and biological evaluation of thiophene analogues of chalcones SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE chalcones; tubulin; colchicine ID ANTIMITOTIC AGENTS; TUBULIN; COLCHICINE; POLYMERIZATION; GROWTH; CANCER AB Chalcones are characterized by possessing an enone moiety between two aromatic rings. A series of chalcone-like agents, in which the double bond of the enone system is embedded within a thiophene ring, were synthesized and evaluated for antiproliferative activity and inhibition of tubulin assembly and colchicine binding to tubulin. The replacement of the double bond with a thiophene maintains antiproliferative activity and therefore must not significantly alter the relative conformation of the two aryl rings. The synthesized compounds were found to inhibit the growth of several cancer cell lines at nanomolar to low micromolar concentrations. In general, all compounds having significant antiproliferative activity inhibited tubulin polymerization with an IC(50) < 2 mu M. Several of these compounds caused K562 cells to arrest in the G2/M phase of the cell cycle. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cara, Carlota Lopez; Cruz-Lopez, Olga; Preti, Delia] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Tolomeo, Manlio; Grimaudo, Stefania; Di Cristina, Antonella] Univ Palermo, Dept Oncol, Policlin P Giaccone, Div Ematol, Palermo, Italy. [Tolomeo, Manlio; Grimaudo, Stefania; Di Cristina, Antonella] Univ Palermo, Dept Oncol, Policlin P Giaccone, AIDS Serv, Palermo, Italy. [Zonta, Nicola; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10, Wales. [Balzarini, Jan] Rega Inst, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Sarkar, Taradas; Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI antonietta, di cristina/I-9251-2012; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Carrion, M. Dora/G-8638-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017; OI Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Carrion, M. Dora/0000-0002-6794-3949; preti, delia/0000-0002-1075-3781; Grimaudo, Stefania/0000-0003-3225-4112 NR 19 TC 62 Z9 62 U1 0 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 15 PY 2008 VL 16 IS 10 BP 5367 EP 5376 DI 10.1016/j.bmc.2008.04.026 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 303PJ UT WOS:000256052400001 PM 18440234 ER PT J AU Heredia-Moya, J Kirk, KL AF Heredia-Moya, Jorge Kirk, Kenneth L. TI An improved synthesis of arsenic-biotin conjugates SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE arsenic; biotin; avidin; conjugates ID PHENYLARSINE OXIDE; CRYSTAL-STRUCTURE; BINDING PROTEINS; AQUEOUS-SOLUTION; LIGANDS; INHIBITION; THIOLS; AVIDIN; CELLS; CHROMATOGRAPHY AB An amide linked conjugate of p-aminophenylarsine oxide and biotin is conveniently prepared in a one-pot procedure by the reaction of biotinyl chloride, formed in situ, with p-aminophenyldichloroarsine. The reaction of the arsine oxide-biotin conjugate with 1,2-ethanedithiol produces the stabilized dithiarsolane. These reagents are now readily available for a variety of applications. Published by Elsevier Ltd. C1 [Heredia-Moya, Jorge; Kirk, Kenneth L.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov FU Intramural NIH HHS [Z01 DK031134-01] NR 31 TC 8 Z9 8 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 15 PY 2008 VL 16 IS 10 BP 5743 EP 5746 DI 10.1016/j.bmc.2008.03.054 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 303PJ UT WOS:000256052400037 PM 18396406 ER PT J AU Noguchi, CT AF Noguchi, Constance Tom TI Where the Epo cells are SO BLOOD LA English DT Editorial Material ID GENE C1 NIH, Bethesda, MD 20892 USA. RP Noguchi, CT (reprint author), NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 4836 EP 4837 DI 10.1182/blood-2008-02-135988 PG 2 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100007 PM 18467604 ER PT J AU Pavletic, SZ Fowler, DH AF Pavletic, Steven Z. Fowler, Daniel H. TI "Regulating" rheumatoid arthritis via autotransplantation SO BLOOD LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; T-CELLS; DISEASES C1 [Pavletic, Steven Z.; Fowler, Daniel H.] NCI, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 4838 EP 4839 DI 10.1182/blood-2008-02-139048 PG 2 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100009 PM 18467606 ER PT J AU Nabel, EG Shurin, SB AF Nabel, Elizabeth G. Shurin, Susan B. TI A recommitment to sickle cell disease research SO BLOOD LA English DT Editorial Material C1 [Nabel, Elizabeth G.; Shurin, Susan B.] NHLBI, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Bethesda, MD 20892 USA. NR 7 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 4852 EP 4853 DI 10.1182/blood-2008-03-143685 PG 2 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100013 PM 18467610 ER PT J AU McKinney-Freeman, SL Lengerke, C Jang, IH Schmitt, S Wang, Y Philitas, M Shea, J Daley, GQ AF McKinney-Freeman, Shannon L. Lengerke, Claudia Jang, Il-Ho Schmitt, Sabine Wang, Yuan Philitas, Marsha Shea, Jessica Daley, George Q. TI Modulation of murine embryonic stem cell-derived CD41(+)c-kit(+) hematopoietic progenitors by ectopic expression of Cdx genes SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DEFINITIVE HEMATOPOIESIS; HOX GENES; TRANSCRIPTION FACTOR; MOUSE EMBRYO; DIFFERENTIATION; GATA-2; T(12/13)(P13,Q12); LEUKEMOGENESIS; ONTOGENY AB Cdx1, Cdx2, and Cdx4 comprise the caudal-like Cdx gene family in mammals, whose homologues regulate hematopoietic development in zebrafish. Previously, we reported that overexpression of Cdx4 enhances hematopoietic potential from murine embryonic stem cells (ESCs). Here we compare the effect of ectopic Cdx1, Cdx2, and Cdx4 on the differentiation of murine ESC-derived hematopoietic progenitors. The 3 Cdx genes differentially influence the formation and differentiation of hematopoietic progenitors within a CD41(+)c-kit(+) population of embryoid body (EB)-derived cells. Cdx1 and Cdx4 enhance, whereas Cdx2 strongly inhibits, the hematopoietic potential of CD41(+)ckit(+) EB-derived cells, changes that are reflected by effects on hematopoietic lineage-specific and Hox gene expression. When we subject stromal cell and colony assay cultures of EB-derived hematopoietic progenitors to ectopic expression of Cdx genes, Cdx4 dramatically enhances, whereas Cdx1 and Cdx2 both inhibit hematopoietic activity, probably by blocking progenitor differentiation. These data demonstrate distinct effects of Cdx genes on hematopoietic progenitor formation and differentiation, insights that we are using to facilitate efforts at in vitro culture of hematopoietic progenitors from ESC. The behavior of Cdx genes in vitro suggests how derangement of these developmental regulators might contribute to leukemogenesis. C1 [McKinney-Freeman, Shannon L.; Lengerke, Claudia; Jang, Il-Ho; Schmitt, Sabine; Wang, Yuan; Philitas, Marsha; Shea, Jessica; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [McKinney-Freeman, Shannon L.; Lengerke, Claudia; Jang, Il-Ho; Schmitt, Sabine; Wang, Yuan; Philitas, Marsha; Shea, Jessica; Daley, George Q.] Harvard Univ, Sch Med, Dept Biochem & Mol Pharmacol, Boston, MA USA. [McKinney-Freeman, Shannon L.; Lengerke, Claudia; Jang, Il-Ho; Schmitt, Sabine; Wang, Yuan; Philitas, Marsha; Shea, Jessica; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA USA. [Lengerke, Claudia] Univ Tubingen, Med Ctr 2, Tubingen, Germany. [Wang, Yuan] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Pediat Hematol Oncol, 300 Longwood Ave,Karp 7, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu OI Lengerke, Claudia/0000-0001-5442-2805 NR 41 TC 28 Z9 30 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 4944 EP 4953 DI 10.1182/blood-2007-11-124644 PG 10 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100025 PM 18252864 ER PT J AU Davis, BR DiCola, MJ Prokopishyn, NL Rosenberg, JB Moratto, D Muul, LM Candotti, F Blaese, RM AF Davis, Brian R. DiCola, Michael J. Prokopishyn, Nicole L. Rosenberg, Jonathan B. Moratto, Daniele Muul, Linda M. Candotti, Fabio Blaese, R. Michael TI Unprecedented diversity of genotypic revertants in lymphocytes of a patient with Wiskott-Aldrich syndrome SO BLOOD LA English DT Article ID IN-VIVO REVERSION; SEVERE COMBINED IMMUNODEFICIENCY; INHERITED MUTATION; SOMATIC MOSAICISM; WASP GENE; DEFICIENCY AB Spontaneous somatic reversions of inherited mutations are poorly understood phenomena that are thought to occur uncommonly in a variety of genetic disorders. When molecularly characterized, revertant cells have rarely exhibited more than one revertant genotype per patient. We analyzed individual allospecific T-cell clones derived from a Wiskott-Aldrich syndrome (WAS) patient identified by flow cytometry to have 10% to 15% revertant, WAS protein-expressing lymphocytes in his blood. Genotypic analysis of the clones revealed a remarkable diversity of deletions and base substitutions resulting in at least 34 different revertant genotypes that restored expression of WASp. A large fraction of these revertant genotypes were also identified in primary T cells purified from peripheral blood. These data suggest that the use of sensitive methods may reveal the presence of wide arrays of individual genotypic revertants in WAS patients and offer opportunities for further understanding of their occurrence. C1 [Davis, Brian R.] Univ Texas Houston, Hlth Sci Ctr, Ctr Stem Cell Res, Brown Fdn,Inst Mol Med, Houston, TX 77030 USA. [Davis, Brian R.; DiCola, Michael J.; Prokopishyn, Nicole L.; Rosenberg, Jonathan B.; Blaese, R. Michael] Inst Inherited Dis Res, Newtown, PA USA. [Moratto, Daniele; Muul, Linda M.; Candotti, Fabio] NHGRI, NIH, Bethesda, MD 20892 USA. RP Davis, BR (reprint author), Univ Texas Houston, Hlth Sci Ctr, Ctr Stem Cell Res, Brown Fdn,Inst Mol Med, 1825 Pressler St, Houston, TX 77030 USA. EM Brian.R.Davis@uth.tmc.edu FU Intramural NIH HHS NR 15 TC 13 Z9 13 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 5064 EP 5067 DI 10.1182/blood-2007-06-095299 PG 4 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100039 PM 18332229 ER PT J AU Chen, J Petrus, M Bryant, BR Nguyen, VP Stamer, M Goldman, CK Bamford, R Morris, JC Janik, JE Waldmann, TA AF Chen, Jing Petrus, Mike Bryant, Bonita R. Nguyen, Vinh Phuc Stamer, Mindy Goldman, Carolyn K. Bamford, Richard Morris, John C. Janik, John E. Waldmann, Thomas A. TI Induction of the IL-9 gene by HTLV-1 Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism SO BLOOD LA English DT Article ID VIRUS TYPE-I; NF-KAPPA-B; TROPICAL SPASTIC PARAPARESIS; HUMAN INTERLEUKIN-9; EXPRESSION; RECEPTOR; ACTIVATION; LINES; SITE; DIFFERENTIATION AB The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type 1 (HTLV-1). The HTLV-1 protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-kappa B motif in its proximal promoter, whereas IL-9 receptor-a. (IL-9R alpha) expression is not induced by Tax. However, supporting a role for IL-9/IL-9R alpha in ATL, a neutralizing monoclonal antibody directed toward IL-9R alpha inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Ra on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9R alpha/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism. C1 [Chen, Jing; Petrus, Mike; Bryant, Bonita R.; Nguyen, Vinh Phuc; Stamer, Mindy; Goldman, Carolyn K.; Morris, John C.; Janik, John E.; Waldmann, Thomas A.] Ctr Canc Res, Natl Canc Inst, Metab Branch, Bethesda, MD USA. [Bamford, Richard] Transponics, Jacobus, PA USA. RP Waldmann, TA (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 4N115, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS NR 42 TC 28 Z9 30 U1 3 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 5163 EP 5172 DI 10.1182/blood-2007-09-113654 PG 10 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100050 PM 18339896 ER PT J AU Kiefmann, R Rifkind, JM Nagababu, E Bhattacharya, J AF Kiefmann, Rainer Rifkind, Joseph M. Nagababu, Enika bhattacharya, Jahar TI Red blood cells induce hypoxic lung inflammation SO BLOOD LA English DT Article ID HEME DEGRADATION; ENDOTHELIAL-CELLS; HEMOGLOBIN; OXYGEN; INCREASES; OXYHEMOGLOBIN; AUTOXIDATION; SUPEROXIDE; MEMBRANE; CATALASE AB Hypoxia, which commonly associates with respiratory and cardiovascular diseases, provokes an acute inflammatory response. However, underlying mechanisms are not well understood. Here we report that red blood cells (RBCs) induce hypoxic inflammation by producing reactive oxygen species (ROS) that diffuse to endothelial cells of adjoining blood vessels. Real-time fluorescence imaging of rat and mouse lungs revealed that in the presence of RBC-containing vascular perfusion, hypoxia increased microvascular ROS, and cytosolic Ca2+, leading to P-selectin-dependent leukocyte recruitment. However, in the presence of RBC-free perfusion, all hypoxia-induced responses were completely inhibited. Because hemoglobin (Hb) autoxidation causes REIC superoxide formation that readily dismutates to H2O2, hypoxia-induced responses were lost when we inhibited Hb autoxidation with CO or nitrite, or when the H2O2 inhibitor, catalase was added to the infusion to neutralize the RBC-derived ROS. By contrast, perfusion with RBCs from BERK-trait mice that are more susceptible to Hb autoxidation and to hypoxia-induced superoxide production enhanced the hypoxia-induced responses. We conclude that in hypoxia, increased Hb autoxidation augments superoxide production in RBCs. Consequently, RBCs release H2O2 that diffuses to the lung microvascular endothelium, thereby initiating Ca2+-dependent leukocyte recruitment. These findings are the first evidence that RBCs contribute to hypoxia-induced inflammation. C1 [Kiefmann, Rainer; bhattacharya, Jahar] Columbia Univ, St Lukes Roosevelt Hosp Ctr, Coll Phys & Surg, Lung Biol Lab, New York, NY USA. [Rifkind, Joseph M.; Nagababu, Enika] NIA, Mol Dynam Sect, NIH, Baltimore, MD 21224 USA. RP Bhattacharya, J (reprint author), 630 W 168th St,BB 8-812, New York, NY 10032 USA. EM jb39@columbia.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL69514, R01 HL057556, R01 HL069514, HL57556] NR 39 TC 53 Z9 55 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2008 VL 111 IS 10 BP 5205 EP 5214 DI 10.1182/blood-2007-09-113902 PG 10 WC Hematology SC Hematology GA 301FZ UT WOS:000255883100055 PM 18270324 ER PT J AU Heuett, WJ Beard, DA Qian, H AF Heuett, William J. Beard, Daniel A. Qian, Hong TI Linear analysis near a steady-state of biochemical networks: Control analysis, correlation metrics and circuit theory SO BMC SYSTEMS BIOLOGY LA English DT Article ID METABOLIC-CONTROL; CONTROL COEFFICIENTS; SYSTEMS ANALYSIS; MOLECULAR MOTOR; TIME-SERIES; THERMODYNAMICS; PATHWAYS; FORCE; LAW AB Background: Several approaches, including metabolic control analysis (MCA), flux balance analysis (FBA), correlation metric construction (CMC), and biochemical circuit theory (BCT), have been developed for the quantitative analysis of complex biochemical networks. Here, we present a comprehensive theory of linear analysis for nonequilibrium steady-state (NESS) biochemical reaction networks that unites these disparate approaches in a common mathematical framework and thermodynamic basis. Results: In this theory a number of relationships between key matrices are introduced: the matrix A obtained in the standard, linear-dynamic-stability analysis of the steady-state can be decomposed as A = SRT where R and S are directly related to the elasticity-coefficient matrix for the fluxes and chemical potentials in MCA, respectively; the control-coefficients for the fluxes and chemical potentials can be written in terms of RTBS and STBS respectively where matrix B is the inverse of A; the matrix S is precisely the stoichiometric matrix in FBA; and the matrix e(At) plays a central role in CMC. Conclusion: One key finding that emerges from this analysis is that the well-known summation theorems in MCA take different forms depending on whether metabolic steady-state is maintained by flux injection or concentration clamping. We demonstrate that if rate- limiting steps exist in a biochemical pathway, they are the steps with smallest biochemical conductances and largest flux control-coefficients. We hypothesize that biochemical networks for cellular signaling have a different strategy for minimizing energy waste and being efficient than do biochemical networks for biosynthesis. We also discuss the intimate relationship between MCA and biochemical systems analysis (BSA). C1 [Heuett, William J.] NIDDKD, Lab Biol Modeling, Natl Inst Hlth, Bethesda, MD 20892 USA. [Beard, Daniel A.] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA. [Beard, Daniel A.] Med Coll Wisconsin, Biotechnol & Bioengn Ctr, Milwaukee, WI 53226 USA. [Qian, Hong] Univ Washington, Dept Appl Math, Seattle, WA 98195 USA. [Qian, Hong] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. RP Heuett, WJ (reprint author), NIDDKD, Lab Biol Modeling, Natl Inst Hlth, Bethesda, MD 20892 USA. EM heuettw@niddk.nih.gov; dbeard@mcw.edu; qian@amath.washington.edu FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM068610, GM068610] NR 35 TC 4 Z9 4 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD MAY 15 PY 2008 VL 2 AR 44 DI 10.1186/1752-0509-2-44 PG 11 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 324ZJ UT WOS:000257557600001 PM 18482450 ER PT J AU Huang, L Cronin, KA Johnson, KA Mariotto, AB Feuer, EJ AF Huang, Lan Cronin, Kathleen A. Johnson, Karen A. Mariotto, Angela B. Feuer, Eric J. TI Improved survival time: What can survival cure models tell us about population-based survival improvements in late-stage colorectal, ovarian, and testicular cancer? SO CANCER LA English DT Article DE survival; cure; cause-specific; life expectancy; ovarian cancer; colorectal cancer; testicular cancer ID ADJUVANT THERAPY; CYTOREDUCTIVE SURGERY; COLON-CANCER; VINBLASTINE; BREAKTHROUGH; FLUOROURACIL; CHEMOTHERAPY; METAANALYSIS; OXALIPLATIN; LEUCOVORIN AB BACKGROUND. The objective of the current study was to investigate the long-term impact of treatment advances on the survival of patients with late-stage ovarian, colorectal (American Joint Committee on Cancer stage III, men), and testicular cancers by estimating the increase in the percentage cured from their disease and the change in survival time of uncured patients. METHODS. Cause-specific survival data from 1973 to 2000 were obtained from the Surveillance, Epidemiology, and End Results Program. Survival cure models were fit and were used to estimate the gain in life expectancy (GLE) attributed to an increase in the fraction of cured patients and to prolonged survival among non-cured patients. RESULTS. Treatment improvement for ovarian cancer resulted in a total GLE of 2 years, and 80% of that GLE was because of an extension of survival time in uncured patients (from 0.9 years to 2.1 years) rather than an increased cure fraction (from 12% to 14%). In contrast, the cure rate rose from 29% to 47% for colorectal cancer, representing 82% of a 2.8-year GLE, and from 23% to 81% for testicular cancer, representing 100% of a 24-year GLE. CONCLUSIONS. The current results suggested that treatment benefits for testicular and colorectal cancer in men with late-stage disease primarily are the result of increases in cure fraction, whereas survival gains for ovarian cancer occur despite persisting disease. Cure models, in combination with population-level data, provide insight into how treatment advances are changing survival and ultimately impacting mortality. Survival patterns reflect the underlying biology of response to cancer treatment and suggest promising directions for future research. C1 [Huang, Lan; Cronin, Kathleen A.; Mariotto, Angela B.; Feuer, Eric J.] NCI, Stat Res & Applicat Branch, Surveillance Res Program, Bethesda, MD 20892 USA. [Johnson, Karen A.] NCI, Canc Prevent Div, Breast & Gynecol Canc Res Grp, Bethesda, MD 20892 USA. RP Huang, L (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, 6116 Execut Blvd,Room 5043, Bethesda, MD 20892 USA. EM huangla@mail.nih.gov NR 29 TC 32 Z9 35 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2008 VL 112 IS 10 BP 2289 EP 2300 DI 10.1002/cncr.23425 PG 12 WC Oncology SC Oncology GA 294WP UT WOS:000255437300026 PM 18393325 ER PT J AU Kefas, B Godlewski, J Comeau, L Li, YQ Abounader, R Hawkinson, M Lee, JW Fine, H Chiocca, EA Lawler, S Purow, B AF Kefas, Benjamin Godlewski, Jakub Comeau, Laurey Li, Yunqing Abounader, Roger Hawkinson, Michael Lee, Jeongwu Fine, Howard Chiocca, E. Antonio Lawler, Sean Purow, Benjamin TI microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma SO CANCER RESEARCH LA English DT Article ID CANCER-CELL LINES; TUMOR-SUPPRESSOR; EXPRESSION; PROLIFERATION; 3'-UTR; RNAS; EGF AB microRNAs are noncoding RNAs inhibiting expression of numerous target genes, and a few have been shown to act as oncogenes or tumor suppressors. We show that microRNA-7 (miR-7) is a potential tumor suppressor in glioblastoma targeting critical cancer pathways. miR-7 potently suppressed epidermal growth factor receptor expression, and furthermore it independently inhibited the Akt pathway via targeting upstream regulators. miR-7 expression was down-regulated in glioblastoma versus surrounding brain, with a mechanism involving impaired processing. Importantly, transfection with miR-7 decreased viability and invasiveness of primary glioblastoma lines. This study establishes miR-7 as a regulator of major cancer pathways and suggests that it has therapeutic potential for glioblastoma. C1 [Kefas, Benjamin; Comeau, Laurey; Li, Yunqing; Abounader, Roger; Hawkinson, Michael; Purow, Benjamin] Univ Virginia Hlth Syst, Div Neurooncol, Dept Neurol, Charlottesville, VA USA. [Godlewski, Jakub; Chiocca, E. Antonio; Lawler, Sean] Ohio State Univ, Dardinger Lab Neurooncol & Neurosci, Dept Neurol Surg, Columbus, OH 43210 USA. [Lee, Jeongwu; Fine, Howard] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Purow, B (reprint author), Univ Virginia, Neurooncol Ctr, Box 800434,Hosp W Complex 6th Floor, Charlottesville, VA 22908 USA. EM bwp5g@virginia.edu RI leng, xianwei/F-9073-2011 NR 19 TC 412 Z9 442 U1 3 U2 13 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 MAY 15 PY 2008 VL 68 IS 10 BP 3566 EP 3572 DI 10.1158/0008-5472.CAN-07-6639 PG 7 WC Oncology SC Oncology GA 301YW UT WOS:000255933600006 PM 18483236 ER PT J AU Raufman, JP Samimi, R Shah, N Khurana, S Shant, J Drachenberg, C Xie, GF Wess, J Cheng, KR AF Raufman, Jean-Pierre Samimi, Roxana Shah, Nirish Khurana, Sandeep Shant, Jasleen Drachenberg, Cinthia Xie, Guofeng Wess, Juergen Cheng, Kunrong TI Genetic ablation of M-3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia SO CANCER RESEARCH LA English DT Article ID BETA-CATENIN GENE; ACETYLCHOLINE-RECEPTOR; CANCER-CELLS; CHOLINERGIC-RECEPTOR; LINE; TRANSACTIVATION; MUTATIONS; PROTEIN; LACKING; KINASE AB Colon epithelial cells express and most colon cancers overexpress M-3 muscarinic receptors (M3R). In human colon cancer cells, post-M3R signaling stimulates proliferation. To explore the importance of M3R expression in vivo, we used the azoxymethane-induced colon neoplasia model. Mice treated with weekly i.p. injection of saline [10 wild-type (WT) mice] or azoxymethane (22 WT and 16 M3R-/- mice) for 6 weeks were euthanized at 20 weeks. At week 20, azoxymethane-treated WT :mice weighed similar to 16% more than M3R-/- mice (33.4 grams +/- 1.0 grams versus 27.9 grams +/- 0.5 grams; mean +/- SE, P < 0.001). In azoxymethane-treated M3R-/- Mice, Cell proliferation (BrdUrd staining) was reduced 43% compared with azoxymethane-treated WT mice (P < 0.05). Whereas control mice (both WT and M3R-/-) had no colon tumors, azoxymethane-treated WT mice had 5.3 +/- 0.5 tumors per animal. Strikingly, azoxymethane-treated M3R-/- mice had only 3.2 +/- 0.3 tumors per mouse (P < 0.05), a 40% reduction. Tumor volume in azoxymethane-treated M3R-/- mice was reduced 60% compared with azoxymethane-treated WT mice (8.1 mm(3) +/- 1.5 mm(3) versus 20.3 mm(3) +/- 4.1 mm(3); P < 0.05). Compared with WT, fewer M3R-/- mice had adenomas (6% versus 36%; P = 0.05), and M3R-/- mice had fewer adenocarcinomas per mouse (0.6 +/- 0.1 versus 1.7 +/- 0.4; P < 0.05). Eleven of 22 WT but no M3R-/- mice had multiple adenocarcinomas (P < 0.001). Compared with WT, azoxymethane-treated M3R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M3R and post-M3R signaling are novel therapeutic targets for colon cancer. C1 [Raufman, Jean-Pierre; Samimi, Roxana; Shah, Nirish; Khurana, Sandeep; Shant, Jasleen; Xie, Guofeng; Cheng, Kunrong] Univ Maryland, Sch Med, Div Gastroenterol & Hepatol, VA Maryland Hlth Care Syst, Baltimore, MD 21201 USA. [Raufman, Jean-Pierre; Samimi, Roxana; Shah, Nirish; Khurana, Sandeep; Shant, Jasleen; Xie, Guofeng; Cheng, Kunrong] Univ Maryland, Sch Med, Program Oncol, Greenbaum Canc Ctr, Baltimore, MD 21201 USA. [Drachenberg, Cinthia] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Wess, Juergen] NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Raufman, JP (reprint author), Univ Maryland, Sch Med, Div Gastroenterol & Hepatol, VA Maryland Hlth Care Syst, 22 S Greene St,N3W62, Baltimore, MD 21201 USA. EM jraufman@medicine.umaryland.edu FU NCI NIH HHS [CA107345, R01 CA107345, R01 CA107345-03]; NIDDK NIH HHS [T32 DK067872, T32 DK067872-03] NR 20 TC 41 Z9 41 U1 0 U2 1 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 MAY 15 PY 2008 VL 68 IS 10 BP 3573 EP 3578 DI 10.1158/0008-5472.CAN-07-6810 PG 6 WC Oncology SC Oncology GA 301YW UT WOS:000255933600007 PM 18483237 ER PT J AU Lu, XD Yang, CY Hill, R Yin, CY Hollander, MC Fornace, AJ Van Dyke, T AF Lu, Xiangdong Yang, Chunyu Hill, Reginald Yin, Chaoyin Hollander, M. Christine Fornace, Albert J., Jr. Van Dyke, Terry TI Inactivation of gadd45a sensitizes epithelial cancer cells to ionizing radiation in vivo resulting in prolonged survival SO CANCER RESEARCH LA English DT Article ID P53-DEPENDENT APOPTOSIS; GENOMIC INSTABILITY; P53; PROGRESSION; CHECKPOINT; EXPRESSION; MICE; P21; RADIOTHERAPY; INDUCTION AB Ionizing radiation (IR) therapy is one of the most commonly used treatments for cancer patients. The responses of tumor cells to IR are often tissue specific and depend on pathway aberrations present in the tumor. Identifying molecules and mechanisms that sensitize tumor cells to IR provides new potential therapeutic strategies for cancer treatment. In this study, we used two genetically engineered mouse carcinoma models, brain choroid plexus carcinoma (CPC) and prostate, to test the effect of inactivating gadd45a, a DNA damage response p53 target gene, on tumor responses to IR. We show that gadd45a deficiency significantly increases tumor cell death after radiation. Effect on survival was assessed in the CPC model and was extended in Ill-treated mice with gadd45a deficiency compared with those expressing wild-type gadd45a. These studies show a significant effect of gadd45a inactivation in sensitizing tumor cells to IR, implicating gadd45a as a potential drug target in radiotherapy management. C1 [Lu, Xiangdong; Yang, Chunyu; Hill, Reginald; Yin, Chaoyin; Van Dyke, Terry] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. [Hollander, M. Christine] NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. [Fornace, Albert J., Jr.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. RP Van Dyke, T (reprint author), Univ N Carolina, Lineberger Canc Ctr, CB7295,100 W Dr, Chapel Hill, NC 27599 USA. EM tvdlab@med.unc.edu RI Hill, Reginald/D-2270-2016; OI Fornace, Albert/0000-0001-9695-085X FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [5-RO1CA46283, R01 CA046283]; NIGMS NIH HHS [T32 GM007092, T32 GM007092-34] NR 26 TC 10 Z9 10 U1 0 U2 2 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 MAY 15 PY 2008 VL 68 IS 10 BP 3579 EP 3583 DI 10.1158/0008-5472.CAN-07-5533 PG 5 WC Oncology SC Oncology GA 301YW UT WOS:000255933600008 PM 18483238 ER PT J AU Chen, HX Lee, JS Liang, XH Zhang, HP Zhu, T Zhang, Z Taylor, ME Zahnow, C Feigenbaum, L Rein, A Sukumar, S AF Chen, Hexin Lee, Ji Shin Liang, Xiaohui Zhang, Huiping Zhu, Tao Zhang, Zhe Taylor, M. Evangeline Zahnow, Cynthia Feigenbaum, Lionel Rein, Alan Sukumar, Saraswati TI Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis SO CANCER RESEARCH LA English DT Article ID ONCOGENE-INDUCED SENESCENCE; HOMEOBOX GENES; EPITHELIAL-CELLS; BREAST-CANCER; GROWTH-FACTOR; HISTOLOGICAL GRADE; EXPRESSION; TUMORIGENESIS; CARCINOMA; MICE AB Our previous studies have shown that HOXB7 mRNA is overexpressed in similar to 50% of invasive breast carcinomas and promotes tumor progression in breast cancer cells grown as xenografts in mice. In silico analysis of published microarray data showed that high levels of HOYB7 predict a poor outcome in HER-2-positive (P = 0.046), but not in HER-2-negative breast cancers (P = 0.94). To study the function of HOXB7 in vivo in the context of HER-2 overexpression, we generated mouse mammary tumor virus (MMTV)-Hoxb7 transgenic mice, and then crossed them with MMTV-HER-2/neu transgenic mice. In the mice carrying both Hoxb7 and HER-2/neu transgenes, Hoxb7 plays a dual role in mammary tumorigenesis. In double transgenic mice, overexpression of Hoxb7 delayed tumor onset and lowered tumor multiplicity. However, consistent with the clinical data, once the tumors appeared, their growth was faster and metastasis to the lungs occurred at a higher frequency. Our data show, for the first time, that deregulated expression of Hoxb7 in mammary tumor cells can significantly modulate HER-2/neu-oncogene induced tumorigenesis in vivo. C1 [Chen, Hexin; Lee, Ji Shin; Liang, Xiaohui; Zhang, Huiping; Zhu, Tao; Zhang, Zhe; Taylor, M. Evangeline; Zahnow, Cynthia; Sukumar, Saraswati] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Breast Canc Program, Baltimore, MD USA. [Feigenbaum, Lionel] Sci Applicat Int Corp, Lab Anim Sci Program, Mclean, VA 22102 USA. [Rein, Alan] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Sukumar, S (reprint author), Johns Hopkins Univ, Sch Med, 1650 Orleans St,CRB-1 Room 143, Baltimore, MD 21231 USA. EM saras@jhmi.edu FU Intramural NIH HHS; NCI NIH HHS [P50 CA88843, P50 CA088843, N01CO12400, N01-CO-12400] NR 35 TC 39 Z9 41 U1 0 U2 3 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 MAY 15 PY 2008 VL 68 IS 10 BP 3637 EP 3644 DI 10.1158/0008-5472.CAN-07-2926 PG 8 WC Oncology SC Oncology GA 301YW UT WOS:000255933600016 PM 18463397 ER PT J AU He, YY Council, SE Feng, L Chignell, CF AF He, Yu-Ying Council, Sarah E. Feng, Li Chignell, Colin F. TI UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/cyclin D1 pathways in keratinocytes SO CANCER RESEARCH LA English DT Article ID FACTOR-RECEPTOR; MOUSE SKIN; ULTRAVIOLET-IRRADIATION; KINASE; INDUCTION; CANCER; WAVELENGTHS; EXPRESSION; ADAMS; AKT AB UVA (315-400 nm), which constitutes similar to 95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer. C1 [He, Yu-Ying] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. [He, Yu-Ying; Council, Sarah E.; Feng, Li; Chignell, Colin F.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP He, YY (reprint author), Univ Chicago, Dept Med, Dermatol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM yyhe@medicine.bsd.uchicago.edu FU Intramural NIH HHS [, NIH0011363100]; PHS HHS [NIH0011363100] NR 34 TC 39 Z9 39 U1 1 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 MAY 15 PY 2008 VL 68 IS 10 BP 3752 EP 3758 DI 10.1158/0008-5472.CAN-07-6138 PG 7 WC Oncology SC Oncology GA 301YW UT WOS:000255933600029 PM 18483258 ER PT J AU Kumaraswamy, S Chinnaiyan, P Shankavaram, UT Lu, X Camphausen, K Tofilon, PJ AF Kumaraswamy, Sandhya Chinnaiyan, Prakash Shankavaram, Uma T. Lue, Xing Camphausen, Kevin Tofilon, Philip J. TI Radiation-induced gene translation profiles reveal tumor type and cancer-specific components SO CANCER RESEARCH LA English DT Article ID MESSENGER-RNA TRANSLATION; EXPRESSION PROFILES; IONIZING-RADIATION; CELLS; MICROARRAY; RESPONSES; PROTEIN; RECRUITMENT; SENSITIVITY; RESISTANCE AB The microarray analysis of total cellular RNA is a common method used in the evaluation of radiation-induced gene expression. However, profiling the cellular transcriptome does not take into account posttranscriptional processes that affect gene expression. To better define the genes whose expression is influenced by ionizing radiation, we used polysome-bound RNA to generate gene translation profiles for a series of tumor and normal cell lines. Cell lines were exposed to 2 Gy, polysome-bound RNA isolated 6 hours later, and then subjected to microarray analysis. To identify the genes whose translation was affected by radiation, the polysome-bound RNA profiles were compared with their corresponding controls using significance analysis of microarrays (<1% false discovery rate). From the statistically significant genes identified for each cell line, hierarchical clustering was performed by average linkage measurement and Pearson's correlation metric. Ingenuity Pathway Analysis was used for distributing genes into biological networks and for evaluation of functional significance. Radiation-induced gene translation profiles clustered according to tissue of origin; the cell lines corresponding to each tissue type contained a significant number of commonly affected genes. Network analyses suggested that the biological functions associated with the genes whose translation was affected by radiation were tumor type-specific. There was also a set of genes/networks that were unique to tumor or normal cells. These results indicate that radiation-induced gene translation profiles provide a unique data set for the analysis of cellular radioresponse and suggest a framework for identifying and targeting differences in the regulation of tumor and normal cell radiosensitivity. C1 [Kumaraswamy, Sandhya; Tofilon, Philip J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA. [Chinnaiyan, Prakash] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Radiat Oncol, Tampa, FL 33612 USA. [Shankavaram, Uma T.; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Lue, Xing] Mol Radiat Therapeut Branch, Bethesda, MD USA. RP Tofilon, PJ (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, 12902 Magnolia Dr,SRB3-DRDIS, Tampa, FL 33612 USA. EM philip.tofilon@moffitt.org FU NCI NIH HHS [CA126943, R01 CA126943, R01 CA126943-01A1] NR 29 TC 21 Z9 22 U1 0 U2 2 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 MAY 15 PY 2008 VL 68 IS 10 BP 3819 EP 3826 DI 10.1158/0008-5472.CAN-08-0016 PG 8 WC Oncology SC Oncology GA 301YW UT WOS:000255933600037 PM 18483266 ER PT J AU Nam, JS Terabe, M Mamura, M Kang, NJ Chae, H Stuelten, C Kohn, E Tang, B Sabzevari, H Anver, MR Lawrence, S Danielpour, D Lonning, S Berzofsky, JA Wakefield, LM AF Nam, Jeong-Seok Terabe, Masaki Mamura, Mizuko Kang, Nu-Jin Chae, Helen Stuelten, Christina Kohn, Ethan Tang, Binwu Sabzevari, Helen Anver, Miriam R. Lawrence, Scott Danielpour, David Lonning, Scott Berzofsky, Jay A. Wakefield, Lalage M. TI An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments SO CANCER RESEARCH LA English DT Article ID PREVENTS TUMOR RECURRENCE; CD8(+) T-CELLS; TGF-BETA; BREAST-CANCER; IN-VIVO; IMMUNE-RESPONSE; MAMMARY-TUMOR; MOUSE; THERAPY; MICE AB Overexpression of transforming growth factor beta (TGF-beta) is frequently associated with metastasis and poor prognosis, and TGF-beta antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti-TGF-beta antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rael gamma) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-beta expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-beta antibodies reverse this effect, and the absence of a major effect of TGF-beta antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications. C1 [Nam, Jeong-Seok; Mamura, Mizuko] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea. [Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Nam, Jeong-Seok; Mamura, Mizuko; Kang, Nu-Jin; Chae, Helen; Stuelten, Christina; Kohn, Ethan; Tang, Binwu; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Sabzevari, Helen] NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. [Anver, Miriam R.; Lawrence, Scott] Sci Applicat Int Corp Frederick Inc, Pathol Histotechnol Lab, Frederick, MD USA. [Danielpour, David] Case Western Reserve Univ, Ireland Canc Ctr, Cleveland, OH 44106 USA. [Lonning, Scott] Genzyme Corp, Framingham, MA 01701 USA. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 4032A,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM lw34g@nih.gov OI Mamura, Mizuko/0000-0003-4531-0144 FU Intramural NIH HHS [Z01 BC005785-12]; NCI NIH HHS [N01-CO-12400, Z01 BC 005785] NR 48 TC 120 Z9 122 U1 1 U2 4 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 MAY 15 PY 2008 VL 68 IS 10 BP 3835 EP 3843 DI 10.1158/0008-5472.CAN-08-0215 PG 9 WC Oncology SC Oncology GA 301YW UT WOS:000255933600039 PM 18483268 ER PT J AU Nam, JS Terabe, M Kang, MJ Chae, H Voong, N Yang, YA Laurence, A Michalowska, A Mamura, M Lonning, S Berzofsky, JA Wakefield, LM AF Nam, Jeong-Seok Terabe, Masaki Kang, Mi-Jin Chae, Helen Voong, Nga Yang, Yu-an Laurence, Arian Michalowska, Aleksandra Mamura, Mizuko Lonning, Scott Berzofsky, Jay A. Wakefield, Lalage M. TI Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17 SO CANCER RESEARCH LA English DT Article ID REGULATORY T-CELLS; TGF-BETA; IN-VIVO; BREAST-CANCER; KINASE INHIBITOR; PROSTATE-CANCER; IMMUNOSURVEILLANCE; METASTASIS; INDUCTION; MECHANISM AB Overexpression of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) is one strategy that tumors have developed to evade effective immunesurveillance. Using transplantable models of breast and colon cancer, we made the unexpected finding that CD8+ cells in tumor-bearing animals can directly promote tumorigenesis, by a mechanism that is dependent on TGF-beta. We showed that CD8+ splenocytes from tumor-bearing mice expressed elevated interleukin (IL)-17 when compared with naive mice, and that CD8+ T cells could be induced to make IL-17 on addition of TGF-beta and IL-6 in vitro. Treatment of mice with anti-TGF-beta antibodies in vivo reduced IL-17 expression both in the tumor and the locoregional lymph nodes. Although IL-17 has not previously been shown to act as a survival factor for epithelial cells, we found that IL-17 suppressed apoptosis of several tumor cell lines in vitro, suggesting that this altered T-cell polarization has the potential to promote tumorigenesis directly, rather than indirectly through inflammatory sequelae. Consistent with this hypothesis, knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. Thus, in addition to suppressing immune surveillance, tumor-induced TGF-beta may actively subvert the CD8+ arm of the immune system into directly promoting tumor growth by an IL-17-dependent mechanism. C1 [Nam, Jeong-Seok] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon, South Korea. [Nam, Jeong-Seok; Kang, Mi-Jin; Chae, Helen; Voong, Nga; Yang, Yu-an; Michalowska, Aleksandra; Mamura, Mizuko; Wakefield, Lalage M.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Terabe, Masaki; Berzofsky, Jay A.] NCI, Vaccine Branch, Bethesda, MD 20892 USA. [Laurence, Arian] NIAMSD, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Lonning, Scott] Genzyme Corp, Framingham, MA 01701 USA. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Bldg 37,Room 4032A,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM lw34g@nih.gov RI Laurence, Arian/A-8770-2009; OI Laurence, Arian/0000-0003-0942-8292; Mamura, Mizuko/0000-0003-4531-0144 FU Intramural NIH HHS [Z01 BC005785-12] NR 51 TC 147 Z9 156 U1 0 U2 3 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 MAY 15 PY 2008 VL 68 IS 10 BP 3915 EP 3923 DI 10.1158/0008-5472.CAN-08-0206 PG 9 WC Oncology SC Oncology GA 301YW UT WOS:000255933600048 PM 18483277 ER PT J AU Strasak, AM Rapp, K Brant, LJ Hilbe, W Gregory, M Oberaigner, W Ruttmann, E Concin, H Diem, G Pfeiffer, KP Ulmer, H AF Strasak, Alexander M. Rapp, Kilian Brant, Larry J. Hilbe, Wolfgang Gregory, Martin Oberaigner, Willi Ruttmann, Elfriede Concin, Hans Diem, Guenter Pfeiffer, Karl P. Ulmer, Hanno CA VHM TI Association of gamma-glutamyltransferase and risk of cancer incidence in men: A prospective study SO CANCER RESEARCH LA English DT Article ID YOUNG-ADULTS CARDIA; MIDDLE-AGED MEN; SERUM URIC-ACID; CARDIOVASCULAR-DISEASE; METABOLIC SYNDROME; DRUG-RESISTANCE; NATIONAL-HEALTH; DOSE-RESPONSE; HEART-DISEASE; TRANSPEPTIDASE AB Although several epidentiologic studies have shown that gamma-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages :! 65 years. Our findings, for the first time, show that elevated GGT is significantly associated with increased cancer risk in men. C1 [Strasak, Alexander M.; Pfeiffer, Karl P.; Ulmer, Hanno] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria. [Hilbe, Wolfgang] Innsbruck Med Univ, Dept Haematol & Oncol, A-6020 Innsbruck, Austria. [Ruttmann, Elfriede] Innsbruck Med Univ, Dept Cardiac Surg, A-6020 Innsbruck, Austria. [Oberaigner, Willi] Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. [Rapp, Kilian] Univ Ulm, Dept Epidemiol, Ulm, Germany. [Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Gregory, Martin] SAS Inst Inc, Heidelberg, Germany. [Concin, Hans; Diem, Guenter; Ulmer, Hanno] Agcy Prevent & Social Med, Bregenz, Austria. RP Strasak, AM (reprint author), Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Schoepfstr 41, A-6020 Innsbruck, Austria. EM alexander.strasak@i-med.ac.at RI Ruttmann, Elfriede/D-6501-2011; vhmpp, aks/F-9756-2012; Ulmer, Hanno/C-3488-2011 OI Ulmer, Hanno/0000-0001-5911-1002 FU Intramural NIH HHS NR 45 TC 51 Z9 53 U1 0 U2 2 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 MAY 15 PY 2008 VL 68 IS 10 BP 3970 EP 3977 DI 10.1158/0008-5472.CAN-07-6686 PG 8 WC Oncology SC Oncology GA 301YW UT WOS:000255933600054 PM 18483283 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, Vivek Aravind, L. TI Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of sirtuin domain deacetylases by NAD metabolites SO CELL CYCLE LA English DT Article DE chromatin modification; nucleoside disphosphate; O-acetyl ADP ribose; TRPM2; RNA-binding ID DEINOCOCCUS-RADIODURANS; SWISS-MODEL; PSI-BLAST; BINDING; PROTEINS; FAMILY; EUKARYOTES; RNA AB Deleted in Breast Cancer-1 ( DBC1) and its paralog CARP-1 are large multi-domain proteins, with a nuclear or perinuclear localization, and a role in promoting apoptosis upon processing by caspases. Recent studies on human DBC1 show that it is a specific inhibitor of the sirtuin-type deacetylase, Sirt1, which deacetylates histones and p53. Using sensitive sequence profile searches and HMM-HMM comparisons we show that the central conserved globular domain present in the DBC1 and it homologs from diverse eukaryotes is a catalytically inactive version of the Nudix hydrolase ( MutT) domain. Given that Nudix domains are known to bind nucleoside diphosphate sugars and NAD, we predict that this domain in DBC1 and its homologs binds NAD metabolites such as ADP- ribose. Hence, we propose that DBC1 and its homologs are likely to regulate the activity of SIRT1 or related deacetylases by sensing the soluble products or substrates of the NAD-dependent deacetylation reaction. The complex domain architectures of the members of the DBC1 family, which include fusions to the RNA-binding S1-like domain, the DNA-binding SAP domain and EF-hand domains, suggest that they are likely to function as integrators of distinct regulatory signals including chromatin protein modification, soluble compounds in NAD metabolism, apoptotic stimuli and RNA recognition. C1 [Anantharaman, Vivek; Aravind, L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@mail.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU Intramural NIH HHS [Z99 LM999999, Z01 LM594244-01] NR 32 TC 21 Z9 21 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2008 VL 7 IS 10 BP 1467 EP 1472 DI 10.4161/cc.7.10.5883 PG 6 WC Cell Biology SC Cell Biology GA 309CO UT WOS:000256438500023 PM 18418069 ER PT J AU Gulley, JL Arlen, PM Tsang, KY Yokokawa, J Palena, C Poole, DJ Remondo, C Cereda, V Jones, JL Pazdur, MP Higgins, JP Hodge, JW Steinberg, SM Kotz, H Dahut, WL Schlom, J AF Gulley, James L. Arlen, Philip M. Tsang, Kwong-Yok Yokokawa, Junko Palena, Claudia Poole, Diane J. Remondo, Cinzia Cereda, Vittore Jones, Jacquin L. Pazdur, Mary P. Higgins, Jack P. Hodge, James W. Steinberg, Seth M. Kotz, Herbert Dahut, William L. Schlom, Jeffrey TI Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID COLONY-STIMULATING FACTOR; HUMAN CARCINOEMBRYONIC ANTIGEN; INDEPENDENT PROSTATE-CANCER; T-LYMPHOCYTE EPITOPE; PHASE-I; IMMUNE-RESPONSES; DENDRITIC CELLS; COSTIMULATORY MOLECULES; PANCREATIC-CANCER; DIVERSIFIED PRIME AB Purpose: Poxviral vectors have a proven safety record and can be used to incorporate multiple transgenes. Prior clinical trials with poxviral vaccines have shown that immunologic tolerance to self-antigens can be broken. Carcinoembryonic antigen (CEA) and MUC-1 are overexpressed in a substantial proportion of common solid carcinomas. The primary end point of this study was vaccine safety, with immunologic and clinical responses as secondary end points. Experimental Design: We report here a pilot study of 25 patients treated with a poxviral vaccine regimen consisting of the genes for CEA and MUC-11, along with a triad of costimulatory molecules (TRICOM; composed of B7.1, intercellular adhesion molecule 1, and lymphocyte function - associated antigen 3) engineered into vaccinia (PANVAC-V) as a prime vaccination and into fowlpox (PANVAC-F) as a booster vaccination. Results: The vaccine was well tolerated. Apart from injection-site reaction, no grade >= 2 toxicity was seen in more than 2% of the cycles. Immune responses to MUC-1 and/or CEA were seen following vaccination in 9 of 16 patients tested. A patient with clear cell ovarian cancer and symptomatic ascites had a durable (18-month) clinical response radiographically and biochemically, and one breast cancer patient had a confirmed decrease of >20% in the size of large liver metastasis. Conclusions: This vaccine strategy seems to be safe, is associated with both CD8 and CD4 immune responses, and has shown evidence of clinical activity. Further trials with this agent, either alone or in combination with immunopotentiating and other therapeutic agents, are warranted. C1 [Gulley, James L.; Arlen, Philip M.; Tsang, Kwong-Yok; Yokokawa, Junko; Palena, Claudia; Poole, Diane J.; Remondo, Cinzia; Cereda, Vittore; Pazdur, Mary P.; Higgins, Jack P.; Hodge, James W.; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jones, Jacquin L.; Kotz, Herbert; Dahut, William L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010425-09] NR 56 TC 112 Z9 113 U1 1 U2 7 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 MAY 15 PY 2008 VL 14 IS 10 BP 3060 EP 3069 DI 10.1158/1078-0432.CCR-08-0126 PG 10 WC Oncology SC Oncology GA 303AW UT WOS:000256012700021 PM 18483372 ER PT J AU Karp, JE Smith, BD Gojo, I Lancet, JE Greer, J Klein, M Morris, L Levis, MJ Gore, SD Wright, JJ Garrett-Mayer, E AF Karp, Judith E. Smith, B. Douglas Gojo, Ivana Lancet, Jeffrey E. Greer, Jacqueline Klein, Maureen Morris, Larry Levis, Mark J. Gore, Steven D. Wright, John J. Garrett-Mayer, Elizabeth TI Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FARNESYL TRANSFERASE INHIBITOR; HEALTH-ORGANIZATION CLASSIFICATION; STEM-CELL TRANSPLANTATION; COUNCIL AML11 TRIAL; MYELODYSPLASTIC SYNDROME; POSTREMISSION THERAPY; DOSE CYTARABINE; OLDER PATIENTS; HEMATOLOGIC MALIGNANCIES AB Purpose: Acute myelogenous leukemia (AML) does not have a high cure rate, particularly in patients with poor-risk features. Such patients might benefit from additional therapy in complete remission (CR). Tipifarnib is an oral farnesyltransferase inhibitor with activity in AML. We conducted a phase II trial of maintenance tipifarnib monotherapy for 48 adults with poor-risk AML in first CR. Experimental Design: Tipifarnib 400 mg twice daily for 14 of 21 days was initiated after recovery from consolidation chemotherapy, for a maximum of 16 cycles (48 weeks). Results: Twenty (42%) patients completed 16 cycles, 24 (50%) were removed from study for relapse, and 4 (8%) discontinued drug prematurely for intolerance. Nonhematologic toxicities were rare, but tipifarnib dose was reduced in 58% for myelosuppression. Median disease-free survival (DFS) was 13.5 months (range, 3.5-59+ months), with 30% having DFS >2 years. Comparison of CR durations for 25 patients who received two-cycle timed sequential therapy followed by tipifarnib maintenance with 23 historically similar patients who did not receive tipifarnib showed that tipifarnib was associated with DFS prolongation for patients with secondary AML and adverse cytogenetics. Conclusions: This study suggests that some patients with poor-risk AML, including patients with secondary AML and adverse cytogenetics, may benefit from tipifarnib maintenance therapy. Future studies are warranted to examine alternative tipifarnib dosing and continuation beyond 16 cycles. C1 [Karp, Judith E.; Smith, B. Douglas; Greer, Jacqueline; Levis, Mark J.; Gore, Steven D.; Garrett-Mayer, Elizabeth] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Gojo, Ivana; Klein, Maureen] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Lancet, Jeffrey E.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Morris, Larry] Bone Marrow Transplant Grp Georgia, Atlanta, GA USA. [Wright, John J.] NCI, Investigat Drug Branch, Clin Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Karp, JE (reprint author), Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St,CRB 1 Room 289, Baltimore, MD 21231 USA. EM jkarp2@jhmi.edu FU NCI NIH HHS [U01 CA069854, U01 CA069854-07, CA 69854, U01 CA070095, U01 CA70095] NR 30 TC 29 Z9 29 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 MAY 15 PY 2008 VL 14 IS 10 BP 3077 EP 3082 DI 10.1158/1078-0432.CCR-07-4743 PG 6 WC Oncology SC Oncology GA 303AW UT WOS:000256012700023 PM 18483374 ER PT J AU Lewis, SL Khoo, PL De Young, RA Steiner, K Wilcock, C Mukhopadhyay, M Westphal, H Jamieson, RV Robb, L Tam, PPL AF Lewis, Samara L. Khoo, Poh-Lynn De Young, R. Andrea Steiner, Kirsten Wilcock, Chris Mukhopadhyay, Mahua Westphal, Heiner Jamieson, Robyn V. Robb, Lorraine Tam, Patrick P. L. TI Dkk1 and Wnt3 interact to control head morphogenesis in the mouse SO DEVELOPMENT LA English DT Article DE head development; WNT signalling; Dkk1; WNT3; mouse ID ANTERIOR PRIMITIVE ENDODERM; POSTERIOR AXIS POLARIZATION; EMBRYONIC STEM-CELLS; EXPRESSION PATTERN; VISCERAL ENDODERM; NEURAL PLATE; GENE-EXPRESSION; POSTIMPLANTATION DEVELOPMENT; DEFINITIVE ENDODERM; NEGATIVE REGULATOR AB Loss of Dkk1 results in ectopic WNT/beta-catenin signalling activity in the anterior germ layer tissues and impairs cell movement in the endoderm of the mouse gastrula. The juxtaposition of the expression domains of Dkk1 and Wnt3 is suggestive of an antagonist-agonist interaction. The downregulation of Dkk1 when Wnt3 activity is reduced reveals a feedback mechanism for regulating WNT signalling. Compound Dkk1; Wnt3 heterozygous mutant embryos display head truncation and trunk malformation, which are not found in either Dkk1(+/-) or Wnt3(+/-) embryos. Reducing the dose of Wnt3 gene in Dkk1(-/-) embryos partially rescues the truncated head phenotype. These findings highlight that head development is sensitive to the level of WNT3 signalling and that DKK1 is the key antagonist that modulates WNT3 activity during anterior morphogenesis. C1 [Lewis, Samara L.; Khoo, Poh-Lynn; De Young, R. Andrea; Steiner, Kirsten; Jamieson, Robyn V.; Tam, Patrick P. L.] Univ Sydney, Childrens Med Res Inst, Embryol Unit, Wentworthville, NSW 2145, Australia. [Wilcock, Chris; Jamieson, Robyn V.; Tam, Patrick P. L.] Univ Sydney, Fac Med, Wentworthville, NSW 2145, Australia. [Mukhopadhyay, Mahua; Westphal, Heiner] NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. [Robb, Lorraine] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. RP Tam, PPL (reprint author), Univ Sydney, Childrens Med Res Inst, Embryol Unit, Locked Bag 23, Wentworthville, NSW 2145, Australia. EM ptam@cmri.usyd.edu.au NR 67 TC 34 Z9 35 U1 1 U2 3 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 MAY 15 PY 2008 VL 135 IS 10 BP 1791 EP 1801 DI 10.1242/dev.018853 PG 11 WC Developmental Biology SC Developmental Biology GA 293LX UT WOS:000255337900007 PM 18403408 ER PT J AU Shin, CH Chung, WS Hong, SK Ober, EA Verkade, H Field, HA Huisken, J Stainier, DYR AF Shin, Chong Hyun Chung, Won-Suk Hong, Sung-Kook Ober, Elke A. Verkade, Heather Field, Holly A. Huisken, Jan Stainier, Didier Y. R. TI Multiple roles for Med12 in vertebrate endoderm development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Casanova; sox32; her5; kohtalo; liver; pancreas; glucagon ID ZEBRAFISH DANIO-RERIO; MEDIATOR COMPLEX; LIVER SPECIFICATION; DIGESTIVE-SYSTEM; NEURAL CREST; GENE; PROTEIN; TRANSCRIPTION; DIFFERENTIATION; RECEPTOR AB In zebrafish, the endoderm originates at the blastula stage from the most marginal blastomeres. Through a series of complex morphogenetic movements and differentiation events, the endodermal germ layer gives rise to the epithelial lining of the digestive tract as well as its associated organs such as the liver, pancreas, and swim bladder. How endodermal cells differentiate into distinct cell types such as hepatocytes or endocrine and exocrine pancreatic cells remains a major question. In a forward genetic screen for genes regulating endodermal organ development, we identified mutations at the shiri locus that cause defects in the development of a number of endodermal organs including the liver and pancreas. Detailed phenotypic analyses indicate that-these defects are partially due to a reduction in endodermal expression of the hairy/enhancer of splitrelated gene, her-5, at mid to late gastrulation stages. Using the Tg(0.71her5:EGFP)(ne2067) line, we show that her5 is expressed in the endodermal precursors that populate the pharyngeal region as well as the organ-forming region. We also find that knocking down her5 recapitulates some of the endodermal phenotypes of shiri mutants, further revealing the role of her-5 in endoderm development. Positional cloning reveals that shiri encodes Med12, a regulatory subunit of the transcriptional Mediator complex recently associated with two human syndromes. Additional studies indicate that Med12 modulates the ability of Casanova/Sox32 to induce sox17 expression. Thus, detailed phenotypic analyses of embryos defective in a component of the Mediator complex have revealed new insights into discrete aspects of vertebrate endoderm development, and provide possible explanations for the craniofacial and digestive system defects observed in humans with mutations in MED12. (C) 2008 Elsevier Inc. All rights reserved. C1 [Shin, Chong Hyun; Chung, Won-Suk; Ober, Elke A.; Verkade, Heather; Field, Holly A.; Huisken, Jan; Stainier, Didier Y. R.] Univ Calif San Francisco, Dept Biochem & Biophys, Program Dev Biol, San Francisco, CA 94158 USA. [Shin, Chong Hyun; Chung, Won-Suk; Ober, Elke A.; Verkade, Heather; Field, Holly A.; Huisken, Jan; Stainier, Didier Y. R.] Univ Calif San Francisco, Dept Biochem & Biophys, Genet Program, San Francisco, CA 94158 USA. [Shin, Chong Hyun; Chung, Won-Suk; Ober, Elke A.; Verkade, Heather; Field, Holly A.; Huisken, Jan; Stainier, Didier Y. R.] Univ Calif San Francisco, Dept Biochem & Biophys, Program Human Genet, San Francisco, CA 94158 USA. [Shin, Chong Hyun; Chung, Won-Suk; Ober, Elke A.; Verkade, Heather; Field, Holly A.; Huisken, Jan; Stainier, Didier Y. R.] Univ Calif San Francisco, Ctr Liver, San Francisco, CA 94158 USA. [Hong, Sung-Kook] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Shin, CH (reprint author), Univ Calif San Francisco, Dept Biochem & Biophys, Program Dev Biol, San Francisco, CA 94158 USA. EM chong.shin@ucsf.edu; didier_stainier@biochem.ucsf.edu RI Huisken, Jan/B-2472-2009; Verkade, Heather/J-2401-2013; Chung, Won Suck/B-9011-2016; OI Verkade, Heather/0000-0002-2817-0509 FU NIDDK NIH HHS [F32 DK068891, F32DK068891, R01 DK058181, R01 DK058181-07, R01 DK058181-08, R01 DK060322, R01 DK060322-06A1, R01 DK060322-07, R01 DK075032, R01 DK075032-02] NR 65 TC 29 Z9 29 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 15 PY 2008 VL 317 IS 2 BP 467 EP 479 DI 10.1016/j.ydbio.2008.02.031 PG 13 WC Developmental Biology SC Developmental Biology GA 301LV UT WOS:000255898600008 PM 18394596 ER PT J AU Lu, T Finkel, T AF Lu, Teng Finkel, Toren TI Free radicals and senescence SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE reactive oxygen species; senescence; hydrogen peroxide; telomere; antioxidant ID ENDOTHELIAL-CELL SENESCENCE; OXIDATIVE STRESS; GROWTH ARREST; SUPEROXIDE-DISMUTASE; HUMAN FIBROBLASTS; LIFE-SPAN; DNA-DAMAGE; PATHWAY; P53; ACCUMULATION AB There is a significant body of experimental evidence that a rise in intracellular reactive oxygen species (ROS) contributes to senescence. Here we review experiments where entry into senescence has been evaluated in cells whose intracellular ROS levels have been modulated by growth in either high or low ambient oxygen concentrations, or where the cellular antioxidant status has been perturbed. In addition, we discuss the observations that senescence triggered by oncogene expression also appears to be in part mediated by a rise in ROS levels. Finally, we discuss the emerging evidence that in vivo senescence might also be triggered by a rise in cellular oxidant levels. Although these data tend to support a role for ROS in mediating senescence, significant questions remain as to whether ROS act in a random or specific fashion and what precise oxidant species acts as the potential senescence trigger. Published by Elsevier Inc. C1 [Lu, Teng; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,CRC 5-3330,T 301-402-4081, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU Intramural NIH HHS [Z01 HL005012-11, Z99 HL999999] NR 36 TC 149 Z9 160 U1 1 U2 9 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2008 VL 314 IS 9 BP 1918 EP 1922 DI 10.1016/j.yexcr.2008.01.011 PG 5 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 308UP UT WOS:000256415800003 PM 18282568 ER PT J AU Ogi, H Wang, CZ Nakal, W Kawasaki, Y Masumoto, H AF Ogi, Hiroo Wang, Cheng-Zhong Nakal, Wataru Kawasaki, Yasuo Masumoto, Hiroshi TI The role of the Saccharomyces cerevisiae Cdc7-Dbf4 complex in the replication checkpoint SO GENE LA English DT Article DE cell cycle; DNA replication; Rad53; Dun1 ID DNA-DAMAGE CHECKPOINT; PROTEIN-KINASE; S-PHASE; SIGNAL-TRANSDUCTION; FISSION YEAST; BUDDING YEAST; RAD53 KINASE; ACTIVATION; INITIATION; PATHWAY AB The Cdc7-Dbf4 complex is a conserved serine/threonine protein kinase essential for the initiation of eukaryotic DNA replication. Although an mcm5-bob1 mutation bypasses lethality conferred by mutations in CDC7 or DBF4, the Delta cdc7 mcm5-bob1 mutant is sensitive to hydroxyurea (H-U), which induces replication stress. To elucidate the reasons for HU sensitivity conferred by deletion of CDC7, we examined the role of Cdc7-Dbf4 in the replication checkpoint. We found that in Cdc7-Dbf4-deficient cells exposed to replication stress, Rad53 remains in a hypophosphorylated form, anaphase spindle is elongated, and checkpoint-specific transcription is not induced. The hypophosphorylated Rad53 exhibits a low autophosphorylation activity, and recombinant Cdc7-Dbf4 phosphorylates Rad53 in vitro. These results suggest that Cdc7-Dbf4 is required for full activation of Rad53 in response to replication stress. (c) 2008 Elsevier B.V. All rights reserved. C1 [Ogi, Hiroo; Masumoto, Hiroshi] Univ Tsukuba, Grad Sch Life & Environm Sci, Initiat Promot Young Scientists Independent Res, Tsukuba, Ibaraki 3058571, Japan. [Ogi, Hiroo; Wang, Cheng-Zhong; Kawasaki, Yasuo; Masumoto, Hiroshi] Osaka Univ, Grad Sch Frontier Biosci, Labs Biomol Networks, Osaka 5650871, Japan. [Ogi, Hiroo] St Jude Childrens Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. [Nakal, Wataru] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Ogi, H (reprint author), Univ Tsukuba, Grad Sch Life & Environm Sci, Initiat Promot Young Scientists Independent Res, 1-1-1 Tennoudai, Tsukuba, Ibaraki 3058571, Japan. EM oogi@fbs.osaka-u.ac.jp; himasumo@fbs.osaka-u.ac.jp NR 33 TC 12 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAY 15 PY 2008 VL 414 IS 1-2 BP 32 EP 40 DI 10.1016/j.gene.2008.02.010 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 299RG UT WOS:000255772100004 PM 18372119 ER PT J AU Xiao, Y Gao, XG Gannot, G Emmert-Buck, MR Srivastava, S Wagner, PD Amos, MD Barker, PE AF Xiao, Yan Gao, Xiugong Gannot, Gallya Emmert-Buck, Michael R. Srivastava, Sudhir Wagner, Paul D. Amos, Michael D. Barker, Peter E. TI Quantitation of HER2 and telomerase biomarkers in solid tumors with IgY antibodies and nanocrystal detection SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IgY antibody; cancer biomarker; HER2; telomerase; quantum dots ID REVERSE-TRANSCRIPTASE HTERT; OVARIAN-CANCER; HENS; RECEPTOR; PROTEIN; YOLKS; TESTS AB In an effort to improve affinity biomarker validation in fixed patient tissue specimens, we have developed a novel quantum dot-based bioimaging system that utilizes chicken IgY antibody for high sensitivity and specificity relative quantitation of cancer proteins. Monospecific, polyclonal IgYs were generated against human HER2 and telomerase, and analytically validated for specificity by western blot and immunohistochemistry on tumor and normal cells and for relative affinity by layered peptide array (LPA). IgYs bound desired targets in cell lines and fixed tissues and showed greater affinity than commercial mammalian antibodies for both HER2 and telomerase proteins. In tissue microarray experiments, HER2 quantitation with IgY antibody and quantum dot imaging correlated well with chromogenic in situ hybridization (CISH), whereas telomerase quantitation suggested a trend toward correlation with prostate cancer Gleason Grade and differentiation. Although patient numbers were small, these findings demonstrate the feasibility of relative quantitation of cancer biomarkers with IgY and quantum dot fluorophores, and show promise for rigorous clinical validation in large patient cohorts. (C) 2008 Wiley-Liss, Inc. C1 NIST, Div Biochem Sci, DNA Measurement Grp, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Xiao, Yan; Barker, Peter E.] NIST, Canc Biomarker Ref Lab, NCI EDRN, Gaithersburg, MD 20899 USA. [Xiao, Yan] Sci Applicat Int Corp, Arlington, VA USA. [Gao, Xiugong] Translab, Clarksburg, MD USA. [Gannot, Gallya; Emmert-Buck, Michael R.] NCI, Ctr Canc Res, Pathol Lab, Pathogenet Unit, Bethesda, MD 20892 USA. [Gannot, Gallya; Emmert-Buck, Michael R.] NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. [Srivastava, Sudhir; Wagner, Paul D.] NCI, Div Canc Prevent, Canc Biomarker Res Grp, Bethesda, MD 20892 USA. RP Xiao, Y (reprint author), NIST, Div Biochem Sci, DNA Measurement Grp, Chem Sci & Technol Lab, 100 Bureau Dr, Gaithersburg, MD 20899 USA. EM yan.xiao@nist.gov FU NCI NIH HHS [Y1-CN-45016] NR 22 TC 33 Z9 39 U1 0 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2008 VL 122 IS 10 BP 2178 EP 2186 DI 10.1002/ijc.23320 PG 9 WC Oncology SC Oncology GA 288JQ UT WOS:000254983100002 PM 18214859 ER PT J AU Andreotti, G Chen, JB Gao, YT Rashid, A Chang, SC Shen, MC Wang, BS Han, TQ Zhang, BH Danforth, KN Althuis, MD Hsing, AW AF Andreotti, Gabriella Chen, Jinbo Gao, Yu-Tang Rashid, Asif Chang, Shih-Chen Shen, Ming-Chang Wang, Bing-Sheng Han, Tian-Quan Zhang, Bai-He Danforth, Kim N. Althuis, Michelle D. Hsing, Ann W. TI Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population-based study in China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE serum lipid levels; gallstones; biliary tract cancer ID LOW-DENSITY-LIPOPROTEIN; GALLBLADDER-DISEASE; CHOLESTEROL GALLSTONES; DEOXYCHOLIC-ACID; NUCLEATION TIME; UNITED-STATES; JAPANESE MEN; A-I; PLASMA; CHOLANGIOCARCINOMA AB Biliary tract cancers, encompassing the gallbladder, extrahepatic bile diicts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (>= 160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI = 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI = 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI = 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/di). Participants in the lowest quintile of high-density lipoprotein (HDL) (<30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI = 3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% Cl = 7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI = 9.1-30.9), relative to the reference group (third quintile: 40-49 mg/di). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis. (C) 2007 Wiley.Liss, Inc. C1 [Andreotti, Gabriella; Danforth, Kim N.; Althuis, Michelle D.; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Bethesda, MD 20892 USA. [Chen, Jinbo] Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Chang, Shih-Chen] AstraZeneca, Dept Discovery Med & Epidemiol, Wilmington, DE USA. [Shen, Ming-Chang] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, Bing-Sheng] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Quan] Second Med Univ, Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. [Zhang, Bai-He] Second Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. RP Andreotti, G (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, NIH, 6120 Execut Blvd,EPS 8011,MSC 7240, Bethesda, MD 20892 USA. EM andreotg@mail.nih.gov FU Intramural NIH HHS [ZIA CP010158-09] NR 55 TC 27 Z9 30 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2008 VL 122 IS 10 BP 2322 EP 2329 DI 10.1002/ijc.23307 PG 8 WC Oncology SC Oncology GA 288JQ UT WOS:000254983100020 PM 18076041 ER PT J AU Freedman, ND Park, Y Subar, AF Hollenbeck, AR Leitzmann, MF Schatzkin, A Abnet, CC AF Freedman, Neal D. Park, Yikyung Subar, Amy F. Hollenbeck, Albert R. Leitzmann, Michael F. Schatzkin, Arthur Abnet, Christian C. TI Fruit and vegetable intake and head and neck cancer risk in a large United States prospective cohort study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE head and neck cancer; fruits; vegetables; cohort ID UPPER AERODIGESTIVE TRACT; ALCOHOL; MEN; ASSOCIATION; PREVENTION AB Squamous head and neck cancers include cancers of the oral cavity, pharynx and larynx are the sixth leading cause of cancer mortality worldwide, resulting in more than 350,000 deaths annually. Intake of fruit and vegetables may protect against head and neck cancer incidence, although few prospective studies have examined this association. We investigated this relation in 490,802 United States participants of the NIH-AARP Diet and Health cohort using Cox proportional hazard models adjusted for potential confounders. During 2,193,751 person years of follow-up from 1995/1996-2000, 787 participants were diagnosed with head and neck cancer. We found an inverse association between total fruit and vegetable intake and head and neck cancer risk (per serving/day/1,000 calories, Hazard Ratio, 95% Confidence interval: 0.94, 0.89-0.99). In models mutually adjusted for fruit and vegetable intake, the association was stronger for vegetables (fifth vs. first quintile: 0.65, 0.50-0.85) than for fruits (fifth vs. first quintile: 0.87, 0.68-1.11). When further subclassified into botanical groups, those in the highest tertile of leguminosae (dried beans, string beans and peas, 0.80, 0.67-0.96), rosaceae (apples, peach, nectarines, plums, pears and strawberries, 0.60, 0.49-0.73), solanaceae (peppers and tomatoes, 0.82, 0.69-0.98) and umbelliferae (carrots, 0.73, 0.60-0.89) had decreased risk of head and neck cancer, but no significant associations were seen for 9 other botanical groups. Results from this large prospective observational study are consistent with previous case-control studies and support the hypothesis that total fruit and vegetable intake is associated with reduced risk of head and neck cancer. (C) 2007 Wiley-Liss, Inc. C1 [Freedman, Neal D.; Park, Yikyung; Leitzmann, Michael F.; Schatzkin, Arthur; Abnet, Christian C.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Rockville, MD 20852 USA. [Freedman, Neal D.] NCI, Canc Prevent Div, Canc Prevent Fellowship Program, NIH, Rockville, MD 20852 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, DHHS, NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Freedman, ND (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, 6120 Execut Blvd,EPS 320,MSC 7232, Rockville, MD 20852 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Park, Yikyung/0000-0002-6281-489X NR 24 TC 88 Z9 88 U1 2 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2008 VL 122 IS 10 BP 2330 EP 2336 DI 10.1002/ijc.23319 PG 7 WC Oncology SC Oncology GA 288JQ UT WOS:000254983100021 PM 18092323 ER PT J AU Weiss, JM Huang, WY Rinaldi, S Fears, TR Chatterjee, N Hsing, AW Crawford, ED Andriole, GL Kaaks, R Hayes, RB AF Weiss, Jocelyn M. Huang, Wen-Yi Rinaldi, Sabina Fears, Thomas R. Chatterjee, Nilanjan Hsing, Ann W. Crawford, E. David Andriole, Gerald L. Kaaks, Rudolf Hayes, Richard B. TI Endogenous sex hormones and the risk of prostate cancer: A prospective study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate; hormones; testosterone; 3 alpha-diolG; sex hormone-binding globulin; androstenedione ID BINDING GLOBULIN; STEROID-HORMONES; SERUM ANDROGENS; FREE TESTOSTERONE; SCREENING TRIAL; RECEPTOR; EPIDEMIOLOGY; ESTROGENS; INTERMEDIACY; STIMULATION AB Sex steroid hormones influence prostate development and maintenance through their roles in prostate cellular proliferation, differentiation and apoptosis. Although suspected to be involved in prostate carcinogenesis, an association between circulating androgens and prostate cancer has not been clearly established in epidemiologic studies. We conducted a nested case-control study with prospectively collected samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, to examine associations of prostate cancer with androstenedione (Delta 4-A), testosterone (T), sex hormone-binding globulin (SHBG) and 3 alpha-androstanediol glucuronide (3a-diolG). A total of 727 incident Caucasian prostate cancer cases (age >= 65 years, N = 396) and 889 matched controls were selected for this analysis. Overall, prostate cancer risks were unrelated to serum T, estimated free and bioavailable T, and SHBG; however, risks increased with increasing T:SHBG ratio (P-trend = 0.01), mostly related to risk in older men (>= 65 years, Ptrend = 0.001), particularly for aggressive disease [highest versus lowest quartile: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.50-5.091. No clear patterns were noted for Delta 4-A and 3 alpha-diolG. In summary, our large prospective study did not show convincing evidence of a relationship between serum sex hormones and prostate cancer. T:SHBG ratio was related to risk in this older population of men, but the significance of this ratio in steroidal biology is unclear. (C) 2008 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH, Rockville, MD 20852 USA. [Rinaldi, Sabina] Int Agcy Res Canc, F-69372 Lyon, France. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Div Urol Oncol, Denver, CO USA. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Kaaks, Rudolf] German Natl Canc Ctr, Div Canc Epidemiol, Heidelberg, Germany. RP Weiss, JM (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM weissjoc@mail.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Hayes, Richard/0000-0002-0918-661X FU Intramural NIH HHS NR 46 TC 38 Z9 41 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2008 VL 122 IS 10 BP 2345 EP 2350 DI 10.1002/ijc.23326 PG 6 WC Oncology SC Oncology GA 288JQ UT WOS:000254983100023 PM 18172860 ER PT J AU Kalab, P Heald, R AF Kalab, Petr Heald, Rebecca TI The RanGTP gradient - a GPS for the mitotic spindle SO JOURNAL OF CELL SCIENCE LA English DT Editorial Material DE Ran; importin; exportin; mitotic spindle; cancer ID DEPENDENT MICROTUBULE NUCLEATION; PROTEIN IMPORT CYCLE; NUCLEOCYTOPLASMIC TRANSPORT; AURORA-A; SOMATIC-CELLS; IN-VIVO; CHROMOSOME SEGREGATION; CENTROSOME DUPLICATION; DROSOPHILA EMBRYOS; ENVELOPE BREAKDOWN AB The GTPase Ran has a key role in nuclear import and export, mitotic spindle assembly and nuclear envelope formation. The cycling of Ran between its GTP- and GDP-bound forms is catalyzed by the chromatin-bound guanine nucleotide exchange factor RCC1 and the cytoplasmic Ran GTPase-activating protein RanGAP. The result is an intracellular concentration gradient of RanGTP that equips eukaryotic cells with a 'genome-positioning system' (GPS). The binding of RanGTP to nuclear transport receptors (NTRs) of the importin beta superfamily mediates the effects of the gradient and generates further downstream gradients, which have been elucidated by fluorescence resonance energy transfer (FRET) imaging and computational modeling. The Ran-dependent GPS spatially directs many functions required for genome segregation by the mitotic spindle during mitosis. Through exportin 1, RanGTP recruits essential centrosome and kinetochore components, whereas the RanGTP-induced release of spindle assembly factors (SAFs) from importins activates SAFs to nucleate, bind and organize nascent spindle microtubules. Although a considerable fraction of cytoplasmic SAFs is active and RanGTP induces only partial further activation near chromatin, bipolar spindle assembly is robustly induced by cooperativity and positive-feedback mechanisms within the network of Ran-activated SAFs. The RanGTP gradient is conserved, although its roles vary among different cell types and species, and much remains to be learned regarding its functions. C1 [Kalab, Petr] NCI, Lab Cell & Mol Biol, Bethesda, MD 20892 USA. [Kalab, Petr; Heald, Rebecca] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Kalab, P (reprint author), NCI, Lab Cell & Mol Biol, Bethesda, MD 20892 USA. EM pkalab@yahoo.com RI Kalab, Petr/B-2478-2009; OI Heald, Rebecca/0000-0001-6671-6528 NR 106 TC 145 Z9 146 U1 1 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAY 15 PY 2008 VL 121 IS 10 BP 1577 EP 1586 DI 10.1242/jcs.005959 PG 10 WC Cell Biology SC Cell Biology GA 299IC UT WOS:000255748300002 PM 18469014 ER PT J AU Kelly, T Gray, TR Huestis, MA AF Kelly, Tamsin Gray, Teresa R. Huestis, Marilyn A. TI Development and validation of a liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry method for simultaneous analysis of 10 amphetamine-, methamphetamine- and 3,4-methylenedioxymethamphetamine-related (MDMA) analytes in human meconium SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE meconium; amphetamines; LC-MS/MS ID UTERO DRUG EXPOSURE; TOXICOLOGICAL DETECTION; COCAINE METABOLITES; MAJOR METABOLITES; FETAL EXPOSURE; LIFE-STYLE; URINE; PREGNANCY; ABUSE; IMMUNOASSAY AB A liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry (LC-APCI-MS/MS) method for quantification of 10 amphetamine-related analytes in 1 g meconium is presented. Specimen preparation included homogenization and solid-phase extraction. Two multiple reaction monitoring transitions were monitored per analyte. Ten and 1 mu L injection volumes permitted quantification up to 10,000 ng/g, with sufficient sensitivity to quantify minor metabolites. Lower limits of quantification ranged from 1.25 to 40 ng/g. Precision was less than 14.2%, with accuracy between 79 and 115%. Meconium from a methamphetamine-exposed neonate was analyzed. Metabolites p-hydroxymethamphetamine, norephedrine and 4-hydroxy-3-methoxymethamphetamine were identified in meconium for the first time. Published by Elsevier B.V. C1 [Kelly, Tamsin; Gray, Teresa R.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program, Natl Inst Hlth, 251 Bayview Blvd,Suite 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI Kelly, Tamsin/A-2456-2009 OI Kelly, Tamsin/0000-0002-8946-9686 FU Intramural NIH HHS [Z01 DA000433-08, Z01 DA000468-04, NIH0012986137] NR 50 TC 27 Z9 28 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 15 PY 2008 VL 867 IS 2 BP 194 EP 204 DI 10.1016/j.jchromb.2008.03.029 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 311MW UT WOS:000256605300005 PM 18424195 ER PT J AU Zohar, O Reiter, Y Bennink, JR Lev, A Cavallaro, S Paratore, S Pick, CG Brooker, G Yewdell, JW AF Zohar, Ofer Reiter, Yoram Bennink, Jack R. Lev, Avital Cavallaro, Sebastiano Paratore, Sabrina Pick, Chaim G. Brooker, Gary Yewdell, Jonathan W. TI MHC class I-Ly49 interaction regulates neuronal function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-I MHC; CENTRAL-NERVOUS-SYSTEM; GENE-EXPRESSION; PLASTICITY; CNS; MOLECULES; PROTEIN AB MHC class I molecules (MHC-I) have been implicated in nervous system development in the mouse. In this study we present evidence for the interaction of MHC-I with the NK cell receptor Ly49 in primary cortical neuronal cultures. We show that MHC-I and Ly49 are expressed on neuronal soma and axon surfaces, with Ly49 also present on dendrites. Anti-MHC-I Abs reduce synapsin-I expression and enhance neurite outgrowth and neuronal death. Conversely, anti-Ly49 mAbs increase synapsin-I expression, reduce neurite outgrowth, and promote neuron viability. Because we show that Ly49 genes are selectively expressed in the adult brain, these findings suggest an unsuspected role for the MHC-I-Ly49 interaction in the development and function of the brain. C1 [Zohar, Ofer] Johns Hopkins Univ, Blanchette Rockefeller Neurosci Inst, Rockville, MD 20850 USA. [Reiter, Yoram] Technion Israel Inst Technol, Fac Biol, Haifa, Israel. [Bennink, Jack R.; Lev, Avital; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Cavallaro, Sebastiano; Paratore, Sabrina] Italian Natl Res Council, Inst Neurol Sci, Funct Genom Ctr, Catania, Italy. [Pick, Chaim G.] Tel Aviv Univ, Sackler Sch Med, Dept Anat & Anthropol, IL-69978 Tel Aviv, Israel. [Brooker, Gary] Johns Hopkins Univ, Microscopy Ctr, Dept Chem, Rockville, MD 20850 USA. RP Zohar, O (reprint author), Johns Hopkins Univ, Blanchette Rockefeller Neurosci Inst, Montgomery Cty Campus,9601 Med Ctr Dr, Rockville, MD 20850 USA. EM zohar@brni-jhu.org RI Pick, Chaim/D-4789-2009; yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS [Z01 AI001054-01] NR 18 TC 28 Z9 28 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6447 EP 6451 PG 5 WC Immunology SC Immunology GA 324GW UT WOS:000257507100004 PM 18453559 ER PT J AU Huang, V Lonsdorf, AS Fang, L Kakinuma, T Lee, VC Cha, E Zhang, H Nagao, K Zaleska, M Olszewski, WL Hwang, ST AF Huang, Victor Lonsdorf, Anke S. Fang, Lei Kakinuma, Takashi Lee, Vivian C. Cha, Emily Zhang, Hong Nagao, Keisuke Zaleska, Marzanna Olszewski, Waldemar L. Hwang, Sam T. TI Rapid accumulation of epidermal CCL27 in skin-draining lymph nodes following topical application of a contact sensitizer recruits CCR10-expressing T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ATOPIC-DERMATITIS; CHEMOKINE; LYMPHOCYTES; RECEPTOR; PROTEIN; INFLAMMATION; ISOFORMS; IMMUNITY; ESKINE; CCR10 AB CC chemokine receptor 10 and its ligand, CCL27, are important components of T cell-mediated cutaneous immunity, hut whether they influence lymph node (LN) homing by T cells is unknown. In this study, CCL27 protein was detected in skin-draining LN by Western blotting and ELISA although CCL27 mRNA transcripts were low. CCL27 protein was present at higher levels in skin-draining LN compared with gut-draining LN and spleen. A single topical treatment of mouse skin with the contact sensitizer 2,4-dinitro-1-fluorobenzene (DNFB) resulted in a 13-fold increase in CCL27 protein accumulation in skin-draining LN within 1 h and a 5-fold elevation in CCR10 mRNA (normalized to the T cell marker CD2) within 6 h. DNFB treatment also resulted in rapid depletion of similar to 75% of CCL27 from the epidermis. In summary, we describe a novel mechanism for the recruitment of CCR10-positive T cells to skin-draining LN following the rapid release of preformed CCL27 from the epidermis. C1 [Huang, Victor; Lonsdorf, Anke S.; Fang, Lei; Lee, Vivian C.; Cha, Emily; Zhang, Hong; Nagao, Keisuke; Hwang, Sam T.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Zaleska, Marzanna; Olszewski, Waldemar L.] Polish Acad Sci, Med Res Ctr, Warsaw, Poland. RP Hwang, ST (reprint author), NCI, Dermatol Branch, Ctr Canc Res, 10 Ctr Dr,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM hwangs@mail.nih.gov RI Nagao, Keisuke/J-5116-2013 OI Nagao, Keisuke/0000-0002-7005-3138 FU Intramural NIH HHS NR 22 TC 14 Z9 14 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6462 EP 6466 PG 5 WC Immunology SC Immunology GA 324GW UT WOS:000257507100007 PM 18453562 ER PT J AU Chen, X Subleski, JJ Kopf, H Howard, OMZ Mannel, DN Oppenheim, JJ AF Chen, Xin Subleski, Jeffrey J. Kopf, Heather Howard, O. M. Zack Maennel, Daniela N. Oppenheim, Joost J. TI Expression of TNFR2 defines a maximally suppressive subset of mouse CD4(+)CD25(+)FoxP3(+) T regulatory cells: Applicability to tumor-infiltrating T regulatory cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; THERAPY; CD25(+) AB TNFR2 is predominantly expressed by a subset of human and mouse CD4(+)CD25A(+)FoxP3(+) T regulatory cells (Tregs). In this study, we characterized the phenotype and function of TNFR2(+) Tregs in peripheral lymphoid tissues Of normal and tumor-bearing C57BL/6 mice. We found that TNFR2 was expressed on 30-40% of the Tregs of the peripheral activated/memory subset that were most highly suppressive. In contrast, TNFR2(-) Tregs exhibited the phenotype of naive cells and only bad minimal suppressive activity. Although not typically considered to be Tregs, CD4(+) CD25(-) TNFR2(+) cells nevertheless possessed moderate suppressive activity. Strikingly, the suppressive activity of TNFR2(+) Tregs was considerably more potent than that of reportedly highly suppressive CD103(+) Tregs. In the Lewis lung carcinoma model, more highly suppressive TNFR2(+) Tregs accumulated intratumorally than in the periphery. Thus, TNFR2 identifies a unique subset of mouse Tregs with an activated/memory phenotype and maximal suppressive activity that may account for tumor-infiltrating lymphocyte-mediated immune evasion by tumors. C1 [Chen, Xin] NCI, Basic Res Program, SAIC Frederick Inc, Mol Immunoregulat Lab,Canc Inflammat Program, Frederick, MD 21702 USA. [Kopf, Heather; Howard, O. M. Zack; Oppenheim, Joost J.] NCI, Canc Inflammat Program, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Subleski, Jeffrey J.] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Maennel, Daniela N.] Univ Regensburg, Inst Immunol, Regensburg, Germany. RP Chen, X (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Mol Immunoregulat Lab,Canc Inflammat Program, POB B,Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010707-02]; NCI NIH HHS [N01 CO 12400, N01CO12400] NR 12 TC 107 Z9 113 U1 1 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6467 EP 6471 PG 5 WC Immunology SC Immunology GA 324GW UT WOS:000257507100008 PM 18453563 ER PT J AU Melenhorst, JJ Lay, MDH Price, DA Adams, SD Zeilah, J Sosa, E Hensel, NF Follmann, D Douek, DC Davenport, MP Barrett, AJ AF Melenhorst, J. Joseph Lay, Matthew D. H. Price, David A. Adams, Sharon D. Zeilah, Josette Sosa, Edgardo Hensel, Nancy F. Follmann, Dean Douek, Daniel C. Davenport, Miles P. Barrett, A. John TI Contribution of TCR-beta locus and HLA to the shape of the mature human V beta repertoire SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; SEGMENT FREQUENCIES; V(D)J RECOMBINATION; GENE REARRANGEMENT; ALPHA-BETA; SOMATIC GENERATION; PRE-TCR; EXPRESSION; SELECTION; ENHANCER AB T cells that survive thymic selection express a diverse array of unique heterodimeric alpha beta TCRs that mediate peptide-MHC Ag recognition. The proportion of the total T cell repertoire that expresses a particular V beta protein may be determined by a variety of factors: 1) germline preference for use of particular V beta genes; 2) allelic effects on the expression of different V beta genes; and 3) HLA effects on the expression of different V beta genes (acting via thymic selection and/or peripheral mechanisms). In this study, we show that V beta usage by human CD4(+) and CD8(+) T cells in neonatal and adult donors is highly correlated between unrelated individuals, suggesting that a large proportion of the observed pattern of V beta expression is determined by factors intrinsic to the TCR-beta locus. The presence of identical TCR alleles (within an individual) leads to a significantly better correlation between CD4(+) and CD8(+) T cells with respect to V beta expression; these effects are, however, relatively minor. The sharing of HLA alleles between individuals also leads to an increased correlation between their V beta expression patterns, although this did not reach statistical significance. We therefore conclude that the correlation in V beta expression patterns between CD4(+) and CD8(+) T cells can be explained predominantly by germline TCR-beta locus factors and not TCR-beta allelic or HLA effects. C1 [Melenhorst, J. Joseph; Zeilah, Josette; Sosa, Edgardo; Hensel, Nancy F.; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Adams, Sharon D.] NIAID, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. [Follmann, Dean] NIAID, Biostat Branch, NIH, Bethesda, MD 20892 USA. [Lay, Matthew D. H.; Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Kensington, NSW 2033, Australia. [Price, David A.] Cardiff Univ, Dept Med Biochem & Immunol, Sch Med, Cardiff, S Glam, Wales. RP Melenhorst, JJ (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10-CRC,Room 3-5320,10 Ctr Dr, Bethesda, MD 20892 USA. EM melenhoj@nhlbi.nih.gov RI Lay, Matthew/C-3041-2011; Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Intramural NIH HHS; Medical Research Council [G0501963] NR 39 TC 7 Z9 7 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6484 EP 6489 PG 6 WC Immunology SC Immunology GA 324GW UT WOS:000257507100011 PM 18453566 ER PT J AU Thomas, R Yamada, E Alter, G Martin, MP Bashirova, AA Norman, PJ Altfeld, M Parham, P Anderson, SK McVicar, DW Carrington, M AF Thomas, Rasmi Yamada, Eriko Alter, Galit Martin, Maureen P. Bashirova, Arman A. Norman, Paul J. Altfeld, Marcus Parham, Peter Anderson, Stephen K. McVicar, Daniel W. Carrington, Mary TI Novel KIR3DL1 alleles and their expression levels on NK cells: Convergent evolution of KIR3DL1 phenotype variation? SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; HLA-B; CUTTING EDGE; KIR; RECEPTOR; IDENTIFICATION; POLYMORPHISM; RECOGNITION; DIVERSITY; RECOMBINATION AB KIR3DL1 shows extensive polymorphism, and its variation has functional significance in terms of cell-surface expression levels and inhibitory capacity. We characterized nine KIR3DL1 alleles (*022, *028, *029, *033, *035, *051, *052, *053, and *054), four of which were identified for the first time in this study, and compared them to known alleles in phylogenetic analysis. Blood was available from eight individuals with these alleles, and cell-surface expression on NK cells could be determined for six of them using the KIR3DL1-specific Ab DX9. Four of the alleles were expressed at clearly detectable levels, and two others showed exceptionally low levels of expression. Site-directed mutagenesis demonstrated that single amino acid changes can result in either diminished or enhanced DX9 staining compared with the respective related KIR3DL1 allotypes. These results raise the possibility that KIR3DL1 evolution maintains variation in KIR3DL1 cell-surface expression levels, potentially due to the effect of such variation on functional capacity. C1 [Thomas, Rasmi; Yamada, Eriko; Martin, Maureen P.; Anderson, Stephen K.; McVicar, Daniel W.; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, Sci Applicat Int Frederick, Frederick, MD 21702 USA. [Alter, Galit; Altfeld, Marcus] Massachusetts Gen Hosp, Infect Dis Unit, Partners AIDS Res Ctr, Boston, MA 02129 USA. [Alter, Galit; Altfeld, Marcus] Harvard Univ, Sch Med, Div AIDS, Boston, MA 02129 USA. [Bashirova, Arman A.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA. [Norman, Paul J.; Parham, Peter] Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. RP Carrington, M (reprint author), NCI, Canc & Inflammat Program, Expt Immunol Lab, Sci Applicat Int Frederick, Frederick, MD 21702 USA. EM carringt@ncifcrf.gov RI Anderson, Stephen/B-1727-2012; McVicar, Daniel/G-1970-2015 OI Anderson, Stephen/0000-0002-7856-4266; FU Intramural NIH HHS; NCI NIH HHS [N01 CO012400]; NIDA NIH HHS [DA 13324, R01 DA013324] NR 38 TC 40 Z9 43 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6743 EP 6750 PG 8 WC Immunology SC Immunology GA 324GW UT WOS:000257507100039 PM 18453594 ER PT J AU Mattapallil, MJ Sahin, A Silver, PB Sun, SH Chan, CC Remmers, EF Hejtmancik, JF Caspi, RR AF Mattapallil, Mary J. Sahin, Azize Silver, Phyllis B. Sun, Shu-Hui Chan, Chi-Chao Remmers, Elaine F. Hejtmancik, J. Fielding Caspi, Rachel R. TI Common genetic determinants of uveitis shared with other autoimmune disorders SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; ACUTE ANTERIOR UVEITIS; BEHCETS-DISEASE; MULTIPLE-SCLEROSIS; PARS PLANITIS; ANKYLOSING-SPONDYLITIS; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY GENES; CLASS-II; POLYMORPHISMS AB Uveitis is a complex multifactorial autoimmune disease of the eye characterized by inflammation of the uvea and retina, degeneration of the retina, and blindness in genetically predisposed patients. Using the rat model of experimental autoimmune uveitis (EAU), we previously identified three quantitative trait loci (QTL) associated with EAU on rat chromosomes 4, 12, and 10 (Eau1, Eau2, and Eau3). The primary goal of the current study is to delineate additional non-MHC chromosomal regions that control susceptibility to EAU, and to identify any QTLs that overlap with the QTLs of other autoimmune diseases. Using a set of informative microsatellite markers and F-2 generations of resistant and susceptible MHC class II-matched rat strains (F344 and LEW), we have identified several new significant or suggestive QTLs on rat chromosomes 2, 3, 7, 10, and 19 that control susceptibility to EAU. A protective allele was identified in the susceptible LEW strain in the Eau5 locus at D7Wox18, and epistatic interactions between QTLs were found to influence the severity of disease. The newly identified regions (Eau4 through Eau9) colocalize with the genetic determinants of other autoimmune disease models, and to disease-regulating syntenic regions identified in autoimmune patients on human chromosomes 4q21-31, 5q31-33, 16q22-24, 17p11-q12, 20q11-13, and 22q12-13. Our results suggest that uveitis shares some of the pathogenic mechanisms associated with other autoimmune diseases, and lends support to the "common gene, common pathway" hypothesis for autoimmune disorders. C1 [Mattapallil, Mary J.; Sahin, Azize; Silver, Phyllis B.; Sun, Shu-Hui; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Hejtmancik, J. Fielding] NEI, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. [Remmers, Elaine F.] NIAMSD, Arthrit & Rheumatism Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, Natl Inst Hlth, Bldg 10,Room 10N222,10 Ctr Dr, Bethesda, MD 20892 USA. EM mattapallilm@nei.nih.gov; rcaspi@helix.nih.gov FU Intramural NIH HHS [Z01 EY000184-25, Z99 EY999999] NR 63 TC 14 Z9 14 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6751 EP 6759 PG 9 WC Immunology SC Immunology GA 324GW UT WOS:000257507100040 PM 18453595 ER PT J AU De la Rosa, G Yang, D Tewary, P Varadhachary, A Oppenheim, JJ AF De la Rosa, Gonzalo Yang, De Tewary, Poonam Varadhachary, Atul Oppenheim, Joost J. TI Lactoferrin acts as an alarmin to promote the recruitment and activation of APCs and antigen-specific immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL-DEATH APOPTOSIS; DENDRITIC CELLS; ADHESION MOLECULES; T-CELLS; LEUKOCYTES; MONOCYTES; DEFENSE; SYSTEM; TUMORS; ALPHA AB Lactoferrin is an 80-kDa iron-binding protein present at high concentrations in milk and in the granules of neutrophils. It possesses multiple activities, including antibacterial, antiviral, antifungal, and even antitumor effects. Most of its antimicrobial effects are due to direct interaction with pathogens, but a few reports show that it has direct interactions with cells of the immune system. In this study, we show the ability of recombinant human lactoferrin (talactoferrin alfa (TLF)) to chemoattract monocytes. What is more, addition of TLF to human peripheral blood or monocyte-derived dendritic cell cultures resulted in cell maturation, as evidenced by up-regulated expression of CD80, CD83, and CD86, production of proinflammatory cytokines, and increased capacity to stimulate the proliferation of allogeneic lymphocytes. When injected into the mouse peritoneal cavity, lactoferrin also caused a marked recruitment of neutrophils and macrophages. Immunization of mice with OVA in the presence of TLF promoted Thl-polarized Ag-specitic immune responses. These results suggest that lactoferrin contributes to the activation of both the innate and adaptive immune responses by promoting the recruitment of leukocytes and activation of dendritic cells. C1 [De la Rosa, Gonzalo; Tewary, Poonam; Oppenheim, Joost J.] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Yang, De] NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Varadhachary, Atul] Agennix, Houston, TX 77046 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, POB B,Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM oppenhei@ncifcrf.gov FU Intramural NIH HHS [NIH0012494754, Z01 BC009369-16]; NCI NIH HHS [N01 CO 12400, N01CO12400] NR 52 TC 77 Z9 79 U1 2 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2008 VL 180 IS 10 BP 6868 EP 6876 PG 9 WC Immunology SC Immunology GA 324GW UT WOS:000257507100052 PM 18453607 ER PT J AU Adib, AB AF Adib, Artur B. TI Stochastic actions for diffusive dynamics: Reweighting, sampling, and minimization SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PATH AB In numerical studies of diffusive dynamics, two different action functionals are often used to specify the probability distribution of trajectories, one of which requires the evaluation of the second derivative of the potential in addition to the force. Here it is argued that both actions are equivalent prescriptions for the purposes of reweighting and sampling trajectories, whereas the most probable path is more generally given by the global minimum of the action involving the second derivative term. The answer to this apparent paradox lies in the nondifferentiable character of Brownian paths, as well as in the "entropy" associated with a given trajectory. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Adib, AB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM adiba@mail.nih.gov FU Intramural NIH HHS NR 19 TC 17 Z9 17 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 5910 EP 5916 DI 10.1021/jp0751458 PG 7 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600006 PM 17999482 ER PT J AU Klauda, JB Eldho, NV Gawrisch, K Brooks, BR Pastor, RW AF Klauda, Jeffery B. Eldho, Nadukkudy V. Gawrisch, Klaus Brooks, Bernard R. Pastor, Richard W. TI Collective and noncollective models of NMR relaxation in lipid vesicles and multilayers SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; MOLECULAR-DYNAMICS SIMULATION; BILAYER DYNAMICS; MACROMOLECULES; FREQUENCY; MEMBRANES; ENERGY; H-2 AB NMR C-13 spin lattice relaxation (1/T-1) rates of dipalmitoylphosphatidylcholine (DPPC) bilayers obtained from molecular dynamics simulations of 72 and 288 lipids are compared with each other, with experimental values from large liposomes obtained by magic angle spinning, and with previously published experimental data from small vesicles. The experimental results for multilayers and vesicles at the same frequencies differ only slightly. The simulation results indicate that T-1 relaxation in the 15.1 to 201.2 MHz carbon frequency range and up to 100 angstrom length scale is dominated by fast isomerizations and slower lipid wobble (D-perpendicular to approximate to 2.5 x 10(8) s(-1)). Rotational diffusion about the lipid long axis (described by D-parallel to) does not make a substantial contribution to the T-1. Modifications to the acyl chain torsional potential energy function used for the simulations substantially improve agreement with experiment. C1 [Klauda, Jeffery B.; Brooks, Bernard R.; Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Eldho, Nadukkudy V.; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Pastor, RW (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Intramural NIH HHS NR 26 TC 24 Z9 24 U1 3 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 5924 EP 5929 DI 10.1021/jp075641w PG 6 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600008 PM 18179193 ER PT J AU Godoy-Ruiz, R Henry, ER Kubelka, J Hofrichter, J Munoz, V Sanchez-Ruiz, JM Eaton, WA AF Godoy-Ruiz, Raquel Henry, Eric R. Kubelka, Jan Hofrichter, James Munoz, Victor Sanchez-Ruiz, Jose M. Eaton, William A. TI Estimating free-energy barrier heights for an ultrafast folding protein from calorimetric and kinetic data SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID VILLIN HEADPIECE SUBDOMAIN; TRANSITION-STATE ENSEMBLE; MOLAR HEAT-CAPACITY; GLOBULAR-PROTEINS; LOOP FORMATION; LANDSCAPE PERSPECTIVE; THERMAL-DENATURATION; AQUEOUS-SOLUTION; DIFFUSION-MODEL; MOLTEN GLOBULE AB Differential scanning calorimetry was used to measure the temperature dependence of the absolute heat capacity of the 35-residue subdomain of the villin headpiece, a protein that folds in 5 mu s and is therefore assumed to have a small free-energy barrier separating folded and unfolded states. To obtain an estimate of the barrier height from the calorimetric data, two models, a variable-barrier model and an Ising-like model, were used to fit the heat capacity in excess of the folded state over the temperature range 15-125 degrees C. The variable-barrier model is based on an empirical mathematical form for the density of states, with four adjustable parameters and the enthalpy (H) as a reaction coordinate. The Ising-like model is based on the inter-residue contact map of the X-ray structure with exact enumeration of similar to 10(5) possible conformations, with two adjustable parameters in the partition function, and either the fraction of native contacts (Q) or the number of ordered residues (P) as reaction coordinates. The variable-barrier model provides an excellent fit to the data and yields a barrier height at the folding temperature ranging from 0.4 to 1.1 kcal mol(-1), while the Ising-like model provides a less good fit and yields barrier heights of 2.3 +/- 0.1 kcal mol(-1) and 2.1 +/- 0.1 kcal mol(-1) for the Q and P reaction coordinates, respectively. In both models, the barrier to folding increases with increasing temperature. Assuming a sufficiently large activation energy for diffusion on the free-energy surfaces, both models are consistent with the observation of a temperature-independent folding rate in previously published laser temperature-jump experiments. Analysis of this kinetic data, using an approximate form for the pre-exponential factor of Kramers theory and the 70 ns relaxation time for the fast phase that precedes the unfolding/ refolding relaxation to determine the diffusion coefficient, results in a barrier height of 1.6 +/- 0.3 kcal mol(-1) for an unspecified reaction coordinate. Although no independent test of the validity. of the H, Q, or P reaction coordinates is given, the barrier-height estimates obtained with the three reaction coordinates are in quite good agreement with the value derived from a Kramers analysis of the kinetics that makes no assumptions about the reaction coordinate. However, the higher estimates obtained using Q or P appear more consistent with the finding of barrier-crossing kinetics of a villin mutant that folds in 700 ns, corresponding to a 1.3 kcal mol(-1) reduction in the folding barrier relative to wild-type. All of the results suggest that the free-energy barrier to folding is sufficiently low that it should be possible to engineer this protein or find solution conditions that would eliminate the barrier to create the "downhill" folding scenario of Wolynes and Onuchic. C1 [Godoy-Ruiz, Raquel; Sanchez-Ruiz, Jose M.] Univ Granada, Fac Ciencias, Dept Quim Fis, E-18071 Granada, Spain. [Henry, Eric R.; Kubelka, Jan; Hofrichter, James; Eaton, William A.] NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. [Kubelka, Jan] Univ Wyoming, Dept Chem, Laramie, WY 82071 USA. [Godoy-Ruiz, Raquel; Munoz, Victor] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Godoy-Ruiz, Raquel; Munoz, Victor] Univ Maryland, Ctr Biomol Struct & Org, College Pk, MD 20742 USA. [Munoz, Victor] CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. RP Sanchez-Ruiz, JM (reprint author), Univ Granada, Fac Ciencias, Dept Quim Fis, E-18071 Granada, Spain. EM sanchezr@ugr.es; eaton@helix.nih.gov RI Henry, Eric/J-3414-2013; Sanchez-Ruiz, Jose/H-2849-2015 OI Henry, Eric/0000-0002-5648-8696; Sanchez-Ruiz, Jose/0000-0002-9056-3928 NR 95 TC 52 Z9 56 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 5938 EP 5949 DI 10.1021/jp0757715 PG 12 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600010 PM 18278894 ER PT J AU Best, RB Paci, E Hummer, G Dudko, OK AF Best, Robert B. Paci, Emanuele Hummer, Gerhard Dudko, Olga K. TI Pulling direction as a reaction coordinate for the mechanical unfolding of single molecules SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ATOMIC-FORCE MICROSCOPY; NUCLEIC-ACID; DYNAMICS SIMULATIONS; ADHESION BONDS; PROTEIN; TRANSITION; UBIQUITIN; MODELS; DOMAIN; SPECTROSCOPY AB The folding and unfolding kinetics of single molecules, such as proteins or nucleic acids, can be explored by mechanical pulling experiments. Determining intrinsic kinetic information, at zero stretching force, usually requires an extrapolation by fitting a theoretical model. Here, we apply a recent theoretical approach describing molecular rupture in the presence of force to unfolding kinetic data obtained from coarse-grained simulations of ubiquitin. Unfolding rates calculated from simulations over a broad range of stretching forces, for different pulling directions, reveal a remarkable "turnover" from a force-independent process at low force to a force-dependent process at high force, akin to the "roll-over" in unfolding rates sometimes seen in studies using chemical denaturant. While such a turnover in rates is unexpected in one dimension, we demonstrate that it can occur for dynamics in just two dimensions. We relate the turnover to the quality of the pulling direction as a reaction coordinate for the intrinsic folding mechanism. A novel pulling direction, designed to be the most relevant to the intrinsic folding pathway, results in the smallest turnover. Our results are in accord with protein engineering experiments and simulations which indicate that the unfolding mechanism at high force can differ from the intrinsic mechanism. The apparent similarity between extrapolated and intrinsic rates in experiments, unexpected for different unfolding barriers, can be explained if the turnover occurs at low forces. C1 [Dudko, Olga K.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Best, Robert B.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Paci, Emanuele] Univ Leeds, Sch Phys & Astron, Leeds, W Yorkshire, England. RP Dudko, OK (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM dudko@physics.ucsd.edu RI Paci, Emanuele/B-1893-2010; Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Paci, Emanuele/0000-0002-4891-2768; Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 FU Intramural NIH HHS NR 55 TC 77 Z9 77 U1 1 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 5968 EP 5976 DI 10.1021/jp075955j PG 9 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600014 PM 18251532 ER PT J AU Yao, L Vogeli, B Torchia, DA Bax, A AF Yao, Lishan Voegeli, Beat Torchia, Dennis A. Bax, Ad TI Simultaneous NMR study of protein structure and dynamics using conservative mutagenesis SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; LIQUID-CRYSTALLINE MEDIUM; MODEL-FREE APPROACH; BIOLOGICAL MACROMOLECULES; MOLECULAR ALIGNMENT; BACKBONE DYNAMICS; BIOMOLECULAR NMR; SCALAR COUPLINGS; ORDER PARAMETERS; BINDING DOMAIN AB A novel iterative procedure is described that allows both the orientation and dynamics of internuclear bond vectors to be determined from direct interpretation of NMR dipolar couplings, measured under at least three orthogonal alignment conditions. If five orthogonal alignments are available, the approach also yields information on the degree of motional anisotropy and the direction in which the largest amplitude internal motion of each bond vector takes place. The method is demonstrated for the backbone N-15-H-1, C-13(alpha)-H-1(alpha), and C-13(alpha)-C-13' interactions in the previously well-studied protein domain GB3, dissolved in a liquid crystalline suspension of filamentous phage Pf1. Alignment variation is achieved by using conservative mutations of charged surface residues. Results indicate remarkably uniform backbone dynamics, with amplitudes that agree well with those of previous N-15 relaxation studies for most residues involved in elements of secondary structure, but larger amplitude dynamics than those found by N-15 relaxation for residues in loop and turn regions. In agreement with a previous analysis of dipolar couplings, the N-H bonds in the second beta-strand, which is involved in antibody recognition, show elevated dynamics with largest amplitudes orthogonal to the chain direction. C1 [Torchia, Dennis A.] NIH, Natl Inst Dent & Cranofacial Res, Bethesda, MD 20892 USA. [Yao, Lishan; Voegeli, Beat; Bax, Ad] NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIH, Natl Inst Dent & Cranofacial Res, Bldg 5,Room 126, Bethesda, MD 20892 USA. EM bax@nih.gov RI Yao, Lishan /C-6961-2009; yao, lishan/H-3662-2012 OI yao, lishan/0000-0003-1797-922X FU Intramural NIH HHS NR 60 TC 59 Z9 60 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6045 EP 6056 DI 10.1021/jp0772124 PG 12 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600021 PM 18358021 ER PT J AU Buchete, NV Hummer, G AF Buchete, Nicolae-Viorel Hummer, Gerhard TI Coarse master equations for peptide folding dynamics SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; EXPLICIT SOLVENT; BETA-HAIRPIN; ALPHA-HELIX; ALANINE DIPEPTIDE; TRANSITION-STATES; BAYESIAN-ANALYSIS; COMPLEX-SYSTEMS; HYDROGEN-BONDS AB We construct coarse master equations for peptide folding dynamics from atomistic molecular dynamics simulations. A maximum-likelihood propagator-based method allows us to extract accurate rates for the transitions between the different conformational states of the small helix-forming peptide Ala5. Assigning the conformational states by using transition paths instead of instantaneous molecular coordinates suppresses the effects of fast non-Markovian dynamics. The resulting master equations are validated by comparing their analytical correlation functions with those obtained directly from the molecular dynamics simulations. We find that the master equations properly capture the character and relaxation times of the entire spectrum of conformational relaxation processes. By using the eigenvectors of the transition rate matrix, we are able to systematically coarse-grain the system. We find that a two-state description, with a folded and an unfolded state, roughly captures the slow conformational dynamics. A four-state model, with two folded and two unfolded states, accurately recovers the three slowest relaxation process with time scales between 1.5 and 7 ns. The master equation models not only give access to the slow conformational dynamics but also shed light on the molecular mechanisms of the helix-coil transition. C1 [Buchete, Nicolae-Viorel; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; Buchete, Nicolae-Viorel/C-6200-2015 OI Hummer, Gerhard/0000-0001-7768-746X; Buchete, Nicolae-Viorel/0000-0001-9861-1157 FU Intramural NIH HHS NR 83 TC 225 Z9 227 U1 7 U2 50 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6057 EP 6069 DI 10.1021/jp0761665 PG 13 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600022 PM 18232681 ER PT J AU Schwieters, CD Clore, GM AF Schwieters, Charles D. Clore, G. Marius TI A pseudopotential for improving the packing of ellipsoidal protein structures determined from NMR data SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID CRYSTAL-STRUCTURE; MEAN-FORCE; PHOSPHOTRANSFERASE SYSTEM; 3-DIMENSIONAL STRUCTURES; TUMOR-SUPPRESSOR; TERMINAL DOMAIN; ENZYME-I; SIV GP41; ACCURACY; DNA AB A pseudopotential has been introduced into NMR protein structure determination that effectively restrains molecular volume based on the observation that rigid, well-packed protein structures are approximately ellipsoidal. Allowing an ellipsoidal shape is more general than the single approximately spherical shape imposed by the radius of gyration pseudopotential introduced previously. We demonstrate that this new gyration volume term improves structures both during the calculation of an initial unknown fold and during final refinement. C1 [Schwieters, Charles D.] NIH, Imaging Sci Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Clore, G. Marius] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, Imaging Sci Lab, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. EM Charles.Schwieters@nih.gov; mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS NR 27 TC 14 Z9 14 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6070 EP 6073 DI 10.1021/jp076244o PG 4 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600023 PM 18088109 ER PT J AU Tycko, R AF Tycko, Robert TI Theory of Stochastic dipolar recoupling in solid-state nuclear magnetic resonance SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ECHO DOUBLE-RESONANCE; ANGLE-SPINNING NMR; MULTIPLE-QUANTUM DYNAMICS; BETA-AMYLOID FIBRILS; DISTANCE MEASUREMENTS; ROTATIONAL-ECHO; MOLECULAR-STRUCTURE; OPERATOR-FORMALISM; HIGH-FIELD; SPECTROSCOPY AB Dipolar recoupling techniques in solid-state nuclear magnetic resonance (NMR) consist of radio frequency (rf) pulse sequences applied in synchrony with magic-angle spinning (MAS) that create nonzero average magnetic dipole-dipole couplings under MAS. Stochastic dipolar recoupling (SDR) is a variant in which randomly chosen rf carrier frequency offsets are introduced to cause random phase modulations of individual pairwise couplings in the dipolar spin Hamiltonian. Several aspects of SDR are investigated through analytical theory and numerical simulations: (1) An analytical expression for the evolution of nuclear spin polarization under SDR in a two-spin system is derived and verified through simulations, which show a continuous evolution from coherent, oscillatory polarization exchange to incoherent, exponential approach to equilibrium as the range of random carrier offsets (controlled by a parameterf(max)) increases; (2) in a many-spin system, polarization transfers under SDR are shown to be described accurately by a rate matrix in the limit of large f(max), with pairwise transfer rates that are proportional to the inverse sixth power of pairwise internuclear distances; (3) quantum mechanical interferences among noncommuting pairwise dipole-dipole couplings, which are a complicating factor in solid-state NMR studies of molecular structures by traditional dipolar recoupling methods, are shown to be absent from SDR data in the limit of large f(max), provided that coupled nuclei have distinct NMR chemical shifts. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS [Z01 DK029029-11] NR 47 TC 13 Z9 14 U1 3 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6114 EP 6121 DI 10.1021/jp076808o PG 8 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600028 PM 18085769 ER PT J AU Gopich, IV AF Gopich, Irina V. TI Concentration effects in "Single-Molecule" spectroscopy SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID RESONANCE ENERGY-TRANSFER; PHOTON-COUNTING HISTOGRAM; FLUORESCENCE SPECTROSCOPY; CONFORMATIONAL DYNAMICS; PROTEIN; DIFFUSION; FRET; DISTRIBUTIONS; STATISTICS AB A concentration as low as 0. 1 molecule per observation volume may not be small enough for single-molecule Forster resonance energy transfer (FRET) efficiency measurements of molecules diffusing through a laser spot. This result follows from a rigorous theory that takes many molecules into account. We consider the distributions of the number of photons (photon counting histograms) and show that multiple-molecule effects are pronounced at large photon counts even at low concentrations. FRET efficiency distributions reveal multiple-molecule effects at large threshold values. This might be misinterpreted as multiple conformational states. Multiple-molecule effects strongly depend on the brightness of fluorophores. A simple test is suggested to determine parameters for which the single-molecule description is applicable. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM irinag@niddk.nih.gov FU Intramural NIH HHS NR 26 TC 15 Z9 15 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6214 EP 6220 DI 10.1021/jp0764182 PG 7 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600041 PM 18154285 ER PT J AU Berezhkovskii, AM Bezrukov, SM AF Berezhkovskii, Alexander M. Bezrukov, Sergey M. TI Fluctuation theorem for channel-facilitated membrane transport of interacting and noninteracting solutes SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID DYNAMICAL ENSEMBLES; STOCHASTIC DYNAMICS; STEADY-STATES; BINDING AB In this paper, we discuss the fluctuation theorem for channel-facilitated transport of solutes through a membrane separating two reservoirs. The transport is characterized by the probability, P-n(t), that n solute particles have been transported from one reservoir to the other in time t. The fluctuation theorem establishes a relation between P-n(t) and P-(n)(t): The ratio P-n(t)/P-(n)(t) is independent of time and equal to exp(n beta A), where beta A is the affinity measured in the thermal energy units. We show that the same fluctuation theorem is true for both single- and multichannel transport of noninteracting particles and particles which strongly repel each other. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Bezrukov, Sergey M.] NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Bezrukov, SM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 34 TC 3 Z9 3 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6228 EP 6232 DI 10.1021/jp075870i PG 5 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600043 PM 18269272 ER PT J AU Miller, BT Zheng, WJ Venable, RM Pastor, RW Brooks, BR AF Miller, Benjamin T. Zheng, Wenjun Venable, Richard M. Pastor, Richard W. Brooks, Bernard R. TI Langevin network model of myosin SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID COLLECTIVE VIBRATIONS; DYNAMICS; MACROMOLECULES; PROTEINS; MOTOR; TRANSITIONS; DIFFUSION; DOMAINS; MOTIONS AB Langevin mode theory and the coarse-grained elastic network model (ENM) for proteins are combined to yield the Langevin network model (LNM). Hydrodynamic radii of 6 angstrom were assigned to each alpha-carbon on the basis of matching experimental translational and rotational diffusion constants of lysozyme, myoglobin, and hemoglobin with those calculated using a rigid body bead model with hydrodynamic interactions described by the Rome-Prager tensor. LNM analysis of myosin II indicates that all ENM-like modes are overdamped at water viscosities. The low-frequency LNM modes in the pre-power stroke structure (PDB code: 1VOM) are substantially less mixed than the corresponding modes of the post-power stroke structure (1Q5G). Results from a four-bead model of the myosin "lever arm" indicate that coupling between modes increases as the array departs from linearity and are consistent with the results for 1VOM and 1Q5G. The decay times for all overdamped Langevin modes are shorter than the calculated rotational tumbling times found for lysozyme and myosin. C1 [Miller, Benjamin T.; Zheng, Wenjun; Venable, Richard M.; Pastor, Richard W.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Brooks, BR (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM brb@nih.gov OI Miller, Benjamin/0000-0003-1647-0122; Zheng, Wenjun/0000-0002-6236-9765 NR 34 TC 10 Z9 10 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 15 PY 2008 VL 112 IS 19 BP 6274 EP 6281 DI 10.1021/jp077042v PG 8 WC Chemistry, Physical SC Chemistry GA 297XB UT WOS:000255649600048 PM 18311963 ER PT J AU Scholz, S Singleton, A AF Scholz, Sonja Singleton, Andrew TI Susceptibility genes in movement disorders SO MOVEMENT DISORDERS LA English DT Review DE movement disorder; susceptibility gene; linkage study; candidate gene; whole genome association study ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; CREUTZFELDT-JAKOB-DISEASE; HETEROZYGOUS PINK1 MUTATIONS; EARLY-ONSET PARKINSONISM; ALPHA-SYNUCLEIN; LOCUS TRIPLICATION; RISK LOCI; VARIANTS; REPEAT AB During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The Successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care. (c) 2008 Movement Disorder Society. C1 [Scholz, Sonja; Singleton, Andrew] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. RP Singleton, A (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, 35 Convent Dr,Room 1A-1015, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; OI Scholz, Sonja/0000-0002-6623-0429 FU Intramural NIH HHS NR 47 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAY 15 PY 2008 VL 23 IS 7 BP 927 EP 934 DI 10.1002/mds.21983 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 308MF UT WOS:000256393700001 PM 18311830 ER PT J AU Fauci, AS AF Fauci, Anthony S. TI 25 years of HIV SO NATURE LA English DT Editorial Material ID AIDS C1 NIAID, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 6 TC 52 Z9 59 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 15 PY 2008 VL 453 IS 7193 BP 289 EP 290 DI 10.1038/453289a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 301AI UT WOS:000255868400026 PM 18480799 ER PT J AU Riddler, SA Haubrich, R DiRienzo, AG Peeples, L Powderly, WG Klingman, KL Garren, KW George, T Rooney, JF Brizz, B Lalloo, UG Murphy, RL Swindells, S Havlir, D Mellors, JW AF Riddler, Sharon A. Haubrich, Richard DiRienzo, A. Gregory Peeples, Lynne Powderly, William G. Klingman, Karin L. Garren, Kevin W. George, Tania Rooney, James F. Brizz, Barbara Lalloo, Umesh G. Murphy, Robert L. Swindells, Susan Havlir, Diane Mellors, John W. CA AIDS Clin Trials Grp Study A5142 T TI Class-sparing regimens for initial treatment of HIV-1 infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; PROTEASE INHIBITORS; CLINICAL-TRIALS; PLUS STAVUDINE; EFAVIRENZ; LOPINAVIR/RITONAVIR; NELFINAVIR; LAMIVUDINE; RESISTANCE; THERAPY AB Background: The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. Methods: In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log(10) copies per milliliter to the three groups. Results: At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. Conclusions: Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895.). C1 [Riddler, Sharon A.; Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Haubrich, Richard] Univ Calif San Diego, San Diego, CA 92103 USA. [DiRienzo, A. Gregory; Peeples, Lynne] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Powderly, William G.] Univ Coll Dublin, Dublin 2, Ireland. [Klingman, Karin L.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Garren, Kevin W.] Abbott Labs, Abbott Pk, IL 60064 USA. [George, Tania] Bristol Myers Squibb Co, Plainsboro, NJ USA. [Rooney, James F.] Gilead Sci Inc, Foster City, CA 94404 USA. [Brizz, Barbara] Social & Sci Syst, Silver Spring, MD USA. [Lalloo, Umesh G.] Univ KwaZulu Natal, Durban, South Africa. [Murphy, Robert L.] Northwestern Univ, Chicago, IL 60611 USA. [Swindells, Susan] Univ Nebraska Med Ctr, Omaha, NE USA. [Havlir, Diane] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Riddler, SA (reprint author), 613 Falk Bldg,3601 5th Ave, Pittsburgh, PA 15213 USA. EM riddler@dom.pitt.edu OI Murphy, Robert/0000-0003-3936-2052 FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [M01 RR000032, M01 RR000039, M01 RR000044, M01 RR000046, M01 RR000047, M01 RR000051, M01 RR000052, M01 RR000096, M01 RR002635, RR 00032, RR 00039, RR 00044, RR 00046, RR 00047, RR 00051, RR 00052, RR 00075, RR 00096, RR 02635]; NIAID NIH HHS [U01 AI069424, AI 060354, AI 064086, AI 068634, AI 068636, AI 069411, AI 069418, AI 069419, AI 069423, AI 069424, AI 069432, AI 069434, AI 069439, AI 069447, AI 069450, AI 069452, AI 069465, AI 069470, AI 069471, AI 069472, AI 069474, AI 069477, AI 069484, AI 069494, AI 069495, AI 069501, AI 069502, AI 069513, AI 069532, AI 069556, AI 25859, AI 27661, AI 27673, AI 32782, AI 32783, AI 34853, AI 36214, AI 38858, AI 45008, AI 46370, AI 46376, AI 46381, AI 50410, K24 AI064086, P30 AI036214, P30 AI045008, P30 AI050410, P30 AI060354, U01 AI025859, U01 AI027661, U01 AI027673, U01 AI032782, U01 AI032783, U01 AI034853, U01 AI038858, U01 AI046370, U01 AI046376, U01 AI046381, U01 AI068634, U01 AI068636, U01 AI069411, U01 AI069418, U01 AI069419, U01 AI069423, U01 AI069432, U01 AI069434, U01 AI069439, U01 AI069447, U01 AI069450, U01 AI069452, U01 AI069465, U01 AI069470, U01 AI069471, U01 AI069472, U01 AI069474, U01 AI069477, U01 AI069484, U01 AI069494, U01 AI069495, U01 AI069501, U01 AI069502, U01 AI069513, U01 AI069532, U01 AI069556, UM1 AI068634, UM1 AI068636, UM1 AI069411, UM1 AI069418, UM1 AI069419, UM1 AI069423, UM1 AI069424, UM1 AI069432, UM1 AI069434, UM1 AI069439, UM1 AI069447, UM1 AI069450, UM1 AI069452, UM1 AI069465, UM1 AI069470, UM1 AI069471, UM1 AI069472, UM1 AI069474, UM1 AI069477, UM1 AI069484, UM1 AI069494, UM1 AI069495, UM1 AI069501, UM1 AI069502, UM1 AI069513, UM1 AI069532, UM1 AI069556]; NIDA NIH HHS [DA 12121] NR 20 TC 443 Z9 451 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 15 PY 2008 VL 358 IS 20 BP 2095 EP 2106 DI 10.1056/NEJMoa074609 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 300TY UT WOS:000255849300003 PM 18480202 ER PT J AU Agalliu, I Suuriniemi, M Prokunina-Olsson, L Johanneson, B Collins, FS Stanford, JL Ostrander, EA AF Agalliu, Ilir Suuriniemi, Miia Prokunina-Olsson, Ludmila Johanneson, Bo Collins, Francis S. Stanford, Janet L. Ostrander, Elaine A. TI Evaluation of a variant in the transcription factor 7-like 2 (TCF7L2) gene and prostate cancer risk in a population-based study SO PROSTATE LA English DT Article DE prostate cancer; diabetes; TCF7L2 (rs12255372); Wnt signaling pathway ID BETA-CATENIN MUTATIONS; FAMILY-HISTORY; DIABETES-MELLITUS; ANDROGEN RECEPTOR; BREAST-CANCER; MEN; CELLS; WNT; ASSOCIATION; PATHWAY AB BACKGROUND. Transcription factor 7-like 2 (TCF7L2) is a high mobility group-box containing protein that is a critical member of the Wnt/beta-catenin canonical signaling pathway. In addition to its recently recognized role in diabetes, aberrant TCF7L2 expression has been implicated in cancer through regulation of cell proliferation and apoptosis by c-MYC and cyclin D. It has been hypothesized that germline variants within the TCF7L2 gene previously associated with diabetes may affect cancer risk through the Wnt/beta-catenin signaling pathway. Specifically, the same risk allele of single nucleotide polymorphism (SNP) rs12255372 that is associated with diabetes (T allele) has recently been associated with an increased risk of breast cancer. METHODS. Here, we investigated associations between rs12255372 and prostate cancer risk among 1,457 cases and 1,351 controls from a population-based study. RESULTS. The variant TT genotype was not associated with overall prostate cancer risk. However, there was evidence that men homozygous for the variant T allele had an elevated relative risk of more aggressive prostate cancer, as defined by high Gleason score (OR = 1.7,95% CI = 1.0-2.8) or regional/distant stage (OR = 1.7, 95% CI = 1.1-2.6) disease. CONCLUSIONS. Our findings suggest that this variant in the TCF7L2 gene may be associated with risk of developing more clinically significant disease. These results need to be confirmed, but provide initial evidence that the TCF7L2 gene may alter risk of developing more aggressive prostate cancer. C1 [Suuriniemi, Miia; Johanneson, Bo; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Agalliu, Ilir; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Prokunina-Olsson, Ludmila; Collins, Francis S.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, NIH, 50 South Dr,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Ostrander, Elaine/0000-0001-6075-9738 FU NCI NIH HHS [R01 CA092579, R01 CA56678, R01 CA080122, R01 CA080122-01, R01 CA82664] NR 41 TC 22 Z9 25 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAY 15 PY 2008 VL 68 IS 7 BP 740 EP 747 DI 10.1002/pros.20732 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 296VO UT WOS:000255574100005 PM 18302196 ER PT J AU Jee, J Byeon, IJL Louis, JM Gronenborn, AM AF Jee, JunGoo Byeon, In-Ja L. Louis, John M. Gronenborn, Angela M. TI The point mutation A34F causes dimerization of GB1 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE GB1 mutants; NMR structure; dimerization; oligomerization ID IMMUNOGLOBULIN-BINDING DOMAIN; STREPTOCOCCAL PROTEIN-G; LIQUID-CRYSTALLINE PHASE; TORSION ANGLE DYNAMICS; AROMATIC RESIDUES; CHEMICAL-EXCHANGE; CORE MUTATIONS; NMR; COMPLEXES; COUPLINGS AB The immunoglobulin-binding domain B1 of streptococcal protein G (GB1), a very stable, small, single-domain protein, is one of the most extensively used models in the area of protein folding and design. Variants derived from a library of randomized hydrophobic core residues previously revealed alternative folds, namely a completely intertwined tetramer (Frank et al., Nat Struct Biol 2002,9:877-885) and a domain-swapped dimer (Byeon et al., I Mol Biol 2003;333:141-152). Here, we report the NMR structure of the single amino acid mutant Ala-34-Phe which exists as side-by-side dimer. The dimer dissociation constant is 27 +/- 4 mu M. The dimer interface comprises two structural elements: First, the beta-sheets of the two monomers pair in an antiparallel arrangement, thereby forming an eight-stranded beta-sheet. Second, the at-helix is shortened, ending in a loop that engages in intermolecular contacts. The largest difference between the monomer unit in the A34F dimer and the monomeric wild-type GB1 is the dissolution of the C-terminal half of the a-helix associated with a pronounced slow conformational motion of the interface loop. This involves a large movement of the Tyr-33 side chain that swings out from the monomer to engage in dimer contacts. C1 [Jee, JunGoo; Byeon, In-Ja L.; Gronenborn, Angela M.] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15261 USA. [Jee, JunGoo; Byeon, In-Ja L.; Louis, John M.; Gronenborn, Angela M.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), Univ Pittsburgh, Sch Med, Dept Biol Struct, 1051 Biomed Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15261 USA. EM amg100@pitt.edu OI Gronenborn, Angela M/0000-0001-9072-3525 NR 35 TC 21 Z9 21 U1 0 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAY 15 PY 2008 VL 71 IS 3 BP 1420 EP 1431 DI 10.1002/prot.21831 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 292MC UT WOS:000255269200031 PM 18076051 ER PT J AU Sato, S Shirakawa, H Tomita, S Ohsaki, Y Haketa, K Tooi, O Santo, N Tohkin, M Furukawa, Y Gonzalez, FJ Komai, M AF Sato, Shoko Shirakawa, Hitoshi Tomita, Shuhei Ohsaki, Yusuke Haketa, Keiichi Tooi, Osamu Santo, Noriaki Tohkin, Masahiro Furukawa, Yuji Gonzalez, Frank J. Komai, Michio TI Low-dose dioxins alter gene expression related to cholesterol biosynthesis, lipogenesis, and glucose metabolism through the aryl hydrocarbon receptor-mediated pathway in mouse liver SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE dioxin; low dose; mouse liver; DNA microarray ID PLANAR AROMATIC-COMPOUNDS; YA-SUBUNIT GENE; AH RECEPTOR; INDUCIBLE EXPRESSION; REGULATORY ELEMENTS; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD; ALDEHYDE DEHYDROGENASE; CYTOCHROME P4501A1; RESPONSIVE ELEMENT; DIABETES-MELLITUS AB 2,3,7,8-Tetracblorodibenzo-p-dioxin (TCDD) is a common environmental contaminant. TCDD binds and activates the transcription factor aryl hydrocarbon receptor (AHR), leading to adverse biological responses via the alteration of the expression of various AHR target genes. Although small amounts of TCDD are consumed via contaminated daily foodstuffs and environmental exposures, the effects of low-dose TCDD on gene expression in animal tissues have not been clarified, while a number of genes affected by high-dose TCDD were reported. In this study, we comprehensively analyzed gene expression profiles in livers of C57BL/6N mice that were orally administered relatively low doses of TCDD (5, 50, or 500 ng/kg body weight (bw) day(-1)) for 18 days. The hepatic TCDD concentrations, measured by gas chromatography-mass spectrometry, were 1.2, 17, and 1063 pg toxicity equivalent quantity (TEQ)/g, respectively. The mRNA level of the cytochrome P450 CYP1A1 was significantly increased by treatment with only TCDD 500 ng/kg bw day(-1). DNA microarray and quantitative RT-PCR analyses revealed changes in the expression of genes involved in the circadian rhythm, cholesterol biosynthesis, fatty acid synthesis, and glucose metabolism in the liver with at all doses of TCDD employed. However, repression of expression of genes involved in energy metabolism was not observed in the livers of Ahr-null mice that were administered the same dose of TCDD. These results indicate that changes in gene expression by TCDD are mediated by AHR and that exposure to low-dose TCDD could affect energy metabolism via alterations of gene expression. (C) 2008 Elsevier Inc. All rights reserved. C1 [Sato, Shoko; Shirakawa, Hitoshi; Ohsaki, Yusuke; Haketa, Keiichi; Furukawa, Yuji; Komai, Michio] Tohoku Univ, Grad Sch Agr Sci, Lab Nutr, Sendai, Miyagi 9818555, Japan. [Tomita, Shuhei] Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan. [Tooi, Osamu] Towa Environm Sci Co Ltd, Biotechnol Res Lab, Hiroshima 7390046, Japan. [Santo, Noriaki] Med & Environm Technol Co Ltd, Hiroshima 7348553, Japan. [Santo, Noriaki] Fukuyama Univ, Res Ctr Green Sci, Fukuyama, Hiroshima 7290292, Japan. [Tohkin, Masahiro] Natl Inst Hlth Sci, Div Med Safety Sci, Setagaya Ku, Tokyo 1588501, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Shirakawa, H (reprint author), 1-1 Tsutsumidori Amamiyamachi,Aoba Ku, Sendai, Miyagi 9818555, Japan. EM shirakah@biochem.tohoku.ac.jp RI Shirakawa, Hitoshi/D-1406-2009 NR 52 TC 65 Z9 70 U1 5 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 15 PY 2008 VL 229 IS 1 BP 10 EP 19 DI 10.1016/j.taap.2007.12.029 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 299CE UT WOS:000255732600002 PM 18295293 ER PT J AU Rehman, H Connor, HD Ramshesh, VK Theruvath, TP Mason, RP Wright, GL Lemasters, JJ Zhong, Z AF Rehman, Hasibur Connor, Henry D. Ramshesh, Venkat K. Theruvath, Tom P. Mason, Ronald P. Wright, Gary L. Lemasters, John J. Zhong, Zhi TI Ischemic preconditioning prevents free radical production and mitochondrial depolarization in small-for-size rat liver grafts SO TRANSPLANTATION LA English DT Article DE ischemic preconditioning; mitochondrial permeability transition; partial liver transplantation; free radical; heat shock protein ID HEAT-SHOCK PROTEINS; SINUSOIDAL ENDOTHELIAL-CELLS; N-TERMINAL-KINASE; PERMEABILITY TRANSITION; REPERFUSION INJURY; OXIDATIVE STRESS; LIVING-DONOR; MYOCARDIAL PROTECTION; SUPEROXIDE-DISMUTASE; NITRIC-OXIDE AB Background. Ischemic preconditioning (IP) renders tissues more tolerant to subsequent longer episodes of ischemia, This study tested whether IP attenuates injury of small-for-size liver grafts by preventing free radical production and mitochondrial dysfunction. Methods. IP was induced by clamping the portal vein and hepatic artery for 9 min. Livers were harvested 5 min after releasing the clamp. Mitochondrial polarization and cell death were assessed by intravital confocal/multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide. Free radicals were trapped with alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone and measured using electron spin resonance. Results. After quarter-size liver transplantation, alanine aminotransferase, serum bilirubin, necrosis, and apoptosis all increased. IP blocked these increases by more than 58%. 5-Bromo-2'-deoxyuridine labeling and increases of graft weight were only similar to 3% and 0.2% in quarter-size grafts without IP, respectively, but increased to 32% and 60% in ischemic-preconditioned grafts, indicating better liver regeneration. Eighteen hours after implantation, viable cells with depolarized mitochondria in quarter-size grafts were 15 per high power field, and dead cells were less than 1 per high power field, indicating that depolarization preceded necrosis. A free radical adduct signal was detected in bile from quarter-size grafts. IP decreased this free radical formation and prevented mitochondrial depolarization. IP did not increase heat shock proteins 10, 27, 32, 60, 70, 72, 75 and Cu/Zn-superoxide dismutase (SOD) but increased heat shock protein-90, a chaperone that facilitates protein import into mitochondria, and mitochondrial Mn-SOD. Conclusion. Taken together, IP decreases injury and improves regeneration of small-for-size liver grafts, possibly by increasing mitochondrial Mn-SOD, thus protecting against free radical production and mitochondrial dysfunction. C1 [Rehman, Hasibur; Ramshesh, Venkat K.; Theruvath, Tom P.; Wright, Gary L.; Lemasters, John J.; Zhong, Zhi] Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. [Connor, Henry D.; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. [Lemasters, John J.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Zhong, Z (reprint author), Med Univ S Carolina, Dept Pharmaceut Sci, 280 Calhoun St,POB 250140, Charleston, SC 29425 USA. EM zhong@musc.edu FU NCRR NIH HHS [C06 RR015455]; NIDDK NIH HHS [K01 DK62089, DK70844] NR 74 TC 27 Z9 32 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 2008 VL 85 IS 9 BP 1322 EP 1331 DI 10.1097/TP.0b013e31816de302 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 301OB UT WOS:000255904400018 PM 18475191 ER PT J AU Pecon-Slattery, J Troyer, JL Johnson, WE O'Brien, SJ AF Pecon-Slattery, Jill Troyer, Jennifer L. Johnson, Warren E. O'Brien, Stephen J. TI Evolution of feline immunodeficiency virus in Felidae: Implications for human health and wildlife ecology SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 8th International Feline Retrovirus Research Symposium CY OCT 08-11, 2006 CL Washington, DC DE FIV; evolution; lion; Felidae ID LIONS PANTHERA-LEO; NUCLEOTIDE-SEQUENCE ANALYSIS; RESPIRATORY SYNDROME SARS; CAT FAMILY FELIDAE; PUMA PUMA-CONCOLOR; AFRICAN LIONS; GENOMIC ORGANIZATION; GENETIC DIVERSITY; VIRAL-INFECTIONS; DOMESTIC CAT AB Genetic analyses of feline immunodeficiency viruses provide significant insights on the worldwide distribution and evolutionary history of this emerging pathogen. Large-scale screening of over 3000 samples from all species of Felidae indicates that at least some individuals from most species possess antibodies that cross react to FIV. Phylogenetic analyses of genetic variation in the pol-RT gene demonstrate that FIV lineages are species-specific and suggest that there has been a prolonged period of viral-host co-evolution. The clinical effects of FIV specific to species other than domestic cat are controversial. Comparative genomic analyses of all full-length FIV genomes confirmed that FIV is host specific. Recently sequenced lion subtype E is marginally more similar to Pallas cat FIV though env is more similar to that of domestic cat FIV, indicating a possible recombination between two divergent strains in the wild. Here we review global patterns of FIV seroprevalence and endemnicity, assess genetic differences within and between species-specific FIV strains, and interpret these with patterns of felid speciation to propose an ancestral origin of FIV in Africa followed by interspecies transmission and global dissemination to Eurasia and the Americas. Continued comparative genomic analyses of full-length FIV from all seropositive animals, along with whole genome sequence of host species, will greatly advance our understanding of the role of recombination, selection and adaptation in retroviral emergence. Published by Elsevier B.V. C1 [Pecon-Slattery, Jill; Troyer, Jennifer L.; Johnson, Warren E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Pecon-Slattery, J (reprint author), NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. EM slattery@nciferf.gov RI Troyer, Jennifer/B-8415-2012; Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 94 TC 33 Z9 33 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 EI 1873-2534 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAY 15 PY 2008 VL 123 IS 1-2 BP 32 EP 44 DI 10.1016/j.vetimm.2008.01.010 PG 13 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 305WH UT WOS:000256208000005 PM 18359092 ER PT J AU Troyer, JL VandeWoude, S Pecon-Slattery, J McIntosh, C Franklin, S Antunes, A Johnson, W O'Brien, SJ AF Troyer, Jennifer L. VandeWoude, Sue Pecon-Slattery, Jill McIntosh, Carl Franklin, Sam Antunes, Agostinho Johnson, Warren O'Brien, Stephen J. TI FIV cross-species transmission: An evolutionary prospective SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 8th International Feline Retrovirus Research Symposium CY OCT 08-11, 2006 CL Washington, DC DE FIV; lentiviruses; cross-species transmission ID FELINE IMMUNODEFICIENCY VIRUS; LIONS PANTHERA-LEO; AFRICAN LIONS; LENTIVIRUS INFECTION; RETROVIRAL INFECTION; DOMESTIC CATS; PHYLOGENETIC ASPECTS; PUMA LENTIVIRUSES; VIRAL-INFECTIONS; IMMUNE-SYSTEM AB Feline and primate immunodeficiency viruses (FIVs, SIVs, and HIV) are transmitted via direct contact (e.g. fighting, sexual contact, and mother-offspring transmission). This dynamic likely poses a behavioral barrier to cross-species transmission in the wild. Recently, several host intracellular anti-viral proteins that contribute to species-specificity of primate lentiviruses have been identified revealing adaptive mechanisms that further limit spread of lentiviruses between species. Consistent with these inter-species transmission barriers, phylogenefic evidence supports the prediction that FIV transmission is an exceedingly rare event between free-ranging cat species, though it has occurred occasionally in captive settings. Recently we documented that puma and bobcats in Southern California share an FIV strain, providing an opportunity to evaluate evolution of both viral strains and host intracellular restriction proteins. These studies are facilitated by the availability of the 2x cat genome sequence annotation. In addition, concurrent viral and host genetic analyses have been used to track patterns of migration of the host species and barriers to transmission of the virus within the African lion. These studies illustrate the utility of FIV as a model to discover the variables necessary for establishment and control of lentiviral infections in new species. Published by Elsevier B.V. C1 [Troyer, Jennifer L.] NCI, SAIC Frederick Inc, Lab Genom Divers, Frederick, MD 21702 USA. [VandeWoude, Sue; Franklin, Sam] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. RP Troyer, JL (reprint author), NCI, SAIC Frederick Inc, Lab Genom Divers, Frederick, MD 21702 USA. EM jtroyer@ncifcrf.gov RI Troyer, Jennifer/B-8415-2012; Scientific output, CIIMAR/E-5122-2012; Johnson, Warren/D-4149-2016; OI Scientific output, CIIMAR/0000-0001-6270-2153; Johnson, Warren/0000-0002-5954-186X; Antunes, Agostinho/0000-0002-1328-1732 FU Intramural NIH HHS [Z01 BC010537-05, Z99 CA999999]; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI052055, R01 AI052055-01A1, R29 AI041871-03] NR 54 TC 36 Z9 36 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAY 15 PY 2008 VL 123 IS 1-2 BP 159 EP 166 DI 10.1016/j.vetimm.2008.01.023 PG 8 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 305WH UT WOS:000256208000022 PM 18299153 ER PT J AU Basu, MK Makalowski, W Rogozin, IB Koonin, EV AF Basu, Malay Kumar Makalowski, Wojciech Rogozin, Igor B. Koonin, Eugene V. TI U12 intron positions are more strongly conserved between animals and plants than U2 intron positions SO BIOLOGY DIRECT LA English DT Article ID SPLICE SITES; U12-TYPE INTRONS; MINOR CLASS; GENES; GAIN; EUKARYOTES; EVOLUTION AB We report that the positions of minor, U12 introns are conserved in orthologous genes from human and Arabidopsis to an even greater extent than the positions of the major, U2 introns. The U12 introns, especially, conserved ones are concentrated in 5'-portions of plant and animal genes, where the U12 to U2 conversions occurs preferentially in the 3'-portions of genes. These results are compatible with the hypothesis that the high level of conservation of U12 intron positions and their persistence in genomes despite the unidirectional U12 to U2 conversion are explained by the role of the slowly excised U12 introns in down-regulation of gene expression. Reviewers: This article was reviewed by John Logsdon and Manyuan Long. For the full reviews, please go to the Reviewers' Reports section. C1 [Basu, Malay Kumar; Rogozin, Igor B.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Makalowski, Wojciech] Univ Munster, Inst Bioinformat, Fac Med, Munster, Germany. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM mbasu@ncbi.nlm.nih.gov; wojmaka@aim.com; rogozin@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov RI Makalowski, Wojciech/I-2843-2016 FU Intramural NIH HHS NR 25 TC 15 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 14 PY 2008 VL 3 AR 19 DI 10.1186/1745-6150-3-19 PG 5 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 314RV UT WOS:000256827400002 PM 18479526 ER PT J AU Dember, LM Beck, GJ Allon, M Delmez, JA Dixon, BS Greenberg, A Himmelfarb, J Vazquez, MA Gassman, JJ Greene, T Radeva, MK Braden, GL Ikizler, TA Rocco, MV Davidson, IJ Kaufman, JS Meyers, CM Kusek, JW Feldman, HI AF Dember, Laura M. Beck, Gerald J. Allon, Michael Delmez, James A. Dixon, Bradley S. Greenberg, Arthur Himmelfarb, Jonathan Vazquez, Miguel A. Gassman, Jennifer J. Greene, Tom Radeva, Milena K. Braden, Gregory L. Ikizler, T. Alp Rocco, Michael V. Davidson, Ingemar J. Kaufman, James S. Meyers, Catherine M. Kusek, John W. Feldman, Harold I. CA Dialysis Access Consortium Study G TI Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DOUBLE-BLIND; TICLOPIDINE; PREVENTION; THROMBOSIS; SALVAGE AB Context The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. Objective To determine whether clopidogrel reduces early failure of hemodialysis fistulas. Design, Setting, and Participants Randomized, double- blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003- 2007. Eight hundred seventy- seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. Intervention Participants were randomly assigned to receive clopidogrel ( 300- mg loading dose followed by daily dose of 75 mg; n= 441) or placebo ( n= 436) for 6 weeks starting within 1 day after fistula creation. Main Outcome Measures The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/ min or more during 8 of 12 dialysis sessions. Results Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 ( 12.2%) participants assigned to clopidogrel compared with 84 ( 19.5%) participants assigned to placebo ( relative risk, 0.63; 95% confidence interval, 0.46- 0.97; P=. 018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups ( 61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.941.17; P=. 40). Conclusion Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials. gov Identifier: NCT00067119. C1 [Dember, Laura M.; Kaufman, James S.] Boston Univ, Sch Med, Renal Sect, Boston, MA 02118 USA. [Kaufman, James S.] VA Boston Healthcare Syst, Boston, MA USA. [Beck, Gerald J.; Gassman, Jennifer J.; Radeva, Milena K.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Allon, Michael] Univ Alabama, Birmingham, AL USA. [Delmez, James A.] Washington Univ, St Louis, MO USA. [Dixon, Bradley S.] Univ Iowa, Iowa City, IA USA. [Greenberg, Arthur] Duke Univ, Durham, NC USA. [Himmelfarb, Jonathan] Maine Med Ctr, Portland, ME 04102 USA. [Vazquez, Miguel A.; Davidson, Ingemar J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Greene, Tom] Univ Utah, Salt Lake City, UT USA. [Braden, Gregory L.] Baystate Med Ctr, Springfield, MA USA. [Ikizler, T. Alp] Vanderbilt Univ, Nashville, TN USA. [Rocco, Michael V.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Meyers, Catherine M.; Kusek, John W.] NIDDKD, NIH, Bethesda, MD 20892 USA. [Feldman, Harold I.] Univ Penn, Philadelphia, PA 19104 USA. RP Dember, LM (reprint author), Boston Univ, Sch Med, Renal Sect, EBRC 504,650 Albany St, Boston, MA 02118 USA. EM ldember@bu.edu FU NIDDK NIH HHS [U01 DK058966, U01 DK058968, U01 DK058973, U01 DK058978, U01 DK058981, U01 DK058982, U01 DK058985, U01 DK058986, U01DK058966, U01DK058968, U01DK058973, U01DK058978, U01DK058981, U01DK058982, U01DK058985, U01DK058986] NR 23 TC 317 Z9 325 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 14 PY 2008 VL 299 IS 18 BP 2164 EP 2171 DI 10.1001/jama.299.18.2164 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 299XX UT WOS:000255790000023 PM 18477783 ER PT J AU Applbaum, AI Tilburt, JC Collins, MT Wendler, D AF Applbaum, Arthur Isak Tilburt, Jon C. Collins, Michael T. Wendler, David TI A family's request for complementary medicine after patient brain death SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OF-LIFE CARE; FUTILITY AB A 19- year- old woman living with relatives in the United States who was admitted for elective cranial surgery for complications related to a congenital disorder developed an acute intracranial hemorrhage 10 days after surgery. The patient was declared dead following repeat negative apnea tests. The patient's father requested that the treating team administer an unverified traditional medicinal substance to the patient. Because of the unusual nature of this request, the treating team called an ethics consultation. The present article reviews this case and discusses other cases that share key features to determine whether and when it is appropriate to accommodate requests for interventions on patients who have been declared dead. C1 [Wendler, David] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Applbaum, Arthur Isak] Harvard Univ, John F Kennedy Sch Govt, Cambridge, MA 02138 USA. [Applbaum, Arthur Isak] Harvard Univ, Edmond J Safra Fdn Ctr Eth, Cambridge, MA 02138 USA. [Tilburt, Jon C.] Mayo Clin, Rochester, MN USA. [Collins, Michael T.] NIDR, Clin Studies Unit, Cranial Facial & Skeletal Dis Branch, Bethesda, MD 20892 USA. [Collins, Michael T.] Natl Inst Craniofacial Res, Clin Studies Unit, Cranial Facial & Skeletal Dis Branch, Bethesda, MD USA. [Wendler, David] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, 1C-119 Bldg 10, Bethesda, MD 20892 USA. EM dwendler@cc.nih.gov FU Intramural NIH HHS [Z01 DE000649-13] NR 9 TC 12 Z9 12 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 14 PY 2008 VL 299 IS 18 BP 2188 EP 2193 DI 10.1001/jama.299.18.2188 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 299XX UT WOS:000255790000026 PM 18477786 ER PT J AU Nakamura, K Matsumoto, M Hikosaka, O AF Nakamura, Kae Matsumoto, Masayuki Hikosaka, Okihide TI Reward-dependent modulation of neuronal activity in the primate dorsal raphe nucleus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE serotonin; dopamine; raphe; saccade; primate; reinforcement; reward ID CENTRAL 5-HYDROXYTRYPTAMINE DEPLETION; CENTRAL 5-HT DEPLETION; SACCADIC EYE-MOVEMENT; CAT BRAIN-STEM; DOPAMINE NEURONS; MIDBRAIN RAPHE; SUBSTANTIA-NIGRA; BASAL GANGLIA; SEROTONERGIC NEURONS; IMPULSIVE BEHAVIOR AB The dopamine system has been thought to play a central role in guiding behavior based on rewards. Recent pharmacological studies suggest that another monoamine neurotransmitter, serotonin, is also involved in reward processing. To elucidate the functional relationship between serotonin neurons and dopamine neurons, we performed single-unit recording in the dorsal raphe nucleus (DRN), a major source of serotonin, and the substantia nigra pars compacta, a major source of dopamine, while monkeys performed saccade tasks in which the position of the target indicated the size of an upcoming reward. After target onset, but before reward delivery, the activity of many DRN neurons was modulated tonically by the expected reward size with either large- or small-reward preference, whereas putative dopamine neurons had phasic responses and only preferred large rewards. After reward delivery, the activity of DRN neurons was modulated tonically by the received reward size with either large- or small-reward preference, whereas the activity of dopamine neurons was not modulated except after the unexpected reversal of the position-reward contingency. Thus, DRN-neurons encode the expected and received rewards, whereas dopamine neurons encode the difference between the expected and received rewards. These results suggest that the DRN, probably including serotonin neurons, signals the reward value associated with the current behavior. C1 [Nakamura, Kae; Matsumoto, Masayuki; Hikosaka, Okihide] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Nakamura, K (reprint author), Kansai Med Univ, Sch Med, Dept Physiol, 10-15 Fumizono Cho, Moriguchi, Osaka 5708506, Japan. EM nakamkae@takii.kmu.ac.jp FU Intramural NIH HHS [ZIA EY000415-07] NR 94 TC 119 Z9 121 U1 2 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 14 PY 2008 VL 28 IS 20 BP 5331 EP 5343 DI 10.1523/JNEUROSCI.0021-08.2008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 301BF UT WOS:000255870700021 PM 18480289 ER PT J AU Hafkemeyer, P Brinkmann, U Brinkmann, E Pastan, I Blum, HE Baumert, TF AF Hafkemeyer, Peter Brinkmann, Ulrich Brinkmann, Elizabeth Pastan, Ira Blum, Hubert E. Baumert, Thomas F. TI Pseudomonas exotoxin antisense RNA selectively kills hepatitis B virus infected cells SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE gene therapy; Pseudomonas exotoxin; retrovirus; reverse transcription ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4-PSEUDOMONAS EXOTOXIN; COMPLETE REGRESSION; HUMAN CARCINOMA; IMMUNOTOXIN; PROTEIN; MICE; HIV; DNA; RETROVIRUSES AB AIM: To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. METHODS: PE antisense toxin RNA has palindromic stem loops at its 5' and 3' ends enabling self-primed generation of cDNA in the presence of RT. The RT activity expressed in retrovirus-infected cells converts "antisense-toxin-RNA" into a lethal toxin gene exclusively in these cells. RESULTS: Using cotransfection studies with PE-expressing RNAs and P-gal expressing reporter plasmids, we show that, in HepG2 and HepG2.2.15 hepatoma cells as well as in duck hepatitis B virus (DHBV) infected cells, HBV or DHBV-polymerase reverse transcribe a lethal cDNA copy of an antisense toxin RNA, which is composed of sequences complementary to a PE gene and eukaryotic transcription and translation signals. CONCLUSION: This finding may have important implications as a novel therapeutic strategy aimed at the elimination of HBV infection. (C) 2008 WJG. All rights reserved. C1 [Hafkemeyer, Peter; Blum, Hubert E.] Univ Hosp Freiburg, Dept Med 2, D-79106 Freiburg, Germany. [Brinkmann, Ulrich] Roche Diagnost, D-82377 Penzberg, Germany. [Pastan, Ira] NCI, NIH, Bethesda, MD USA. [Baumert, Thomas F.] Univ Strasbourg 1, INSERM, Unit 748, F-67000 Strasbourg, France. RP Hafkemeyer, P (reprint author), Univ Hosp Freiburg, Dept Med 2, Hugstetterstr 55, D-79106 Freiburg, Germany. EM phafkemeyer@gmx.net NR 30 TC 0 Z9 0 U1 0 U2 0 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 14 PY 2008 VL 14 IS 18 BP 2810 EP 2817 DI 10.3748/wjg.14.2810 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 301OP UT WOS:000255905800005 PM 18473403 ER PT J AU Hendler, RW Meuse, CW AF Hendler, Richard W. Meuse, Curtis W. TI Electrogenic proton-pumping capabilities of the M-fast and M-slow photocycles of bacteriorhodopsin SO BIOCHEMISTRY LA English DT Article ID PURPLE MEMBRANE; ACTINIC LIGHT; LIPOSOMES; ENERGY; MODEL; SPECTROSCOPY; ABSORPTION; DEPENDENCE; SIGNALS; SURFACE AB The parallel model for the bacteriorhodopsin (BR) photocycle at neutral pH and a temperature near 20 degrees C contains an M-fast cycle with steps BR -> K -> L -> M(f) -> N -> O -> BR and an M-slow cycle which contains steps BR -> K -> L -> M(s) -> BR. With increasing actinic laser strength, the M-fast cycle at first rises faster than the M-slow cycle, but reaches saturation sooner and at a lower level than the M-slow cycle. The O-intermediate shows the same saturation behavior as Mf. In this paper, we show that the peak current of proton flux and the apparent voltages developed by this flux show the same saturation behavior as M(s), which is very different from that of both M(f) and O. It. is further shown that most of the proton-charge displacement is connected with the step M(s) -> BR. The optical and electrical data in these studies were collected simultaneously by a newly designed and built spectrometer which is described separately. C1 [Hendler, Richard W.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Hendler, Richard W.; Meuse, Curtis W.] Natl Inst Stand & Technol, Div Biochem Sci, Biospect Grp, Gaithersburg, MD 20899 USA. RP Hendler, RW (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM rwh@helix.nih.gov FU Intramural NIH HHS [Z01 HL000518-04, Z99 HL999999] NR 31 TC 1 Z9 1 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 13 PY 2008 VL 47 IS 19 BP 5396 EP 5405 DI 10.1021/bi701748n PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 296MB UT WOS:000255547600015 PM 18422349 ER PT J AU Hendler, RW Shrager, RI Meuse, CW AF Hendler, Richard W. Shrager, Richard I. Meuse, Curtis W. TI The ability of actinic light to modify the bacteriorhodopsin photocycle revisited: Heterogeneity vs photocooperativity SO BIOCHEMISTRY LA English DT Article ID PURPLE MEMBRANES; COOPERATIVITY; SPECTROSCOPY; MOLECULES; CYCLE; MODEL AB In 1995, evidence both for photocooperativity and for heterogeneity as possible explanations for the ability of actinic light to modify the kinetics and pathways of the bacteriorhodopsin (BR) photocycle was reviewed (Shrager, R. I., Hendler, R. W., and Bose, S. (1995) Eur. J. Biochem. 229, 589-595). Because both concepts could be successfully modeled to experimental data and there was suggestive published evidence for both, it was concluded that both photocooperativity and heterogeneity may be involved in the adaptation of the BR photocycle to different levels of actinic light. Since that time, more information has become available and it seemed appropriate to revisit. the original question. In addition to the traditional models based on all intermediates in strict linear sequences, we have considered both homogeneous and heterogeneous models with branches. It is concluded that an explanation based on heterogeneity is more likely to be the true basis for the variation of the properties of the photocycle caused by changes in actinic light intensity. On the basis of new information presented here, it seems that a heterogeneous branched model is more likely than one with separate linear sequences. C1 [Hendler, Richard W.] NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. [Shrager, Richard I.] NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. [Hendler, Richard W.; Meuse, Curtis W.] Natl Inst Stand & Technol, Div Biochem Sci, Biospect Grp, Gaithersburg, MD 20899 USA. RP Hendler, RW (reprint author), NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. EM rwh@helix.nih.gov FU Intramural NIH HHS [Z01 HL000518-04] NR 19 TC 3 Z9 3 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 13 PY 2008 VL 47 IS 19 BP 5406 EP 5416 DI 10.1021/bi701749y PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 296MB UT WOS:000255547600016 PM 18422347 ER PT J AU Menashe, I Rosenberg, PS Chen, BE AF Menashe, Idan Rosenberg, Philip S. Chen, Bingshu E. TI PGA: power calculator for case-control genetic association analyses SO BMC GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMPLEX TRAITS; SAMPLE-SIZE; LINKAGE; 8Q24 AB Background: Statistical power calculations inform the design and interpretation of genetic association studies, but few programs are tailored to case-control studies of single nucleotide polymorphisms (SNPs) in unrelated subjects. Results: We have developed the "Power for Genetic Association analyses" (PGA) package which comprises algorithms and graphical user interfaces for sample size and minimum detectable risk calculations using SNP or haplotype effects under different genetic models and study constrains. The software accounts for linkage disequilibrium and statistical multiple comparisons. The results are presented in graphs or tables and can be printed or exported in standard file formats. Conclusion: PGA is user friendly software that can facilitate decision making for association studies of candidate genes, fine-mapping studies, and whole-genome scans. Stand-alone executable files and a Matlab toolbox are available for download at: http://dceg.cancer.gov/bb/tools/pga. C1 [Menashe, Idan; Rosenberg, Philip S.; Chen, Bingshu E.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Chen, Bingshu E.] Concordia Univ, Dept Math & Stat, Montreal, PQ H4B 1R6, Canada. RP Menashe, I (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. EM menashei@mail.nih.gov; rosenbep@mail.nih.gov; bingshu@chenstat.com FU Intramural NIH HHS NR 22 TC 183 Z9 189 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD MAY 13 PY 2008 VL 9 AR 36 DI 10.1186/1471-2156-9-36 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 308FI UT WOS:000256373300001 PM 18477402 ER PT J AU Smith, NF Baker, SD Gonzalez, FJ Harris, JW Figg, WD Sparreboom, A AF Smith, N. F. Baker, S. D. Gonzalez, F. J. Harris, J. W. Figg, W. D. Sparreboom, A. TI Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100 SO BRITISH JOURNAL OF CANCER LA English DT Article DE tarceva; OSI-774; OSI-420; grapefruit; metabolism; CYP3A4 transgenic ID RECEPTOR TYROSINE KINASE; JUICE-DRUG INTERACTIONS; GRAPEFRUIT JUICE; BIOAVAILABILITY; METABOLISM; BIOEQUIVALENCE; EXPRESSION; EXPOSURE; OSI-774; CANCER AB Administration of BAS 100, a novel mechanism-based CYP3A4 inhibitor isolated from grapefruit juice, resulted in a 2.1-fold increase in erlotinib exposure following oral administration to wild-type and humanised CYP3A4 transgenic mice. This study illustrates the potential of BAS 100 to increase the low and variable oral bioavailability of erlotinib in cancer patients. C1 [Figg, W. D.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Baker, S. D.] Sidney Kimmel Comprehens Canc Ctr John Hopkins, Baltimore, MD 21231 USA. [Gonzalez, F. J.] Natl Canc Inst, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Harris, J. W.] Bioavailabil Syst LLC, Cocoa Beach, FL 32931 USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS [Z01 BC010627-04] NR 19 TC 12 Z9 14 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 13 PY 2008 VL 98 IS 10 BP 1630 EP 1632 DI 10.1038/sj.bjc.6604353 PG 3 WC Oncology SC Oncology GA 301LN UT WOS:000255897800006 PM 18475295 ER PT J AU Hamburg, NM Keyes, MJ Larson, MG Vasan, RS Schnabel, R Pryde, MM Mitchell, GF Sheffy, J Vita, JA Benjamin, EJ AF Hamburg, Naomi M. Keyes, Michelle J. Larson, Martin G. Vasan, Ramachandran S. Schnabel, Renate Pryde, Moira M. Mitchell, Gary F. Sheffy, Jacob Vita, Joseph A. Benjamin, Emelia J. TI Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study SO CIRCULATION LA English DT Article DE cohort studies; epidemiology; vasodilation ID FLOW-MEDIATED DILATION; OBESE ZUCKER RATS; ENDOTHELIAL FUNCTION; MICROVASCULAR FUNCTION; REACTIVE HYPEREMIA; METABOLIC SYNDROME; SKELETAL-MUSCLE; NITRIC-OXIDE; DYSFUNCTION; AMPLITUDE AB Background-Digital pulse amplitude augmentation in response to hyperemia is a novel measure of peripheral vasodilator function that depends partially on endothelium-derived nitric oxide. Baseline digital pulse amplitude reflects local peripheral arterial tone. The relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community is unknown. Methods and Results-Using a fingertip peripheral arterial tonometry (PAT) device, we measured digital pulse amplitude in Framingham Third Generation Cohort participants (n = 1957; mean age, 40 +/- 9 years; 49% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia induced by 5-minute forearm cuff occlusion. To evaluate the vascular response in relation to baseline, adjusting for systemic effects and skewed data, we expressed the hyperemic response (called the PAT ratio) as the natural logarithm of the ratio of postdeflation to baseline pulse amplitude in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of the PAT ratio to cardiovascular risk factors was strongest in the 90- to 120-second postdeflation interval (overall model R-2 = 0.159). In stepwise multivariable linear regression models, male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering treatment were inversely related to PAT ratio, whereas increasing age was positively related to PAT ratio (all P < 0.01). Conclusions-Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further investigations to define the clinical utility and predictive value of digital pulse amplitude. C1 [Keyes, Michelle J.; Larson, Martin G.; Vasan, Ramachandran S.; Schnabel, Renate; Pryde, Moira M.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, NHLBI, Framingham, MA 01702 USA. [Hamburg, Naomi M.; Vasan, Ramachandran S.; Vita, Joseph A.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Prevent Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Dept Stat, Boston, MA 02215 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Holliston, MA USA. [Sheffy, Jacob] Itamar Med Ltd, Caesarea, Israel. RP Benjamin, EJ (reprint author), Boston Univ, Framingham Heart Study, NHLBI, 73 Mt Wayte Ave 2, Framingham, MA 01702 USA. EM emelia@bu.edu RI Schnabel, Renate/F-6527-2014; OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K12 HL083781, 2K24 HL 4334, HL076784, HL083781, HL70100, K24 HL004334, K24 HL004334-04, K24 HL004334-05, K24 HL004334-06, N01 HC025195, N01-HC25195, N01HC25195, R01 HL 080124, R01 HL070100, R01 HL070100-01, R01 HL070100-02, R01 HL070100-03, R01 HL070100-04, R01 HL076784, R01 HL076784-01, R01 HL076784-02, R01 HL076784-03, R01 HL076784-04, R01 HL076784-05, R01 HL080124, R01 HL080124-01, R01 HL080124-02, R01 HL080124-03]; NIA NIH HHS [AG028321, R01 AG028321, R01 AG028321-01, R01 AG028321-02, R01 AG028321-03] NR 23 TC 328 Z9 336 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 13 PY 2008 VL 117 IS 19 BP 2467 EP 2474 DI 10.1161/CIRCULATIONAHA.107.748574 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 299TA UT WOS:000255776700007 PM 18458169 ER PT J AU McDermott, MM Guralnik, JM Ferrucci, L Tian, L Liu, K Liao, YH Green, D Sufit, R Hoff, F Nishida, T Sharma, L Pearce, WH Schneider, JR Criqui, MH AF McDermott, Mary M. Guralnik, Jack M. Ferrucci, Luigi Tian, Lu Liu, Kiang Liao, Yihua Green, David Sufit, Robert Hoff, Frederick Nishida, Takashi Sharma, Leena Pearce, William H. Schneider, Joseph R. Criqui, Michael H. TI Asymptomatic peripheral arterial disease is associated with more adverse lower extremity characteristics than intermittent claudication SO CIRCULATION LA English DT Article DE claudication; epidemiology; inflammation; peripheral vascular disease ID PHYSICAL-ACTIVITY; WOMENS HEALTH; PREVALENCE; DISABILITY; MORTALITY; CLASSIFICATION; OSTEOARTHRITIS; IMPAIRMENT; ISCHEMIA; CRITERIA AB Background-This study assessed functional performance, calf muscle characteristics, peripheral nerve function, and quality of life in asymptomatic persons with peripheral arterial disease (PAD). Methods and Results-PAD participants (n = 465) had an ankle brachial index <0.90. Non-PAD participants (n = 292) had an ankle brachial index of 0.90 to 1.30. PAD participants were categorized into leg symptom groups including intermittent claudication (n = 215) and always asymptomatic (participants who never experienced exertional leg pain, even during the 6-minute walk; n = 72). Calf muscle was measured with computed tomography. Analyses were adjusted for age, sex, race, ankle brachial index, comorbidities, and other confounders. Compared with participants with intermittent claudication, always asymptomatic PAD participants had smaller calf muscle area (4935 versus 5592 mm(2); P < 0.001), higher calf muscle percent fat (16.10% versus 9.45%; P < 0.001), poorer 6-minute walk performance (966 versus 1129 ft; P = 0.0002), slower usual-paced walking speed (P = 0.0019), slower fast-paced walking speed (P < 0.001), and a poorer Short-Form 36 Physical Functioning score (P = 0.016). Compared with an age-matched, sedentary, non-PAD cohort, always asymptomatic PAD participants had smaller calf muscle area (5061 versus 5895 mm2; P = 0.009), poorer 6-minute walk performance (1126 versus 1452 ft; P < 0.001), and poorer Walking Impairment Questionnaire speed scores (40.87 versus 57.78; P = 0.001). Conclusions-Persons with PAD who never experience exertional leg symptoms have poorer functional performance, poorer quality of life, and more adverse calf muscle characteristics compared with persons with intermittent claudication and a sedentary, asymptomatic, age-matched group of non-PAD persons. C1 [Guralnik, Jack M.; Ferrucci, Luigi] NIA, Bethesda, MD 20892 USA. [McDermott, Mary M.; Tian, Lu; Liu, Kiang; Liao, Yihua; Green, David; Sufit, Robert; Hoff, Frederick; Nishida, Takashi; Sharma, Leena; Pearce, William H.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Schneider, Joseph R.] Cent DuPage Hosp, Winfield, IL USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU Intramural NIH HHS; NCRR NIH HHS [M01 RR000048, M01 RR000048-45S16166, RR-00048]; NHLBI NIH HHS [R01 HL058099-04, R01 HL064739, R01 HL064739-04, R01 HL071223, R01 HL071223-04, R01 HL076298, R01 HL076298-04, R01-HL076298, R01-HL58099, R01-HL64739, R01-HL71223, R01 HL058099] NR 31 TC 64 Z9 68 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 13 PY 2008 VL 117 IS 19 BP 2484 EP 2491 DI 10.1161/CIRCULATIONAHA.107.736108 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 299TA UT WOS:000255776700009 PM 18458172 ER PT J AU Sachdev, V Matura, LA Sidenko, S Ho, VB Arai, AE Rosing, DR Bondy, CA AF Sachdev, Vandana Matura, Lea Ann Sidenko, Stanislav Ho, Vincent B. Arai, Andrew E. Rosing, Douglas R. Bondy, Carolyn A. TI Aortic valve disease in turner syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR MALFORMATIONS; TRANSCRIPTION FACTOR; CYSTIC HYGROMA; ASSOCIATION; DISSECTION; MORPHOLOGY; CHILDREN; ADULTS; ECHOCARDIOGRAPHY; DILATATION AB Objectives Our goal was to determine the prevalence and characteristics of aortic valve disease in girls and women with monosomy for the X chromosome, or Turner syndrome (TS). Background Complications from congenital aortic valve disease are a major source of premature mortality in TS, but accurate data on the prevalence of aortic valve abnormalities and their association with aortic root dilation are not available. Methods This prospective study characterized the aortic valve and proximal aorta in 253 individuals with TS age 7 to 67 years using transthoracic echocardiography as our primary screening tool, supplemented with magnetic resonance imaging. Results Transthoracic echocardiography revealed a normal tricuspid aortic valve (TAV) in 172 and a bicuspid aortic valve (BAV) in 66 subjects. Transthoracic echocardiography could not visualize the aortic valve in 15 of 253 or 6%. Magnetic resonance imaging diagnosed 12 of 15 of these cases (8 BAV and 4 TAV), so that only 3 of 253 (1.2%) could not be visualized by either modality. The aortic valve was bicuspid in 74 of 250 (30%) adequately imaged subjects. The prevalence was equal in pediatric (<18 years, n = 89) and adult populations. Over 95% of abnormal aortic valves in TS resulted from fusion of the right and left coronary leaflets. Ascending aortic diameters were significantly greater at the annulus, sinuses, sinotubular junction, and ascending aorta in the BAV group, with aortic root dilation in 25% of subjects with BAV versus 5% of those with TAV. Conclusions Girls and women with TS need focused screening of the aortic valve and root to identify the many asymptomatic individuals with abnormal valvular structure and/or aortic root dilation. C1 [Matura, Lea Ann; Bondy, Carolyn A.] NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Sachdev, Vandana; Sidenko, Stanislav; Arai, Andrew E.; Rosing, Douglas R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. [Ho, Vincent B.] Uniformed Serv Univ Hlth Sci, Dept Radiol Sci, Bethesda, MD 20814 USA. RP Bondy, CA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, CRC 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov FU Intramural NIH HHS NR 44 TC 64 Z9 69 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 13 PY 2008 VL 51 IS 19 BP 1904 EP 1909 DI 10.1016/j.jacc.2008.02.035 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 301LO UT WOS:000255897900012 PM 18466808 ER PT J AU Zhang, L Volinia, S Bonome, T Calin, GA Greshock, J Yang, N Liu, CG Giannakakis, A Alexiou, P Hasegawa, K Johnstone, CN Megraw, MS Adams, S Lassus, H Huang, J Kaur, S Liang, S Sethupathy, P Leminen, A Simossis, VA Sandaltzopoulos, R Naomoto, Y Katsaros, D Gimotty, PA DeMichele, A Huang, Q Butzow, R Rustgi, AK Weber, BL Birrer, MJ Hatzigeorgiou, AG Croce, CM Coukos, G AF Zhang, Lin Volinia, Stefano Bonome, Tomas Calin, George Adrian Greshock, Joel Yang, Nuo Liu, Chang-Gong Giannakakis, Antonis Alexiou, Pangiotis Hasegawa, Kosei Johnstone, Cameron N. Megraw, Molly S. Adams, Sarah Lassus, Heini Huang, Jia Kaur, Sippy Liang, Shun Sethupathy, Praveen Leminen, Arto Simossis, Victor A. Sandaltzopoulos, Raphael Naomoto, Yoshio Katsaros, Dionyssios Gimotty, Phyllis A. DeMichele, Angela Huang, Qihong Butzow, Ralf Rustgi, Anil K. Weber, Barbara L. Birrer, Michael J. Hatzigeorgiou, Artemis G. Croce, Carlo M. Coukos, George TI Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Dlk1-Gtl2 domain; noncoding RNA ID CHRONIC LYMPHOCYTIC-LEUKEMIA; DIFFERENTIAL REGULATION; CELL-PROLIFERATION; DOWN-REGULATION; PROGNOSIS; APOPTOSIS; GENES; P53; PROFILES; MIR-34A AB MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelia[ ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of approximate to 15% and at least approximate to 36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer. C1 [Zhang, Lin; Yang, Nuo; Giannakakis, Antonis; Hasegawa, Kosei; Adams, Sarah; Liang, Shun; Coukos, George] Univ Penn, Ctr Res Early Detect & Cure Ovarian Canc & Gyneco, Philadelphia, PA 19104 USA. [Greshock, Joel; Huang, Jia; Weber, Barbara L.; Hatzigeorgiou, Artemis G.; Coukos, George] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Zhang, Lin; Adams, Sarah; Coukos, George] Univ Penn, Dept Obstet, Philadelphia, PA 19104 USA. [Johnstone, Cameron N.; DeMichele, Angela; Rustgi, Anil K.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Megraw, Molly S.; Sethupathy, Praveen; Hatzigeorgiou, Artemis G.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Gimotty, Phyllis A.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Volinia, Stefano; Calin, George Adrian; Liu, Chang-Gong] Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. [Volinia, Stefano; Calin, George Adrian; Liu, Chang-Gong] Ohio State Univ, Dept Immunol, Columbus, OH 43210 USA. [Volinia, Stefano; Calin, George Adrian; Liu, Chang-Gong] Ohio State Univ, Dept Med Genet, Columbus, OH 43210 USA. [Bonome, Tomas; Birrer, Michael J.] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20814 USA. [Giannakakis, Antonis; Sandaltzopoulos, Raphael] Democritus Univ Thrace, Lab Gene Express Modern Diag & Therapeut Methods, Alexandroupolis 68100, Greece. [Alexiou, Pangiotis; Simossis, Victor A.; Hatzigeorgiou, Artemis G.] Biomed Sci Res Ctr Alexander Fleming, Inst Mol Oncol, Varkiza 16672, Greece. [Lassus, Heini; Kaur, Sippy; Leminen, Arto; Butzow, Ralf] Univ Helsinki, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Naomoto, Yoshio] Okayama Univ, Dept Surg Oncol, Okayama 7008530, Japan. [Katsaros, Dionyssios] Univ Turin, Dept Obstet & Gynecol, I-10124 Turin, Italy. [Huang, Qihong] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. RP Zhang, L (reprint author), Univ Penn, Ctr Res Early Detect & Cure Ovarian Canc & Gyneco, Philadelphia, PA 19104 USA. EM linzhang@mail.med.upenn.edu; hatzigeorgiou@fleming.gr; carlo.croce@osumc.edu; gcks@mail.med.upenn.edu RI Megraw, Molly/D-1988-2009; ALEXIOU, PANAGIOTIS/C-8906-2011; Volinia, Stefano/A-3029-2010; OI Volinia, Stefano/0000-0003-0910-3893; Lassus, Heini/0000-0003-0598-5147; Megraw, Molly/0000-0001-6793-6151 FU NCI NIH HHS [P01-CA83638, P50 CA083638]; NIDDK NIH HHS [R01-DK056645, R01 DK056645] NR 49 TC 321 Z9 347 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2008 VL 105 IS 19 BP 7004 EP 7009 DI 10.1073/pnas.0801615105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 301UN UT WOS:000255921200040 PM 18458333 ER PT J AU Alper, S Laws, R Lackford, B Boyd, WA Dunlap, P Freedman, JH Schwartz, DA AF Alper, Scott Laws, Rebecca Lackford, Brad Boyd, Windy A. Dunlap, Paul Freedman, Jonathan H. Schwartz, David A. TI Identification of innate immunity genes and pathways using a comparative genomics approach SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Caenorhabditis elegans; macrophage ID TOLL-LIKE RECEPTORS; TLR SIGNALING PATHWAYS; CAENORHABDITIS-ELEGANS; SYSTEMIC INFLAMMATION; C-ELEGANS; PROTEIN; MAP; EXPRESSION; INFECTION; DISEASE AB To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered innate immune responsiveness in C elegans were validated in murine macrophages, resulting in the discovery of 11 genes that regulate the innate immune response in both systems and the subsequent identification of a protein interaction network with a conserved role in innate immunity regulation. We confirmed the role of four of these 11 genes in antimicrobial gene regulation using available mutants in C elegans. Several of these genes (acy-1, tub-2, and tbc-1) also regulate susceptibility to the pathogen Pseudomonas aeruginosa. These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases. C1 [Alper, Scott; Lackford, Brad; Schwartz, David A.] NHLBI, Lab Environm Lung Dis, Durham, NC 27709 USA. [Boyd, Windy A.; Dunlap, Paul; Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, Mol Toxicol Lab, NIH, Durham, NC 27709 USA. [Alper, Scott] Duke Univ, Dept Med, Durham, NC 27707 USA. [Laws, Rebecca] Duke Univ, Dept Biol, Durham, NC 27708 USA. RP Alper, S (reprint author), NHLBI, Lab Environm Lung Dis, 111 TW Alexander Dr, Durham, NC 27709 USA. EM alpers@nhlbi.nih.gov OI Boyd, Windy/0000-0003-3803-3716 FU Intramural NIH HHS NR 62 TC 42 Z9 86 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 13 PY 2008 VL 105 IS 19 BP 7016 EP 7021 DI 10.1073/pnas.0802405105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 301UN UT WOS:000255921200042 PM 18463287 ER PT J AU Varma, R AF Varma, Rajat TI TCR Triggering by the pMHC Complex: Valency, Affinity, and Dynamics SO SCIENCE SIGNALING LA English DT Article AB The interaction between the T cell receptor (TCR) and a peptide-loaded major histo compatibility complex (pMHC) is one of the most-studied interactions in immunology, and yet the precise mechanism by which this system operates is still not fully understood. One key issue is whether TCR triggering minimally requires monomeric pMHC complexes or higher-order multimers (two or more pMHCs). Any model of TCR triggering must explain the high sensitivity, specificity, and dynamic range of ligand responsiveness that this receptor system exhibits. Most models of TCR triggering have not fully appreciated the dynamic aspects of TCR triggering. TCR triggering happens very quickly, and the properties of sensitivity and specificity can be explained by a model that accounts for the interaction dynamics of such a receptor system. In this paper, it is proposed that the important parameter in TCR triggering is the immobilization of the TCR-pMHC complex in the plasma membrane. Whether this involves monomeric or multimeric pMHCs may depend on the affinity of the TCR for the pMHC. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Varma, R (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM varmarajat@mail.nih.gov RI Varma, Rajat/I-1209-2012 OI Varma, Rajat/0000-0001-5131-0402 NR 37 TC 9 Z9 9 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAY 13 PY 2008 VL 1 IS 19 AR pe21 DI 10.1126/stke119pe21 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA V10VY UT WOS:000207492700001 PM 18480017 ER PT J AU Qian, F Rausch, KM Muratova, O Zhou, H Song, GH Diouf, A Lambert, L Narum, DL Wu, YM Saul, A Miller, LH Long, CA Mullen, GED AF Qian, Feng Rausch, Kelly M. Muratova, Olga Zhou, Hong Song, Guanhong Diouf, Ababacar Lambert, Lynn Narum, David L. Wu, Yimin Saul, Allan Miller, Louis H. Long, Carole A. Mullen, Gregory E. D. TI Addition of CpG ODN to recombinant Pseudomonas aeruginosa ExoProtein A conjugates of AMA1 and Pfs25 greatly increases the number of responders SO VACCINE LA English DT Article DE malaria; AMA1; pfs25; conjugation; CPG 7909; rEPA; vaccine ID MEROZOITE SURFACE PROTEIN-1; APICAL MEMBRANE ANTIGEN-1; TRANSMISSION-BLOCKING ACTIVITY; PLASMODIUM-FALCIPARUM MALARIA; ANTIBODY-RESPONSES; VACCINE CANDIDATES; IN-VITRO; IMMUNOGENICITY; OLIGODEOXYNUCLEOTIDE; TITER AB Both the blood-stage protein apical membrane antigen 1 (AMA1) and the 25-kDa sexual-stage protein (Pfs25) of Plasmodium falciparum are two leading candidates in malarial vaccine development. We have previously demonstrated that conjugation of these malarial antigens to recombinant Pseudomonas aeruginosa ExoProtein A (rEPA) significantly increased the mean-specific functional antibody responses in mice; however, some mice responded poorly and were unable to demonstrate a functional response. We hypothesized that the immuno-genicities of these two malarial antigens could be further enhanced by the inclusion of a CpG oligodeoxynucleotide in the formulation. Mice were immunized with either rEPA-conjugated or unconjugated AMA1 and Pfs25 formulated on Alhydrogel with or without the addition of CPG 7909. Mice received the formulations on days 0 and 28, and mouse sera were collected on day 42. ELISA analyses on these sera showed that the addition of CPG 7909 to AMA1-rEPA and Pfs25-rEPA formulated on Alhydrogel induced significantly higher mean antibody titers than the formulations without CPG 7909, and led to a mixed Th1/Th2 response as demonstrated by the production of mouse IgG1 and IgG2a subclasses. The presence of CPG 7909 in the formulations of both conjugated antigens greatly increased the proportion of responders with antibody titers sufficient to inhibit blood-stage parasite growth in vitro or block transmission of sexual-stage parasites to mosquitoes. The results obtained in this study indicate the potential use of a combination strategy to increase the number of responders to malarial antigens in humans. Published by Elsevier Ltd. C1 [Qian, Feng; Rausch, Kelly M.; Muratova, Olga; Zhou, Hong; Song, Guanhong; Diouf, Ababacar; Lambert, Lynn; Narum, David L.; Wu, Yimin; Saul, Allan; Miller, Louis H.; Long, Carole A.; Mullen, Gregory E. D.] NIAID, NIH, Malaria Vaccine Dev Branch, Rockville, MD 20852 USA. RP Mullen, GED (reprint author), Kings Coll London, Rayne Inst, Div Imaging Sci, St Thomas Hosp, 4th Floor,Lambeth Wing, London SE1 7EH, England. EM greg.mullen@kcl.ac.uk RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU Intramural NIH HHS [, NIH0012094647]; PHS HHS [NIH0012094647] NR 24 TC 23 Z9 25 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAY 12 PY 2008 VL 26 IS 20 BP 2521 EP 2527 DI 10.1016/j.vaccine.2008.03.005 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 303XL UT WOS:000256074200009 PM 18423804 ER PT J AU Liu, AY Wu, CQ Schisterman, EF AF Liu, Aiyi Wu, Chengqing Schisterman, Enrique F. TI Nonparametric sequential evaluation of diagnostic biomarkers SO STATISTICS IN MEDICINE LA English DT Article DE biomarkers; correlated measurements; diagnostic tests; interim looks and early stopping; correlated U-statistics ID OPERATING CHARACTERISTIC CURVES; CLINICAL-TRIALS; EXPONENTIAL DISTRIBUTION; ROC CURVE; DESIGN; AREA; TESTS AB We consider evaluation and comparison of the diagnostic accuracy of biomarkers with continuous test outcomes, possibly correlated due to repeated measurements. We develop nonparametric group sequential testing procedures to evaluate and compare the area of biomarkers under their receiver operating characteristic curves, with either independent or paired test outcomes. These procedures rely on the construction of a two-dimensional statistic of Whitehead (Statist. Med. 1999; 18:2271-2286) so that design methods based on Brownian motion can be applied. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Liu, Aiyi; Wu, Chengqing; Schisterman, Enrique F.] NICHHD, Biometry & Math Stat Branch, Dept Hlth & Human Services, Rockville, MD 20852 USA. RP Liu, AY (reprint author), NICHHD, Biometry & Math Stat Branch, Dept Hlth & Human Services, 6100 Execut Blvd, Rockville, MD 20852 USA. EM Liua@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [NIH0014367067, Z01 HD008761-05] NR 22 TC 4 Z9 4 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2008 VL 27 IS 10 BP 1667 EP 1678 DI 10.1002/sim.3203 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 290BI UT WOS:000255097300007 PM 18241080 ER PT J AU Dodd, LE Korn, EL AF Dodd, Lori E. Korn, Edward L. TI Lack of generalizability of sensitivity and specificity with treatment effects SO STATISTICS IN MEDICINE LA English DT Article DE biomarkers; classification probabilities; predictive values; Prentice criterion; surrogate ID DIAGNOSTIC-TESTS; CYTOLOGY INTERPRETATIONS; RANDOMIZED-TRIAL; END-POINTS; CANCER; BIOMARKERS; MANAGEMENT; BIAS AB In biomarker development, two types of summary measures are often used to describe marker accuracy. Positive and negative predictive values describe how well a marker predicts clinical states of interest, while sensitivity and specificity describe how well a marker discriminates between the two states. Insofar as predictive values depend heavily on the prevalence of the clinical states and sensitivity and specificity may not, sensitivity and specificity are preferred in early biomarker development. In many applications, an ideal property of a biomarker is fulfillment of the first Prentice criterion. Under this condition, predictive values do not depend on a covariate (such as treatment) because the biomarker captures all relevant information about the clinical state of interest. A similar condition can be defined for sensitivity and specificity which states that these measures do not depend on a covariate (e.g. treatment). This condition, which we refer to as the equal discriminatory accuracy (EDA) condition, is desirable because it allows sensitivity and specificity from one treatment setting (or covariate value) to be applied to a different setting. We demonstrate, however, that the Prentice condition and EDA are incompatible. Further, under a simple proportional hazards model for a time-to-event outcome, EDA will not be satisfied. We present numerical examples as well as examples of a potential marker in late-stage prostate cancer and another for cervical cancer screening. These results demonstrate that evaluating sensitivity and specificity within treatment (or other covariate) groups is necessary even when simple proportional hazards models or the Prentice criterion holds. Copyright (C) 2007 John Wiley & Sons, Ltd. C1 [Dodd, Lori E.; Korn, Edward L.] NIH, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NIH, Biometr Res Branch, Div Canc Treatment & Diag, 6130 Execut BLVD,MSC 7434, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov NR 16 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 10 PY 2008 VL 27 IS 10 BP 1734 EP 1744 DI 10.1002/sim.3101 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 290BI UT WOS:000255097300012 PM 17940996 ER PT J AU Patterson, LJ Beal, J Dernberg, T Florese, RH Malkevich, N Venzon, D Aldrich, K Richardson, E Kalyanaraman, VS Kalisz, I Lee, EM Montefiori, DC Robey, FA Robert-Guroff, M AF Patterson, L. Jean Beal, Jennifer Dernberg, Thorsten Florese, Ruth H. Malkevich, Nina Venzon, David Aldrich, Kris Richardson, Ersell Kalyanaraman, V. S. Kalisz, Irene Lee, Eun Mi Montefiori, David C. Robey, Frank A. Robert-Guroff, Marjorie TI Replicating adenovirus HIV/SIV recombinant priming alone or in combination with a gp140 protein boost results in significant control of viremia following a SHIV89.6P challenge in Mamu-A*01 negative rhesus macaques SO VIROLOGY LA English DT Article DE replicating adenovirus vectors; prime/boost; HIV/SIV vaccines; SHIV89.6P challenge; Rhesus macaques ID HUMAN-IMMUNODEFICIENCY-VIRUS; DEPENDENT CELLULAR CYTOTOXICITY; CD4(+) T-CELLS; IMMUNE-RESPONSES; SIV INFECTION; NEUTRALIZING ANTIBODIES; VACCINE REGIMEN; SIVMAC251 CHALLENGE; HIV-1 VACCINE; C4 DOMAIN AB Previously, replicating adenovirus type 5 host range (Ad5hr)-HIV/SIV recombinant priming in combination with SIV envelope boosting, resulted in significant, durable protection in 39% of rhesus macaques after SIVmac251 challenge. Both Env-specific antibody mediating ADCC, and cellular immunity correlated with protection. Here we evaluate the relative immunogenicities of novel HIV proteins and their contribution to protection in a SHIV89.6P model. All groups were primed with Ad-HIVenv(89.6P), SlVgag(239), and SIVnef(239) recombinants. One group was not boosted, one received HIV(89.6P)gp140 Delta CFI protein, and one a novel HIV-1 poly-peptide "peptomer". The HIV(89.6P)gp140 Delta CFI protein in adjuvant strongly boosted Env-specific antibody and memory T cell responses in blood and tissue, resulting in significant reductions in acute and set point viremia. Macaques not boosted, showed a significant reduction in set point viremia, a full 32 weeks after the last Ad priming immunization. The HIV peptomer-boosted group showed a trend toward chronic viremia reduction, but was not protected. (c) 2008 Elsevier Inc. All rights reserved. C1 [Patterson, L. Jean; Beal, Jennifer; Dernberg, Thorsten; Florese, Ruth H.; Malkevich, Nina; Aldrich, Kris; Richardson, Ersell; Robert-Guroff, Marjorie] NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kalyanaraman, V. S.; Kalisz, Irene; Lee, Eun Mi] Adv BioSci Labs Inc, Kensington, MD 20895 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC USA. [Robey, Frank A.] AriaVax, Gaithersburg, MD 20850 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffTn@mail.nih.gov FU NIAID NIH HHS [AI 30034] NR 44 TC 18 Z9 19 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2008 VL 374 IS 2 BP 322 EP 337 DI 10.1016/j.virol.2007.12.037 PG 16 WC Virology SC Virology GA 299DL UT WOS:000255735900012 PM 18252262 ER PT J AU Filippone, C Zhi, N Wong, S Lu, J Kajigaya, S Gallinella, G Kakkola, L Soderlund-Venenno, M Young, NS Brown, KE AF Filippone, Claudia Zhi, Ning Wong, Susan Lu, Jun Kajigaya, Sachiko Gallinella, Giorgio Kakkola, Laura Soderlund-Venenno, Maria Young, Neal S. Brown, Kevin E. TI VP1u phospholipase activity is critical for infectivity of full-length parvovirus B19 genomic clones SO VIROLOGY LA English DT Article DE parvovirus B19; PLA(2)-like motif; infectious clone ID MINOR CAPSID PROTEIN; SICKLE-CELL-ANEMIA; NONSTRUCTURAL PROTEIN; VP1-UNIQUE REGION; UNIQUE REGION; NS1 PROTEIN; IDENTIFICATION; VIRUS; TRANSCRIPTION; INVITRO AB Three full-length genomic clones (pB19-M20, pB19-FL and pB19-HG1) of parvovirus B 19 were produced in different laboratories. pB19-M20 was shown to produce infectious virus. To determine the differences in infectivity, all three plasmids were tested by transfection and infection assays. All three clones were similar in viral DNA replication, RNA transcription, and viral capsid protein production. However, only pB19-M20 and pB19-HG1 produced infectious virus. Comparison of viral sequences showed no significant differences in ITR or NS regions. In the capsid region, there was a nucleotide sequence difference conferring an amino acid substitution (E176K) in the phospholipase A(2)-like motif of the VP1-unique (VP1u) region. The recombinant VP1u with the E176K mutation bad no catalytic activity as compared with the wild-type. When this mutation was introduced into pB19-M20, infectivity was significantly attenuated, confirming the critical role of this motif Investigation of the original serum from which pB19-FL was cloned confirmed that the phospholipase mutation was present in the native B19 virus. (c) 2008 Elsevier Inc. All rights reserved. C1 [Filippone, Claudia; Zhi, Ning; Wong, Susan; Lu, Jun; Kajigaya, Sachiko; Young, Neal S.] NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. [Gallinella, Giorgio] Univ Bologna, Dept Clin & Expt Med, I-40126 Bologna, Italy. [Kakkola, Laura; Soderlund-Venenno, Maria] Univ Helsinki, Haartman Inst, Dept Virol, FIN-00014 Helsinki, Finland. [Brown, Kevin E.] Hlth Protect Agcy, Ctr Infect, London, England. RP Zhi, N (reprint author), NHLBI, NIH, Hematol Branch, Bldg 10-CRC,Rm 3E5272,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhin@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999, Z01 HL002315-25] NR 43 TC 26 Z9 27 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2008 VL 374 IS 2 BP 444 EP 452 DI 10.1016/j.virol.2008.01.002 PG 9 WC Virology SC Virology GA 299DL UT WOS:000255735900023 PM 18252260 ER PT J AU Senkevich, TG Wyatt, LS Weisberg, AS Koonin, EV Moss, B AF Senkevich, Tatiana G. Wyatt, Linda S. Weisberg, Andrea S. Koonin, Eugene V. Moss, Bernard TI A conserved poxvirus NlpC/P60 superfamily protein contributes to vaccinia virus virulence in mice but not to replication in cell culture SO VIROLOGY LA English DT Article DE vaccinia virus G6R gene; virus pathogenesis; papain fold; cysteine-histidine dyad ID MUTANT; HERPESVIRIDAE; SEQUENCE; GENE; FORM AB Of the vaccinia virus genes that are conserved in all sequenced poxviruses, each one except for VACWR084 (G6R) has been at least partially characterized. The poxvirus protein encoded by G6R belongs to the NlpC/P60 superfamily, which consists of proteins with a papain-like fold and known or predicted protease, amidase or acyltransferase activity. The G6 protein was synthesized late in infection and localized to the interior of virions, primarily between the membrane and core. Unlike other conserved poxvirus genes, G6R was not required for virus propagation and spread in a variety of cells. Nevertheless, G6R null mutants caused less severe disease in mice than the parent or revertant virus. Moreover, mutation of the predicted catalytic cysteine led to the same level of attenuation as a null mutant, suggesting that the G6 protein has enzymatic activity that is important in vivo. Conservation of G6R amongst poxviruses and the disparity between its role in vitro and in vivo imply that the protein is involved in an aspect of the virus-host interaction that is common to vertebrates and insects. Published by Elsevier Inc. C1 [Senkevich, Tatiana G.; Wyatt, Linda S.; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS [Z01 AI000979-02] NR 22 TC 21 Z9 21 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 0042-6822 J9 VIROLOGY JI Virology PD MAY 10 PY 2008 VL 374 IS 2 BP 506 EP 514 DI 10.1016/j.virol.2008.01.009 PG 9 WC Virology SC Virology GA 299DL UT WOS:000255735900029 PM 18281072 ER PT J AU Cheng, KT Liu, XB Ong, HL Ambudkar, IS AF Cheng, Kwong Tai Liu, Xibao Ong, Hwei Ling Ambudkar, Indu S. TI Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED CALCIUM-CHANNELS; SALIVARY-GLAND CELLS; CRAC CHANNEL; CA2+ INFLUX; TRPC CHANNELS; PORE SUBUNIT; ENTRY; STIM1; PROTEIN; MICE AB Orai1 and TRPC1 have been proposed as core components of store-operated calcium release-activated calcium ( CRAC) and store-operated calcium (SOC) channels, respectively. STIM1, a Ca(2+) sensor protein in the endoplasmic reticulum, interacts with and mediates store-dependent regulation of both channels. We have previously reported that dynamic association of Orai1, TRPC1, and STIM1 is involved in activation of store-operated Ca(2+) entry ( SOCE) in salivary gland cells. In this study, we have assessed the molecular basis of TRPC1-SOC channels in HEK293 cells. We report that TRPC1+STIM1-dependent SOCE requires functional Orai1. Thapsigargin stimulation of cells expressing Orai1 + STIM1 increased Ca(2+) entry and activated typical I(CRAC) current. STIM1 alone did not affect SOCE, whereas expression of Orai1 induced a decrease. Expression of TRPC1 induced a small increase in SOCE, which was greatly enhanced by co-expression of STIM1. Thapsigargin stimulation of cells expressing TRPC1 + STIM1 activated a non-selective cation current, I(SOC), that was blocked by 1 mu M Gd(3+) and 2-APB. Knockdown of Orai1 decreased endogenous SOCE as well as SOCE with TRPC1 alone. siOrai1 also significantly reduced SOCE and ISOC in cells expressing TRPC1 + STIM1. Expression of R91WOrai1 or E106QOrai1 induced similar attenuation of TRPC1 + STIM1-dependent SOCE and ISOC, whereas expression of Orai1 with TRPC1 + STIM1 resulted in SOCE that was larger than that with Orai1 + STIM1 or TRPC1 + STIM1 but not additive. Additionally, Orai1, E106QOrai1, and R91WOrai1 co-immunoprecipitated with similar levels of TRPC1 and STIM1 from HEK293 cells, and endogenous TRPC1, STIM1, and Orai1 were co-immunoprecipitated from salivary glands. Together, these data demonstrate a functional requirement for Orai1 in TRPC1 + STIM1-dependent SOCE. C1 [Cheng, Kwong Tai; Liu, Xibao; Ong, Hwei Ling; Ambudkar, Indu S.] NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, Mol Physiol & Therapeut Branch, NIH, Bldg 10,Rm 1N-113, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov NR 36 TC 118 Z9 121 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 9 PY 2008 VL 283 IS 19 BP 12935 EP 12940 DI 10.1074/jbc.C800008200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295UQ UT WOS:000255499800030 PM 18326500 ER PT J AU Sayer, JM Liu, FL Ishima, R Weber, IT Louis, JM AF Sayer, Jane M. Liu, Fengling Ishima, Rieko Weber, Irene T. Louis, John M. TI Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RESOLUTION CRYSTAL-STRUCTURES; DRUG-RESISTANCE; RETROVIRAL PROTEASES; SUBSTRATE COMPLEX; VIRAL INFECTIVITY; DIMER STABILITY; INHIBITION; MUTANTS; MONOMER AB All aspartic proteases, including retroviral proteases, share the triplet DTG critical for the active site geometry and catalytic function. These residues interact closely in the active, dimeric structure of HIV-1 protease (PR). We have systematically assessed the effect of the D25N mutation on the structure and stability of the mature PR monomer and dimer. The D25N mutation (PRD25N) increases the equilibrium dimer dissociation constant by a factor > 100-fold (1.3 +/- 0.09 mu M) relative to PR. In the absence of inhibitor, NMR studies reveal clear structural differences between PR and PRD25N in the relatively mobile P1 loop (residues 79-83) and flap regions, and differential scanning calorimetric analyses show that the mutation lowers the stabilities of both the monomer and dimer folds by 5 and 7.3 C, respectively. Only minimal differences are observed in high resolution crystal structures of PRD25N complexed to darunavir (DRV), a potent clinical inhibitor, or a non-hydrolyzable substrate analogue, Ac-Thr-Ile-Nle-r-Nle-Gln-Arg-NH2 (RPB), as compared with PR center dot DRV and PR center dot RPB complexes. Although complexation with RPB stabilizes both dimers, the effect on their T-m is smaller for PRD25N (6.2 degrees C) than for PR (8.7 degrees C). The Tm of PRD25N center dot DRV increases by only 3 C relative to free PRD25N, as compared with a 22 degrees C increase for PR center dot DRV, and the mutation increases the ligand dissociation constant of PRD25N . DRV by a factor of similar to 10(6) relative to PR center dot DRV. These results suggest that interactions mediated by the catalytic Asp residues make a major contribution to the tight binding of DRV to PR. C1 [Sayer, Jane M.; Louis, John M.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Liu, Fengling; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Ishima, Rieko] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. RP Louis, JM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm B2-29, Bethesda, MD 20892 USA. EM johnl@intra.niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999]; NIGMS NIH HHS [R01 GM062920-09, R01 GM062920-10, GM62920, R01 GM062920] NR 46 TC 51 Z9 51 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 9 PY 2008 VL 283 IS 19 BP 13459 EP 13470 DI 10.1074/jbc.M708506200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 295UQ UT WOS:000255499800085 PM 18281688 ER PT J AU Trachtenberg, S Dorward, LM Speransky, VV Jaffe, H Andrews, SB Leapman, RD AF Trachtenberg, Shlomo Dorward, Lori M. Speransky, Vladislav V. Jaffe, Howard Andrews, S. Brian Leapman, Richard D. TI Structure of the cytoskeleton of Spiroplasma melliferum BC3 and its interactions with the cell membrane SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE bacterial cytoskeleton; bacterial motility; cryoelectron tomography; linear motor; Spiroplasma ID ELONGATION-FACTOR-TU; BACTERIAL LINEAR MOTOR; CORN STUNT DISEASE; ESCHERICHIA-COLI; ELECTRON-MICROSCOPY; LEAFHOPPER VECTOR; CITRI; ACTIN; FILAMENTS; PROTEIN AB Spiroplasma melliferum is a wall-less bacterium with dynamic helical symmetry. Taking advantage of the simplicity of this primitive lifeform, we have used structural (electron tomography and freeze fracture of whole cells; cryoelectron tomography and diffraction analysis of isolated cytoskeletons) and proteomic approaches to elucidate the basic organizing principles of its minimal. yet functional cytoskeleton. From among similar to 30 Spiroplasma proteins present in a highly purified cytoskeletal fraction, we identify three major putative structural proteins: Fib, MreB, and elongation factor Tu. Fib assembles into a single flattened ribbon that follows the shortest helical line just under the plasma membrane and acts as a linear motor, whereas MreB is present as a matching array of membrane-associated fibrils parallel and associated with the motor. We also identify a prominent previously unknown filamentous network that occupies much of the cytoplasm and appears to cross-link the ribosomes. The abundant potentially filament-forming protein elongation factor Tu may be a component of this network, but the tomography data are most consistent with DNA as the core component. The results provide new information on the minimal organization necessary to support the scaffolding and motile functions of a minimal cytoskeleton. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Trachtenberg, Shlomo] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Membrane & Ultrastruct Res, IL-91120 Jerusalem, Israel. [Dorward, Lori M.; Speransky, Vladislav V.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Jaffe, Howard] Natl Inst Neurol Disorders & Stroke, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. [Andrews, S. Brian] Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Trachtenberg, S (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Membrane & Ultrastruct Res, POB 12272, IL-91120 Jerusalem, Israel. EM shlomot@cc.huji.ac.il FU Intramural NIH HHS NR 44 TC 13 Z9 14 U1 0 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 9 PY 2008 VL 378 IS 4 BP 778 EP 789 DI 10.1016/j.jmb.2008.02.020 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 305LO UT WOS:000256180100002 PM 18400234 ER PT J AU Batra, VK Beard, WA Shock, DD Pedersen, LC Wilson, SH AF Batra, Vinod K. Beard, William A. Shock, David D. Pedersen, Lars C. Wilson, Samuel H. TI Structures of DNA polymerase beta with active-site mismatches suggest a transient abasic site intermediate during misincorporation SO MOLECULAR CELL LA English DT Article ID INDUCED-FIT MECHANISM; NUCLEOTIDE INCORPORATION; REPLICATION FIDELITY; CRYSTAL-STRUCTURES; BASE SUBSTITUTION; MINOR-GROOVE; INSIGHTS; MOTIONS; REPAIR; CHECKPOINTS AB We report the crystallographic structures of DNA polymerase beta with dG-dAMPCPP and dC-dAMPCPP mismatches in the active site. These premutagenic structures were obtained with a nonhydrolyzable incoming nucleoticle analog, dAMPCPP, and Mn2+ Substituting Mn2+ for Mg2+ significantly decreases the fidelity of DNA synthesis. The structures reveal that the enzyme is in a closed conformation like that observed with a matched Watson-Crick base pair. The incorrect dAMPCPP binds in a conformation identical to that observed with the correct nucleotide. To accommodate the incorrect nucleotide and closed protein conformation, the template strand in the vicinity of the active site has shifted upstream over 3 A, removing the coding base from the active site and generating an abasic templating pocket. The primer terminus rotates as its complementary template base is repositioned. This rotation moves 03' of the primer terminus away from the alpha-phosphate of the incoming nucleotide, thereby deterring misincorporation. C1 [Batra, Vinod K.; Beard, William A.; Shock, David D.; Pedersen, Lars C.; Wilson, Samuel H.] NIEHS, Natl Inst Hlth, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Natl Inst Hlth, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050158-11, Z01 ES050159-11]; NCI NIH HHS [1U19CA105010, U19 CA105010] NR 47 TC 71 Z9 72 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 9 PY 2008 VL 30 IS 3 BP 315 EP 324 DI 10.1016/j.molcel.2008.02.025 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 299NB UT WOS:000255761200009 PM 18471977 ER PT J AU Xiromerisiou, G Hadjigeorgiou, GM Papadimitriou, A Katsarogiannis, E Gourbali, V Singleton, AB AF Xiromerisiou, Georgia Hadjigeorgiou, Georgios M. Papadimitriou, Alexandros Katsarogiannis, Evaggelos Gourbali, Vasiliki Singleton, Andrew B. TI Association between AKT1 gene and Parkinson's disease: A protective haplotype SO NEUROSCIENCE LETTERS LA English DT Article DE AKT1; Parkinson's disease; association; haplotypes ID LINKAGE DISEQUILIBRIUM; SIGNALING PATHWAY; SCHIZOPHRENIA; POLYMORPHISMS; POPULATIONS; APOPTOSIS AB Variation in AKT1 has been associated with schizophrenia, bipolar disease and type 11 diabetes. The aim of the present study was to investigate the potential role of variability within AKT1 as a risk factor for Parkinson's disease (PD). We performed a case-control association analysis of AKT1 in a Greek cohort of PD using four tagging SNPs and five constructed haplotypes. To assess the structure of this locus in different populations we have performed linkage disequilibrium (LD) analysis using these variants [dunning]. In multilocus analysis, the frequency of a four-SNP1 /2/3/4 haplotype was significantly higher in controls in comparison with PD patients (chi(2) = 19.76, p = 0.00009, OR = 0.11 C.I. = 0.03-0.35). The association remained significant even after Bonferroni correction for the number of haplotypes (p = 0.0002). So, this certain haplotype was significantly associated with reduced risk of the disease. The data presented here suggest the involvement of AKT1 in protection of PD through many possible mechanisms involving different signaling pathways that could be potential therapeutic targets in the future. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Xiromerisiou, Georgia; Hadjigeorgiou, Georgios M.; Papadimitriou, Alexandros; Katsarogiannis, Evaggelos; Gourbali, Vasiliki] Univ Thessaly, Sch Med, Dept Neurol, Neurogenet Unit, Larisa 41222, Greece. [Xiromerisiou, Georgia; Singleton, Andrew B.] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hadjigeorgiou, GM (reprint author), Univ Thessaly, Sch Med, Dept Neurol, Neurogenet Unit, Papakyriazi 22 St, Larisa 41222, Greece. EM geoksirom@med.uth.gr RI Singleton, Andrew/C-3010-2009 NR 22 TC 32 Z9 33 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 9 PY 2008 VL 436 IS 2 BP 232 EP 234 DI 10.1016/j.neulet.2008.03.026 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 305TN UT WOS:000256200800033 PM 18395980 ER PT J AU Minh, DDL Adib, AB AF Minh, David D. L. Adib, Artur B. TI Optimized free energies from bidirectional single-molecule force spectroscopy SO PHYSICAL REVIEW LETTERS LA English DT Article ID MONTE-CARLO DATA; NONEQUILIBRIUM MEASUREMENTS; FLUCTUATION THEOREM; JARZYNSKIS EQUALITY; EQUILIBRIUM; TRAJECTORIES; SYSTEMS AB An optimized method for estimating path-ensemble averages using data from processes driven in opposite directions is presented. Based on this estimator, bidirectional expressions for reconstructing free energies and potentials of mean force from single-molecule force spectroscopy-valid for biasing potentials of arbitrary stiffness-are developed. Numerical simulations on a model potential indicate that these methods perform better than unidirectional strategies. C1 [Minh, David D. L.; Adib, Artur B.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Minh, DDL (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM daveminh@gmail.com RI Minh, David/A-4655-2009 OI Minh, David/0000-0002-4802-2618 FU Intramural NIH HHS [Z01 DK029052-01] NR 28 TC 62 Z9 62 U1 1 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 EI 1079-7114 J9 PHYS REV LETT JI Phys. Rev. Lett. PD MAY 9 PY 2008 VL 100 IS 18 AR 180602 DI 10.1103/PhysRevLett.100.180602 PG 4 WC Physics, Multidisciplinary SC Physics GA 299QZ UT WOS:000255771400009 PM 18518359 ER PT J AU Newman, DJ AF Newman, David J. TI Natural products as leads to potential drugs: An old process or the new hope for drug discovery? SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SOLID-PHASE SYNTHESIS; COMPOUND LIBRARY DEVELOPMENT; II/MANNOSE 6-PHOSPHATE RECEPTOR; TYROSINE KINASE INHIBITORS; LEUKOTRIENE A(4) HYDROLASE; ORIENTED ORGANIC-SYNTHESIS; COMBINATORIAL LIBRARIES; PRIVILEGED STRUCTURES; PHOSPHATASE INHIBITORS; EXTENDED 5-SUBSTITUENT C1 NCI Frederick, Dev Therapeut Program, Nat Prod Branch, Frederick, MD 21702 USA. RP Newman, DJ (reprint author), NCI Frederick, Dev Therapeut Program, Nat Prod Branch, POB B, Frederick, MD 21702 USA. EM dn22a@nih.gov NR 77 TC 319 Z9 331 U1 4 U2 77 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 8 PY 2008 VL 51 IS 9 BP 2589 EP 2599 DI 10.1021/jm0704090 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295US UT WOS:000255500000002 PM 18393402 ER PT J AU Gutierrez-Lugo, MT Bewley, CA AF Gutierrez-Lugo, Maria-Teresa Bewley, Carole A. TI Natural products, small molecules, and genetics in tuberculosis drug development SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO; STATIONARY-PHASE; GENOME SEQUENCE; INHIBITORS; EXPRESSION; TARGETS; GROWTH; TB; IDENTIFICATION C1 [Gutierrez-Lugo, Maria-Teresa; Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov NR 67 TC 63 Z9 68 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 8 PY 2008 VL 51 IS 9 BP 2606 EP 2612 DI 10.1021/jm070719i PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295US UT WOS:000255500000004 PM 18393405 ER PT J AU Hsin, LW Chang, LT Rothman, RB Dersch, CM Jacobson, AE Rice, KC AF Hsin, Ling-Wei Chang, Li-Te Rothman, Richard B. Dersch, Christina M. Jacobson, Arthur E. Rice, Kenner C. TI Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: Role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ABUSE THERAPEUTIC AGENTS; COCAINE-ABUSE; RHESUS-MONKEYS; NOREPINEPHRINE; INHIBITORS; DERIVATIVES; LIGANDS; SITES; RESPONSIVENESS; MECHANISMS AB Novel derivatives of 1- [2- [bis(4-fluorophenyl)methoxy] ethyl] -4-(3 -phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethy1]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp(2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT. C1 [Hsin, Ling-Wei; Chang, Li-Te] Natl Taiwan Univ, Inst Pharmaceut Sci, Coll Med, Taipei 10018, Taiwan. [Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, DHHS, Bethesda, MD 20892 USA. [Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Chem Biol Res Branch, Drug Design & Synth Sect, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Clin Psychopharmacol Sect,Chem Biol Res Branch, Natl Inst Hlth,DHHS, Baltimore, MD 21224 USA. RP Hsin, LW (reprint author), Natl Taiwan Univ, Inst Pharmaceut Sci, Coll Med, 1 Sect 1,Jen Ai Rd,Room 1336, Taipei 10018, Taiwan. EM lwhsin@ntu.edu.tw OI HSIN, LING-WEI/0000-0001-5018-4491 FU Intramural NIH HHS NR 44 TC 9 Z9 10 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 8 PY 2008 VL 51 IS 9 BP 2795 EP 2806 DI 10.1021/jm701270n PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 295US UT WOS:000255500000025 PM 18393401 ER PT J AU Rosta, E Haranczyk, M Chu, ZT Warshel, A AF Rosta, Edina Haranczyk, Maciej Chu, Zhen T. Warshel, Arieh TI Accelerating QM/MM free energy calculations: Representing the surroundings by an updated mean charge distribution SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID SOLVENT ELECTROSTATIC POTENTIALS; QUANTUM-MECHANICAL CALCULATIONS; AB-INITIO CALCULATIONS; HYDRATION FREE-ENERGY; ENZYMATIC-REACTIONS; BIOLOGICAL-SYSTEMS; CHEMICAL-PROCESSES; CHORISMATE MUTASE; LIQUID WATER; DENSITY AB Reliable studies of enzymatic reactions by combined quantum mechanical/molecular mechanics (QM(ai)/ MM) approaches with an ab initio description of the quantum region presents a major challenge to computational chemists. The main problem is the need for very large computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. One of the most obvious options for accelerating QM/MM simulations is the use of an average solvent potential. In fact, the idea of using an average solvent potential is rather obvious and has implicitly been used in Langevin dipole/QM calculations. However, in the case of explicit solvent models the practical implementations are more challenging, and the accuracy of the averaging approach has not been validated. The present study introduces the average effect of the fluctuating solvent charges by using equivalent charge distributions, which are updated every m steps. Several models are evaluated in terms of the resulting accuracy and efficiency. The most effective model divides the system into an inner region with N explicit solvent atoms and an external region with two effective charges. Different models are considered in terms of the division of the solvent system and the update frequency. Another key element of our approach is the use of the free energy perturbation (FEP) and/or linear response approximation treatments that guarantees the evaluation of the rigorous solvation free energy. Special attention is paid to the convergence of the calculated solvation free energies and the corresponding solute polarization. The performance of the method is examined by evaluating the solvation of a water molecule and a formate ion in water and also the dipole moment of water in water solution. Remarkably, it is found that different averaging procedures eventually converge to the same value but some protocols provide optimal ways of obtaining the final QM(ai)/MM converged results. The current method can provide computational time saving of 1000 for properly converging, simulations relative to calculations that evaluate the QM(ai)/MM energy every time step. A specialized version of our approach that starts with a classical FEP charging and then evaluates the free energy of moving from the classical potential to the QM/MM potential appears to be particularly effective. This approach should provide a very powerful tool for QM(ai)/MM evaluation of solvation free energies in aqueous solutions and proteins. C1 [Rosta, Edina; Haranczyk, Maciej; Chu, Zhen T.; Warshel, Arieh] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Rosta, Edina] NIDDKD, Chem Phys Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Haranczyk, Maciej] Univ Gdansk, Dept Chem, PL-80952 Gdansk, Poland. RP Warshel, A (reprint author), Univ So Calif, Dept Chem, 418 SGM Bldg,3620 McClintock Ave, Los Angeles, CA 90089 USA. EM warshel@usc.edu RI Haranczyk, Maciej/A-6380-2014; OI Haranczyk, Maciej/0000-0001-7146-9568; Rosta, Edina/0000-0002-9823-4766 FU NIGMS NIH HHS [GM24492, R01 GM024492, R01 GM024492-30] NR 56 TC 38 Z9 38 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 8 PY 2008 VL 112 IS 18 BP 5680 EP 5692 DI 10.1021/jp711496y PG 13 WC Chemistry, Physical SC Chemistry GA 295VV UT WOS:000255502900014 PM 18412414 ER PT J AU Abbondanzieri, EA Bokinsky, G Rausch, JW Zhang, JX Le Grice, SFJ Zhuang, XW AF Abbondanzieri, Elio A. Bokinsky, Gregory Rausch, Jason W. Zhang, Jennifer X. Le Grice, Stuart F. J. Zhuang, Xiaowei TI Dynamic binding orientations direct activity of HIV reverse transcriptase SO NATURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DEPENDENT DNA-POLYMERASE; RNASE-H-FUNCTION; ANGSTROM RESOLUTION; PRIMED INITIATION; CRYSTAL-STRUCTURE; ENERGY-TRANSFER; RNA/DNA HYBRID; MECHANISM; COMPLEX AB The reverse transcriptase of human immunodeficiency virus ( HIV) catalyses a series of reactions to convert the single- stranded RNA genome of HIV into double- stranded DNA for host- cell integration. This task requires the reverse transcriptase to discriminate a variety of nucleic- acid substrates such that active sites of the enzyme are correctly positioned to support one of three catalytic functions: RNA- directed DNA synthesis, DNA- directed DNA synthesis and DNA- directed RNA hydrolysis. However, the mechanism by which substrates regulate reverse transcriptase activities remains unclear. Here we report distinct orientational dynamics of reverse transcriptase observed on different substrates with a single- molecule assay. The enzyme adopted opposite binding orientations on duplexes containing DNA or RNA primers, directing its DNA synthesis or RNA hydrolysis activity, respectively. On duplexes containing the unique polypurine RNA primers for plus- strand DNA synthesis, the enzyme can rapidly switch between the two orientations. The switching kinetics were regulated by cognate nucleotides and non- nucleoside reverse transcriptase inhibitors, a major class of anti- HIV drugs. These results indicate that the activities of reverse transcriptase are determined by its binding orientation on substrates. C1 [Abbondanzieri, Elio A.; Bokinsky, Gregory; Zhang, Jennifer X.; Zhuang, Xiaowei] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Rausch, Jason W.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Zhuang, XW (reprint author), Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. EM zhuang@chemistry.harvard.edu FU Howard Hughes Medical Institute; Intramural NIH HHS [Z01 BC010493-05]; NIGMS NIH HHS [GM 068518, R01 GM068518, R01 GM068518-05] NR 41 TC 112 Z9 115 U1 1 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 8 PY 2008 VL 453 IS 7192 BP 184 EP U2 DI 10.1038/nature06941 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 297BP UT WOS:000255592400031 PM 18464735 ER PT J AU Bartali, B Ferrucci, L Gill, T AF Bartali, Benedetta Ferrucci, Luigi Gill, Thomas TI Vitamin E concentration and physical decline in older persons - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Bartali, Benedetta; Gill, Thomas] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Bethesda, MD 20892 USA. RP Bartali, B (reprint author), Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. EM benedetta.bartali@yale.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 7 PY 2008 VL 299 IS 17 BP 2021 EP 2021 DI 10.1001/jama.299.17.2021-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 296NI UT WOS:000255552700013 ER PT J AU Machado, RF Hsue, PY Barnett, CF AF Machado, Roberto F. Hsue, Priscilla Y. Barnett, Christopher F. TI Normal range for pulmonary artery systolic pressure - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Machado, Roberto F.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Hsue, Priscilla Y.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA. [Barnett, Christopher F.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Machado, RF (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM robertom@nhlbi.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 7 PY 2008 VL 299 IS 17 BP 2022 EP 2023 DI 10.1001/jama.299.17.2022-c PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 296NI UT WOS:000255552700017 ER PT J AU Miller, FG Kaptchuk, TJ AF Miller, Franklin G. Kaptchuk, Ted J. TI Deception of subjects in neuroscience: An ethical analysis - Commentary SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID PLACEBO ANALGESIA C1 [Miller, Franklin G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Kaptchuk, Ted J.] Massachusetts Gen Hosp, MIT, Harvard Med Sch, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02215 USA. [Kaptchuk, Ted J.] Osher Res Ctr, Harvard Med Sch, Boston, MA 02215 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU NCCIH NIH HHS [K24 AT004095, P01 AT002048, 1K24 AT004095] NR 14 TC 11 Z9 12 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 7 PY 2008 VL 28 IS 19 BP 4841 EP 4843 DI 10.1523/JNEUROSCI.1493-08.2008 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 298IN UT WOS:000255681500001 PM 18463235 ER PT J AU Alia-Klein, N Goldstein, RZ Kriplani, A Logan, J Tomasi, D Williams, B Telang, F Shumay, E Biegon, A Craig, IW Henn, F Wang, GJ Volkow, ND Fowler, JS AF Alia-Klein, Nelly Goldstein, Rita Z. Kriplani, Aarti Logan, Jean Tomasi, Dardo Williams, Benjamin Telang, Frank Shumay, Elena Biegon, Anat Craig, Ian W. Henn, Fritz Wang, Gene-Jack Volkow, Nora D. Fowler, Joanna S. TI Brain monoamine oxidase a activity predicts trait aggression SO JOURNAL OF NEUROSCIENCE LA English DT Article DE MAOA; aggression; violence; personality; clorgyline; human ID MAO-A; NEURAL MECHANISMS; MAJOR DEPRESSION; GENE PROMOTER; FOLLOW-UP; BEHAVIOR; SEROTONIN; VIOLENCE; MICE; PET AB The genetic deletion of monoamine oxidaseA(MAOA), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression ( but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression ( in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. C1 [Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Shumay, Elena; Biegon, Anat; Henn, Fritz; Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Williams, Benjamin; Craig, Ian W.] Kings Coll London, London WC2R 2LS, England. [Wang, Gene-Jack; Fowler, Joanna S.] Mt Sinai Sch Med, New York, NY 10029 USA. [Telang, Frank] NIAAA, Bethesda, MD 20892 USA. RP Alia-Klein, N (reprint author), Brookhaven Natl Lab, Dept Med, Bldg 490, Upton, NY 11973 USA. EM nellyklein@bnl.gov; fowler@bnl.gov RI Tomasi, Dardo/J-2127-2015; OI Craig, Ian/0000-0002-4063-1005; Logan, Jean/0000-0002-6993-9994 FU NCRR NIH HHS [M01 RR010710, MO1RR10710]; NIDA NIH HHS [L30 DA018402-01, K05 DA020001, K05DA020001, L30 DA018402-02] NR 40 TC 111 Z9 115 U1 4 U2 35 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 7 PY 2008 VL 28 IS 19 BP 5099 EP 5104 DI 10.1523/JNEUROSCI.0925-08.2008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 298IN UT WOS:000255681500029 PM 18463263 ER PT J AU Yabroff, KR Lamont, EB Mariotto, A Warren, JL Topor, M Meekins, A Brown, ML AF Yabroff, K. Robin Lamont, Elizabeth B. Mariotto, Angela Warren, Joan L. Topor, Marie Meekins, Angela Brown, Martin L. TI Cost of care for elderly cancer patients in the United States SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID STAGE BREAST-CANCER; SEER-MEDICARE DATA; COLORECTAL-CANCER; RETROSPECTIVE ANALYSIS; ECONOMIC BURDEN; ENROLLEES; DIAGNOSIS; PAYMENTS; PROSTATE; THERAPY AB Background Timely estimates of the costs of care for cancer patients are an important element in the formulation of national cancer programs and policies. We estimated net costs of care for elderly cancer patients in the United States for the 18 most prevalent cancers and for all other tumor sites combined. Methods We used Surveillance, Epidemiology, and End Results-Medicare files to identify 718 907 cancer patients and 1 623 651 noncancer control subjects. Within each tumor site, noncancer control subjects were matched to patients by sex, age group, geographic location, and phase of care (ie, initial, continuing, and last year of life). Costs of care were estimated for each phase by use of Medicare claims data from January 1, 1999, through December 31, 2003. Per-patient net costs of care were applied to the 5-year survival of cancer patients by phase of care to estimate 5-year costs of care and extrapolated to the elderly US Medicare population diagnosed with cancer in 2004. Results Across tumor sites, mean net costs of care were highest in the initial and last year of life phases of care and lowest in the continuing phase. Mean 5-year net costs varied widely, from less than $20 000 for patients with breast cancer or melanoma of the skin to more than $40 000 for patients with brain or other nervous system, esophageal, gastric, or ovarian cancers or lymphoma. For elderly cancer patients diagnosed in 2004, aggregate 5-year net costs of care to Medicare were estimated to be approximately $21.1 billion. Costs to Medicare were highest for lung, colorectal, and prostate cancers, reflecting underlying incidence, stage distribution at diagnosis, survival, and phase-specific costs for these tumor sites. Conclusions The costs of cancer care to Medicare are substantial and vary by tumor site, phase of care, stage at diagnosis, and survival. C1 [Yabroff, K. Robin; Mariotto, Angela; Warren, Joan L.; Brown, Martin L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control Populat Sci, Bethesda, MD 20892 USA. [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Boston, MA USA. [Lamont, Elizabeth B.] Massachusetts Gen Hosp, Ctr Canc, Dept Hlth Care Policy, Boston, MA USA. [Topor, Marie; Meekins, Angela] Informat Management Syst Inc, Rockville, MD USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 35 TC 279 Z9 283 U1 2 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2008 VL 100 IS 9 BP 630 EP 641 DI 10.1093/jnci/djn103 PG 12 WC Oncology SC Oncology GA 299LN UT WOS:000255757200011 PM 18445825 ER PT J AU Shanker, A Brooks, AD Tristan, CA Wine, JW Elliott, PJ Yagita, H Takeda, K Smyth, MJ Murphy, WJ Sayers, TJ AF Shanker, Anil Brooks, Alan David Tristan, Carlos Alberto Wine, John William Elliott, Peter John Yagita, Hideo Takeda, Kazuyoshi Smyth, Mark John Murphy, William Joseph Sayers, Thomas Joseph TI Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROTEASOME INHIBITOR BORTEZOMIB; PANCREATIC-CANCER CELLS; OVERCOMES DRUG-RESISTANCE; MEDIATED APOPTOSIS; SIGNALING PATHWAYS; MULTIPLE-MYELOMA; TRAIL RESISTANCE; PROSTATE-CANCER; TNF-ALPHA; IN-VIVO AB Background Resistance of tumors to cell death signals poses a complex clinical problem. We explored the therapeutic potential and in vivo toxicity of a combination of bortezomib, a proteasome inhibitor, and MD5-1, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor (DR5) agonist monoclonal antibody, in mouse carcinomas. Methods Mice bearing Renca-FLAG (renal) or 4T1 (mammary) tumors were treated with bortezomib and/or MD5-1 and examined for lung metastases (Renca-FLAG: n = 93; 4T1: n = 40) or monitored for survival (Renca-FLAG: n = 143). Toxicity was assessed by histopathology and hematology. Viability and apoptotic signaling in Renca-FLAG and 4T1 cells treated with bortezomib alone or in combination with TRAIL were analyzed using 3-[4,5-dimethyiazol-2-yl-5]-[3-carboxymethyloxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium assay and by measuring mitochondrial membrane depolarization and caspase-8 and caspase-3 activation. All statistical tests were two-sided. Results Bortezomib (20 nM) sensitized Renca-FLAG and 4T1 cells to TRAIL-mediated apoptosis (mean percent decrease in numbers of viable cells, bortezomib + TRAIL vs TRAIL: Renca-FLAG, 95% vs 34%, difference = 61%, 95% confidence interval [CI] = 52% to 69%, P < .001; 4T1, 85% vs 20%, difference = 65%, 95% CI = 62% to 69%, P < .001). Sensitization involved activation of caspase-8 and caspase-3 but not mitochondrial membrane depolarization, suggesting an amplified signaling of the extrinsic cell death pathway. Treatment with bortezomib and MD5-1 reduced lung metastases in mice carrying Renca and 4T1 tumors (mean number of metastases, bortezomib + MD5-1 vs MD5-1: Renca-FLAG, 1 vs 8, difference = 7, 95% CI = 5 to 9, P < .001; 4T1, 1 vs 12, difference = 11, 95% CI = 9 to 12, P < .001) and increased median survival of mice bearing Renca-FLAG tumors (bortezomib + MD5-1 vs bortezomib + control isotype antibody: 22 of 30 [73%] were still alive at day 180 vs median survival of 42 days [95% CI = 41 to 44 days, P < .001]) in the absence of obvious toxicity. Conclusion Bortezomib combined with DR5 agonist monoclonal antibody may be a useful treatment for metastatic solid tumors. C1 [Shanker, Anil; Brooks, Alan David; Tristan, Carlos Alberto; Wine, John William; Sayers, Thomas Joseph] SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, NCI Frederick, Frederick, MD 21702 USA. [Elliott, Peter John] Sirtris Pharmaceut Inc, Cambridge, MA USA. [Yagita, Hideo; Takeda, Kazuyoshi] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. [Smyth, Mark John] Peter MacCallum Canc Ctr, Canc Immunol Program, Melbourne, Vic, Australia. [Murphy, William Joseph] Univ Nevada, Sch Med, Dept Microbiol & Immunol, Reno, NV 89557 USA. RP Sayers, TJ (reprint author), SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, NCI Frederick, Frederick, MD 21702 USA. EM sayerst@mail.nih.gov RI Sayers, Thomas/G-4859-2015; Smyth, Mark/H-8709-2014; OI Smyth, Mark/0000-0001-7098-7240; Shanker, Anil/0000-0001-6372-3669 FU Intramural NIH HHS; NCI NIH HHS [N01 CO012400, N01-CO-12400, N01CO12400] NR 52 TC 57 Z9 58 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2008 VL 100 IS 9 BP 649 EP 662 DI 10.1093/jnci/djn113 PG 14 WC Oncology SC Oncology GA 299LN UT WOS:000255757200013 PM 18445820 ER PT J AU McGlynn, KA Quraishi, SM Graubard, BI Weber, JP Rubertone, MV Erickson, RL AF McGlynn, Katherine A. Quraishi, Sabah M. Graubard, Barry I. Weber, Jean-Philippe Rubertone, Mark V. Erickson, Ralph L. TI Persistent organochlorine pesticides and risk of testicular germ cell tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ENVIRONMENTAL DDT EXPOSURE; POLYCHLORINATED-BIPHENYLS; SERUM-LEVEL; YOUNG MEN; CANCER; CRYPTORCHIDISM; ESTROGENS; P,P'-DDE; HEALTH; TESTIS AB Background Exposure to endocrine-disrupting chemicals, such as persistent organochlorine pesticides, has been suggested to increase the risk of testicular germ cell tumors (TGCTs). Methods To study the relationship of POP exposure to TGCT risk, prediagnostic serum samples from 754 case subjects and 928 control subjects enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study were analyzed for cis-nonachlor, trans-nonachlor, oxychlordane, total chlordanes, beta-hexachlorocyclohexane, mirex, p,p '-dichlorodiphenyldichloroethylene (p,p '-DDE), and p,p '-dichlorodiphenyltrichloroethane. Adjusted odds ratios (ORs) and their associated 95% confidence intervals (CIs) for the risk of TGCT overall and for the histological subgroups, seminoma and nonseminoma, were estimated using multivariable logistic regression. All statistical tests were two-sided. Results TGCT risk was statistically significantly associated with higher plasma levels of p,p '-DDE (for highest quartile [Q4] vs lowest quartile [Q1], OR = 1.71, 95% CI = 1.23 to 2.38, P-trend = .0002) and of two chlordane components, cis-nonachlor (Q4 vs Q1, OR = 1.56, 95% CI = 1.11 to 2.18, P-trend = .009) and trans-nonachlor (Q4 vs Q1, OR = 1.46, 95% CI = 1.07 to 2.00, P-trend = .026). Seminoma risk was statistically significantly associated with p,p '-DDE (Q4 vs Q1, OR = 1.91, 95% CI = 1.22 to 2.99, P-trend = .0008), cis-nonachlor (Q4 vs Q1, OR = 1.93, 95% CI = 1.27 to 2.93, P-trend = .0045), trans-nonachlor (Q4 vs Q1, OR = 1.72, 95% CI = 1.11 to 2.67, P-trend = .033), and a chlordane metabolite, oxychlordane (Q4 vs Q1, OR = 1.64, 95% CI = 1.04 to 2.60, P-trend = .048), whereas nonseminoma risk showed a statistically significant association with p,p '-DDE only (Q4 vs Q1, OR = 1.63, 95% CI = 1.10 to 2.42, P-trend = .0044). Conclusions Increased exposure to p,p'-DDE may be associated with the risk of both seminomatous and nonseminomatous TGCTs, whereas exposure to chlordane compounds and metabolites may be associated with the risk of seminoma. Because evidence suggests that TGCT is initiated in very early life, it is possible that exposure to these persistent organic pesticides during fetal life or via breast feeding may increase the risk of TGCT in young men. C1 [McGlynn, Katherine A.; Quraishi, Sabah M.; Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Weber, Jean-Philippe] Inst Natl Sante Publ Quebec, Toxicol Ctr, Quebec City, PQ, Canada. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Washington, DC 20310 USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, GEIS, Div Prevent Med, Silver Spring, MD USA. RP McGlynn, KA (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS Ste 550,6120 Execut Blvd, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov NR 39 TC 80 Z9 80 U1 0 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2008 VL 100 IS 9 BP 663 EP 671 DI 10.1093/jnci/djn101 PG 9 WC Oncology SC Oncology GA 299LN UT WOS:000255757200014 PM 18445826 ER PT J AU Gail, MH Bernstein, L Costantino, JP Pee, D Ursin, G AF Gail, Mitchell H. Bernstein, Leslie Costantino, Joseph P. Pee, David Ursin, Giske TI Re: Projecting individualized absolute invasive breast cancer risk in African American women - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Beckman Res Inst, Duarte, CA USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Dept Canc Etiol, Duarte, CA USA. [Costantino, Joseph P.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Pee, David] Informat Management Serv Inc, Rockville, MD USA. [Ursin, Giske] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Ursin, Giske] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Rm 8032, Bethesda, MD 20892 USA. EM gailm@mail.nih.gov NR 6 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 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 7 PY 2008 VL 100 IS 9 BP 684 EP 684 DI 10.1093/jnci/djn110 PG 1 WC Oncology SC Oncology GA 299LN UT WOS:000255757200022 ER PT J AU Movsesyan, N Ghochikyan, A Mkrtichyan, M Petrushina, I Davtyan, H Olkhanud, PB Head, E Biragyn, A Cribbs, DH Agadjanyan, MG AF Movsesyan, Nina Ghochikyan, Anahit Mkrtichyan, Mikayel Petrushina, Irina Davtyan, Hayk Olkhanud, Purevdorj B. Head, Elizabeth Biragyn, Arya Cribbs, David H. Agadjanyan, Michael G. TI Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine - A Novel Immunotherapeutic Strategy SO PLOS ONE LA English DT Article AB Background: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-A beta antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of A beta(42) (A beta(1-11)), a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype. Methods and Findings: We generated pMDC-3A beta(1-11)-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3-4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-A beta antibody, which in turn inhibited accumulation of A beta pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. Conclusions: Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials. C1 [Movsesyan, Nina; Ghochikyan, Anahit; Mkrtichyan, Mikayel; Davtyan, Hayk; Agadjanyan, Michael G.] Inst Mol Med, Dept Mol Immunol, Huntington Beach, CA USA. [Movsesyan, Nina; Petrushina, Irina; Head, Elizabeth; Cribbs, David H.; Agadjanyan, Michael G.] Univ Calif Irvine, Inst Brain Aging & Dementia, Irvine, CA USA. [Olkhanud, Purevdorj B.; Biragyn, Arya] NIA, Lab Immunol, Immunotherapeut Unit, Baltimore, MD USA. [Head, Elizabeth; Cribbs, David H.] Univ Calif Irvine, Dept Neurol, Irvine, CA USA. RP Movsesyan, N (reprint author), Inst Mol Med, Dept Mol Immunol, Huntington Beach, CA USA. EM magadjanyan@immed.org OI Ghochikyan, Anahit/0000-0001-5436-0616 FU NIH [AG20241, NS50895, NS057395, AG00538, AG00096, P50 AG16573]; Alzheimers Association [IIRG036279, IIRG0728314] FX This work was supported by funding from the NIH: AG20241 (DHC & MGA), NS50895 (DHC & MGA), NS057395 (MGA), AG00538(DHC) and from the Alzheimers Association IIRG036279 (MGA & DHC), IIRG0728314 (AG). NM was supported by NIA training grant AG00096. The 3xTg-AD homozygous mice and amyloid peptides were provided by UCI-Alzheimers Disease Research Center (ADRC) under the NIH/NIA P50 AG16573 grant. NR 53 TC 61 Z9 65 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 7 PY 2008 VL 3 IS 5 AR e2124 DI 10.1371/journal.pone.0002124 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 382YX UT WOS:000261642400045 PM 18461171 ER PT J AU Taylor, JG Nolan, VG Mendelsohn, L Kato, GJ Gladwin, MT Steinberg, MH AF Taylor, James G. V., I Nolan, Vikki G. Mendelsohn, Laurel Kato, Gregory J. Gladwin, Mark T. Steinberg, Martin H. TI Chronic Hyper-Hemolysis in Sickle Cell Anemia: Association of Vascular Complications and Mortality with Less Frequent Vasoocclusive Pain SO PLOS ONE LA English DT Article AB Background: Intravascular hemolysis in sickle cell anemia could contribute to complications associated with nitric oxide deficiency, advancing age, and increased mortality. We have previously reported that intense hemolysis is associated with increased risk of vascular complications in a small cohort of adults with sickle cell disease. These observations have not been validated in other populations. Methods: The distribution of serum lactic dehydrogenase (LDH) values was used as a surrogate measure of intravascular hemolysis in a contemporaneous patient group and an historical adult population from the Cooperative Study of Sickle Cell Disease (CSSCD), all with sickle cell anemia. Chronic hyper-hemolysis was defined by the top LDH quartile and was compared to the lowest LDH quartile. Results: Hyper-hemolysis subjects had higher systolic blood pressure, higher prevalence of leg ulcers (OR 3.27, 95% CI 1.925.53, P, 0.0001), priapism (OR 2.62, 95% CI 1.13-6.90, P = 0.03) and pulmonary hypertension (OR 4.32, 95% CI 2.12-8.60, P < 0.0001), while osteonecrosis (OR 0.32, 95% CI 0.19-0.54, P < 0.0001) and pain (OR 0.23, 95% CI 0.09-0.55, P = 0.0004) were less prevalent. Hyper-hemolysis was influenced by fetal hemoglobin and a thalassemia, and was a risk factor for early death in the CSSCD population (Hazard Ratio = 1.97, P = 0.02). Conclusions: Steady state LDH measurements can identify a chronic hyper-hemolysis phenotype which includes less frequent vasooclusive pain and earlier mortality. Clinicians should consider sickle cell specific therapies for these patients, as is done for those with more frequent acute pain. The findings also suggest that an important class of disease modifiers in sickle cell anemia affect the rate of hemolysis. C1 [Taylor, James G. V., I; Mendelsohn, Laurel; Kato, Gregory J.; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Nolan, Vikki G.; Steinberg, Martin H.] Boston Univ, Sch Med, Dept Med, Boston, MA USA. [Kato, Gregory J.; Gladwin, Mark T.] NIH, Clin Ctr, Crit Care Med Dept, Bethesda, MD USA. RP Taylor, JG (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jamesta@mail.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Steinberg, Martin/0000-0001-8800-8020; Taylor, James/0000-0002-4421-1809 FU Intramural NIH research program [R01 HL68970, U54 HL70819, T32 HL007501]; NHLBI [R01 HL68970, U54 HL70819, T32 HL007501] FX This study was supported by the Intramural NIH research program and NHLBI grants R01 HL68970 (MHS); U54 HL70819 (MHS) and T32 HL007501 (VGN). The sponsor had no role in the design, data analysis, interpretation, or writing of the report. The manuscript was reviewed and cleared for publication by the Division of Intramural Research, National Institutes of Health prior to submission. NR 44 TC 76 Z9 78 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 7 PY 2008 VL 3 IS 5 AR e2095 DI 10.1371/journal.pone.0002095 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 382YX UT WOS:000261642400017 PM 18461136 ER PT J AU Malozowski, S AF Malozowski, Saul TI Comparative efficacy: What we know, what we need to know, and how we can get there SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID PLACEBO-CONTROLLED TRIALS; ACTIVE-CONTROL TRIALS; OSTEOPOROSIS; ISSUES C1 NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. RP Malozowski, S (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, Democracy Two,6707 Democracy Blvd,Room 607, Bethesda, MD 20892 USA. EM sm87j@nih.gov NR 10 TC 4 Z9 4 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 6 PY 2008 VL 148 IS 9 BP 702 EP 703 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 299BW UT WOS:000255731800008 PM 18458283 ER PT J AU Wu, Y Rawtani, N Thazhathveetil, AK Kenny, MK Seidman, MM Brosh, RM AF Wu, Yuliang Rawtani, Nina Thazhathveetil, Arun Kalliat Kenny, Mark K. Seidman, Michael M. Brosh, Robert M., Jr. TI Human replication protein A melts a DNA triple helix structure in a potent and specific manner SO BIOCHEMISTRY LA English DT Article ID C-MYC; MAMMALIAN-CELLS; BINDING-PROTEIN; G-QUADRUPLEX; IN-VITRO; G4 DNA; HELICASE; TRANSCRIPTION; RPA; SEQUENCES AB Alternate DNA structures other than double-stranded B-form DNA can potentially impede cellular processes such as transcription and replication. The DNA triplex helix and G4 tetraplex structures that form by Hoogsteen hydrogen bonding are two examples of alternate DNA structures that can be a source of genomic instability. In this study, we have examined the ability of human replication protein A (RPA), a single-stranded DNA binding protein that is implicated in all facets of DNA metabolism, to destabilize DNA triplexes and tetraplexes. Biochemical studies demonstrate that RPA efficiently melts an intermolecular DNA triple helix consisting of a pyrimidine motif third strand annealed to a 4 kb duplex DNA fragment at protein concentrations equimolar to the triplex substrate. Heterologous single-stranded DNA binding proteins (Escherichia coli SSB, T4 gene 32) melt the triplex substrate very poorly or not at all, suggesting that the triplex destabilizing effect of RPA is specific. In contrast to the robust activity on DNA triplexes, RPA does not melt intermolecular G4 tetraplex structures. Cellular assays demonstrated increased triplex DNA content when RPA is transiently repressed, suggesting that RPA melting of triple helical structures is physiologically important. On the basis of our results, we suggest that the abundance of RPA known to exist in vivo is likely to be a strong deterrent to the stability of triplexes that can potentially form from human genomic DNA sequences. C1 [Wu, Yuliang; Rawtani, Nina; Thazhathveetil, Arun Kalliat; Seidman, Michael M.; Brosh, Robert M., Jr.] NIA, NIH, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Kenny, Mark K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Emergency Med, Bronx, NY 10467 USA. RP Brosh, RM (reprint author), NIA, NIH, Lab Mol Gerontol, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM broshr@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000741-07] NR 54 TC 10 Z9 10 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 6 PY 2008 VL 47 IS 18 BP 5068 EP 5077 DI 10.1021/bi702102d PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 294TQ UT WOS:000255429200002 PM 18410127 ER PT J AU Liao, W Xiao, Q Tchikov, V Fujita, KI Yang, W Wincovitch, S Garfield, S Conze, D El-Deiry, WS Schutze, S Srinivasula, SM AF Liao, Wentao Xiao, Qi Tchikov, Vladimir Fujita, Ken-ichi Yang, Wensheng Wincovitch, Stephen Garfield, Susan Conze, Dietrich El-Deiry, Wafik S. Schuetze, Stefan Srinivasula, Srinivasa M. TI CARP-2 is an endosome-associated ubiquitin ligase for RIP and regulates TNF-induced NF-kappa B activation SO CURRENT BIOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; RING FINGER; RECEPTOR; PROTEIN; INTERNALIZATION; DOMAIN; INHIBITION; EXPRESSION; APOPTOSIS; PATHWAY AB Background: The proinflarnmatory cytokine tumor necrosis factor-alpha (TNF-alpha) elicits cellular responses by signaling through a receptor complex that includes the essential adaptor molecule RIP. One important consequence of signaling is activation of the transcription factor NF-kappa B, and failure to downregulate TNF-induced NF-kappa B transcriptional activity results in chronic inflammation and death. Internalization of the receptor complex plays an important regulatory role in TNF signaling. Results: We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappa B activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation. Knockdown of CARP-2 stabilized TNFR1-associated polyubiquitinated RIP levels after TNF simulation and enhanced activation of NF-kappa B. Conclusions: CARP-2 acts at the level of endocytic vesicles to limit the intensity of TNF-induced NF-kappa B activation by the regulated elimination of a necessary signaling component within the receptor complex. C1 [Liao, Wentao; Xiao, Qi; Fujita, Ken-ichi; Wincovitch, Stephen; Garfield, Susan; Conze, Dietrich; Srinivasula, Srinivasa M.] NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. [Xiao, Qi; Schuetze, Stefan] Univ Hosp Schleswig Holstein, Inst Immunol, D-24105 Kiel, Germany. [Yang, Wensheng; El-Deiry, Wafik S.] Univ Penn, Sch Med,Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut, Dept Med Hematol Oncol, Philadelphia, PA 19104 USA. [Yang, Wensheng; El-Deiry, Wafik S.] Univ Penn, Sch Med,Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut, Dept Genet, Philadelphia, PA 19104 USA. [Yang, Wensheng; El-Deiry, Wafik S.] Univ Penn, Sch Med,Lab Mol Oncol & Cell Cycle Regulat, Inst Translat Med & Therapeut, Dept Pharmacol, Philadelphia, PA 19104 USA. [Yang, Wensheng; El-Deiry, Wafik S.] Univ Penn, Abramson Comprehens Canc Ctr, Philadelphia, PA 19104 USA. RP Srinivasula, SM (reprint author), NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. EM srinivsr@mail.nih.gov RI Schutze, Stefan/C-8596-2011; Liao, Wentao/F-7913-2011 FU Intramural NIH HHS [Z01 BC010629-04, Z99 CA999999]; NCI NIH HHS [CA 97100, R01 CA097100] NR 33 TC 38 Z9 41 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 6 PY 2008 VL 18 IS 9 BP 641 EP 649 DI 10.1016/j.cub.2008.04.017 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 298EE UT WOS:000255668400023 PM 18450452 ER PT J AU Lindblad, AS Clemons, T Lindblad, RW Sykes, R Meador, KJ Odenkirchen, JC Hart, RG AF Lindblad, A. S. Clemons, T. Lindblad, R. W. Sykes, R. Meador, K. J. Odenkirchen, J. C. Hart, R. G. TI Applicability of NINDS-sponsored studies to community-based physician involvement SO NEUROLOGY LA English DT Review AB Background: The National Institute of Neurological Disorders and Stroke (NINDS) Clinical Trials Group established the Clinical Research Collaboration (CRC) Project in 2005 to increase community-based physician involvement in NINDS-sponsored research. Methods: We assessed a random sample of 112 of the more than 1,000 current NINDS-sponsored clinical research studies to determine which could involve community physicians in enrollment or follow-up. Scoring factors were based on the premise that participation is feasible for noninvasive studies with simple screening, and follow-up criteria and visit frequency consistent with usual care. Scored studies included 26 Phase III, 31 Phase I/II, and 55 nonclinical trials. Results: Overall, 41% of the sampled research studies were considered conducive to community physician participation that exceeds referral only; 21% with participation in all study activities and 20% with ability to provide some follow-up. Specialized neuropsychological or neurologic scale testing was judged to exclude community physician participation in 16% of studies. Conclusion: Many National Institute of Neurological Disorders and Stroke studies are available in which community-based physicians could participate. Involving community physicians may increase efficiency of completing clinical research and encourage application of research findings in community practices. C1 [Lindblad, A. S.; Clemons, T.; Lindblad, R. W.] EMMES Corp, Rockville, MD USA. [Sykes, R.] Qual Res Syst, Chicago, IL USA. [Meador, K. J.] Univ Florida, Gainesville, FL USA. [Odenkirchen, J. C.; Hart, R. G.] NINDS, Bethesda, MD 20892 USA. RP Lindblad, AS (reprint author), CRC Operat Ctr, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM alindblad@emmes.com FU PHS HHS [HHSN265200523641] NR 3 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 6 PY 2008 VL 70 IS 19 BP 1688 EP 1690 DI 10.1212/01.wnl.0000284608.57974.ba PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 312YA UT WOS:000256707100008 PM 18057316 ER PT J AU Simpson, DM Blitzer, A Brashear, A Comella, C Dubinsky, R Hallett, M Jankovic, J Karp, B Ludlow, CL Miyasaki, JM Naumann, M So, Y AF Simpson, D. M. Blitzer, A. Brashear, A. Comella, C. Dubinsky, R. Hallett, M. Jankovic, J. Karp, B. Ludlow, C. L. Miyasaki, J. M. Naumann, M. So, Y. TI Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review) - Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology SO NEUROLOGY LA English DT Article ID TOXIN TYPE-A; PLACEBO-CONTROLLED TRIAL; ESSENTIAL HAND TREMOR; DOUBLE-BLIND; CERVICAL DYSTONIA; SPASMODIC DYSPHONIA; WRITERS CRAMP; EFFICACY; SAFETY; BLEPHAROSPASM AB Objective: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I-IV). Results: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data. C1 [Simpson, D. M.] Mt Sinai Med Ctr, Dept Neurol, New York, NY 10029 USA. [Blitzer, A.] St Lukes Roosevelt Hosp, Dept Otolaryngol, New York, NY USA. [Brashear, A.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Comella, C.] Rush Univ, Med Ctr, Dept Neurol, Chicago, IL 60612 USA. [Dubinsky, R.] Univ Kansas, Dept Neurol, Kansas City, KS USA. [Hallett, M.; Karp, B.; Ludlow, C. L.] NINDS, Bethesda, MD 20892 USA. [Jankovic, J.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Miyasaki, J. M.] Toronto Western Hosp, Toronto, ON, Canada. [Naumann, M.] Klinikum Augsburg, Dept Neurol, Augsburg, Germany. [So, Y.] Stanford Univ, Stanford, CA 94305 USA. RP Simpson, DM (reprint author), 1080 Montreal Ave, St Paul, MN 55116 USA. EM guidelines@aan.com RI Brashear, Allison/G-3853-2015; OI Miyasaki, Janis/0000-0002-6372-6007; Ludlow, Christy/0000-0002-2015-6171 NR 35 TC 202 Z9 210 U1 1 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 MAY 6 PY 2008 VL 70 IS 19 BP 1699 EP 1706 DI 10.1212/01.wnl.0000311389.26145.95 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 312YA UT WOS:000256707100010 PM 18458230 ER PT J AU Chattopadhyay, MK Park, MH Tabor, H AF Chattopadhyay, Manas K. Park, Myung Hee Tabor, Herbert TI Hypusine modification for growth is the major function of spermidine in Saccharomyces cerevisiae polyamine auxotrophs grown in limiting spermidine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eIF5A; protein synthesis; yeast ID INITIATION-FACTOR 5A; CELL-CYCLE PROGRESSION; AMINO-ACID; POSTTRANSLATIONAL SYNTHESIS; ORNITHINE-DECARBOXYLASE; PROTEIN-SYNTHESIS; FACTOR EIF-4D; EIF5A MUTANT; YEAST; TRANSLATION AB Spermidine and its derivative, hypusinated eIF5A, are essential for the growth of Saccharomyces cerevisiae. Very low concentrations of spermidine (10(-8) M) are sufficient for the growth of S. cerevisiae polyamine auxotrophs (spe1 Delta, spe2 Delta, and spe3 Delta). Under these conditions, even though the growth rate is near normal, the internal concentration of spermidine is <0.2% of the spermidine concentration present in wild-type cells. When spe2 Delta cells are grown with low concentrations of spermidine, there is a large decrease in the amount of hypusinated eukaryotic initiation factor 5A (eIF5A) (1/20 of normal), even though there is no change in the amount of total (modified plus unmodified) eIF5A. It is striking that, as intracellular spermidine becomes limiting, an increasing portion of it (up to 54%) is used for the hypusine modification of eIF5A. These data indicate that hypusine modification of eIF5A is a most important function for spermidine in supporting the growth of S. cerevisiae polyamine auxotrophs. C1 [Chattopadhyay, Manas K.; Tabor, Herbert] NIDDKD, Natl Inst Hlth, Lab Biochem & Genet, Bethesda, MD 20892 USA. [Park, Myung Hee] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Tabor, H (reprint author), NIDDKD, Natl Inst Hlth, Lab Biochem & Genet, Bethesda, MD 20892 USA. EM tabor@helix.nih.gov FU Intramural NIH HHS NR 35 TC 50 Z9 53 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 6 PY 2008 VL 105 IS 18 BP 6554 EP 6559 DI 10.1073/pnas.0710970105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 300QZ UT WOS:000255841600010 PM 18451031 ER PT J AU Readinger, JA Schiralli, GM Jiang, JK Thomas, CJ August, A Henderson, AJ Schwartzberg, PL AF Readinger, Julie A. Schiralli, Gillian M. Jiang, Jian-Kang Thomas, Craig J. August, Avery Henderson, Andrew J. Schwartzberg, Pamela L. TI Selective targeting of ITK blocks multiple steps of HIV replication SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T cell signaling; transcription; tyrosine kinase; viral entry; kinase inhibitors ID HUMAN-IMMUNODEFICIENCY-VIRUS; TEC-FAMILY KINASES; HELPER-CELL-DIFFERENTIATION; T-CELLS; IMMUNE-RESPONSES; CYCLOPHILIN-A; TYPE-1; ACTIVATION; INFECTION; ACTIN AB Treatment for HIV has relied on the use of antiretroviral agents that can be subject to the development of resistant viruses. The study of inhibitors directed against cellular proteins required for HIV replication is therefore of growing interest. Inducible T cell kinase (ITK) is a Tec family tyrosine kinase that regulates T cell receptor (TCR)-induced activation of PLC gamma-1, Ca2+ mobilization and transcription factor activation, and actin rearrangement downstream of both TCR and chemokine receptors. Because productive infection of T cells with HIV requires T cell activation, chemokine receptors and actin reorganization, we asked whether ITK affects HIV infection using ITK-specific siRNA, a kinase-inactive ITK mutant or an ITK inhibitor. We demonstrate that loss of ITK function resulted in marked reductions in intracellular p24 levels upon HIV infection. Loss of ITK function after establishment of HIV infection also decreased virus spread within the culture. Inhibition of ITK did not affect expression of the HIV coreceptors CD4 or CXCR4 but partially blocked HIV viral entry, an effect that correlated with decreased actin polarization to gp120. Additionally, ITK was required for efficient HIV transcription, and overexpression of ITK increased both viral transcription and virus-like particle formation. Our data suggest that inhibition of ITK blocks HIV infection by affecting multiple steps of HIV replication. C1 [Schiralli, Gillian M.; August, Avery; Henderson, Andrew J.] Penn State Univ, Ctr Mol Immunol & Infect Dis, Integrated Biosci Grad Program, Dept Vet Sci, University Pk, PA 16802 USA. [Readinger, Julie A.; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NIDDKD, Chem Biol Core Facil, NIH, Bethesda, MD 20892 USA. [Jiang, Jian-Kang; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Schiralli, Gillian M.; Henderson, Andrew J.] Boston Univ, Sch Med, Dept Med, Ctr HIV AIDS Care & Res, Boston, MA 02118 USA. RP Henderson, AJ (reprint author), Penn State Univ, Ctr Mol Immunol & Infect Dis, Integrated Biosci Grad Program, Dept Vet Sci, University Pk, PA 16802 USA. EM andrew.henderson@bmc.org; pams@nhgri.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI62467, R01 AI062467, R21 AI062467] NR 38 TC 37 Z9 37 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 6 PY 2008 VL 105 IS 18 BP 6684 EP 6689 DI 10.1073/pnas.0709659105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 300QZ UT WOS:000255841600032 PM 18443296 ER PT J AU Miller, M Conrad, P James, ER Packham, A Toy-Choutka, S Murray, MJ Jessup, D Grigg, M AF Miller, Melissa Conrad, Patricia James, E. R. Packham, Andrea Toy-Choutka, Sharon Murray, Michael J. Jessup, David Grigg, Michael TI Transplacental toxoplasmosis in a wild southern sea otter (Enhydra lutris nereis) SO VETERINARY PARASITOLOGY LA English DT Article DE Toxoplasma gondii; sea otter; Enhydra lutris; transplacental; genotype X; congenital brain malformation ID WATERBORNE TOXOPLASMOSIS; GONDII; MENINGOENCEPHALITIS; PROTOZOAN; MORTALITY; STRAINS; BRAZIL; FIELD; GENE AB In September 2004, a neonatal sea otter pup was found alive on the beach in northern Monterey Bay, CA. Efforts to locate the mother were unsuccessful. Due to a poor prognosis for successful rehabilitation, the pup was euthanized. Postmortem examination revealed emaciation, systemic lymphadenopathy and a malformation of the left cerebral temporal lobe. On histopathology, free tachyzoites and tissue cysts compatible with Toxoplasma gondii were observed in the brain, heart, thymus, liver, lymph nodes and peri-umbilical adipose. The presence of T gondii within host tissues was associated with lymphoplasmacytic inflammation and tissue necrosis. Immunofluorescent antibody tests using postmortem serum were positive for anti-T gondii IgM and IgG (at 1:320 and 1: 1280 serum dilution, respectively), but were negative for IgG directed against Sarcocystis neurona and Neospora caninum (< 1:40 each). Brain immunohistochemistry revealed positive staining for tachyzoites and tissue cysts using antiserum raised to T gondii, but not S. neurona or N. caninum. T gondii parasite DNA was obtained from extracts of brain and muscle by PCR amplification using the diagnostic B1 locus. Restriction enzyme digestion followed by gel electrophoresis and DNA sequencing confirmed the presence of Type X T gondii, the strain identified in the majority of southern sea otter infections. (C) 2008 Elsevier B.V. All fights reserved. C1 [Miller, Melissa; Toy-Choutka, Sharon; Jessup, David] Calif Dept Fish & Game, Marine Wildlife Vet Care & Res Ctr, Off Spill Prevent & Response, Santa Cruz, CA 95060 USA. [Conrad, Patricia; Packham, Andrea] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. [Murray, Michael J.] Monterey Bay Aquarium, Monterey, CA 93940 USA. [James, E. R.; Grigg, Michael] NIAID, Parasit Dis Lab, Mol Parasitol Unit, Bethesda, MD 20892 USA. RP Miller, M (reprint author), Calif Dept Fish & Game, Marine Wildlife Vet Care & Res Ctr, Off Spill Prevent & Response, 1451 Shaffer Rd, Santa Cruz, CA 95060 USA. EM mmiller@ospr.dfg.ca.gov RI James, Erick/D-4725-2012 FU Intramural NIH HHS NR 25 TC 20 Z9 20 U1 3 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD MAY 6 PY 2008 VL 153 IS 1-2 BP 12 EP 18 DI 10.1016/j.vetpar.2008.01.015 PG 7 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 298DM UT WOS:000255666600004 PM 18304737 ER PT J AU Calcagno, AM Fostel, JM To, KK Salcido, CD Martin, SE Chewning, KJ Wu, CP Varticovski, L Bates, SE Caplen, NJ Ambudkar, SV AF Calcagno, A. M. Fostel, J. M. To, K. K. W. Salcido, C. D. Martin, S. E. Chewning, K. J. Wu, C-P Varticovski, L. Bates, S. E. Caplen, N. J. Ambudkar, S. V. TI Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes SO BRITISH JOURNAL OF CANCER LA English DT Article DE multidrug resistance (MDR); doxorubicin; ABCG2; epigenetics; single-step selection ID MULTIDRUG-RESISTANCE PROTEINS; BREAST-CANCER; CARCINOMA-CELLS; SUBSTRATE-SPECIFICITY; FUMITREMORGIN C; P-GLYCOPROTEIN; MDR1 GENE; IDENTIFICATION; EXPRESSION; MUTATION AB Understanding the mechanisms of multidrug resistance (MDR) could improve clinical drug efficacy. Multidrug resistance is associated with ATP binding cassette (ABC) transporters, but the factors that regulate their expression at clinically relevant drug concentrations are poorly understood. We report that a single-step selection with low doses of anti-cancer agents, similar to concentrations reported in vivo, induces MDR that is mediated exclusively by ABCG2. We selected breast, ovarian and colon cancer cells (MCF-7, IGROV-1 and S-1) after exposure to 14 or 21 nM doxorubicin for only 10 days. We found that these cells overexpress ABCG2 at the mRNA and protein levels. RNA interference analysis confirmed that ABCG2 confers drug resistance. Furthermore, ABCG2 upregulation was facilitated by histone hyperacetylation due to weaker histone deacetylase 1-promoter association, indicating that these epigenetic changes elicit changes in ABCG2 gene expression. These studies indicate that the MDR phenotype arises following low-dose, single-step exposure to doxorubicin, and further suggest that ABCG2 may mediate early stages of MDR development. This is the first report to our knowledge of single-step, low-dose selection leading to overexpression of ABCG2 by epigenetic changes in multiple cancer cell lines. C1 [Calcagno, A. M.; Chewning, K. J.; Wu, C-P; Ambudkar, S. V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Fostel, J. M.] Alpha Gamma Technol Inc, Raleigh, NC 27609 USA. [To, K. K. W.; Bates, S. E.] NCI, Med Oncol Branch, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Salcido, C. D.; Varticovski, L.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. [Martin, S. E.; Caplen, N. J.] NCI, Gene Silencing Sect, Genet Branch,DHHS, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI Calcagno, Anna Maria/A-5617-2012; To, Kenneth /M-4500-2013; Caplen, Natasha/H-2768-2016; OI To, Kenneth /0000-0003-2755-0283; Caplen, Natasha/0000-0002-0001-9460; Calcagno, Anna Maria/0000-0002-0804-2753 FU Intramural NIH HHS [Z01 BC010030-11, Z01 BC010609-02, Z01 BC010622-03]; NCI NIH HHS [R01 CA053094-09] NR 44 TC 59 Z9 63 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 5 PY 2008 VL 98 IS 9 BP 1515 EP 1524 DI 10.1038/sj.bjc.6604334 PG 10 WC Oncology SC Oncology GA 297AQ UT WOS:000255588000005 PM 18382425 ER PT J AU Kim, Y Heuser, JE Waterman, CM Cleveland, DW AF Kim, Yumi Heuser, John E. Waterman, Clare M. Cleveland, Don W. TI CENP-E combines a slow, processive motor and a flexible coiled coil to produce an essential motile kinetochore tether SO JOURNAL OF CELL BIOLOGY LA English DT Article ID END-DIRECTED MOTOR; MITOTIC HELA-CELLS; IN-VITRO; MICROTUBULE DEPOLYMERIZATION; CHROMOSOME ALIGNMENT; SPINDLE MICROTUBULES; SPECKLE MICROSCOPY; CYTOPLASMIC DYNEIN; NDC80 COMPLEX; LIVING CELLS AB The mitotic kinesin centromere protein E (CENP-E) is an essential kinetochore component that directly contributes to the capture and stabilization of spindle microtubules by kinetochores. Although reduction in CENP-E leads to high rates of whole chromosome missegregation, neither its properties as a microtubule-dependent motor nor how it contributes to the dynamic linkage between kinetochores and microtubules is known. Using single-molecule assays, we demonstrate that CENP-E is a very slow, highly processive motor that maintains microtubule attachment for long periods. Direct visualization of full-length Xenopus laevis CENP-E reveals a highly flexible 230-nm coiled coil separating its kinetochore-binding and motor domains. We also show that full-length CENP-E is a slow plus end-directed motor whose activity is essential for metaphase chromosome alignment. We propose that the highly processive microtubule-dependent motor activity of CENP-E serves to power chromosome congression and provides a flexible, motile tether linking kinetochores to dynamic spindle microtubules. C1 [Kim, Yumi; Cleveland, Don W.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Kim, Yumi] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. [Cleveland, Don W.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Cleveland, Don W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Heuser, John E.] Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. [Waterman, Clare M.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Cleveland, DW (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM dcleveland@ucsd.edu RI Heuser, John/H-5940-2012; OI Waterman, Clare/0000-0001-6142-6775 FU NIGMS NIH HHS [GM29513, R01 GM029513, R37 GM029513] NR 57 TC 72 Z9 75 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 5 PY 2008 VL 181 IS 3 BP 411 EP 419 DI 10.1083/jcb.200802189 PG 9 WC Cell Biology SC Cell Biology GA 299XW UT WOS:000255789900004 PM 18443223 ER PT J AU Wu, J Cho, HP Rhee, DB Johnson, DK Dunlap, J Liu, Y Wang, YS AF Wu, Jun Cho, Hyekyung P. Rhee, David B. Johnson, Dabney K. Dunlap, John Liu, Yie Wang, Yisong TI Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication SO JOURNAL OF CELL BIOLOGY LA English DT Article ID REGULATES CENTROSOME DUPLICATION; XENOPUS EGG EXTRACTS; CELL-CYCLE; CHROMOSOME SEGREGATION; MAMMALIAN-CELLS; C-ELEGANS; PHOSPHATASE; KINASE; MITOSIS; CANCER AB Centrosome duplication is tightly controlled in coordination with DNA replication. The molecular mechanism of centrosome duplication remains unclear. Previous studies found that a fraction of human proline-directed phosphatase Cdc14B associates with centrosomes. However, Cdc14B's involvement in centrosome cycle control has never been explored. Here, we show that depletion of Cdc14B by RNA interference leads to centriole amplification in both HeLa and normal human fibroblast BJ and MRC-5 cells. Induction of Cdc14B expression through a regulatable promoter significantly attenuates centriole amplification in prolonged S phase arrested cells and proteasome inhibitor Z-L3VS-treated cells. This inhibitory function requires centriole-associated Cdc14B catalytic activity. Together, these results suggest a potential function for Cdc14B phosphatase in maintaining the fidelity of centrosome duplication cycle. C1 [Wu, Jun; Cho, Hyekyung P.; Rhee, David B.; Johnson, Dabney K.; Wang, Yisong] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. [Dunlap, John] Univ Tennessee, Div Biol, Microscopy Facil, Knoxville, TN 37996 USA. [Rhee, David B.; Liu, Yie] NIA, Gerontol Res Ctr, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Wang, YS (reprint author), Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. EM liuyie@grc.nia.nih.gov; ywa@ornl.gov FU Intramural NIH HHS NR 46 TC 31 Z9 31 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAY 5 PY 2008 VL 181 IS 3 BP 475 EP 483 DI 10.1083/jcb.200710127 PG 9 WC Cell Biology SC Cell Biology GA 299XW UT WOS:000255789900010 PM 18458157 ER PT J AU Nelson, JK Burns, CT Smith, MP Twamley, B Natale, NR AF Nelson, Jared K. Burns, Christopher T. Smith, Miles P. Twamley, Brendan Natale, N. R. TI Synthetic utility of epoxides for chiral functionalization of isoxazoles SO TETRAHEDRON LETTERS LA English DT Article ID ORGANOLITHIUM CHEMISTRY; LATERAL LITHIATION; LITHIUM; LIGANDS; EPOXIDATION; METALATION; COMPLEXES; SYSTEMS; ROUTE; ESTER AB The lithio-anion of isoxazole 2 was found to ring open propylene oxide in good yields with complete regioselectivity. Vinylic and benzylic epoxides were utilized as key examples of electrophiles and found to produce a mixture of regioisomeric adducts. Additionally, the use of chiral epoxides was explored, and absolute configuration was determined by X-ray crystallography to prove that nucleophilic attack at the benzylic carbon of (R)-styrene oxide proceeds with 100% inversion at the benzylic carbon to afford the (S)-alcohol (4b). (C) 2008 Elsevier Ltd. All rights reserved. C1 [Nelson, Jared K.; Burns, Christopher T.; Smith, Miles P.; Twamley, Brendan; Natale, N. R.] Univ Idaho, Dept Chem, Moscow, ID 83844 USA. [Natale, N. R.] Univ Montana, NIH, COBRE Ctr Struct & Funct Neurosci, Missoula, MT 59812 USA. RP Natale, NR (reprint author), Univ Idaho, Dept Chem, Moscow, ID 83844 USA. EM Nicholas.natale@umontana.edu FU NCRR NIH HHS [P20 RR015583, P20 RR015583-086827, P20 RR016454]; NINDS NIH HHS [R15 NS038444-04, R15 NS038444] NR 44 TC 3 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD MAY 5 PY 2008 VL 49 IS 19 BP 3078 EP 3082 DI 10.1016/j.tetlet.2008.03.059 PG 5 WC Chemistry, Organic SC Chemistry GA 299SG UT WOS:000255774700012 PM 21103024 ER PT J AU Croteau, DL Peng, Y Van Houten, B AF Croteau, Deborah L. Peng, Ye Van Houten, Bennett TI DNA repair gets physical: Mapping an XPA-binding site on ERCC1 SO DNA REPAIR LA English DT Article DE DNA repair; nucleotide excision repair; ERCC1; XPA; NMR; X-ray crystallography; structure-function ID NUCLEOTIDE-EXCISION-REPAIR; GROUP-C PROTEIN; INTERACTION DOMAINS; ENDONUCLEASE ERCC1-XPF; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; RECOGNITION; NUCLEASE; REVEALS; COMPLEX AB Two recent reports provide new physical information on how the XPA protein recruits the ERCC1-XPF heterodimer to the site of damage during the process of mammalian nucleotide excision repair (NER). Using chemical shift perturbation NMR experiments, the contact sites between a central fragment of ERCC1 and an XPA fragment have been mapped. While both studies agree with regard to the XPA-binding site, they differ on whether the ERCC1-XPA complex can simultaneously bind DNA. These studies have important implications for both the molecular process and the design of potential inhibitors of NER. Published by Elsevier B.V. C1 [Croteau, Deborah L.; Peng, Ye; Van Houten, Bennett] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Van Houten, B (reprint author), NIEHS, Mol Genet Lab, NIH, 111 T W Alexander Dr,MD D3-01, Res Triangle Pk, NC 27709 USA. EM vanhoutl@niehs.nih.gov FU Intramural NIH HHS [Z01 ES061060-09] NR 50 TC 12 Z9 19 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 3 PY 2008 VL 7 IS 5 BP 819 EP 826 DI 10.1016/j.dnarep.2008.01.018 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 306BQ UT WOS:000256222400016 PM 18343204 ER PT J AU Freundt, EC Bidere, N Lenardo, MJ AF Freundt, Eric C. Bidere, Nicolas Lenardo, Michael J. TI A different TIPE of immune homeostasis SO CELL LA English DT Editorial Material ID CELL-DEATH; ACTIVATION; PROLIFERATION; APOPTOSIS; KINASE; MICE AB Proteins with death effector domains (DED) are key signal transducers involved in cell death and inflammation. In this issue of Cell, Sun et al. (2008) describe TIPE2, a DED protein that negatively regulates both T cell receptor and Toll-like receptor signaling. These findings reveal a new element critical to the maintenance of homeostasis in both the adaptive and innate immune systems. C1 [Freundt, Eric C.; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bidere, Nicolas] Univ Paris 11, Hop Paul Brousse, INSERM, Unite 542, F-94804 Villejuif, France. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mlenardo@nih.gov RI bidere, nicolas/K-8887-2015 OI bidere, nicolas/0000-0001-9177-0008 FU Intramural NIH HHS [Z01 AI000718-13] NR 8 TC 40 Z9 47 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 2 PY 2008 VL 133 IS 3 BP 401 EP 402 DI 10.1016/j.cell.2008.04.017 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 295WD UT WOS:000255503900011 PM 18455981 ER PT J AU Sen, A Heymann, JB Cheng, NQ Qiao, J Mindich, L Steven, AC AF Sen, Anindito Heymann, J. Bernard Cheng, Naiqian Qiao, Jian Mindich, Leonard Steven, Alasdair C. TI Initial location of the RNA-dependent RNA polymerase in the bacteriophage Phi 6 procapsid determined by cryo-electron microscopy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DSRNA BACTERIOPHAGE-PHI-6; PHI-6; COMPLEX; REPLICATION; SPECIFICITY; PARTICLES; PROTEINS; SEGMENTS; GENOME AB The RNA-dependent RNA polymerases (RdRPs) of Cystoviridae bacteriophages, like those of eukaryotic viruses of the Reoviridae, function inside the inner capsid shell in both replication and transcription. In bacteriophage Phi 6, this inner shell is first assembled as an icosahedral procapsid with recessed 5-fold vertices that subsequently undergoes major structural changes during maturation. The tripartite genome is packaged as single-stranded RNA molecules via channels on the 5-fold vertices, and transcripts probably exit the mature capsid by the same route. The RdRP (protein P2) is assembled within the procapsid, and it was thought that it should be located on the 5-fold axes near the RNA entry and exit channels. To determine the initial location of the RdRP inside the procapsid of bacteriophage Phi 6, we performed cryo-electron microscopy of wild type and mutant procapsids and complemented these data with biochemical determinations of copy numbers. We observe ring-like densities on the 3-fold axes that are strong in a mutant that has similar to 10 copies of P2 per particle; faint in wild type, reflecting the lower copy number of similar to 3; and completely absent in a P2-null mutant. The dimensions and shapes of these densities match those of the known crystal structure of the P2 monomer. We propose that, during maturation, the P2 molecules rotate to occupy positions closer to adjacent 5-fold vertices where they conduct replication and transcription. C1 [Sen, Anindito; Heymann, J. Bernard; Cheng, Naiqian; Steven, Alasdair C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Qiao, Jian; Mindich, Leonard] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Microbiol, Publ Hlth Res Inst Ctr, Newark, NJ 07103 USA. RP Heymann, JB (reprint author), NIAMS, Struct Biol Lab, NIH, Bldg 50,Rm 1515,50 S Dr,MSC 8025, Bethesda, MD 20892 USA. EM Bernard_Heymann@nih.gov RI Heymann, Bernard/F-6825-2011 FU Intramural NIH HHS; NIGMS NIH HHS [GM34352] NR 20 TC 27 Z9 27 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 2 PY 2008 VL 283 IS 18 BP 12227 EP 12231 DI 10.1074/jbc.M710508200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 293MS UT WOS:000255340000038 PM 18287088 ER PT J AU Yoshida, Y Yang, J Peaker, PE Kato, H Bush, CA Cisar, JO AF Yoshida, Yasuo Yang, Jinghua Peaker, Paule-Esther Kato, Hirohisa Bush, C. Allen Cisar, John O. TI Molecular and antigenic characterization of a Streptococcus oralis coaggregation receptor polysaccharide by carbohydrate engineering in Streptococcus gordonii SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-SURFACE POLYSACCHARIDE; VIRIDANS GROUP STREPTOCOCCI; CAPSULAR POLYSACCHARIDE; GENETIC-TRANSFORMATION; ACTINOMYCES-VISCOSUS; WALL POLYSACCHARIDES; FUNCTIONAL-ANALYSIS; BIOSYNTHESIS; COMPETENCE; IDENTIFICATION AB The coaggregation receptor polysaccharides (RPS) of Streptococcus oralis and related species are recognized by lectin-like adhesins on other members of the oral biofilm community and by RPS-specific antibodies. The former interactions involve beta-GalNAc or beta-Gal containing host-like motifs in the oligosaccharide repeating units of these polysaccharides, whereas the latter involves features of these molecules that are immunogenic. In the present investigation, the molecular and corresponding structural basis for the serotype specificity of S. oralis ATCC 10557 RPS was determined by engineering the production of this polysaccharide in transformable Streptococcus gordonii 38. This involved the systematic replacement of genes in the rps cluster of strain 38 with different but related genes from S. oralis 10557 and structural characterization of the resulting polysaccharides. The results identify four unique genes in the rps cluster of strain 10557. These include wefI for an alpha-Gal transferase, wefJ for a GalNAc-1-phosphotransferase that has a unique acceptor specificity, wefK for an acetyl transferase that acts at two positions in the hexasaccharide repeating unit, and a novel wzy associated with the beta 1-3 linkage between these units. The serotype specificity of engineered polysaccharides correlated with the wefI-dependent presence of alpha-Gal in these molecules rather than with partial O-acetylation or with the linkage between repeating units. The findings illustrate a direct approach for defining the molecular basis of polysaccharide structure and antigenicity. C1 [Yoshida, Yasuo; Yang, Jinghua; Cisar, John O.] NIH, NIDCR, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. [Yoshida, Yasuo; Kato, Hirohisa] Iwate Med Univ, Sch Dent, Dept Dent Pharmacol, Morioka, Iwate 0208505, Japan. [Peaker, Paule-Esther; Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Cisar, JO (reprint author), NIH, NIDCR, Oral Infect & Immun Branch, Bldg 30,Rm 3A-301,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov FU Intramural NIH HHS NR 39 TC 19 Z9 23 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 2 PY 2008 VL 283 IS 18 BP 12654 EP 12664 DI 10.1074/jbc.M801412200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 293MS UT WOS:000255340000082 PM 18303023 ER PT J AU Zhang, H Zhao, Q Bhattacharya, S Waheed, AA Tong, X Hong, A Heck, S Curreli, F Goger, M Cowburn, D Freed, EO Ebnath, AK AF Zhang, Hongtao Zhao, Qian Bhattacharya, Shibani Waheed, Abdul A. Tong, Xiaohe Hong, Anita Heck, Susanne Curreli, Francesca Goger, Michael Cowburn, David Freed, Eric O. Ebnath, Asim K. TI A cell-penetrating helical peptide as a potential HIV-1 inhibitor SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cell-penetrating peptide; HIV-1 capsid; viral assembly; electron microscopy; nuclear magnetic resonance ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTIOUS-ANEMIA VIRUS; ASSEMBLY IN-VITRO; CAPSID PROTEIN; TERMINAL DOMAIN; DIMERIZATION DOMAIN; VIRION MATURATION; GAG PROTEINS; TYPE-1; STABILITY AB The capsid domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is a critical determinant of virus assembly, and is therefore a potential target for developing drugs for AIDS therapy. Recently, a 12-mer alpha-helical peptide (CAI) was reported to disrupt immature- and mature-like capsid particle assembly in vitro; however, it failed to inhibit HIV-1 in cell culture due to its inability to penetrate cells. The same group reported the X-ray crystal structure of CAI in complex with the C-terminal domain of capsid (C-CA) at a resolution of 1.7 angstrom Using this structural information, we have utilized a structure-based rational design approach to stabilize the alpha-helical structure of CAI and convert it to a cell-penetrating peptide (CPP). The modified peptide (NYAD-1) showed enhanced alpha-helicity. Experiments with laser scanning confocal microscopy indicated that NYAD-1 penetrated cells and colocalized with the Gag polyprotein during its trafficking to the plasma membrane where virus assembly takes place. NYAD-1 disrupted the assembly of both immature- and mature-like virus particles in cell-free and cell-based in vitro systems. NMR chemical shift perturbation analysis mapped the binding site of NYAD-1 to residues 169-191 of the C-terminal domain of HIV-1 capsid encompassing the hydrophobic cavity and the critical dimerization domain with an improved binding affinity over CAI. Furthermore, experimental data indicate that NYAD-1 most likely targets capsid at a post-entry stage. Most significantly, NYAD-1 inhibited a large panel of HIV-1 isolates in cell culture at low micromolar potency. Our study demonstrates how a structure-based rational design strategy can be used to convert a cell-impermeable peptide to a cell-permeable peptide that displays activity in cell-based assays without compromising its mechanism of action. This proof-of-concept cell-penetrating peptide may aid validation of capsid as an anti-HIV-1 drug target and may help in designing peptidomimetics accepted 28 February 2008 and small molecule drugs targeted to this protein. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Zhang, Hongtao; Zhao, Qian; Curreli, Francesca; Ebnath, Asim K.] New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Molecular Codeling & Drug Design, New York, NY 10021 USA. [Heck, Susanne] New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Flow Cytometry, New York, NY 10021 USA. [Bhattacharya, Shibani; Goger, Michael; Cowburn, David] New York Struct Biol Ctr, New York, NY 10027 USA. [Tong, Xiaohe; Hong, Anita] Anaspec Corp, San Jose, CA 95131 USA. [Waheed, Abdul A.; Freed, Eric O.] Natl Canc Inst, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. RP Ebnath, AK (reprint author), New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Molecular Codeling & Drug Design, 310 E 67th St, New York, NY 10021 USA. EM adebnath@nybloodcenter.org RI Cowburn, David/A-8448-2008; OI Cowburn, David/0000-0001-6770-7172 FU Intramural NIH HHS [Z01 BC010778-01]; NIGMS NIH HHS [P41 GM066354-05, GM-66354, P41 GM066354, P41 GM066354-01] NR 48 TC 112 Z9 117 U1 1 U2 20 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 2 PY 2008 VL 378 IS 3 BP 565 EP 580 DI 10.1016/j.jmb.2008.02.066 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302JW UT WOS:000255965600008 PM 18374356 ER PT J AU Canagarajah, BJ Hummer, G Prinz, WA Hurley, JH AF Canagarajah, Bertram J. Hummer, Gerhard Prinz, William A. Hurley, James H. TI Dynamics of cholesterol exchange in the oxysterol binding protein family SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cholesterol transfer protein; lipid transfer protein; molecular dynamics simulation; protein conformational change ID OSBP-RELATED PROTEINS; MOLECULAR-DYNAMICS; PLASMA-MEMBRANE; TRANSPORT; YEAST; TRAFFICKING; ACTIVATION; MECHANISM; HOMOLOGS; SENSORS AB The oxysterol-binding protein-related protein (ORP) family is essential to sterol transfer and sterol-dependent signal transduction in eukaryotes. The crystal structure of one ORP family member, yeast Osh4, is known in apo and sterol-bound states. In the bound state, a 29 residue N-terminal lid region covers the opening of the cholesterol-binding tunnel, preventing cholesterol exchange. Equilibrium and steered molecular dynamics (MD) simulations of Osh4 were carried out to characterize the mechanism of cholesterol exchange. While most of the structural core was stable during the simulations, the lid was partly opened in the apo equilibrium MD simulation. Helix alpha 7, which undergoes the largest conformational change in the crystallized bound and apo states, is conformationally coupled to the opening of the lid. The movement of alpha 7 helps create a docking site for donor or acceptor membranes in the open state. In the steered MD simulations of cholesterol dissociation, we observed complete opening of the lid covering the cholesterol-binding tunnel. Cholesterol was found to exit the binding pocket in a step-wise process involving (i) the breaking of water-mediated hydrogen bonds and van der Waals contacts within the binding pocket, (ii) opening of the lid covering the binding pocket, and (iii) breakage of transient cholesterol contacts with the rim of the pocket and hydrophobic residues on the interior face of the lid. Published by Elsevier Ltd. C1 [Hummer, Gerhard] US Dept HHS, NIH, NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. [Canagarajah, Bertram J.; Hurley, James H.] US Dept HHS, NIH, NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Prinz, William A.] US Dept HHS, NIH, NIDDK, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), US Dept HHS, NIH, NIDDK, Chem Phys Lab, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov; hurley@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS [Z01 DK036129-01] NR 30 TC 16 Z9 16 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 2 PY 2008 VL 378 IS 3 BP 737 EP 748 DI 10.1016/j.jmb.2008.01.075 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302JW UT WOS:000255965600022 PM 18377932 ER PT J AU Flores-Ortega, A Jimenez, AI Cativiela, C Nussinov, R Aleman, C Casanovas, J AF Flores-Ortega, Alejandra Jimenez, Ana I. Cativiela, Carlos Nussinov, Ruth Aleman, Carlos Casanovas, Jordi TI Conformational preferences of alpha-substituted proline analogues SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID CIS-TRANS ISOMERIZATION; HELICAL SCREW SENSE; AMINO-ACIDS; AMINOISOBUTYRIC-ACID; STEREOSELECTIVE-SYNTHESIS; METHYLPROLINE PEPTIDES; SOLID-STATE; C-ALPHA,ALPHA-DISUBSTITUTED GLYCINES; STRUCTURAL VERSATILITY; LINEAR OLIGOPEPTIDES AB DFT calculations at the B3LYP/6-31 +G(d,p) level have been used to investigate how the replacement of the alpha hydrogen by a more sterically demanding group affects the conformational preferences of proline. Specifically, the N-acetyl-N'-methylamide derivatives of L-proline, L-alpha-methylproline, and L-alpha-phenylproline have been calculated, with both the cis/trans isomerism of the peptide bonds and the puckering of the pyrrolidine ring being considered. The effects of solvation have been evaluated by using a Self-Consistent Reaction Field model. As expected, tetrasubstitution at the alpha carbon destabilizes the conformers with one or more peptide bonds arranged in cis. The lowest energy minimum has been found to be identical for the three compounds investigated, but important differences are observed regarding other energetically accessible backbone conformations. The results obtained provide evidence that the distinct steric requirements of the substituent at C(alpha) may play a significant role in modulating the conformational preferences of proline. C1 [Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. [Flores-Ortega, Alejandra; Aleman, Carlos] Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. [Jimenez, Ana I.; Cativiela, Carlos] Univ Zaragoza, CSIC, Inst Ciencia Mat Aragon, Dept Quim Organ, E-50009 Zaragoza, Spain. [Nussinov, Ruth] Tel Aviv Univ, Sch Med, Dept Human Genet Sackler, IL-69978 Tel Aviv, Israel. [Casanovas, Jordi] Univ Lleida, Escola Politecn Super, Dept Quim, Lleida 25001, Spain. RP Nussinov, R (reprint author), NCI, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. EM carlos.aleman@upc.edu; jcasanovas@quimica.udl.cat RI Casanovas, Jordi/B-5435-2013 OI Casanovas, Jordi/0000-0002-4914-9194 FU NCI NIH HHS [N01CO12400, N01 CO012400, N01-CO-12400] NR 105 TC 32 Z9 32 U1 2 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAY 2 PY 2008 VL 73 IS 9 BP 3418 EP 3427 DI 10.1021/jo702710x PG 10 WC Chemistry, Organic SC Chemistry GA 293MO UT WOS:000255339600014 PM 18351745 ER PT J AU Giesel, FL Choyke, PL Mehndiratta, A Zechmann, CM von Tengg-Kobligk, H Kayser, K Bischoff, H Hintze, C Delorme, S Weber, MA Essig, M Kauczor, HU Knopp, MV AF Giesel, Frederik L. Choyke, Peter L. Mehndiratta, Amit Zechmann, Christian M. von Tengg-Kobligk, Henrik Kayser, Klaus Bischoff, Helge Hintze, Christian Delorme, Stefan Weber, M. A. Essig, Marco Kauczor, Hans-Ulrich Knopp, Michael V. TI Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34) SO ACADEMIC RADIOLOGY LA English DT Article DE angiogenesis; malignant mesothelioma; dynamic contrast enhanced MRI; pharmacokinetic analysis; microvascular density; CD-34 ID CONTRAST-ENHANCED MRI; MAGNETIC-RESONANCE; IMAGING BIOMARKER; LUNG-CARCINOMA; CANCER; ANGIOGENESIS; SURVIVAL; BREAST; DIAGNOSIS; ASBESTOS AB Rationale and Objectives. Malignant mesothelioma (MM) of the pleura is an aggressive and often fatal neoplasm. Because MM frequently demonstrates marked angiogenesis, it may be responsive to antiangiogenic therapy, but effective methods for selecting and monitoring of patients are further needed. We employed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and quantitative immunohistochemistry (IHC) to characterize the microvascularity of MM using both a physiologic and ultrastructural method. Materials and Methods. Nineteen patients diagnosed with MM were enrolled and DCE-MRI was performed before antiangiogenic treatment. For each patient, tumor regions were characterized by their DCE-MRI-derived pharmacokinetic parameters (Amp, k(ep), k(el)), which were also compared to those of normal tissue (aorta, liver, spleen, and muscle). In addition, quantitative ITIC of representative samples was performed with CD-34 staining to compare the calculated microvessel density (MVD) results with DCE-MRI results. Results. MM demonstrated markedly abnormal pharmacokinetic properties compared with normal tissues. Among the parameters tested, Amp was significantly different in MM (P :5.001) compared to normal organs. Despite the observation that the MVD of mesotheliomas in this series was high compared to other tumors, DCE-MRI pharmacokinetic parameters had a moderately positive correlation with MVD (r = 0.5). Conclusions. DCE-MRI and IHC can be used in patients with MM to visualize tumor microvascularity and to characterize tumor heterogeneity. DCE-MRI and IHC results positively correlated, though moderately, but these two methods present as essential tumor biomarkers. This multimodal characterization may be useful in selecting possible tumor subtypes that would benefit from antiangiogenic therapy. C1 [Giesel, Frederik L.; Mehndiratta, Amit; Zechmann, Christian M.; von Tengg-Kobligk, Henrik; Bischoff, Helge; Hintze, Christian; Delorme, Stefan; Weber, M. A.; Essig, Marco; Kauczor, Hans-Ulrich] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Choyke, Peter L.] NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Mehndiratta, Amit] Indian Inst Technol, Sch Med Sci & Technol, Kharagpur, W Bengal, India. [Kayser, Klaus] UICC TPCC, Inst Pathol, Charite, Berlin, Germany. [Giesel, Frederik L.; Knopp, Michael V.] Ohio State Univ, Columbus, OH 43210 USA. RP Giesel, FL (reprint author), German Canc Res Ctr, INF 280, D-69120 Heidelberg, Germany. EM f.giesel@egiesel.com RI Weber, Marc-Andre/C-4452-2016; von Tengg-Kobligk, Hendrik/A-1420-2017; OI von Tengg-Kobligk, Hendrik/0000-0003-3207-3223; Delorme, Stefan/0000-0002-1000-2582; Zechmann, Christian M/0000-0002-8454-0877 NR 28 TC 19 Z9 19 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAY PY 2008 VL 15 IS 5 BP 563 EP 570 DI 10.1016/j.acra.2007.12.014 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 294BX UT WOS:000255380200003 PM 18423312 ER PT J AU Tu, C Tan, YH Shaw, G Zhou, Z Bai, Y Luo, R Ji, XH AF Tu, Chao Tan, Yu-Hong Shaw, Gary Zhou, Zheng Bai, Yawen Luo, Ray Ji, Xinhua TI Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstrom resolution SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CRYSTAL-STRUCTURE; TUMOR-SUPPRESSOR; CORE DOMAIN; MOLECULAR-DYNAMICS; CANCER; MECHANISM; RESCUE; SYSTEM; SITE AB Tumor suppressor p53 is a sequence-specific DNA-binding protein and its central DNA-binding domain (DBD) harbors six hotspots (Arg175, Gly245, Arg248, Arg249, Arg273 and Arg282) for human cancers. Here, the crystal structure of a low-frequency hotspot mutant, p53DBD(R282Q), is reported at 1.54 A resolution together with the results of molecular-dynamics simulations on the basis of the structure. In addition to eliminating a salt bridge, the R282Q mutation has a significant impact on the properties of two DNA-binding loops (L1 and L3). The L1 loop is flexible in the wild type, but it is not flexible in the mutant. The L3 loop of the wild type is not flexible, whereas it assumes two conformations in the mutant. Molecular-dynamics simulations indicated that both conformations of the L3 loop are accessible under biological conditions. It is predicted that the elimination of the salt bridge and the inversion of the flexibility of L1 and L3 are directly or indirectly responsible for deactivating the tumor suppressor p53. C1 [Tu, Chao; Shaw, Gary; Ji, Xinhua] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Tan, Yu-Hong; Luo, Ray] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Zhou, Zheng; Bai, Yawen] NCI, Biochem & Mol Biol Lab, Bethesda, MD 20892 USA. RP Ji, XH (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Tu, Chao/D-3637-2009; Ji, Xinhua/C-9664-2012; Luo, Ray/I-6928-2012 OI Ji, Xinhua/0000-0001-6942-1514; Luo, Ray/0000-0002-6346-8271 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM069620, GM069620] NR 34 TC 6 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAY PY 2008 VL 64 BP 471 EP 477 DI 10.1107/S0907444908003338 PN 5 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 289TX UT WOS:000255077900001 PM 18453682 ER PT J AU Grujic, O Grigg, ME Boulanger, MJ AF Grujic, Ognjen Grigg, Michael E. Boulanger, Martin J. TI Insect-cell expression, crystallization and X-ray data collection of the bradyzoite-specific antigen BSR4 from Toxoplasma gondii SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID SURFACE-ANTIGEN; SRS SUPERFAMILY; TISSUE CYSTS; ENCEPHALITIS; TACHYZOITES; PROTEINS; FAMILY; MICE AB Toxoplasma gondii is an important global pathogen that infects nearly one third of the world's adult population. A family of developmentally expressed structurally related surface-glycoprotein adhesins (SRSs) mediate attachment to and are utilized for entry into host cells. The latent bradyzoite form of T. gondii persists for the life of the host and expresses a distinct family of SRS proteins, of which the bradyzoite-specific antigen BSR4 is a prototypical member. Structural studies of BSR4 were initiated by first recombinantly expressing BSR4 in insect cells, which was followed by crystallization and preliminary X-ray data collection to 1.95 angstrom resolution. Data processing showed that BSR4 crystallized with one molecule in the asymmetric unit of the P4(1)2(1)2 or P4(3)2(1)2 space group, with a solvent content of 60% and a corresponding Matthews coefficient of 2.98 angstrom(3) Da(-1). C1 [Grujic, Ognjen; Boulanger, Martin J.] Univ Victoria, Victoria, BC V8W 3P6, Canada. [Grigg, Michael E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Boulanger, MJ (reprint author), Univ Victoria, POB 3055 STN CSC, Victoria, BC V8W 3P6, Canada. EM mboulang@uvic.ca NR 22 TC 3 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD MAY PY 2008 VL 64 BP 425 EP 427 DI 10.1107/S1744309108010920 PN 5 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 295ZN UT WOS:000255513400022 PM 18453717 ER PT J AU Nystad, W Haberg, SE London, SJ Nafstad, P Magnus, P AF Nystad, Wenche Haberg, Siri E. London, Stephanie J. Nafstad, Per Magnus, Per TI Baby swimming and respiratory health SO ACTA PAEDIATRICA LA English DT Article DE baby swimming; respiratory health ID POOL ATTENDANCE; ASTHMA; INTEGRITY; EXPOSURE; RISK AB Aim: To estimate the effect of baby swimming in the first 6 months of life on respiratory diseases from 6 to 18 months. Methods: We used data from The Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health in children born between 1999 and 2005 followed from birth to the age of 18 months (n = 30 870). Health outcomes: lower respiratory tract infections (LRTI), wheeze and otitis media between 6 and 18 months of age. Exposure: baby swimming at the age of 6 months. The effect of baby swimming was estimated by logistic regression analysis adjusting for potential confounders. Results: About 25% of the children participated in baby swimming. The prevalence of LRTI was 13.3%, wheeze 40.0% and otitis media 30.4%. Children who were baby swimming were not more likely to have LRTI, to wheeze or to have otitis media. However, children with atopic mothers who attended baby swimming had an increased risk of wheeze, adjusted odds ratios (aOR) 1.24 (95% CI 1.11, 1.39), but not LRTI or otitis media. This was also the case for children without respiratory diseases before 6 months aOR 1.08 (95%CI 1.02-1.15). Conclusion: Baby swimming may be related to later wheeze. However, these findings warrant further investigation. C1 [Nystad, Wenche; Haberg, Siri E.; Nafstad, Per; Magnus, Per] Norwegian Inst Publ Hlth, Div Epidemiol, NO-0403 Oslo, Norway. [London, Stephanie J.] NIEHS, NIH, Epidemiol Branch, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [London, Stephanie J.] NIEHS, NIH, Epidemiol Branch, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. [Nafstad, Per] Univ Oslo, Fac Med, Dept Gen Practice & Community Med, N-0316 Oslo, Norway. RP Nystad, W (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, POB 4404, NO-0403 Oslo, Norway. EM wenche.nystad@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS [Z01 ES049019-12]; NIEHS NIH HHS [N01ES85433, N01-ES-85433]; NINDS NIH HHS [U01 NS047537, 1 UO1 NS 047537-01] NR 14 TC 24 Z9 25 U1 1 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD MAY PY 2008 VL 97 IS 5 BP 657 EP 662 DI 10.1111/j.1651-2227.2008.00756.x PG 6 WC Pediatrics SC Pediatrics GA 288LT UT WOS:000254988600028 PM 18394113 ER PT J AU Stevens, KN Lang, IA Guralnik, JM Melzer, D AF Stevens, Kara N. Lang, Iain A. Guralnik, Jack M. Melzer, David TI Epidemiology of balance and dizziness in a national population: findings from the English Longitudinal Study of Ageing SO AGE AND AGEING LA English DT Article DE balance; dizziness; socio-economic status; elderly ID POSSIBLE GERIATRIC SYNDROME; OLDER-ADULTS; ALCOHOL-CONSUMPTION; ELDERLY POPULATION; RISK-FACTORS; COMMUNITY; PEOPLE; FALLS; PREVALENCE; DISABILITY AB Objective: to identify socio-economic, behavioural and disease status risks for impaired balance or self-reported dizziness in older people from a large population-based study. Methods: data were from the English Longitudinal Study of Ageing (ELSA), for 2,925 participants, aged 65+. Multivariate models were used to assess the associations between balance and dizziness and disease status, health behaviours, grip strength and socio-economic markers. Results: there were 21.5% (n=619) participants with impaired balance and 11.1% (n=375) reported dizziness. Impaired balance was statistically significantly associated with age, diabetes (OR = 1.53), arthritis (OR = 1.33), eyesight (OR = 1.94) and grip strength. The wealthiest 20% of participants were less likely to have impaired balance than the poorest 20% (OR = 0.46). Dizziness problems were not associated with age, gender or wealth, but were significantly associated with an abnormal heart rhythm (OR = 1.85), hearing (OR = 1.81), eyesight (OR = 1.72) and grip strength. Conclusion: the epidemiology of impaired balance differs from that of dizziness, and risk assessment approaches to prevent falls may need to elicit information on different problem-specific factors. Impaired balance test performance in older people may be added to the many outcomes showing strong socio-economic gradients. C1 [Stevens, Kara N.; Lang, Iain A.; Melzer, David] Peninsula Med Sch, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. [Guralnik, Jack M.] NIA, Epidemiol & Demog Sect, Bethesda, MD 20892 USA. RP Lang, IA (reprint author), Peninsula Med Sch, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. EM iain.lang@pms.ac.uk RI Lang, Iain/B-8255-2008; OI Lang, Iain/0000-0002-8473-2350; Melzer, David/0000-0002-0170-3838 NR 29 TC 49 Z9 52 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAY PY 2008 VL 37 IS 3 BP 300 EP 305 DI 10.1093/ageing/afn019 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 296DY UT WOS:000255524900013 PM 18270246 ER PT J AU Konda, KA Lescano, AG Leontsini, E Fernandez, P Klausner, JD Coates, TJ Caceres, CF AF Konda, Kelika Anne Lescano, Andres G. Leontsini, Elli Fernandez, Percy Klausner, Jeffrey D. Coates, Thomas J. Caceres, Carlos F. CA NIMH Collaborative STD HIV TI High rates of sex with men among high-risk, heterosexually-identified men in low-income, coastal Peru SO AIDS AND BEHAVIOR LA English DT Article; Proceedings Paper CT 16th Biennial Meeting of the International-Society-for-Sexually-Transmitted-Diseases-Research CY JUL 10-13, 2005 CL Amsterdam, NETHERLANDS SP Int Soc Sexually Transmitted Dis Res DE bisexual behavior; HIV bridge populations; MSM; condom use; Peru ID VIRUS TYPE-2 INFECTION; HIV-INFECTION; TRANSMISSION; WOMEN; EPIDEMIOLOGY; PREVENTION; BEHAVIORS; SYPHILIS; AIDS AB In this paper we describe sex with men, including the frequency of sex and unprotected sex, among high-risk, heterosexually-identified men in urban, low-income, coastal Peru. During 2001-2002, a random community-based sample of these men was administered an epidemiologic survey collecting sexual risk behavior data. Among the 924 high-risk heterosexually-identified men, 131 (14.2%) reported at least one male partner in the past 6 months. Of these, 113 (86.3%) reported male and female partners and among those with partners of both sexes, 84.2% and 57.0% of sex acts with female and male partners, respectively, were unprotected, (RR 1.48, 95% CI = 1.31-1.68). We observed a high rate of recent bisexual behavior compared to past studies showing frequent, unprotected sex with male and female partners. This population has substantial potential to act as a bridge population between and their male and female partners and should be addressed by prevention programs. C1 [Konda, Kelika Anne; Coates, Thomas J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Lescano, Andres G.] USN, Med Res Ctr Detachment, Lima, Peru. [Lescano, Andres G.; Fernandez, Percy; Caceres, Carlos F.] Univ Peruana Cayetano Heredia, Lima, Peru. [Leontsini, Elli] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Klausner, Jeffrey D.] San Franciso Dept Publ Hlth, San Francisco, CA USA. [Klausner, Jeffrey D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [NIMH Collaborative STD HIV] NIMH, Multisite Int Grp, Bethesda, MD 20892 USA. RP Konda, KA (reprint author), 445 Av Armendariz, Lima 18, Peru. EM kelika_konda@hotmail.com RI Lescano, Andres/B-8479-2008; OI Lescano, Andres/0000-0001-9779-633X; Caceres, Carlos/0000-0002-8101-0790 FU FIC NIH HHS [D43 TW007393]; NIMH NIH HHS [U10 MH061536, U10 MH061536-08, U10 MH61536] NR 27 TC 13 Z9 13 U1 2 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD MAY PY 2008 VL 12 IS 3 BP 483 EP 491 DI 10.1007/s10461-007-9221-z PG 9 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 285CT UT WOS:000254755600017 PM 17377837 ER PT J AU Kuo, PH Kalsi, G Prescott, CA Hodgkinson, CA Goldman, D van den Oord, EJ Alexander, J Jiang, C Sullivan, PF Patterson, DG Walsh, D Kendler, KS Riley, BP AF Kuo, Po-Hsiu Kalsi, Gursharan Prescott, Carol A. Hodgkinson, Colin A. Goldman, David van den Oord, Edwin J. Alexander, Jeffry Jiang, Cizhong Sullivan, Patrick F. Patterson, Diana G. Walsh, Dermot Kendler, Kenneth S. Riley, Brien P. TI Association of ADH and ALDH genes with alcohol dependence in the Irish Affected Sib Pair Study of alcohol dependence (IASPSAD) sample SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE ethanol metabolism genes; alcohol dehydrogenase; aldehyde dehydrogenase; gene interaction; epistasis ID DEHYDROGENASE POLYMORPHISMS; ALDEHYDE DEHYDROGENASE; PROMOTER POLYMORPHISMS; ADH2-ASTERISK-3 ALLELE; FALSE DISCOVERIES; METABOLISM GENES; NATIVE-AMERICANS; DRUG-DEPENDENCE; FAMILY-HISTORY; LIVER-DISEASE AB Background: The genes coding for ethanol metabolism enzymes [alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] have been widely studied for their influence on the risk to develop alcohol dependence (AD). However, the relation between polymorphisms of these metabolism genes and AD in Caucasian subjects has not been clearly established. The present study examined evidence for the association of alcohol metabolism genes with AD in the Irish Affected Sib Pair Study of alcohol dependence. Methods: We conducted a case-control association study with 575 independent subjects who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, AD diagnosis and 530 controls. A total of 77 single nucleotide polymorphisms (SNPs) in the seven ADH (ADH1-7) and two ALDH genes (ALDH1A1 and ALDH2) were genotyped using the Illumina GoldenGate protocols. Several statistical procedures were implemented to control for false discoveries. Results: All markers with minor allele frequency greater than 0.01 were in Hardy-Weinberg equilibrium. Numerous SNPs in ADH genes showed association with AD, including one marker in the coding region of ADH1C (rs1693482 in exon6, Ile271Gln). Haplotypic association was observed in the ADH5 and ADH1C genes, and in a long haplotype block formed by the ADH1A and ADH1B loci. We detected two significant interactions between pairs of markers in intron 6 of ADH6 and intron 12 of ALDH2 (p = 5 x 10(-5)), and 5' of both ADH4 and A DH1A (p = 2 x 10(-4)). Conclusion: We found evidence for the association of several ADH genes with AD in a sample of Western European origin. The significant interaction effects between markers in ADH and ALDH genes suggest possible epistatic roles between alcohol metabolic enzymes in the risk for AD. C1 [Kuo, Po-Hsiu; Kalsi, Gursharan; Alexander, Jeffry; Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Prescott, Carol A.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, DICBR, Rockville, MD 20852 USA. [van den Oord, Edwin J.] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA USA. [Jiang, Cizhong] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Sullivan, Patrick F.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Genet & Psychiat, Chapel Hill, NC USA. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. [Patterson, Diana G.] Shaftsbury Sq Hosp, Belfast, Antrim, North Ireland. RP Kuo, PH (reprint author), Natl Cheng Kung Univ, Natl Cheng Kung Univ Hosp 138, Coll Med, Inst Clin Med, Sheng Li Rd, Tainan 704, Taiwan. EM pkuo@mail.ncku.edu.tw RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Kuo, Po-Hsiu/0000-0003-0365-3587 FU Intramural NIH HHS [Z01 AA000306-02]; NIAAA NIH HHS [R01 AA011408, R01-AA-11408] NR 55 TC 58 Z9 59 U1 2 U2 12 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2008 VL 32 IS 5 BP 785 EP 795 DI 10.1111/j.1530-0277.2008.00642.x PG 11 WC Substance Abuse SC Substance Abuse GA 297DT UT WOS:000255598000011 PM 18331377 ER PT J AU Yang, XJ Wang, SL Rice, KC Munro, CA Wand, GS AF Yang, Xiaoju Wang, Shelun Rice, Kenner C. Munro, Cynthia A. Wand, Gary S. TI Restraint stress and ethanol consumption in two mouse, strains SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE ethanol preference; restraint stress; CRF-1 receptor; glucocorticoids receptor; antagonist ID CORTICOTROPIN-RELEASING-FACTOR; ANXIETY-LIKE BEHAVIOR; PITUITARY-ADRENAL AXIS; RECEPTOR ANTAGONIST; PSYCHOSOCIAL STRESS; ALCOHOL-DRINKING; DEPENDENT RATS; IN-VIVO; RELAPSE; EXPOSURE AB Background: This study examined the interaction between restraint stress and ethanol drinking in mice that consume low and high amounts of ethanol. Methods: Two strains of mice (129SVEV and C57BL/6J) underwent I hour of restraint stress twice per day for 4 days in the presence of a CRF-1 receptor antagonist, a glucocorticoid receptor antagonist or vehicle. Ethanol preference and consumption were assessed using a two bottle choice design. In another study, mice were implanted with pellets containing corticosterone; ethanol preference and consumption were assessed using a two bottle choice design. Results: Restraint stress significantly increased ethanol preference and consumption in 129SVEV mice but not in C57BL/6J mice. Then 129SVEV mice underwent the identical stress procedure; however, mice received either the CRF-1 receptor antagonist, R121919 (15 or 20 mg/kg, ip) or vehicle 30 minutes prior to stress. R121919 did not block the stress-induced change in ethanol preference despite causing a significant blunting in the HPA axis. Negative results were also obtained using the CRF-1 receptor antagonist, Antalarmin (20 mg/kg, ip). In another study, 129SVEV mice were administered either the glucocorticoid receptor antagonist Mifepristone (25, 50 or 100 mu g/kg, ip) or vehicle under the same procedure. Mifiepristone did not alter ethanol preference. Moreover, the three receptor antagonist did not alter nonstress ethanol consumption either. In the last study, both mouse strains underwent active or sham adrenalectomy, then pellets containing corticosterone or placebo were implanted and preference for ethanol versus water was tested. Corticosterone administration decreased ethanol consumption in a strain-dependent manner. Conclusion: These data show the restraint model for stress can modestly increase ethanol consumption in 129SVEV mice but not in C57BL/6J mice. Pharmacologic manipulation of CRF and corticosterone did not blunt baseline or stress-induced change in ethanol preference nor did administration of corticosterone mimic the effects of restraint stress on ethanol consumption. These findings suggest the mechanism responsible for increasing ethanol consumption in this model is independent of the HPA axis and extra-hypothalamic CRF. C1 [Yang, Xiaoju; Wang, Shelun; Wand, Gary S.] Johns Hopkins Univ, Sch Med, Endocrine Training Program, Dept Med, Baltimore, MD 21205 USA. [Munro, Cynthia A.; Wand, Gary S.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Rockville, MD USA. [Rice, Kenner C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Wand, GS (reprint author), Johns Hopkins Univ, Sch Med, Endocrine Training Program, Dept Med, 720 Rutland Ave,Ross Bldg,Rm 863, Baltimore, MD 21205 USA. EM gwand@jhmi.edu FU Intramural NIH HHS; NIAAA NIH HHS [R01 AA009000, R37 AA012303-10, AA09000, R01 AA010158, AA12303, R01 AA010158-10, R37 AA012303] NR 38 TC 20 Z9 20 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2008 VL 32 IS 5 BP 840 EP 852 DI 10.1111/j.1530-0277.2008.00632.x PG 13 WC Substance Abuse SC Substance Abuse GA 297DT UT WOS:000255598000017 PM 18336636 ER PT J AU Everson, GT Shiffman, ML Morgan, TR Hoefs, JC Sterling, RK Wagner, DA Kulig, CC Curto, TM Wright, EC AF Everson, G. T. Shiffman, M. L. Morgan, T. R. Hoefs, J. C. Sterling, R. K. Wagner, D. A. Kulig, C. C. Curto, T. M. Wright, E. C. CA Halt-C Trial Grp TI The spectrum of hepatic functional impairment in compensated chronic hepatitis C: results from the hepatitis C anti-viral long-term treatment against cirrhosis trial SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID VENOUS-PRESSURE GRADIENT; LIVER-TRANSPLANTATION; FIBROSIS; VIRUS; MODEL; SEVERITY; THERAPY; DISEASE; MASS AB Background The spectrum of functional impairment in patients with compensated chronic hepatitis C is incompletely defined. Aim To define hepatic impairment by quantitative tests (quantitative liver function tests) and correlate results with disease severity in patients with chronic hepatitis C. Methods We studied 285 adult patients with chronic hepatitis C prior to treatment in the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis Trial; 171 had Ishak fibrosis stages 2-4 (fibrosis) and 114 had stage 5 or 6 (cirrhosis). None had had clinical decompensation. A battery of 12 quantitative liver function test assessed the spectrum of hepatic microsomal, mitochondrial and cytosolic functions, and hepatic and portal blood flow. Results Twenty-six to 63% of patients with fibrosis and 45-89% with cirrhosis had hepatic impairment by quantitative liver function test; patients with cirrhosis had the greatest impairment (P-value ranging from 0.15 to < 0.0001). Cholate Cl-oral, cholate shunt and perfused hepatic mass correlated with cirrhosis, stage of fibrosis (r = -0.51, +0.49, -0.51), varices and variceal size (r = -0.39, +0.36, -0.41). PHM < 95 and cholate shunt > 35% identified 91% of patients with medium- or large-sized varices. Conclusions Hepatic impairment is common in compensated patients with fibrosis or cirrhosis because of chronic hepatitis C. Cholate shunt, and cholate Cl-oral and perfused hepatic mass, identify patients at risk for cirrhosis or varices. C1 [Everson, G. T.; Kulig, C. C.] Univ Colorado, Hlth Sci Ctr, Sch Med, Div Gastroenterol & Hepatol,Sect Hepatol, Denver, CO 80262 USA. [Shiffman, M. L.; Sterling, R. K.] Virginia Commonwealth Univ Hlth Syst, Div Gastroenterol Hepatol & Nutr, Hepatol Sect, Richmond, VA USA. [Morgan, T. R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, T. R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Wagner, D. A.] Metab Solut Inc, Nashua, NH USA. [Curto, T. M.] New England Res Inst, Watertown, MA 02172 USA. [Wright, E. C.] NIDDKD, Off Director, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Everson, GT (reprint author), Univ Colorado, Hlth Sci Ctr, Sch Med, Div Gastroenterol & Hepatol,Sect Hepatol, 4200 E 9th Ave,B-154, Denver, CO 80262 USA. EM greg.everson@uchsc.edu FU NCRR NIH HHS [M01RR-00827, M01RR-00051, M01RR-00065]; NIDDK NIH HHS [N01-DK-9-2322, N01-DK-9-2327, N01-DK-9-2328, N01-DK-9-2320] NR 24 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAY 1 PY 2008 VL 27 IS 9 BP 798 EP 809 DI 10.1111/j.1365-2036.2008.03639.x PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 283AE UT WOS:000254608100010 PM 18266997 ER PT J AU Cook, MB Wild, CP Everett, SM Hardie, LJ Bani-Hani, KE Martin, IG Forman, D AF Cook, M. B. Wild, C. P. Everett, S. M. Hardie, L. J. Bani-Hani, K. E. Martin, I. G. Forman, D. TI Mortality risks associated with Barrett's oesophagus SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter ID CANCER C1 [Cook, M. B.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Everett, S. M.; Hardie, L. J.; Forman, D.] Univ Leeds, Fac Med & Hlth, Leeds Inst Genet Hlth & Therapeut, Ctr Biostat & Epidemiol, Leeds, W Yorkshire, England. [Bani-Hani, K. E.] Jordan Univ Sci & Technol, Fac Med, Dept Surg, Irbid, Jordan. [Martin, I. G.] Univ Auckland, Sch Med, Fac Med & Hlth Sci, Auckland, New Zealand. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural NIH HHS [Z99 CA999999] NR 6 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-2813 J9 ALIMENT PHARM THERAP JI Aliment. Pharmacol. Ther. PD MAY 1 PY 2008 VL 27 IS 9 BP 852 EP 853 DI 10.1111/j.1365-2036.2008.03645.x PG 2 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 283AE UT WOS:000254608100016 PM 18380800 ER PT J AU Mitchell, BD McArdle, PF Shen, HQ Rampersaud, E Pollin, TI Bielak, LF Jaquish, C Douglas, JA Roy-Gagnon, MH Sack, P Naglieri, R Hines, S Horenstein, RB Chang, YPC Post, W Ryan, KA Brereton, NH Pakyz, RE Sorkin, J Damcott, CM O'Connell, JR Mangano, C Corretti, M Vogel, R Herzog, W Weir, MR Peyser, PA Shuldiner, AR AF Mitchell, Braxton D. McArdle, Patrick F. Shen, Haiqing Rampersaud, Evadnie Pollin, Toni I. Bielak, Lawrence F. Jaquish, Cashell Douglas, Julie A. Roy-Gagnon, Marie-Helene Sack, Paul Naglieri, Rosalie Hines, Scott Horenstein, Richard B. Chang, Yen-Pei C. Post, Wendy Ryan, Kathleen A. Brereton, Nga Hong Pakyz, Ruth E. Sorkin, John Damcott, Coleen M. O'Connell, Jeffrey R. Mangano, Charles Corretti, Mary Vogel, Robert Herzog, William Weir, Matthew R. Peyser, Patricia A. Shuldiner, Alan R. TI The genetic response to short-term interventions affecting cardiovascular function: Rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study SO AMERICAN HEART JOURNAL LA English DT Article ID OLD ORDER AMISH; RISK-FACTORS; DISEASE; TWINS; SUSCEPTIBILITY; HERITABILITY; ASSOCIATION; PEDIGREES; DEATH AB Background The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions. Methods The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy. Results The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes. Conclusions Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals. C1 [Mitchell, Braxton D.; McArdle, Patrick F.; Shen, Haiqing; Rampersaud, Evadnie; Pollin, Toni I.; Sack, Paul; Naglieri, Rosalie; Hines, Scott; Horenstein, Richard B.; Chang, Yen-Pei C.; Ryan, Kathleen A.; Brereton, Nga Hong; Pakyz, Ruth E.; Damcott, Coleen M.; O'Connell, Jeffrey R.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med Diabetes & Nutr, Div Endocrinol, Baltimore, MD 21201 USA. [Bielak, Lawrence F.; Peyser, Patricia A.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Jaquish, Cashell] NHLBI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Douglas, Julie A.; Roy-Gagnon, Marie-Helene] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. [Post, Wendy] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Sorkin, John] Univ Maryland, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. [Sorkin, John; Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Mangano, Charles; Corretti, Mary; Vogel, Robert; Herzog, William] Univ Maryland, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21201 USA. [Weir, Matthew R.] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. RP Mitchell, BD (reprint author), Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, 660 W Redwood St,Rm 492, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu OI Mitchell, Braxton/0000-0003-4920-4744 FU NCRR NIH HHS [M01 RR 000052, M01 RR 16500, M01 RR000052, M01 RR000052-45, M01 RR016500, M01 RR016500-040042]; NHLBI NIH HHS [T32 HL072751, T32 HL072751-05, T32HL072751, U01 HL072515, U01 HL072515-05, U01 HL72515]; NIDDK NIH HHS [P30 DK072488, P30 DK072488-029001] NR 16 TC 63 Z9 63 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAY PY 2008 VL 155 IS 5 BP 823 EP 828 DI 10.1016/j.ahj.2008.01.019 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 302WU UT WOS:000256001500005 PM 18440328 ER PT J AU Pearte, CA Myerson, M Coresh, J McNamara, RL Rosamond, W Taylor, H Manolio, TA AF Pearte, Camille A. Myerson, Merle Coresh, Joseph McNamara, Robert L. Rosamond, Wayne Taylor, Herman Manolio, Teri A. TI Variation and temporal trends in the use of diagnostic testing during hospitalization for acute myocardial infarction by age, gender, race, and geography (the atherosclerosis risk in communities study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-REVASCULARIZATION PROCEDURES; CRITICALLY-ILL PATIENTS; RACIAL-DIFFERENCES; CARDIAC PROCEDURES; SEX-DIFFERENCES; HEART-DISEASE; CATHETERIZATION; MANAGEMENT; ECHOCARDIOGRAPHY; ASSOCIATION AB The use of cardiovascular procedures has become routine in the management of acute myocardial infarction (MI). However, diagnostic testing beyond coronary revascularization procedures and use over time has not been well characterized. Records of 35- to 74-year-old adults hospitalized with MI in 4 US communities from 1987 to 2001 were abstracted using standardized data collection methods. Rates of procedure use and outcomes were compared by patient characteristics. Of 11,242 patients (mean age 61 years, 43% women, 22% black), angiography use increased substantially over time, echocardiography use increased more in women than men (interaction p < 0.05), use of right-sided cardiac catheterization decreased, and use of nuclear scans and exercise tests remained constant. Men, whites, and locations with the highest angiography and right-sided cardiac catheterization use had lower noninvasive testing. In multivariate analysis, women had less angiograms and more echocardiograms obtained than men, but only in those with no previous MI before this hospitalization (both interaction p < 0.05). Similarly, in those without previous MI, blacks were even less likely than whites to undergo angiography compared with those with a history of MI (interaction p=0.0001). Adjusted mortality rates were similar by gender, but mortality was higher in blacks than whites, a difference that decreased with adjustment for angiography use. In conclusion, in patients hospitalized with MI, use of many diagnostic cardiovascular procedures varied over time, with differences by gender, age, race, and geography that persisted over time unexplained by many measurable characteristics. There may also be continued perception of lower risk in women and blacks without a known diagnosis of MI. (c) 2008 Elsevier Inc. All rights reserved. C1 [Pearte, Camille A.; Myerson, Merle; Manolio, Teri A.] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. [Pearte, Camille A.] Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Coresh, Joseph] Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. [McNamara, Robert L.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Rosamond, Wayne] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Taylor, Herman] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Pearte, CA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bldg 10, Bethesda, MD 20892 USA. EM carnille.pearte@nyumc.org FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55022, N01-HC-55020, N01 HC055019, N01-HC-55019, N01-HC-55016, N01-HC-55021, N01-HC-55018] NR 26 TC 8 Z9 8 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 1 PY 2008 VL 101 IS 9 BP 1219 EP 1225 DI 10.1016/j.amjcard.2008.01.001 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 298EW UT WOS:000255670200001 PM 18435947 ER PT J AU Bray, GA Jablonski, KA Fujimoto, WY Barrett-Connor, E Haffner, S Hanson, RL Hill, JO Hubbard, V Kriska, A Stamm, E Pi-Sunyer, FX AF Bray, George A. Jablonski, Kathleen A. Fujimoto, Wilfred Y. Barrett-Connor, Elizabeth Haffner, Steven Hanson, Robert L. Hill, James O. Hubbard, Van Kriska, Andrea Stamm, Elizabeth Pi-Sunyer, F. Xavier CA Diabet Prevention Program Res Grp TI Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; FAT DISTRIBUTION; ABDOMINAL ADIPOSITY; WAIST CIRCUMFERENCE; COMPUTED-TOMOGRAPHY; TISSUE DISTRIBUTION; RACIAL-DIFFERENCES; MEXICAN-AMERICANS; RISK-FACTORS; LIFE-STYLE AB Background: Greater central adiposity is related to the risk of diabetes. Objective: We aimed to test the hypothesis that central adiposity measured by computed tomography (CT) is a better predictor of the risk of diabetes than is body mass index (BMI), waist circumference (WC), waist/hip ratio (WHR), or waist/height ratio. Design: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured at the L2-3 and L4-5 disc spaces in 1106 of the 3234 participants in the Diabetes Prevention Program. Sex-specific proportional hazards models were used to evaluate the association between VAT and SAT at both cuts, BMI, and other measures of central adiposity as predictors of the development of diabetes. Results: Men had more VAT than did women. White subjects had more VAT at both cuts than did other ethnic groups. The ratio of VAT to SAT was lowest in African Americans of both sexes. Among men in the placebo group, VAT at both cuts, WC, BMI, waist/height ;ratio, and WHR predicted diabetes (hazard ratio: 1.79-1.44 per 1 SD of variable). Among women in the lifestyle group, VAT at both cuts predicted diabetes as well as did BMI, and L2-3 was a significantly better predictor than was WC or WHR. SAT did not predict diabetes. None of the body fat measurements predicted diabetes in the metformin group. Conclusions: In the placebo and lifestyle groups, VAT at both cuts, WHR, and WC predicted diabetes. No measure predicted diabetes in the metformin group. CT provided no important advantage over these simple measures. SAT did not predict diabetes. C1 [Bray, George A.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Jablonski, Kathleen A.] George Washington Biostat Ctr, Rockville, MD USA. [Fujimoto, Wilfred Y.] Univ Washington, Dept Med, Seattle, WA USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Sch Med, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Haffner, Steven] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Hanson, Robert L.] NIDDK, Phoenix, AZ USA. [Hill, James O.] Univ Colorado, Sch Med, Ctr Human Nutr, Denver, CO USA. [Hubbard, Van] NIDDK, Div Nutr Res, Bethesda, MD USA. [Kriska, Andrea] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Stamm, Elizabeth] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Pi-Sunyer, F. Xavier] St Lukes Roosevelt Hosp, New York, NY 10025 USA. RP Bray, GA (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Coordinating Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS; NIDDK NIH HHS [U01 DK048489, U01 DK048489-06] NR 41 TC 107 Z9 113 U1 0 U2 4 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2008 VL 87 IS 5 BP 1212 EP 1218 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 301EZ UT WOS:000255880500016 PM 18469241 ER PT J AU Frankenfeld, CL Cerhan, JR Cozen, W Davis, S Schenk, M Morton, LM Hartge, P Ward, MH AF Frankenfeld, Cara L. Cerhan, James R. Cozen, Wendy Davis, Scott Schenk, Maryjean Morton, Lindsay M. Hartge, Patricia Ward, Mary H. TI Dietary flavonoid intake and non-Hodgkin lymphoma risk SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID ANTIOXIDANT MICRONUTRIENTS; CIGARETTE-SMOKING; CANCER; EPIDEMIOLOGY; FRUIT AB Background: The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects. Objective: We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk. Design: During 1998-2000, we identified incident NHL cases aged 20-74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake. Results: Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes-diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146). Conclusion: A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk. C1 [Frankenfeld, Cara L.; Morton, Lindsay M.; Hartge, Patricia; Ward, Mary H.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Cerhan, James R.] Coll Med, Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Cozen, Wendy] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Davis, Scott] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA. [Davis, Scott] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Schenk, Maryjean] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Schenk, Maryjean] Karmanos Canc Inst, Detroit, MI USA. RP Ward, MH (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8006, Rockville, MD 20852 USA. EM wardm@mail.nih.gov RI Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Frankenfeld, Cara/0000-0002-2318-0791 FU Intramural NIH HHS [ZIA CP010170-13]; NCI NIH HHS [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105] NR 19 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2008 VL 87 IS 5 BP 1439 EP 1445 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 301EZ UT WOS:000255880500044 PM 18469269 ER PT J AU Morris, MS Picciano, MF Jacques, PF Selhub, J AF Morris, Martha Savaria Picciano, Mar Frances Jacques, Paul F. Selhub, Jacob TI Plasma pyridoxal 5 '-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004 SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CORONARY-ARTERY-DISEASE; ORAL-CONTRACEPTIVE USE; VITAMIN B6 METABOLISM; TRYPTOPHAN-METABOLISM; HOMOCYSTEINE LEVELS; NONPREGNANT WOMEN; ESTROGEN STATUS; RISK-FACTORS; FOLATE; YOUNG AB Background: No large-scale, population-based study has considered the descriptive epidemiology of vitamin B-6 status with use of plasma pyridoxal 5'-phosphate (PLP), the indicator of vitamin B-6 adequacy used to set the current Recommended Dietary Allowance, which is <= 2 mg/d for all subgroups. Objectives: We sought to examine the epidemiology of vitamin B-6 status in the US population. Methods: In >6000 participants aged >= 1 y in the National Health and Nutrition Examination Survey (2003-2004), we considered relations between plasma PLP and various subject characteristics and examined trends in plasma PLP and homocysteine with vitamin B-6 intake, both overall and in selected subgroups. Results: In males, plasma PLP decreased with age after adolescence only in nonusers of supplemental vitamin B-6. Regardless of supplement use, plasma PLP concentrations of women of childbearing age were significantly lower than those of comparably aged men, and most oral contraceptive users had plasma PLP <20 nmol/L. The prevalence of low plasma PLP was significantly >3% at vitamin B-6 intakes from 2 to 2.9 mg/d in all subgroups and at intakes from 3 to 4.9 mg/d in smokers, the elderly, non-Hispanic blacks, and current and former oral contraceptive users. Intakes from 3 to 4.9 mg/d compared with <2 mg/d were associated with significant protection from low plasma PLP in most subgroups and from hyperhomocysteinemia in the elderly. Conclusions: Vitamin B-6 intakes of 3 to 4.9 mg/d appear consistent with the definition of a Recommended Dietary Allowance for most Americans. However, at that intake level, substantial proportions of some population subgroups may not meet accepted criteria for adequate vitamin B-6 status. C1 [Morris, Martha Savaria; Jacques, Paul F.; Selhub, Jacob] Tufts Univ, Nutr Epidemiol Program, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Picciano, Mar Frances] NIH, Off Dietary Supplements, Bethesda, MD USA. RP Morris, MS (reprint author), Tufts Univ, Nutr Epidemiol Program, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St,Romm 901 D, Boston, MA 02111 USA. EM martha.morris@tufts.edu FU NIH HHS [Y1-OD-6516-01] NR 60 TC 57 Z9 58 U1 0 U2 5 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2008 VL 87 IS 5 BP 1446 EP 1454 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 301EZ UT WOS:000255880500045 PM 18469270 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI Ethnic and socioeconomic differences in variability in nutritional biomarkers SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID 3RD NATIONAL-HEALTH; TO-DAY VARIATION; ALPHA-TOCOPHEROL; UNITED-STATES; ELDERLY-WOMEN; VITAMIN-C; BIOLOGICAL VARIABILITY; US POPULATION; SERUM-LIPIDS; RED WINE AB Background: Several studies have reported ethnic, education, and income differentials in concentrations of selected nutritional biomarkers in the US population. Although biomarker measurements are not subject to biased self-reports, biologic variability due to individual characteristics and behaviors related to dietary exposures contributes to within-subject variability and measurement error. Objective: We aimed to establish whether the magnitude of components of variance for nutritional biomarkers also differs in these high-risk groups. Design: We used data from 2 replicate measurements of serum concentrations of vitamins A, C, D, and E; folate; carotenoids; ferritin; and selenium in the third National Health and Nutrition Examination Survey second examination subsample (n = 948) to examine the within-subject and between-subject components of variance. We used multivariate regression methods with log-transformed analyte concentrations as outcomes to estimate the ratios of the within-subject to between-subject components of variance by categories of ethnicity, income, and education. Results: In non-Hispanic blacks, the within-subject to between-subject variance ratio for beta-cryptoxanthin concentration was higher (0.23; 95% CI: 0.17, 0.29) relative to non-Hispanic whites (0.13; 0.11, 0.16) and Mexican Americans (0.11; 0.07, 0.14), and the lutein + zeaxanthin ratio was higher (0.29; 0.21, 0.38) relative to Mexican Americans (0.15; 0.10, 0.19). Higher income was associated with larger within-subject to between-subject variance ratios for serum vitamin C and red blood cell folate concentrations but smaller ratios for serum vitamin A. Overall, there were few consistent up- or down-trends in the direction of covariate-adjusted variability by ethnicity, income, or education. Conclusion: Population groups at high risk of adverse nutritional profiles did not have larger variance ratios for most of the examined biomarkers. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Graubard, Barry I.] Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU Intramural NIH HHS; NCI NIH HHS [CA108274] NR 53 TC 12 Z9 12 U1 0 U2 5 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAY PY 2008 VL 87 IS 5 BP 1464 EP 1471 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 301EZ UT WOS:000255880500047 PM 18469272 ER PT J AU Anttila, V Nyholt, DR Kallela, M Artto, V Vepsalainen, S Jakkula, E Wennerstrom, A Tikka-Kleemola, P Kaunisto, MA Hamalainen, E Widen, E Terwilliger, J Merikangas, K Montgomery, GW Martin, NG Daly, M Kaprio, J Peltonen, L Farkkila, M Wessman, M Palotie, A AF Anttila, Verneri Nyholt, Dale R. Kallela, Mikko Artto, Ville Vepsalainen, Salli Jakkula, Eveliina Wennerstrom, Annika Tikka-Kleemola, Paeivi Kaunisto, Mari A. Hamalainen, Eija Widen, Elisabeth Terwilliger, Joseph Merikangas, Kathleen Montgomery, Grant W. Martin, Nicholas G. Daly, Mark Kaprio, Jaakko Peltonen, Leena Farkkila, Markus Wessman, Maija Palotie, Aarno TI Consistently replicating locus linked to migraine on 10q22-q23 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FAMILIAL HEMIPLEGIC MIGRAINE; GENOME-WIDE ASSOCIATION; LINKAGE ANALYSIS; SUSCEPTIBILITY LOCUS; COMPLEX TRAITS; MACULAR DEGENERATION; MULTIPLE-SCLEROSIS; GENETIC DISSECTION; PROSTATE-CANCER; INFLUENCES RISK AB Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants. C1 [Anttila, Verneri; Jakkula, Eveliina; Wennerstrom, Annika; Tikka-Kleemola, Paeivi; Kaunisto, Mari A.; Hamalainen, Eija; Terwilliger, Joseph; Peltonen, Leena; Wessman, Maija; Palotie, Aarno] Univ Helsinki, Res Program Mol Med, FIN-00290 Helsinki, Finland. [Anttila, Verneri; Jakkula, Eveliina; Wennerstrom, Annika; Tikka-Kleemola, Paeivi; Kaunisto, Mari A.; Hamalainen, Eija; Widen, Elisabeth; Wessman, Maija; Palotie, Aarno] Univ Helsinki, Finnish Genome Ctr, FIN-00290 Helsinki, Finland. [Anttila, Verneri; Wessman, Maija; Palotie, Aarno] Univ Helsinki, Cent Hosp, Dept Clin Chem, Helsinki 00029, Finland. [Nyholt, Dale R.; Montgomery, Grant W.; Martin, Nicholas G.] Queensland Inst Med Res, Genet Epidemiol Lab, Brisbane, Qld 4029, Australia. [Kallela, Mikko; Artto, Ville; Vepsalainen, Salli; Farkkila, Markus] Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki 00029, Finland. [Kaunisto, Mari A.; Wessman, Maija] Folkhalsan Res Ctr, Helsinki 00290, Finland. [Terwilliger, Joseph] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Terwilliger, Joseph] Columbia Univ, Columbia Genome Ctr, New York, NY 10032 USA. [Merikangas, Kathleen] NIMH, NIH, Sect Dev Genet Epidemiol, New York, NY 10032 USA. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. [Kaprio, Jaakko] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, SF-00300 Helsinki, Finland. [Jakkula, Eveliina; Peltonen, Leena] Natl Publ Hlth Inst, Dept Mol Med, Helsinki 00290, Finland. [Jakkula, Eveliina; Daly, Mark; Peltonen, Leena; Palotie, Aarno] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Anttila, Verneri; Peltonen, Leena; Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Palotie, A (reprint author), Univ Helsinki, Res Program Mol Med, FIN-00290 Helsinki, Finland. EM aarno@sanger.ac.uk RI Kaprio, Jaakko/A-1820-2008; Nyholt, Dale/C-8384-2013; Montgomery, Grant/B-7148-2008; OI Montgomery, Grant/0000-0002-4140-8139; Anttila, Verneri/0000-0002-0073-4675; Kaunisto, Mari/0000-0002-6946-9195; Kaprio, Jaakko/0000-0002-3716-2455; Martin, Nicholas/0000-0003-4069-8020 FU NCRR NIH HHS [U54 RR020278]; NIAAA NIH HHS [AA013320, AA013326, AA014041, AA07728, AA11998, P50 AA011998, R01 AA007535, R01 AA007728, R01 AA010249, R01 AA013320, R01 AA013326, R01 AA014041, R37 AA007728]; NINDS NIH HHS [R01 NS037675, R01 NS37675] NR 59 TC 26 Z9 26 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAY PY 2008 VL 82 IS 5 BP 1051 EP 1063 DI 10.1016/j.ajhg.2008.03.003 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 301VJ UT WOS:000255923600005 PM 18423523 ER PT J AU Farasat, SM Morrell, CH Scuteri, A Ting, CT Yin, FCP Spurgeon, HA Chen, CH Lakatta, EG Najjar, SS AF Farasat, S. Morteza Morrell, Christopher H. Scuteri, Angelo Ting, Chih-Tai Yin, Frank C. P. Spurgeon, Harold A. Chen, Chen-Huan Lakatta, Edward G. Najjar, Samer S. TI Do hypertensive individuals have enlarged aortic root diameters? Insights from studying the various subtypes of hypertension SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID ISOLATED SYSTOLIC HYPERTENSION; CARDIOVASCULAR-DISEASE ENTERPRISES; PRESSURE-FLOW RELATIONSHIP; MAJOR SHAREHOLDERS; ARTERIAL; HEART; REGURGITATION; PREVALENCE; ADULTS AB BACKGROUND Aortic root diameter (AoD) increases with aging and is related to body size. AoD is also presumed to increase in hypertension. In prior studies, however, after adjusting for age and body size, AoD did not differ between hypertensive and normotensive (NT) individuals. Hypertension is a heterogeneous condition with various subtypes that differ in pathophysiology and age distribution. We assessed whether AoD differs among subjects with the various subtypes of hypertension and nonhypertensive individuals. METHODS In 1,256 volunteers aged 30-79 years (48% women, 48% hypertensive; all untreated), AoD was measured at the sinuses of Valsalva with transthoracic echocardiography. Using cutoff values based on the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, subjects were identified as NT (23%), or prehypertensive (PH, 29%), or as having isolated diastolic (IDH, 6%), isolated systolic (ISH, 12%), or systolic-diastolic (SDH, 30%) hypertension. Groups were compared using analysis of variance with Bonferroni's correction. RESULTS AoD increased with age and body surface area (BSA) in both men (r=0.25 and 0.19, respectively) and women (r=0.30 and 0.22, respectively) (all P < 0.0001). In men, those identified as having IDH, ISH, and SDH each had a 6% larger AoD than NT individuals (all P < 0.05). In women, those identified with ISH and SDH had a 10 and 8% larger AoD than NT individuals, respectively (all P < 0.05). In both sexes, after indexing to BSA, only ISH individuals exhibited larger AoD compared with NT individuals (both P < 0.05). But, with further adjustment for age, these differences were no longer observed. CONCLUSIONS Even when the subtypes of hypertension are examined separately, age and BSA, not hypertension status, account for the AoD differences between NT and hypertensive subjects. C1 [Farasat, S. Morteza; Morrell, Christopher H.; Spurgeon, Harold A.; Lakatta, Edward G.; Najjar, Samer S.] NIA, Natl Inst Hlth, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Farasat, S. Morteza] NIA, Natl Inst Hlth, Clin Res Branch, Baltimore, MD 21224 USA. [Morrell, Christopher H.] Loyola Coll, Dept Math Sci, Baltimore, MD 21210 USA. [Scuteri, Angelo] Ist Nazl Ricovero E Cura, Unita Operat Geriat, Rome, Italy. [Ting, Chih-Tai; Chen, Chen-Huan] Natl Yang Ming Univ, Res Inst, Inst Clin Med & Cardiovasc, Taipei 112, Taiwan. [Ting, Chih-Tai] Taichung Vet Gen Hosp, Ctr Cardiovasc, Taichung, Taiwan. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. RP Najjar, SS (reprint author), NIA, Natl Inst Hlth, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. EM najjarsa@mall.nih.gov FU Intramural NIH HHS; NIA NIH HHS [N01-AG-1-2118] NR 20 TC 16 Z9 16 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2008 VL 21 IS 5 BP 558 EP 563 DI 10.1038/ajh.2008.10 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 288TP UT WOS:000255009000018 PM 18437147 ER PT J AU Lea, J Cheek, D Thornley-Brown, D Appel, L Agodoa, L Contreras, G Gassman, J Lash, J Miller, ER Randall, O Wang, XL McClellan, W AF Lea, Janice Cheek, Deanna Thornley-Brown, Denise Appel, Lawrence Agodoa, Lawrence Contreras, Gabriel Gassman, Jennifer Lash, Jim Miller, Edgar R., III Randall, Otelio Wang, Xuelei McClellan, William CA AASK Study Investigators TI Metabolic syndrome, proteinuria, and the risk of progressive CKD in hypertensive African Americans SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Nephrology CY NOV 14-19, 2006 CL San Diego, CA SP Amer Soc Nephrol DE hypertension; African Americans; chronic kidney disease; metabolic syndrome ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; BODY-MASS INDEX; INSULIN-RESISTANCE; US ADULTS; DIABETES-MELLITUS; BLOOD-PRESSURE; BETA-BLOCKERS AB Background: Chronic kidney disease (CKD) is more likely to progress to kidney failure (end-stage renal disease) in African Americans, although the reasons for this are unclear. Metabolic syndrome is a risk factor for the development of diabetes and cardiovascular disease and recently was linked to incident CKD. The purpose of this study is to examine whether metabolic syndrome is associated with kidney disease progression in hypertensive African Americans. Design & Participants: The current study design is a secondary analysis of the African-American Study of Hypertension and Kidney Disease, a randomized controlled trial of blood pressure goal and agents in hypertensive African Americans with CKD. Predictors: Metabolic syndrome was defined according to the modified National Cholesterol Education Program guidelines. Outcomes: Decrease in glomerular filtration rate of 50% or 25 mL/min/1.73 m(2), end-stage renal disease (initiation of dialysis therapy or transplantation), death, or a composite outcome of all 3. Results: 842 subjects were included in this analysis, and 41.7% met criteria for metabolic syndrome. Subjects meeting criteria for metabolic syndrome had greater levels of proteinuria. Cox regression analyses adjusted for age, sex, glomerular filtration rate, and other significant covariates except for proteinuria indicated a 31% increased risk, with a 95% confidence interval of 1.03 to 1.7(P = 0.03) for time to reach the composite outcome in those with metabolic syndrome. Adjusting for proteinuria, the effect was abated to 16% (95% confidence interval, 0.9 to 1.5), no longer remained significant (P = 0.2), and was unchanged by adjusting randomized treatment group (blood pressure goal or antihypertensive drug). Limitations: Lack of waist circumference as a better surrogate of abdominal obesity. Conclusions: In summary, metabolic syndrome is associated with proteinuria in hypertensive African Americans, but is not independently associated with CKD progression. C1 [Lea, Janice; McClellan, William] Emory Univ, Atlanta, GA 30322 USA. [Cheek, Deanna] Med Univ S Carolina, Charleston, SC 29425 USA. [Thornley-Brown, Denise] Univ Alabama, Birmingham, AL USA. [Appel, Lawrence; Miller, Edgar R., III] Johns Hopkins Univ, Baltimore, MD USA. [Agodoa, Lawrence] NIDDK, Bethesda, MD USA. [Contreras, Gabriel] Univ Miami, Coral Gables, FL 33124 USA. [Gassman, Jennifer; Wang, Xuelei] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Lash, Jim] Univ Illinois, Chicago, IL USA. [Randall, Otelio] Howard Univ, Washington, DC 20059 USA. RP Lea, J (reprint author), Emory Univ, 101 Woodruff Circle,WMB Rm 338, Atlanta, GA 30322 USA. EM jlea@emory.edu FU NCRR NIH HHS [5K30 RR 022291-08]; NIDDK NIH HHS [U01 DK048643] NR 27 TC 45 Z9 47 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAY PY 2008 VL 51 IS 5 BP 732 EP 740 DI 10.1053/j.ajkd.2008.01.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 295QY UT WOS:000255490200006 PM 18436083 ER PT J AU Pavkov, ME Knowler, WC Hanson, RL Bennett, PH Nelson, RG AF Pavkov, Meda E. Knowler, William C. Hanson, Robert L. Bennett, Peter H. Nelson, Robert G. TI Predictive power of sequential measures of albuminuria for progression to ESRD or death in Pima Indians with type 2 diabetes SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE diabetes; albuminuria; end-stage renal disease; mortality; prediction ID RENAL-DISEASE; BLOOD-PRESSURE; REMISSION; MICROALBUMINURIA; NEPHROPATHY; REGRESSION; RISK; PROTEINURIA; EXCRETION; REVERSAL AB Background: To determine whether historic albuminuria measurements provide additional predictive value for diabetic end-stage renal disease (ESRD) and natural mortality over the most recent measurement, ie, whether "regression" from high albuminuria has a different prognosis than stability at the lower level. Study Design: Observational longitudinal study. Setting & Participants: Pima Indians 15 years or older with type 2 diabetes and at least 2 consecutive measurements of urinary albumin-creatinine ratio (ACR) within 6 years. Predictors: Sequential measurements of urinary ACR. Outcomes & Measurements: Proportional hazards analyses were used to estimate the risk of ESRD and natural death associated with the first and second ACR measurement. The ability of these highly correlated variables to predict outcome was compared with receiver operating characteristic curves calculated by means of the generalized c statistic. Results: In 983 subjects, 136 developed ESRD and 180 died of natural causes during a maximum follow-up of 12.6 years. Each doubling in the second ACR was associated with a 1.71-fold greater incidence of ESRD (95% confidence interval, 1.54 to 1.89) and 1.16-fold greater natural mortality (95% confidence interval, 1.07 to 1.27) adjusted for age, sex, diabetes duration, and anti hypertensive medication. The addition of the first ACR measurement to the model did not add to the predictive value for ESRD or mortality. In pairwise comparisons of c statistics, the second ACR was a significantly better predictor of ESRD than the first ACR. Limitations: The predictive value of ACR measurements is decreased to the extent that its precision is based on a single measure. Conclusion: The predictive power of the latest ACR for ESRD and natural mortality in patients with diabetes is not enhanced by knowledge of the preceding ACR. Therefore, ACR changes over time, ie, regression or progression, add minimal predictive value beyond the latest measurement in the series. C1 [Pavkov, Meda E.; Knowler, William C.; Hanson, Robert L.; Bennett, Peter H.; Nelson, Robert G.] NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. RP Pavkov, ME (reprint author), NIDDK, Diabet Epidemiol & Clin Res Sect, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM mpavkov@cdc.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS [Z01 DK069063-12] NR 28 TC 22 Z9 22 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAY PY 2008 VL 51 IS 5 BP 759 EP 766 DI 10.1053/j.ajkd.2008.01.011 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 295QY UT WOS:000255490200009 PM 18436086 ER PT J AU Lindberg, DAB AF Lindberg, Donald A. B. TI Diagnostic error: Is overconfidence the problem - Introduction SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 Natl Lib Med, NIH, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Lindberg, DAB (reprint author), Natl Lib Med, NIH, Dept Hlth & Human Serv, Bldg 38,Room 2 E17,8600 Rockville Pike, Bethesda, MD 20894 USA. EM lindberg@nlm.nih.gov NR 0 TC 6 Z9 6 U1 1 U2 1 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 MAY PY 2008 VL 121 IS 5 SU 1 BP 1 EP 1 DI 10.1016/j.amjmed.2008.02.007 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 292MU UT WOS:000255271600002 ER PT J AU Komarow, HD Metcalfe, DD AF Komarow, Hirsh D. Metcalfe, Dean D. TI Office-based management of urticaria SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE allergy; angioedema; hives; urticaria ID CHRONIC IDIOPATHIC URTICARIA; CONTROLLED TRIAL; AUTOANTIBODIES; IGE AB Urticaria is a common pruritic skin disorder that is often seen in the office and varies in severity and chronicity. The etiologic cause is frequently not identifiable. Urticaria may be associated with physical factors and triggers, including foods or medications. A significant percentage of patients with chronic urticaria have circulating autoantibodies directed toward immunoglobulin-E or the high-affinity receptor for immunoglobulin-E (Fc epsilon RI), or have antithyroid antibodies that might play a role in the activation of the final common pathway in urticaria: mast cell activation and degranulation. Management begins with a careful investigation and elimination of eliciting factors when identified, followed by treatment of underlying disease. Antihistamines are the current mainstay of pharmacotherapy for urticaria, which provide symptomatic relief in most cases. In severe cases, corticosteroids, hydroxychloroquine sulfate ( Plaquenil; Sanofi-Synthelabo, New York, NY), and immunosuppressive agents, including cyclosporin, are sometimes used by specialists. (C) 2008 Elsevier Inc. All rights reserved. C1 [Komarow, Hirsh D.; Metcalfe, Dean D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Komarow, HD (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11s231,10 Ctr Dr, Bethesda, MD 20892 USA. EM komarowh@niaid.nih.gov FU Intramural NIH HHS NR 12 TC 7 Z9 7 U1 0 U2 2 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 MAY PY 2008 VL 121 IS 5 BP 379 EP 384 DI 10.1016/j.amjmed.2007.10.039 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 295ZI UT WOS:000255512900007 PM 18456030 ER PT J AU Haddad, R Romero, R Gould, BR Tromp, G Gotsch, F Edwin, SS Zingg, HH AF Haddad, Ramsi Romero, Roberto Gould, Barbara R. Tromp, Gerard Gotsch, Francesca Edwin, Samuel S. Zingg, Hans H. TI Angiogenesis gene expression in mouse uterus during the common pathway of parturition SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE anglogenesis; genomics; infection; labor; mouse; parturition; pregnancy; progesterone ID MYOMETRIAL PROGESTERONE RESPONSIVENESS; PLASMINOGEN-ACTIVATOR INHIBITOR-1; GROWTH-FACTOR RECEPTOR-1; INDUCED PRETERM LABOR; ENDOTHELIAL-CELLS; PREMATURE LABOR; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; INTRAUTERINE INFECTION; PROGESTATIONAL AGENTS; FUNCTIONAL GENOMICS AB OBJECTIVE: The objective of the study was to investigate changes in the expression of anglogenesis-related genes during the common terminal pathway of parturition including spontaneous labor at term, as well as preterm labor (PTL), induced by either bacteria or ovarlectomy. STUDY DESIGN: Preterm pregnant mice (14.5 days of gestation) were treated with the following: (1) intrauterine injection of medlar (2) intrauterine injection of heat-inactivated Escherichia coli, (3) ovarlectomy and (4) sham operation. Tissues from mice at term (19.5 days of gestation) were collected at term not in labor, term in labor, and 12 hours postpartum. Anglogenesis-related gene expression levels were quantitated by the measurement of specific mRNAs in uterine tissue by RT-qPCR and analyzed by repeated-measures analysis of variance. RESULTS: The following results were found: (1) microarray analysis of the uterine transcriptome indicated an enrichment for the gene ontol-ogy category of anglogenesis in bacteria-induced PTL samples (P <= .093) (2) several genes related to anglogenesis demonstrated significantly increased expression in samples in either term spontaneous labor or preterm labor and (3) qRT-PCR measurements demonstrated that spontaneous term labor and preterm labor induced by either bacteria or ovarlectomy all substantially increased the expression of multiple anglogenesis-related genes (P <= .0003 Angpt2, Ctgf, Cyr61, Dscr1, Pgf, Serpine1, Thbs1, and Wisp 1). CONCLUSION: Spontaneous labor at term, as well as pathologically induced preterm labor, all result in greatly increased expression of anglogenesis-related genes in the uterus. C1 [Romero, Roberto] Hutzel Womens Hosp, Detroit, MI 48201 USA. [Haddad, Ramsi] Karmanos Canc Inst, Translat Oncogenom Lab, Detroit, MI 48201 USA. [Haddad, Ramsi; Romero, Roberto; Tromp, Gerard; Gotsch, Francesca; Edwin, Samuel S.] Eunice Kennedy Shriver NICHHD, NIH, Div Intramural Res, Perintol Res Branch, Bethesda, MD 20892 USA. [Romero, Roberto; Tromp, Gerard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Gould, Barbara R.] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada. RP Romero, R (reprint author), Hutzel Womens Hosp, 4 Brush,3990 John R St, Detroit, MI 48201 USA. EM haddadr@Karmanos.org; nichdprbchiefstaff@med.wayne.edu RI Tromp, Gerard/B-2677-2017 OI Tromp, Gerard/0000-0002-7761-0806 FU Intramural NIH HHS NR 89 TC 2 Z9 2 U1 0 U2 4 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 MAY PY 2008 VL 198 IS 5 AR 539.e1 DI 10.1016/j.ajog.2007.11.021 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 295YV UT WOS:000255511600021 PM 18455529 ER PT J AU Mobeen, N Jehan, I Banday, N Moore, J McClure, EM Pasha, O Wright, LL Goldenberg, RL AF Mobeen, N. Jehan, I. Banday, N. Moore, J. McClure, E. M. Pasha, O. Wright, L. L. Goldenberg, R. L. TI Periodontal disease and adverse birth outcomes: a study from Pakistan SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med (SMFM) DE dental examination; Pakistan; periodontal disease; neonatal death; preterm birth; stillbirth ID PRETERM BIRTH; CARDIOVASCULAR-DISEASE; RISK; INFECTION; PREGNANCY; DELIVERY; HEALTH; WEIGHT; MECHANISMS; WOMEN AB OBJECTIVE: Periodontal disease may increase the risk of adverse birth outcomes however, results have been mixed. Few studies have examined periodontal disease in developing countries. We describe the relationship between periodontal disease and birth outcomes in a community setting in Pakistan. STUDY DESIGN: This was a prospective cohort study. Enrollment occurred at 20-26 weeks of gestation. A study dentist performed the periodontal examination to assess probing depth, clinical attachment level, gingival index, and plaque index. Outcomes included stillbirth, neonatal death, perinatal death, <32 weeks preterm birth, 32-36 weeks preterm birth, and low birthweight and are presented for increasing periodontal disease severity by quartiles. RESULTS: Dental examinations and outcome data were completed for 1152 women: 81% of the women were multiparous, with a mean age of 27 years 33% of the women had no education. Forty-seven percent of the women had dental caries; 27% of the women had missing teeth, and 91% of the women had had no dental care in the last year, Periodontal disease was common: 76% of the women had >= 3 teeth with a probing depth of >= 3 mm 87% of the women had >= 4 teeth with a clinical attachment level of >= 3 mm 56% of the women had >= 4 teeth with a plaque index of 3 and 60% of the women had >= 4 teeth with a gingival index of 3. As the measures of periodontal disease increased from the 1st to 4th quartile, stillbirth and neonatal and perinatal death also increased, with relative risks of approximately 1.3. Early preterm birth increased, but the results were not significant. Late preterm birth and low birthweight were not related to measures of periodontal disease. CONCLUSION: Pregnant Pakistani women have high levels of moderate-to-severe dental disease. Stillbirth and neonatal and perinatal deaths increased with the severity of periodontal disease. C1 [Goldenberg, R. L.] Drexel Univ, Coll Med, Dept Obstet Gynecol, Philadelphia, PA 19102 USA. [Mobeen, N.; Jehan, I.; Banday, N.; Pasha, O.] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan. [Moore, J.; McClure, E. M.] Res Triangle Inst, Dept Stat & Epidemiol, Res Triangle Pk, NC 27709 USA. [Wright, L. L.] NICHD, Bethesda, MD USA. RP Goldenberg, RL (reprint author), Drexel Univ, Coll Med, Dept Obstet Gynecol, 245 N 15th St, Philadelphia, PA 19102 USA. EM rgoldenb@drexelmed.edu FU NICHD NIH HHS [U01 HD040636, U01HD040607, U01 HD040607]; PHS HHS [U0104063606] NR 37 TC 5 Z9 5 U1 0 U2 4 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 MAY PY 2008 VL 198 IS 5 AR 514.e1 DI 10.1016/j.ajog.2008.03.010 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 295YV UT WOS:000255511600011 PM 18455527 ER PT J AU Oakley, F Caswell, S Parks, R AF Oakley, Frances Caswell, Stacie Parks, Rebecca TI Occupational therapists' role on US army and US public health service commissioned corps disaster mental health response teams SO AMERICAN JOURNAL OF OCCUPATIONAL THERAPY LA English DT Editorial Material DE disaster response; mental health; occupational therapy C1 [Oakley, Frances] Natl Inst Hlth, US Publ Hlth Serv, Occupat Therapy Sect, Dept Rehabil Med,Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Caswell, Stacie] USA, Ft Hood, TX USA. [Parks, Rebecca] Natl Inst Hlth, US Publ Hlth Serv & Occupat Therapy Educ Coordina, Dept Rehabil Med, Mark O Hatfield Clin Res Ctr, Bethesda, MD USA. RP Oakley, F (reprint author), Natl Inst Hlth, US Publ Hlth Serv, Occupat Therapy Sect, Dept Rehabil Med,Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. EM foakley@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 18 TC 2 Z9 2 U1 2 U2 3 PU AMER OCCUPATIONAL THERAPY ASSOC, INC PI BETHESDA PA 4720 MONTGOMERY LANE, BETHESDA, MD 20814-3425 USA SN 0272-9490 J9 AM J OCCUP THER JI Am. J. Occup. Ther. PD MAY-JUN PY 2008 VL 62 IS 3 BP 361 EP 364 PG 4 WC Rehabilitation SC Rehabilitation GA 299NP UT WOS:000255762600012 PM 18557012 ER PT J AU del Castillo, G Factor, VM Fernandez, M Alvarez-Barrientos, A Fabregat, I Thorgeirsson, SS Sanchez, A AF del Castillo, Gaelle Factor, Valentina M. Fernandez, Margarita Alvarez-Barrientos, Alberto Fabregat, Isabel Thorgeirsson, Snorri S. Sanchez, Aranzazu TI Deletion of the met tyrosine kinase in liver progenitor oval cells increases sensitivity to apoptosis in vitro SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; STEM-LIKE CELLS; RAT-LIVER; FACTOR-BETA; C-MET; EPITHELIAL-CELLS; ADULT-RAT; HEPATOCELLULAR-CARCINOMA; SIGNALING PATHWAY; MESSENGER-RNA AB The hepatocyte growth factor (HGF)/Met signaling system is essential for liver development, homeostasis, and function. in this study, we took advantage of a liver-specific, Met-conditional knockout mouse generated in our laboratory to address the molecular mechanisms of HGF/Met signaling in adult liver progenitor cell (oval cell) biology. For this purpose, we isolated oval cells from 3,5-diethoxycarbonyl-1,4-dihydro-collidine-treated Met(flx/flx) mice and established oval cell-derived cell lines that carried either functional (Met(flx/flx)) or a nonfunctional (Met(-/-)) met gene using virus-mediated Cre-loxP recombination. Oval cells lacking Met tyrosine kinase activity displayed neither Met phosphorylation nor activation of downstream targets and were refractory to HGF stimulation. Although Met(-/-) and Met(flx/flx) cells proliferated at similar rates under 10% serum, Met-deficient cells demonstrated decreased cell viability and were more prone to apoptosis when challenged with either serum starvation or the pro-apoptotic cytokine transforming growth factor-beta. Treatment with RGF reduced transforming growth factor-beta-mediated cell death in Met(flx/flx) but not Met(-/-) cells. Importantly, Met(flx/flx) and Met(-/-) cells both constitutively expressed hgf, and conditioned medium from serum-starved oval cells exhibited anti-apoptotic activity in Met(flx/flx) cells. Furthermore, serum-starved Met(flx/flx) cells showed persistent activation of the Met tyrosine kinase, suggesting HGF/Met autocrine regulation. In conclusion, these data reveal a critical, functional role for Met in oval cell survival through an autocrine mechanism. C1 [del Castillo, Gaelle; Fernandez, Margarita; Sanchez, Aranzazu] Univ Complutense Madrid, Fac Farm, Dept Bioquim & Biol Mol 2, E-28040 Madrid, Spain. [Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, NIH, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Alvarez-Barrientos, Alberto] Fdn Ctr Nacl Invest Cadiovasc, Unidad Citometria, Madrid, Spain. [Fabregat, Isabel] Hosp, Ctr Mol Oncol, Fdn Inst Invest Biomed Bellvitge, Barcelona, Spain. RP Sanchez, A (reprint author), Univ Complutense Madrid, Fac Farm, Dept Bioquim & Biol Mol 2, Pl Ramon & Cajal S-N, E-28040 Madrid, Spain. EM munozas@farm.ucm.es RI Alvarez-Barrientos, Alberto/L-9299-2014; Sanchez, Aranzazu/H-7810-2015; Fernandez, Margarita/H-9077-2015 OI Alvarez-Barrientos, Alberto/0000-0003-4761-0212; Sanchez, Aranzazu/0000-0001-9145-6633; Fernandez, Margarita/0000-0001-7207-2028 NR 55 TC 15 Z9 15 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAY PY 2008 VL 172 IS 5 BP 1238 EP 1247 DI 10.2353/ajpath.2008.070793 PG 10 WC Pathology SC Pathology GA 294CP UT WOS:000255382000008 PM 18385520 ER PT J AU Mikolajczyk, RT Zhang, J Troendle, J Chan, L AF Mikolajczyk, Rafael T. Zhang, Jun Troendle, James Chan, Linda TI Risk factors for birth canal lacerations in primiparous women SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article DE laceration; perineum; duration of second stage; episiotomy ID ANAL-SPHINCTER LACERATIONS; VACUUM-ASSISTED DELIVERIES; FETAL HEAD POSITION; VAGINAL DELIVERY; URINARY-INCONTINENCE; PROLONGED 2ND-STAGE; NATURAL EXPERIMENT; FORCEPS; LABOR; EPISIOTOMY AB Lacerations of the birth canal are common side effects of vaginal birth. They are potentially preventable. Although serious long-term consequences have been identified for severe perineal lacerations, less attention has been paid to lacerations in other locations and how the risk factors vary for different lacerations. We analyzed a dataset including 1009 primiparous women with singleton pregnancies and vaginal deliveries, and we examined risk factors for third- and fourth-degree perineal lacerations and periurethral, vaginal, and labial lacerations using logistic regression analysis. Large fetal size (>= 3500 g) substantially increased the risk of perineal (odd ratio [OR], 3.8; 95% confidence interval [CI], 1.8 to 7.9) and periurethral (OR, 2.3; 95% CI, 1.0 to 5.0) lacerations but not other types of lacerations. Episiotomy had no impact on perineal lacerations (OR 0.9) but had very strong protective effects for other lacerations (OR 0.1). Prolonged second stage of labor (> 120 minutes) increased the risk of perineal and vaginal lacerations but reduced the risk for periurethral lacerations. Instrumental deliveries were significant risk factors for third- and fourth-degree perineal lacerations, with by far the strongest effect for low forceps (OR 25.0 versus < 3 for outlet forceps, outlet vacuum, and low vacuum). We concluded that separating different birth canal lacerations is critical in identifying risk factors and potential preventive strategies. C1 [Mikolajczyk, Rafael T.; Zhang, Jun; Troendle, James] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Chan, Linda] Naval Med Ctr San Diego, Dept Gynecol & Obstet, San Diego, CA USA. RP Mikolajczyk, RT (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. OI Mikolajczyk, Rafael/0000-0003-1271-7204 FU Intramural NIH HHS [Z99 HL999999] NR 30 TC 9 Z9 9 U1 0 U2 1 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 MAY PY 2008 VL 25 IS 5 BP 259 EP 264 DI 10.1055/s-2008-1075040 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 305QN UT WOS:000256193000001 PM 18509884 ER PT J AU Deshpande, N Metter, EJ Bandinelli, S Lauretani, F Windham, BG Ferrucci, L AF Deshpande, Nandini Metter, E. Jeffrey Bandinelli, Stefania Lauretani, Fulvio Windham, B. Gwen Ferrucci, Luigi TI Psychological, physical, and sensory correlates of fear of falling and consequent activity restriction in the elderly: The InCHIANTI study SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE fear of falling; aging; personal mastery; activity restriction ID PERSONAL COPING RESOURCES; SOCIAL SUPPORT; OLDER PERSONS; PERFORMANCE; VALIDATION; COMMUNITY; DISEASE; ADULTS; RISK; AGE AB Objective: To identify psychological, physical, and sensory function parameters that are specifically associated with fear of failing (FF) and fear-induced activity restriction in a population-based sample of older adults. Design: FF, fear-induced activity restriction, cognition, depression, personal mastery, chair-stand performance, standing balance, lower-limb and grip strength, visual acuity and contrast sensitivity, and vibrotactile sensitivity were evaluated in the population-based, older cohort (n = 926, age >= 65) enrolled in the InCHIANTI study. Results: Nearly 50% participants reported FF. Of these, 65% reported some activity restriction. Personal mastery (P < 0.001) and chair-standing performance (P = 0.001) were independently associated with FF. In those who did not-have depression, personal mastery, standing balance, lower-limb strength, and visual contrast sensitivity were associated with activity restriction (P < 0.001-0.011). In those who were depressed, total FF was the major factor strongly associated with activity restriction (P < 0.001), with marginal but significant associations for cognition (P = 0.027) and standing balance (P = 0.015). Conclusion: Psychological and physical factors are independently associated with FF. Presence of depression possibly modulates which factors, in addition to fear of falling, affect fear-induced activity restriction. A longitudinal study is warranted to substantiate causal relationships. C1 [Deshpande, Nandini] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Metter, E. Jeffrey; Windham, B. Gwen; Ferrucci, Luigi] NIA, Longitudinal Study Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Rehabil Unit, Florence, Italy. [Lauretani, Fulvio] Tuscany Reg Hlth Agcy, Florence, Italy. RP Deshpande, N (reprint author), Univ Kansas, Med Ctr, 3901 Rainbow Blvd,MS 2002, Kansas City, KS 66160 USA. RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [NIH0011391454, Z01 AG000640-15]; NIA NIH HHS [R01 AG027012, N01 AG5-002, N01-AG-5-0002, N01-AG-821336, N01-AG-916413] NR 32 TC 51 Z9 54 U1 1 U2 8 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 MAY PY 2008 VL 87 IS 5 BP 354 EP 362 DI 10.1097/PHM.0b013e31815e6e9b PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 294RY UT WOS:000255424400002 PM 18174852 ER PT J AU Kunos, G Osei-Hyiaman, D AF Kunos, George Osei-Hyiaman, Douglas TI Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE cannabinoid receptors; metabolic syndrome; appetite; lipogenesis; cardiovascular risk factors ID RECEPTOR ANTAGONIST SR141716; ADIPOSE-TISSUE; CB1 RECEPTORS; INSULIN-SECRETION; ENERGY-BALANCE; WEIGHT-GAIN; FOOD-INTAKE; FA/FA RATS; SYSTEM; ACTIVATION AB Endocannabinoids and Liver Disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 294: G1101-G1104, 2008. First published February 21, 2008; doi:10.1152/ajpgi.00057.2008. Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptin-regulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences. C1 [Kunos, George; Osei-Hyiaman, Douglas] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, 5625 Fishers Ln,Rm 2S-24,MSC-9413, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov NR 25 TC 21 Z9 22 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD MAY PY 2008 VL 294 IS 5 BP G1101 EP G1104 DI 10.1152/ajpgi.00057.2008 PG 4 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 296TS UT WOS:000255569300001 PM 18292184 ER PT J AU Kim, SM Huang, Y Qin, Y Mizel, D Schnermann, J Briggs, JP AF Kim, Soo Mi Huang, Yuning Qin, Yan Mizel, Diane Schnermann, Jurgen Briggs, Josephine P. TI Persistence of circadian variation in arterial blood pressure in beta(1)/beta(2)-adrenergic receptor-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE salt intake; sympathetic nervous system ID SPONTANEOUSLY HYPERTENSIVE-RATS; NACL-SENSITIVE HYPERTENSION; HEART-RATE; TRANSGENIC MICE; RHYTHMS; SLEEP; NOREPINEPHRINE; DEPENDENCY; MORTALITY; LACKING AB Persistence of circadian variation in arterial blood pressure in beta 1/ beta 2-adrenergic receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol 294: R1427-R1434, 2008. First published February 27, 2008; doi:10.1152/ajpregu.00074.2008.-The beta-adrenergic pathway has been considered one important effector of circadian variation in arterial pressure. Experiments were performed in beta 1/ beta 2-adrenergic receptor-deficient mice ( beta 1/ beta 2ADR -/-) to assess whether this pathway is required for circadian variation in mean arterial pressure ( MAP) and to determine the impact of its loss on the response to changes in dietary salt. Twenty-four-hour recordings of MAP, heart rate ( HR), and locomotor activity were made in conscious 16- to 17-wk-old mice [ wild-type, ( WT), n = 7; beta 1/ beta 2ADR -/-, n = 10] by telemetry. Both WT and beta 1/ beta 2ADR -/- mice demonstrated robust circadian variation in MAP and HR, although 24-h mean MAP was 10% lower ( 102.02 +/- 1.81 vs. 92.11 +/- 2.62 mmHg) in beta 1/ beta 2ADR -/- than WT, HR was 16% lower and day-night differences reduced. Both WT and beta 1/ beta 2ADR -/- mice adapted to changed salt intake without changed MAP. However, the beta 1/ beta 2ADR -/- mice demonstrated a striking reduction in locomotor activity in light and dark phases of the day. In WT mice, MAP was markedly affected by locomotor activity, resulting in bimodal distributions in both light and dark. When MAP was analyzed using only intervals without locomotor activity, bimodality and circadian differences were reduced, and there was no significant difference between the two genotypes. The results indicate that there is no direct effect or role for the beta-adrenergic system in circadian variation of arterial pressure in mice, aside from the indirect consequences of altered locomotor activity. Our results also confirm that locomotor activity contributes strongly to circadian variation in blood pressure in mice. C1 [Kim, Soo Mi; Huang, Yuning; Qin, Yan; Mizel, Diane; Schnermann, Jurgen; Briggs, Josephine P.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Briggs, JP (reprint author), NIDDK, NIH, 10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM briggsj@mail.nih.gov RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU Intramural NIH HHS [Z01 DK043410-01] NR 28 TC 13 Z9 13 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAY PY 2008 VL 294 IS 5 BP R1427 EP R1434 DI 10.1152/ajpregu.00074.2008 PG 8 WC Physiology SC Physiology GA 295VC UT WOS:000255501000003 PM 18305025 ER PT J AU Wright, CL Burgoon, PW Bishop, GA Boulant, JA AF Wright, Chadwick L. Burgoon, Penny W. Bishop, Georgia A. Boulant, Jack A. TI Cyclic GMP alters the firing rate and thermosensitivity of hypothalamic neurons SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE guanosine monophosphate; neuronal activity; soluble guanylate cyclase; cyclic nucleotide-gated channel; immunohistochemistry; electrophysiology ID DEPENDENT PROTEIN-KINASE; NITRIC-OXIDE SYNTHASE; GATED ION CHANNELS; SUPRACHIASMATIC NUCLEUS; THERMAL STIMULATION; SIGNALING PATHWAY; GUANYLATE-CYCLASE; BODY-TEMPERATURE; PREOPTIC REGION; NERVOUS-SYSTEM AB The rostral hypothalamus, especially the preoptic-anterior hypothalamus (POAH), contains temperature-sensitive and -insensitive neurons that form synaptic networks to control thermoregulatory responses. Previous studies suggest that the cyclic nucleotide cGMP is an important mediator in this neuronal network, since hypothalamic microinjections of cGMP analogs produce hypothermia in several species. In the present study, immunohistochemisty showed that rostral hypothalamic neurons contain cGMP, guanylate cyclase (necessary for cGMP synthesis), and CNG A2 (an important cyclic nucleotide-gated channel). Extracellular electrophysiological activity was recorded from different types of neurons in rat hypothalamic tissue slices. Each recorded neuron was classified according to its thermosensitivity as well as its firing rate response to 2-100 mu M 8-bromo-cGMP (a membrane-permeable cGMP analog). cGMP has specific effects on different neurons in the rostral hypothalamus. In the POAH, the cGMP analog decreased the spontaneous firing rate in 45% of temperature-sensitive and -insensitive neurons, an effect that is likely due to cGMP-enhanced hyperpolarizing K+ currents. This decreased POAH activity could attenuate thermoregulatory responses and produce hypothermia during exposures to cool or neutral ambient temperatures. Although 8-bromo-cGMP did not affect the thermosensitivity of most POAH neurons, it did increase the warm sensitivity of neurons in other hypothalamic regions located dorsal, lateral, and posterior to the POAH. This increased thermosensitivity may be due to pacemaker currents that are facilitated by cyclic nucleotides. If some of these non-POAH thermosensitive neurons promote heat loss or inhibit heat production, then their increased thermosensitivity could contribute to cGMP-induced decreases in body temperature. C1 [Wright, Chadwick L.; Boulant, Jack A.] Ohio State Univ, Dept Physiol & Cell Biol, Columbus, OH 43210 USA. [Burgoon, Penny W.] NIH, Off Director, Bethesda, MD USA. [Bishop, Georgia A.] Ohio State Univ, Dept Neurosci, Columbus, OH USA. RP Boulant, JA (reprint author), Ohio State Univ, Dept Physiol & Cell Biol, 201 Hamilton Hall,1645 Neil Ave, Columbus, OH 43210 USA. EM boulant.1@osu.edu RI Wright, Chadwick/D-4597-2012 OI Wright, Chadwick/0000-0003-0117-9420 FU NINDS NIH HHS [NS 045758, NS 14644] NR 41 TC 7 Z9 8 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAY PY 2008 VL 294 IS 5 BP R1704 EP R1715 DI 10.1152/ajpregu.00714.2007 PG 12 WC Physiology SC Physiology GA 295VC UT WOS:000255501000037 PM 18321955 ER PT J AU Yasuda, H Leelahavanichkul, A Tsunoda, S Dear, JW Takahashi, Y Ito, S Hu, XZ Zhou, H Doi, K Childs, R Klinman, DM Yuen, PST Star, RA AF Yasuda, Hideo Leelahavanichkul, Asada Tsunoda, Shinichiro Dear, James W. Takahashi, Yoshiyuki Ito, Shuichi Hu, Xuzhen Zhou, Hua Doi, Kent Childs, Richard Klinman, Dennis M. Yuen, Peter S. T. Star, Robert A. TI Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE multiple organ failure; innate immune system; bacterial products; cytokines ID DECREASES LYMPHOCYTE APOPTOSIS; TOLL-LIKE RECEPTOR-3; ACUTE-RENAL-FAILURE; IMPROVES SURVIVAL; CPG-DNA; SYSTEMIC INFLAMMATION; CELL-DEATH; IN-VIVO; MICE; ACTIVATION AB Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and AKI in a clinically relevant polymicrobial sepsis mouse model, even when administered 6 h after the septic insult. Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF-alpha and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development. C1 [Yasuda, Hideo; Leelahavanichkul, Asada; Dear, James W.; Hu, Xuzhen; Zhou, Hua; Doi, Kent; Yuen, Peter S. T.; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Takahashi, Yoshiyuki; Childs, Richard] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Tsunoda, Shinichiro; Ito, Shuichi; Klinman, Dennis M.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. RP Yasuda, H (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Rm 3N108, Bethesda, MD 20892 USA. EM py@nih.gov RI Takahashi, Yoshiyuki/I-1929-2012; Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU Intramural NIH HHS [Z01 DK043403-08] NR 51 TC 77 Z9 83 U1 0 U2 2 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 MAY PY 2008 VL 294 IS 5 BP F1050 EP F1058 DI 10.1152/ajprenal.00461.2007 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 295VE UT WOS:000255501200004 PM 18305095 ER PT J AU Breslau, ES Ballard-Barbash, RR Nelson, DE Canales, M AF Breslau, Erica S. Ballard-Barbash, Rachel R. Nelson, David E. Canales, Mary TI Translation of the 2002 hormone study findings SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Letter ID MEDIA C1 [Breslau, Erica S.; Ballard-Barbash, Rachel R.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Nelson, David E.] Ctr Dis Control & Prevent, Off Smoking & Hlth, Atlanta, GA USA. [Canales, Mary] Mahantucket Pequot Tribal Nation, Bemidji, MN USA. RP Breslau, ES (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM breslaue@mail.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2008 VL 34 IS 5 BP 451 EP 451 DI 10.1016/j.amepre.2008.02.007 PG 1 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 299NE UT WOS:000255761500013 PM 18407015 ER PT J AU Volkow, ND Swanson, JM AF Volkow, Nora D. Swanson, James M. TI Does childhood treatment of ADHD with stimulant medication affect substance abuse in adulthood? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; METHYLPHENIDATE C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Rm 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 14 TC 30 Z9 30 U1 0 U2 4 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 MAY PY 2008 VL 165 IS 5 BP 553 EP 555 DI 10.1176/appi.ajp.2008.08020237 PG 3 WC Psychiatry SC Psychiatry GA 295YT UT WOS:000255511400002 PM 18450933 ER PT J AU Domino, ME Burns, BJ Silva, SG Kratochvil, CJ Vitiello, B Reinecke, MA Mario, J March, JS AF Domino, Marisa Elena Burns, Barbara J. Silva, Susan G. Kratochvil, Christopher J. Vitiello, Benedetto Reinecke, Mark A. Mario, Jeremy March, John S. TI Cost-effectiveness of treatments for adolescent depression: Results from TADS SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSION; PRIMARY-CARE; CHILDREN; HEALTH; LIFE AB Objective: While the evidence base for treatments for adolescent depression is building, little is known about the relative efficiency of such treatments. Treatment costs are a relevant concern given the competing demands on family and health care budgets. The authors evaluated the cost-effectiveness of three active treatments among adolescents with major depressive disorder. Method: Volunteers (N=439) ages 12 to 18 with a primary diagnosis of major depressive disorder participated in a randomized, controlled trial conducted at 13 U. S. academic and community clinics from 2000 to 2004. Subjects included those participants who did not drop out and had evaluable outcome and cost data at 12 weeks (N=369). Subjects were randomly assigned to 12 weeks of either fluoxetine alone (10-40 mg/day), CBT alone, CBT combined with fluoxetine (10-40 mg/day), or placebo (equivalent to 10-40 mg/day). Both placebo and fluoxetine were administered double-blind; CBT alone and CBT in combination with fluoxetine were administered unblinded. Societal cost per unit of improvement on the Children's Depression Rating Scale-Revised and cost per quality-adjusted life year (QALY) were compared. Results: Results ranged from an incremental cost over placebo of $24,000 per QALY for treatment with fluoxetine to $123,000 per QALY for combination therapy treatment. The cost-effectiveness ratio for CBT treatment was not evaluable due to negative clinical effects. The models were robust on a variety of assumptions. Conclusions: Both fluoxetine and combination therapy are at least as cost-effective in the short-term as other treatments commonly used in primary care (using a threshold of $125,000/QALY). Fluoxetine is more cost-effective than combination therapy after 12 weeks of treatment. C1 Univ N Carolina, Sch Publ Hlth, Dept Hlth Policy & Adm, Chapel Hill, NC 27599 USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. Duke Clin Res Inst, Durham, NC USA. Duke Univ, Med Ctr, Dept Child & Adolescent Psychiat, Durham, NC USA. Univ Nebraska, Med Ctr, Dept Psychiat, Omaha, NE 68182 USA. NIMH, Div Serv & Intervent Res, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. RP Domino, ME (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Hlth Policy & Adm, 1104G McGavran Greenberg Hall,CB 7411, Chapel Hill, NC 27599 USA. EM domino@unc.edu FU NIMH NIH HHS [K01 MH-065639, N01 MH-80008] NR 31 TC 41 Z9 41 U1 1 U2 8 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 MAY PY 2008 VL 165 IS 5 BP 588 EP 596 DI 10.1176/appi.ajp.2008.07101610 PG 9 WC Psychiatry SC Psychiatry GA 295YT UT WOS:000255511400012 PM 18413703 ER PT J AU Blum, N Fee, E AF Blum, Nava Fee, Elizabeth TI The Sungari River flood and the Jewish community in Harbin, China SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Blum, Nava] Univ Haifa, Sch Publ Hlth, IL-31905 Haifa, Israel. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Blum, N (reprint author), Univ Haifa, Sch Publ Hlth, IL-31905 Haifa, Israel. EM navablum@hotmail.com NR 4 TC 0 Z9 0 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2008 VL 98 IS 5 BP 823 EP 823 DI 10.2105/AJPH.2007.129742 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 295RY UT WOS:000255492800015 PM 18381983 ER PT J AU Kalkunte, S Chichester, CO Gotsch, F Sentman, CL Romero, R Sharma, S AF Kalkunte, Satyan Chichester, Clinton O. Gotsch, Francesca Sentman, Charles L. Romero, Roberto Sharma, Surendra TI Evolution of non-cytotoxic uterine natural killer cells SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE angiogenic factors; decidua; inducible tertiary lymphoid tissue; natural killer cells; non-cytotoxicity; pregnancy ID DECIDUAL NK CELLS; HUMAN ENDOMETRIUM; PERIPHERAL-BLOOD; BONE-MARROW; EXPRESSION; MICE; PREGNANCY; INFLAMMATION; RECEPTOR; INTERLEUKIN-10 AB The immune tolerance and de novo vascularization are two highly intriguing processes at the maternal-fetal interface that appear to be central to normal pregnancy outcome. Immune tolerance occurs despite the local presence of an active maternal immune system including macrophages, dendritic cells and specialized CD56(bright)CD16(-) uterine natural killer (uNK) cells (65-70%). Recent observations indicate that the phenotypic and functional repertoire of uNK cells is distinct from peripheral blood NK and endometrial NK cells, challenging the understanding of their temporal occurrence and function. Origin and specialized programming of uNK cells continue to be debated. uNK cells, replete with an armamentarium to kill the foreign, tolerate the conceptus and facilitate pregnancy. Why do these uNK cells remain non-cytotoxic? Are these NK cells 'multitasking' in nature harboring beneficial and detrimental roles in pregnancy? Are there distinct subpopulations of NK cells that may populate the decidua? We propose that the endometrium/decidua functions as an 'inducible tertiary lymphoid tissue' that supports the recruitment and expansion of CD56(bright)CD16(-) NK cells and induces transcriptional up-regulation of angiogenic machinery in response to exposure to local hormonal factors, cytokine milieu and perhaps hypoxia. The angiogenic features of uNK cells could further result in a 'multitasking' phenotype that still remains to be characterized. This article discusses the factors and pathways that bridge the angiogenic and non-cytotoxic response machineries at the maternal-fetal interface. C1 [Kalkunte, Satyan; Sharma, Surendra] Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. [Chichester, Clinton O.] Univ Rhode Isl, Sch Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Gotsch, Francesca; Romero, Roberto] NICHHD, Perinatol Res Branch, Detroit, MI USA. [Sentman, Charles L.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Microbiol & Immunol, Hanover, NH 03756 USA. RP Sharma, S (reprint author), Brown Univ, Warren Alpert Med Sch, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. EM ssharma@wihri.org FU NCRR NIH HHS [P20 RR018728, P20 RR018728-05, P20RR018728]; NICHD NIH HHS [HD41701]; NIEHS NIH HHS [P42 ES013660, P42ES013660] NR 47 TC 54 Z9 57 U1 0 U2 8 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD MAY PY 2008 VL 59 IS 5 BP 425 EP 432 DI 10.1111/j.1600-0897.2008.00595.x PG 8 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 286OR UT WOS:000254855800006 PM 18405313 ER PT J AU Shia, J Tang, LH Weiser, MR Brenner, B Adsaj, NV Stelow, EB Saltz, LB Qin, J Landmann, R Leonard, GD Dhall, D Temple, L Guillem, JG Paty, PB Kelsen, D Wong, D Klimstra, DS AF Shia, Jinru Tang, Lattra H. Weiser, Martin R. Brenner, Bartich Adsaj, N. Volkan Stelow, Edward B. Saltz, Leonard B. Qin, Jing Landmann, Ron Leonard, Gregory D. Dhall, Deepti Temple, Larissa Guillem, Jose G. Paty, Philip B. Kelsen, David Wong, Douglas Klimstra, David S. TI Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE large cell neuroendocrine carcinoma; histologic classification; colon and rectum; small cell carcinoma; nonsmall cell carcinoma ID SYNOVIAL SARCOMA; TUMORS; COLON; RECTUM; LYMPHOMAS; PROFILES; AMPULLA; VATER; LUNG AB Although small cell carcinoma of the gastrointestinal (GI) tract is well-recognized, nonsmall cell type high-grade neuroendocrine carcinoma (HGNEC) of this site remains undefined. At the current time, neither the World Health Organization nor American Joint Committee on Cancer includes this condition in the histologic classifications, and consequently it is being diagnosed and treated inconsistently. In this study, we aimed at delineating the histologic and immunophenotypical spectrum of HGNECs of the GI tract with emphasis on histologic subtypes. Guided primarily by the World Health Organization/International Association for the Study of Lung Cancer criteria for pulmonary neuroendocrine tumors, we were able to classify 87 high-grade GI tract tumors that initially carried a diagnosis of either poorly differentiated carcinoma with or without any neuroendocrine characteristics, small cell carcinoma, or combined adenocarcinoma-neuroendocrine carcinoma into the following 4 categories. The first was small cell carcinoma (n = 23), which had features typical of pulmonary small cell carcinoma, although the cells tended to have a more round nuclear contour. The second was large cell neuroendocrine carcinoma (n = 31), which had a morphology similar to its pulmonary counterpart and showed positive immunoreactivity for either chromogranin (71%) or synaptophysin (94/,,) or both. The third was mixed neuroendocrine carcinoma (n = 11), which had intermediate histologic features (eg, cells with an increased nuclear/cytoplasmic ratio but with apparent nucleoli), and positive immunoreactivity for at least 1 neuroendocrine marker. The fourth was poorly differentiated adenocarcinoma (n = 17). In addition, 5 of the 87 tumors showed either nonsmall cell type neuroendocrine morphology (n = 3) or immunohistochemical reactivity for neuroendocrine markers (n = 2), but not both. Further analysis showed that most HGNECs arising in the squamous lined parts (esophagus and anal canal) were small cell type (78%), whereas most involving the glandular mucosa were large cell (53%) or mixed (82%) type; associated adenocarcinomas were more frequent in large cell (61 %) or mixed (36%) type than in small cell type (26%); and focal intracytoplasmic mucin was seen only in large cell or mixed type. As a group, the 2-year disease-specific survival for patients with HGNEC was 25.4% (median follow-up time, 11.3 mo). No significant survival difference was observed among the different histologic subtypes. In conclusion, Our study demonstrates the existence of both small cell and nonsmall cell types of HGNEC in the GI tract, and provides a detailed illustration of their morphologic spectrum. There are differences in certain pathologic. features between small cell and nonsmall cell types, whereas the differences between the subtypes or nonsmall cell category (large cell versus mixed) are less distinct. Given the current uncertainty as to whether large cell neuroendocrine carcinoma is as chemosensitive as small cell carcinoma even in the lung, our data provide further evidence in favor of a dichotomous classification scheme (small cell vs. nonsmall cell) for HGNEC of the GI tract. Separation of nonsmall cell type into large cell and mixed subtypes may not be necessary. These tumors are clinically aggressive. Prospective studies using defined diagnostic criteria are needed to determine their biologic characteristics and optimal management. C1 [Shia, Jinru; Tang, Lattra H.; Dhall, Deepti; Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Weiser, Martin R.; Landmann, Ron; Temple, Larissa; Guillem, Jose G.; Paty, Philip B.; Wong, Douglas] Mem Sloan Kettering Canc Ctr, Colorectal Surg Serv, Dept Surg, New York, NY 10021 USA. [Brenner, Bartich; Saltz, Leonard B.; Leonard, Gregory D.; Kelsen, David] Mem Sloan Kettering Canc Ctr, Dept Med, Gastrointestinal Oncol Serv, New York, NY 10021 USA. [Adsaj, N. Volkan] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Stelow, Edward B.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. [Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Klimstra, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA. EM klimstrd@mskcc.org OI Shia, Jinru/0000-0002-4351-2511; Saltz, Leonard/0000-0001-8353-4670 NR 27 TC 66 Z9 74 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAY PY 2008 VL 32 IS 5 BP 719 EP 731 DI 10.1097/PAS.0b013e318159371c PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 296QB UT WOS:000255559800008 PM 18360283 ER PT J AU McDonald, R Smith, J Meyers, K Mathias, R Portale, A Ikle, D Morrison, Y Bridges, N Harmon, W AF McDonald, Ruth Smith, Jodi Meyers, Kevin Mathias, Robert Portale, Anthony Ikle, David Morrison, Yvonne Bridges, Nancy Harmon, William TI A phase II exploratory study to evaluate the safety of induction therapy with Campath-1H((R)), combined with chronic immunnsuppression with MMF and sirolimus: A study of the cooperative clinical trials in pediatric transplantation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [McDonald, Ruth; Smith, Jodi] Univ Washington, Boston, MA USA. [Meyers, Kevin] CHOP, Boston, MA USA. [Mathias, Robert] Nemours Childrens Serv, Boston, MA USA. [Portale, Anthony] UCSF, Boston, MA USA. [Ikle, David] PPD, Boston, MA USA. [Morrison, Yvonne; Bridges, Nancy] NIAID, NIH, Boston, MA USA. [Harmon, William] Childrens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 192 EP 192 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200052 ER PT J AU Sarwal, M Benfield, M Ettenger, R Dharnidharka, V Mathias, R McDonald, R Harmon, W Kershaw, D Vehaskari, V Kamil, E Baluarte, H Warady, B Ikle, D Bridges, N Salvatierra, O AF Sarwal, Minnie Benfield, M. Ettenger, R. Dharnidharka, V. Mathias, R. McDonald, R. Harmon, W. Kershaw, D. Vehaskari, V. Kamil, E. Baluarte, H. Warady, B. Ikle, D. Bridges, N. Salvatierra, O. TI One year results of a prospective, randomized, Multicenter trial of steroid avoidance in pediatric renal transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Sarwal, Minnie] NIAID, CCTPT, NIH, Bethesda, MD USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 192 EP 193 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200053 ER PT J AU Weaver, TA Charafeddine, AH Agarwal, A Leopardi, F Kampen, R Starost, MF Larsen, CP Kirk, AD AF Weaver, T. A. Charafeddine, A. H. Agarwal, A. Leopardi, F. Kampen, R. Starost, M. F. Larsen, C. P. Kirk, A. D. TI Targeting of costimulation blockade resistant T effector memory (TEM) cells in non-human primate renal transplantation with LFA-3-Ig (alefacept) prolongs allograft survival SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Weaver, T. A.; Charafeddine, A. H.; Agarwal, A.; Leopardi, F.; Kampen, R.; Larsen, C. P.; Kirk, A. D.] Emory Transplant Ctr, Atlanta, GA USA. [Starost, M. F.] NIH, Bethesda, MD USA. RI Kirk, Allan/B-6905-2012; Larsen, Christian/B-6906-2012 OI Larsen, Christian/0000-0001-6573-2649 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 204 EP 205 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200095 ER PT J AU Olthoff, KM Abecassis, MM Emond, JC Merion, RM Gillespie, BW Tong, L AF Olthoff, K. M. Abecassis, M. M. Emond, J. C. Merion, R. M. Gillespie, B. W. Tong, L. TI Comparison of A2ALL and national experience with adult-to-adult living donor liver transplantation (AALDLT) outcomes: Analysis of center experience and mortality risk factors. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Olthoff, K. M.; Abecassis, M. M.; Emond, J. C.; Merion, R. M.; Gillespie, B. W.; Tong, L.] NIDDK, A2ALL Study Grp, NIH, Bethesda, MD 20892 USA. RI Abecassis, Michael/F-7977-2011 NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 224 EP 224 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200173 ER PT J AU Friedman, AL Friedman, EA Macrae, J Eggers, P AF Friedman, Amy L. Friedman, Eli A. Macrae, Jeanne Eggers, Paul TI Transplantation improves survival for ESRD patients across the body mass index spectrum SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Friedman, Amy L.] SUNY Upstate Med Univ, Syracuse, NY USA. [Friedman, Eli A.; Macrae, Jeanne] Suny Downstate Med Ctr, Brooklyn, NY USA. [Eggers, Paul] NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 241 EP 241 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200238 ER PT J AU Shaked, A Ghobrial, RM Merion, RM Shearon, TH Emond, JC Fair, JH Fisher, RA Kulik, LM Pruett, TL Terrault, NA AF Shaked, A. Ghobrial, R. M. Merion, R. M. Shearon, T. H. Emond, J. C. Fair, J. H. Fisher, R. A. Kulik, L. M. Pruett, T. L. Terrault, N. A. TI Association of cold ischemia time and acute rejection after living donor and deceased donor liver transplantation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Shaked, A.; Ghobrial, R. M.; Merion, R. M.; Shearon, T. H.; Emond, J. C.; Fair, J. H.; Fisher, R. A.; Kulik, L. M.; Pruett, T. L.; Terrault, N. A.] NIDDK, A2ALL Study Grp, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 245 EP 245 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200253 ER PT J AU Thuillier, R Cheng, O Mannon, RB AF Thuillier, Raphael Cheng, Orlena Mannon, Roslyn B. TI Under a mac attack: Macrophages are an important agent of fibrosis in human kidney allografts SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Thuillier, Raphael; Cheng, Orlena; Mannon, Roslyn B.] NIDDK, NIH, Kidney Dis Branch, Bethesda, MD USA. RI thuillier, raphael/P-5709-2016 OI thuillier, raphael/0000-0002-7482-0031 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 251 EP 252 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200278 ER PT J AU Haksworth, JS Brown, TS Leeser, DB Stojadinovic, A Tadaki, DK Cheng, O Mannon, RB Elster, EA AF Haksworth, Jason S. Brown, Trevor S. Leeser, David B. Stojadinovic, Alexander Tadaki, Doug K. Cheng, Orlena Mannon, Roz B. Elster, Eric A. TI Probabilistic (Bayesian) modeling of gene expression in transplant glomerulopathy SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Haksworth, Jason S.; Leeser, David B.; Stojadinovic, Alexander] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Brown, Trevor S.; Tadaki, Doug K.; Elster, Eric A.] USN, Med Res Ctr, Silver Spring, MD USA. [Cheng, Orlena; Mannon, Roz B.] NIDDK, NIH, Bethesda, MD USA. [Elster, Eric A.] Natl Naval Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 275 EP 275 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200366 ER PT J AU Gillespie, BW Merion, RM Ojo, AO Shaked, A Brown, RS Nielsen, CA Berg, CL Ortiz-Rios, E Abecassis, MM Ashworth, AS Freise, CE Ghobrial, RM Trotter, JF Everhart, JE AF Gillespie, B. W. Merion, R. M. Ojo, A. O. Shaked, A. Brown, R. S. Nielsen, C. A. Berg, C. L. Ortiz-Rios, E. Abecassis, M. M. Ashworth, A. S. Freise, C. E. Ghobrial, R. M. Trotter, J. F. Everhart, J. E. TI Comparison of patient information in the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the scientific registry of transplant recipients (SRTR) database SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Gillespie, B. W.; Merion, R. M.; Ojo, A. O.; Shaked, A.; Brown, R. S.; Nielsen, C. A.; Berg, C. L.; Ortiz-Rios, E.; Abecassis, M. M.; Ashworth, A. S.; Freise, C. E.; Ghobrial, R. M.; Trotter, J. F.; Everhart, J. E.] NIDDK, A2ALL Study Grp, NIH, Bethesda, MD 20892 USA. RI Abecassis, Michael/F-7977-2011 NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 289 EP 289 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200415 ER PT J AU Cravedi, P Cheng, O Kirk, AD Kleiner, D Mannon, RB AF Cravedi, P. Cheng, O. Kirk, A. D. Kleiner, D. Mannon, R. B. TI Discovering what the eye can't see: Gene expression in baseline biopsies of kidney allografts SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Cravedi, P.; Cheng, O.; Mannon, R. B.] NIDDK, NIH, Bethesda, MD USA. [Kirk, A. D.] NCI, NIH, Bethesda, MD 20892 USA. [Kleiner, D.] Emory Univ Hosp, Div Transplantat, Atlanta, GA 30322 USA. RI Kirk, Allan/B-6905-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 336 EP 336 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763200591 ER PT J AU Chakkera, H Raza, S Wolford, J Vella, A Hanson, R Weil, J Heilman, R Mulliean, D Mazur, M Reddy, S Moss, A Mekeel, K Cerhan, J AF Chakkera, H. Raza, S. Wolford, J. Vella, A. Hanson, R. Weil, J. Heilman, R. Mulliean, D. Mazur, M. Reddy, S. Moss, A. Mekeel, K. Cerhan, J. TI Association of traditional risk factors and genetic polymorphisms with new onset diabetes mellitus (NODM) in kidney transplant recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Chakkera, H.; Raza, S.; Weil, J.; Heilman, R.; Mulliean, D.; Mazur, M.; Reddy, S.; Moss, A.; Mekeel, K.] Mayo Clin, Scottsdale, AZ USA. [Vella, A.; Cerhan, J.] Mayo Clin, Rochester, MN USA. [Hanson, R.] NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 360 EP 360 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763201093 ER PT J AU Strom, TB Suthanthiran, M Ikle, D Putheti, P Ding, R Bridges, ND Sayegh, MH Harmon, WE AF Strom, Terry B. Suthanthiran, Manikkam Ikle, David Putheti, P. Ding, R. Bridges, Nancy D. Sayegh, Mohamed H. Harmon, William E. TI Prediction of acute renal allograft rejection by gene expression in blood, urine and graft biopsies SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Strom, Terry B.; Putheti, P.; Sayegh, Mohamed H.; Harmon, William E.] Harvard Univ, Sch Med, Boston, MA USA. [Suthanthiran, Manikkam] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Ikle, David] PPD Corp, Wilmington, NC USA. [Bridges, Nancy D.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 390 EP 390 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763201207 ER PT J AU Hurst, FP Neff, RT Falta, EM Parker, PM Agodoa, LY Abbott, KC AF Hurst, Frank P. Neff, Robert T. Falta, Edward M. Parker, Patrick M. Agodoa, Lawrence Y. Abbott, Kevin C. TI Incidence, predictors, and associated outcomes of benign prostatic hypertrophy after kidney transplantation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Hurst, Frank P.; Neff, Robert T.; Abbott, Kevin C.] Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. [Falta, Edward M.; Parker, Patrick M.] Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. [Agodoa, Lawrence Y.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 450 EP 450 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763201444 ER PT J AU Charafeddine, AH Gunay-Aygun, M Weaver, TA Maynard, DM Agarwal, A Lwakoshi, N Gahl, WA Kirk, AD AF Charafeddine, Ali H. Gunay-Aygun, Meral Weaver, Timothy A. Maynard, Dawn M. Agarwal, Avi Lwakoshi, Neal Gahl, William A. Kirk, Allan D. TI Compartmentalization of platelet derived CD154: Implications for clinical correlation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Charafeddine, Ali H.; Weaver, Timothy A.; Agarwal, Avi; Lwakoshi, Neal; Kirk, Allan D.] Emory Univ, Atlanta, GA 30322 USA. [Gunay-Aygun, Meral; Maynard, Dawn M.; Gahl, William A.; Kirk, Allan D.] NHGRI, NIH, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 494 EP 494 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763201614 ER PT J AU Sugimoto, R Nakao, A Kohmoto, J Wang, Y Gladwin, MT Billiar, TR McCurry, KR AF Sugimoto, Ryujiro Nakao, Atsunori Kohmoto, Junichi Wang, Yinna Gladwin, Mark T. Billiar, Timothy R. McCurry, Kenneth R. TI Nitrite protects rat lung grafts from ischemia/reperfusion injury via nitric oxide SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Sugimoto, Ryujiro; Nakao, Atsunori; Kohmoto, Junichi; Wang, Yinna; McCurry, Kenneth R.] Univ Pittsburgh, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. [Gladwin, Mark T.] NIH, Vasc Med Branch, Bethesda, MD 20892 USA. [Gladwin, Mark T.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Billiar, Timothy R.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 498 EP 498 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763202013 ER PT J AU Mohiuddin, M Corcoran, P Singh, A Robert, H Thomas, M Eckhaus, M Horvath, K AF Mohiuddin, Muhammad Corcoran, Philip Singh, Avneesh Robert, Hoyt Thomas, Marvin Eckhaus, Michael Horvath, Keith TI Pig to baboon cardiac xenotransplantation: Do hearts from all strains of pigs undergo hyperacute rejection? Not in our experience SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Mohiuddin, Muhammad; Corcoran, Philip; Singh, Avneesh; Horvath, Keith] NHLBI, NIH, Cariothorac Surg Res Program, Bethesda, MD USA. [Robert, Hoyt] NHLBI, NIH, LAMS, Bethesda, MD 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 BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 562 EP 562 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763202257 ER PT J AU Singh, AK Horvath, KA Mohiuddin, MM AF Singh, Avneesh K. Horvath, Keith A. Mohiuddin, Muhammad M. TI Potential role of tregs in xenotransplantation: Ex-vivo expanded Tregs, in presence of rapamycin effectively suppress pig to primate xenogeneic immune response SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Singh, Avneesh K.; Horvath, Keith A.; Mohiuddin, Muhammad M.] NHLBI, NIH, Cardiiothorac Surg Res Program, Bethesda, MD 20892 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 BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 562 EP 562 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763202259 ER PT J AU Singh, KA Kampen, R Kirk, AD AF Singh, Kimberly A. Kampen, Robert Kirk, Allan D. TI Renal tubule cell derived M-CSF is a local informant of renal damage and potentates monocyte recruitment and activation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT 8th American Transplant Congress CY MAY 31-JUN 04, 2008 CL Toronto, CANADA SP Amer Soc Transplant Surg, Amer Soc Transplantat C1 [Singh, Kimberly A.; Kampen, Robert; Kirk, Allan D.] Emory Univ, Atlanta, GA 30322 USA. [Singh, Kimberly A.; Kampen, Robert; Kirk, Allan D.] NIDDK, NIH, Bethesda, MD USA. RI Kirk, Allan/B-6905-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 SU 2 BP 575 EP 575 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 299NV UT WOS:000255763202310 ER PT J AU McDonald, RA Smith, JM Ho, M Lindblad, R Ikle, D Grimm, P Wyatt, R Arar, M Liereman, D Bridges, N Harmon, W AF McDonald, R. A. Smith, J. M. Ho, M. Lindblad, R. Ikle, D. Grimm, P. Wyatt, R. Arar, M. Liereman, D. Bridges, N. Harmon, W. CA CCTPT Study Grp TI Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE EBV; pediatric; PTLD; renal transplant ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; EPSTEIN-BARR-VIRUS; SINGLE-CENTER; RISK FACTOR; EB VIRUS; IMMUNOSUPPRESSION; ANTIBODIES; INFECTIONS; MALIGNANCY; TACROLIMUS AB Pediatric renal transplant recipients were enrolled in a multicenter, randomized, double-blind trial of steroid withdrawal. Subjects received basiliximab, calcineurin inhibitor, sirolimus and steroids. Of 274 subjects enrolled, 19 (6.9%) subjects developed posttransplant lymphoproliferative disorder (PTLD). The relative hazard (RH) for PTLD was 5.3-fold higher in children aged <= 5 versus those > 12 years (p = 0.0017). EBV seronegative subjects had a 4.7-fold higher RH compared to EBV positive subjects (p = 0.02). Among EBV donor+/recipient- (D+/R-) subjects, the RH increased by 6.1-fold (p = 0.0001). In a multivariate model, risk factors included recipient age <= 5 years (RH 3.2, 95% CI: 1.1-9.6, p = 0.034) and EBV D+/R- status (RH 7.7, 95% CI: 1.6-35.9, p = 0.010). Of 19 patients with PTLD, 17 are alive with functioning grafts and 2 lost their grafts, 1 of whom subsequently died of recurrent PTLD. This 'robust' immunosuppression protocol was associated with low rejection rates but an unacceptably high incidence of PTLD. The combination of basiliximab, calcineurin inhibitor, sirolimus and steroids resulted in over-immunosuppression in a high-risk pediatric population and we do not recommend its use. Future studies must include routine viral monitoring to permit early identification of viral activity and a protocol driven reduction of immunosuppression aimed at avoiding complications. C1 [McDonald, R. A.; Smith, J. M.] Univ Washington, Seattle, WA 98195 USA. [McDonald, R. A.; Smith, J. M.] Childrens Hosp, Seattle, WA USA. [McDonald, R. A.; Smith, J. M.] Reg Med Ctr, Seattle, WA USA. [Ho, M.; Lindblad, R.] EMMES Corp, Rockville, MD USA. [Ikle, D.] PPD Inc, Wilmington, NC USA. [Grimm, P.] Univ Calif San Diego, San Diego, CA 92103 USA. [Wyatt, R.] Bonheur Childrens Med Ctr, Memphis, TN USA. [Arar, M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Liereman, D.] British Columbia Childrens Hosp, Vancouver, BC V6H 3V4, Canada. [Bridges, N.] NIAID, Bethesda, MD 20892 USA. [Harmon, W.] Childrens Hosp, Boston, MA 02115 USA. RP McDonald, RA (reprint author), Univ Washington, Seattle, WA 98195 USA. EM ruth.mcdonald@seattlechildrens.org OI Wyatt, Robert/0000-0001-6077-0259 FU PHS HHS [U01-A1-46135] NR 21 TC 75 Z9 75 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2008 VL 8 IS 5 BP 984 EP 989 DI 10.1111/j.1600-6143.2008.02167.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 288LS UT WOS:000254988500012 PM 18416737 ER PT J AU Perdivara, I Deterding, L Moise, A Tomer, KB Przybylski, M AF Perdivara, Irina Deterding, Leesa Moise, Adrian Tomer, Kenneth B. Przybylski, Michael TI Determination of primary structure and microheterogeneity of a beta-amyloid plaque-specific antibody using high-performance LC-tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE beta-amyloid antibody; plaque specific; de novo sequence determination; microheterogeneity; CDR variations; LC-MS; MS ID MONOCLONAL-ANTIBODY; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; OX40 LIGAND; IDENTIFICATION; EXPRESSION; CELLS; IONIZATION; RESOLUTION; RESIDUES AB Using the bottom-up approach and liquid chromatography (LC) in combination with mass spectrometry, the primary structure and sequence microheterogeneity of a plaque-specific anti-beta-amyloid (1-17) monoclonal antibody (clone 6E10) was characterized. This study describes the extent of structural information directly attainable by a high-performance LC-tandem mass spectrometric method in combination with both protein database searching and de novo sequence determination. Using trypsin and chymotrypsin for enzymatic digestion, 95% sequence coverage of the light chain and 82% sequence coverage of the heavy chain of the 6E10 antibody were obtained. The primary structure determination of a large number of peptides from the antibody variable regions was obtained through de novo interpretation of the data. In addition, N-terminal truncations of the heavy chain were identified as well as low levels of pyroglutamic acid formation. Surprisingly, pronounced sequence microheterogeneities were determined for the CDR 2 region of the light chain, indicating that changes at the protein level derived from somatic hypermutation of the Ig V-L genes in mature B-cells might contribute to unexpected structural diversity. Furthermore, the major glycoforms at the conserved heavy chain N-glycosylation site, Asn-292, were determined to be core-fucosylated, biantennary, complex-type structures containing zero to two galactose residues. C1 [Perdivara, Irina; Moise, Adrian; Przybylski, Michael] Univ Konstanz, Dept Chem, Lab Analyt Chem & Biopolymer Struct Anal, D-78457 Constance, Germany. [Perdivara, Irina; Deterding, Leesa; Tomer, Kenneth B.] NIEHS, NIH, Mass Spectrometry Grp, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Przybylski, M (reprint author), Univ Konstanz, Dept Chem, Lab Analyt Chem & Biopolymer Struct Anal, D-78457 Constance, Germany. EM Michael.Przybylski@uni-konstanz.de RI Tomer, Kenneth/E-8018-2013; OI Moise, Adrian/0000-0001-5677-2454 FU Intramural NIH HHS [Z01 ES050171-08] NR 35 TC 9 Z9 9 U1 1 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAY PY 2008 VL 391 IS 1 BP 325 EP 336 DI 10.1007/s00216-008-1941-z PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 291HJ UT WOS:000255185300030 PM 18369607 ER PT J AU Ho, JTC White, JF Grisshammer, R Hess, S AF Ho, Jenny T. C. White, Jim F. Grisshammer, Reinhard Hess, Sonja TI Analysis of a G protein-coupled receptor for neurotensin by liquid chromatography-electro spray ionization-mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE integral membrane protein; intact protein; detergents; Electrospray ionization-mass spectrometry (ESI-MS); G protein-coupled receptor (GPCR); neurotensin receptor ID INTEGRAL MEMBRANE-PROTEINS; POSTTRANSLATIONAL MODIFICATIONS; HYDROPHOBIC PROTEINS; OPIOID RECEPTOR; BINDING-SITE; RHODOPSIN; PURIFICATION; PEPTIDES; IDENTIFICATION; LEVEL AB The type 1 neurotensin receptor (NTS1) belongs to the G protein-coupled receptor (GPCR) family. GPCRs are involved in important physiological processes, but for many GPCRs ligand binding sites and other structural features have yet to be elucidated. Comprehensive analyses by mass spectrometry (MS) could address such issues, but they are complicated by the hydrophobic nature of the receptors. Recombinant NTS1 must be purified in the presence of detergents to maintain solubility and functionality of the receptor, to allow testing of ligand, or to allow G protein interaction. However, detergents are detrimental to MS analyses. Hence, steps need to be taken to substitute the detergents with MS-compatible polar/organic solvents. Here we report the characterization of NTSI by electrospray ionization (ESI)-MS with emphasis on methods to transfer intact NTSI or its proteolytic peptides into compatible solvents by protein precipitation and liquid chromatography (LC) prior to ESI-MS analyses. Molecular mass measurement of intact recombinant NTS1 was performed using a mixture of chloroform/methanol/aqueous trifluoroacetic acid as the mobile phase for size exclusion chromatographyESI-MS analysis. In a separate experiment, NTSI was digested with a combination of cyanogen bromide and trypsin and/or chymotrypsin. Subsequent reversed phase LC-ESI-tandem MS analysis resulted in greater than 80% sequence coverage of the NTSI protein, including all seven transmembrane domains. This work represents the first comprehensive analysis of recombinant NTS1 using MS. (c) 2008 Elsevier Inc. All rights reserved. C1 [Ho, Jenny T. C.; Hess, Sonja] CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA. [White, Jim F.; Grisshammer, Reinhard] NINDS, Membrane Protein Struct & Func Unit, NIH, US Dept HHS, Rockville, MD 20852 USA. RP Hess, S (reprint author), CALTECH, Beckman Inst, Proteome Explorat Lab, MC 139-74, Pasadena, CA 91125 USA. EM shess@caltech.edu RI Hess, Sonja/K-4842-2013; Grisshammer, Reinhard/C-3089-2015 OI Hess, Sonja/0000-0002-5904-9816; FU Intramural NIH HHS [Z01 DK070004-04] NR 38 TC 9 Z9 9 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 EI 1096-0309 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 1 PY 2008 VL 376 IS 1 BP 13 EP 24 DI 10.1016/j.ab.2007.12.025 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 290DS UT WOS:000255104100002 PM 18294946 ER PT J AU Senthilselvan, A Rennie, D Chenard, L Burch, LH Babiuk, L Schwartz, DA Dosman, JA AF Senthilselvan, Ambikaipakan Rennie, Donna Chenard, Liliane Burch, Lauranell H. Babiuk, Lorne Schwartz, David A. Dosman, James A. TI Association of polymorphisms of toll-like receptor 4 with a reduced prevalence of hay fever and atopy SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR-4; TLR4; ASTHMA; MUTATIONS; GENDER; SHOCK; HYPORESPONSIVENESS; PHENOTYPES; RESPONSES; CHILDREN AB Background: The response to innate immune stimuli seems to be critical to conditioning adaptive immunity. Early exposure to endotoxin initiates immune responses that have been shown to alter the risk of asthma and allergic diseases. The toll-like receptor 4 (TLR4) gene encodes the principal innate immunity receptor in humans for bacterial endotoxin. Polymorphisms in the TLR4 gene may regulate the effects of endotoxin exposure and could play a role in the development of asthma and atopy-related phenotypes. Objective: To investigate the association between TLR4 polymorphisms and allergic phenotypes in nonsmokers. Methods: The data from 915 nonsmoking students were available for the study. The TLR4 299 and 399 polymorphisms were genotyped using mouthwash samples. The TLR4 299 and 399 polymorphisms were grouped together to define the TLR4 polymorphic group. Skin prick tests were conducted in a subgroup of healthy participants. A brief questionnaire was administered to determine demographic characteristics and chronic health conditions. Results: The prevalence of hay fever was 0% in the TLR4 polymorphic group and 7.5% in the wild-type group (P = .01). After controlling for age group and sex using logistic regression, the odds of having hay fever were reduced by 88% (P = .009) in the TLR4 polymorphic group compared with the wild-type group. In a subgroup analysis, the association between TLR4 polymorphisms and atopy was only observed among females. Conclusions: To our knowledge, this study is the first to report an association between TLR4 polymorphisms and atopy-related phenotypes in a nonsmoking population. Further investigation of the role of TLR4 polymorphisms in asthma and atopy-related phenotypes is warranted. C1 [Senthilselvan, Ambikaipakan] Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, Edmonton, AB T6G 2G3, Canada. [Rennie, Donna; Dosman, James A.] Univ Saskatchewan, Canadian Ctr Hlth Safety Agr, Saskatoon, SK, Canada. [Burch, Lauranell H.; Schwartz, David A.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Babiuk, Lorne] Univ Saskatchewan, Vaccine & Infect Dis Org, Saskatoon, SK, Canada. [Dosman, James A.] Univ Saskatchewan, Dept Med, Saskatoon, SK S7N 0W0, Canada. RP Senthilselvan, A (reprint author), Univ Alberta, Sch Publ Hlth, Dept Publ Hlth Sci, 13 106B Clin Sci Bldg, Edmonton, AB T6G 2G3, Canada. EM sentil@ualberta.ca FU Intramural NIH HHS NR 27 TC 25 Z9 26 U1 0 U2 2 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD MAY PY 2008 VL 100 IS 5 BP 463 EP 468 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 296EY UT WOS:000255527500011 PM 18517079 ER PT J AU Hariri, G Zhang, Y Fu, A Han, Z Brechbiel, M Tantawy, MN Peterson, TE Mernaugh, R Hallahan, D AF Hariri, G. Zhang, Y. Fu, A. Han, Z. Brechbiel, M. Tantawy, M. N. Peterson, T. E. Mernaugh, R. Hallahan, D. TI Radiation-guided P-selectin antibody targeted to lung cancer SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE P-selectin; radiation; lung cancer; optical imaging; nuclear imaging ID TUMOR BLOOD-VESSELS; IN-VIVO; MONOCLONAL-ANTIBODY; DRUG-DELIVERY; INTEGRIN ALPHA(V)BETA(3); EXPRESSION; THERAPY; MOUSE; XENOGRAFTS AB Purpose: P-selectin expression is significantly increased in tumor microvasculature following exposure to ionizing radiation. The purpose of this study was to image radiation-induced P-selectin expression in vivo using optical imaging and gamma camera imaging in a heterotopic lung cancer model by using ScFv antibodies to P-selectin. Procedures: In vitro studies using endothelial cells were done using 3 Gy radiation and selected ScFv antibodies to P-selectin. In vivo studies were performed using Lewis lung carcinoma cells subcutaneously injected into the hind limbs of nude mice. Mice were treated with 6 Gy radiation and sham radiation 10 days post-inoculation. P-selectin expression was assessed with near-infrared imaging using Cy7 labeled antibody, and gamma camera imaging using In-111-DTPA labeled antibody. Results: In vitro studies showed antibody binding to P-selectin in radiation treated endothelial cells. In vivo optical imaging and gamma camera imaging studies showed significant tumor-specific binding to P-selectin in irradiated tumors compared to unirradiated tumors. Conclusions: Optical imaging and gamma camera imaging are effective methods for visualizing in vivo targeting of radiation-induced P-selectin in lung tumors. This study suggests that fluorescent-labeled and radiolabeled ScFv antibodies can be used to target radiation-induced P-selectin for the tumor-specific delivery of therapeutic drugs and radionuclides in vivo. C1 [Hariri, G.; Zhang, Y.; Fu, A.; Han, Z.; Hallahan, D.] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA. [Brechbiel, M.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Tantawy, M. N.; Peterson, T. E.] Vanderbilt Univ, Vanderbilt Univ Inst Imaging Sci, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Mernaugh, R.; Hallahan, D.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. RP Hallahan, D (reprint author), Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA. EM dennis.hallahan@vanderbilt.edu FU Intramural NIH HHS [Z01 SC006353-24]; NCI NIH HHS [R01-CA112385, R01-CA1256757, R21 CA128456, R21-CA128456, P30 CA068485, P30-CA68485, R01 CA112385] NR 38 TC 14 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD MAY PY 2008 VL 36 IS 5 BP 821 EP 830 DI 10.1007/s10439-008-9444-9 PG 10 WC Engineering, Biomedical SC Engineering GA 285CV UT WOS:000254755800014 PM 18273706 ER PT J AU Howard, R Gilbert, E Lynch, CF Hall, P Storm, H Holowaty, E Pukkala, E Langmark, F Kaijser, M Andersson, M Joensuu, H Fossa, SD Allan, JM Travis, LB AF Howard, Regan Gilbert, Ethel Lynch, Charles F. Hall, Per Storm, Hans Holowaty, Eric Pukkala, Eero Langmark, Froydis Kaijser, Magnus Andersson, Michael Joensuu, Heikki Fossa, Sophie D. Allan, James M. Travis, Lois B. TI Risk of leukemia among survivors of testicular cancer: A population-based study of 42,722 patients SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE testicular neoplasms; leukemia; second primary neoplasms; cohort studies ID LONG-TERM SURVIVORS; GERM-CELL TUMORS; 2ND CANCERS; ETOPOSIDE; COMPLETENESS; ADJUSTMENT; RADIATION; SEMINOMA AB PURPOSE: The aim of this study is to quantify excess absolute risk (EAR) and excess relative risk (ERR) of secondary leukemia among a large population-based group of testicular cancer survivors. METHODS: We identified 42,722 1-year survivors of testicular cancer within 14 population-based cancer registries in Europe and North America (1943-2002). Poisson regression analysis was used to model EAR (per 100,000 person-years [PY]) and ERR of secondary leukemia. Cumulative risks were calculated using a competing risk model. RESULTS: Secondary leukemia developed in 89 patients (EAR = 10.8 per 100,000 PY, 95% confidence interval [CI] = 7.6-14.6; ERR = 1.6, 95%CI = 1.0-2.2). Statistically significantly elevated risks were observed for acute myeloid leukemia (AML) (EAR = 7.2, 95%CI = 4.7-10.2) and acute lymphoblastic leukemia (EAR = 1.3, 95%CI = 0.4-2.8). In multivariate analyses, AML risk was higher among patients whose initial management included chemotherapy compared to those receiving radiotherapy alone (p = 0.1). Excess cumulative leukemia risk was approximately 0.23% by 30 years after testicular cancer diagnosis. CONCLUSIONS: Although ERR of leukemia following testicular cancer is large, EAR and cumulative risk, which are better gauges of the population burden, are small. C1 [Howard, Regan; Gilbert, Ethel; Travis, Lois B.] NCI, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Lynch, Charles F.] State Hlth Registry Iowa, Iowa City, IA USA. [Hall, Per; Kaijser, Magnus] Karolinska Inst, Stockholm, Sweden. [Storm, Hans; Andersson, Michael] Danish Canc Soc, Copenhagen, Denmark. [Holowaty, Eric] Canc Care Ontario, Toronto, ON, Canada. [Pukkala, Eero] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Langmark, Froydis] Norwegian Canc Registry, Oslo, Norway. [Joensuu, Heikki] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Fossa, Sophie D.] Norwegian Radium Hosp, Oslo, Norway. [Allan, James M.] Univ Newcastle Upon Tyne, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Howard, R (reprint author), NCI, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Execut Plaza S,Suite 7091, Bethesda, MD 20892 USA. EM reganho@mail.nih.gov RI Allan, James/B-4448-2009; OI Storm, Hans/0000-0001-7223-8198 FU Intramural NIH HHS [ZIA CP010131-18] NR 22 TC 21 Z9 21 U1 0 U2 2 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 MAY PY 2008 VL 18 IS 5 BP 416 EP 421 DI 10.1016/j.annepidem.2008.01.003 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 296GG UT WOS:000255530900011 PM 18433667 ER PT J AU Li, QZ Zheng, G Li, ZH Yu, K AF Li, Qizhai Zheng, Gang Li, Zhaohai Yu, Kai TI Efficient approximation of P-value of the maximum of correlated tests, with applications to genome-wide association studies SO ANNALS OF HUMAN GENETICS LA English DT Article DE MAX; robust genome; wide scan; case; control ID SAMPLE-SIZE; GENES; RISK; DISEASES; CANCER; POWER; LOCI AB Genome-wide association study (GWAS), typically involving 100,000 to 500,000 single-nucleotide polymorphisms (SNPs), is a powerful approach to identify disease susceptibility loci. In a GWAS, single-marker analysis, which tests one SNP at a time, is usually used as the first stage to screen SNPs across the genome in order to identify a small fraction of promising SNPs with relatively low p-values for further and more focused studies. For single-marker analysis, the trend test derived for an additive genetic model is often used. This may not be robust when the additive assumption is not appropriate for the true underlying disease model. A robust test, MAX, based on the maximum of three trend test statistics derived for recessive, additive, and dominant models, has been proposed recently for GWAS. But its p-value has to be evaluated through a resampling-based procedure, which is computationally challenging for the analysis of GWAS. Obtaining the p-value for MAX with adjustment for the covariates can be even more time-consuming. In this article, we provide a simple approximation for the p-value of the MAX test with or without adjusting for the covariates. The new method avoids resampling steps and thus makes the MAX test readily applicable to GWAS. We use simulation studies as well as real datasets on 17 confirmed disease-associated SNPs to assess the accuracy of the proposed method. We also apply the method to the GWAS of coronary artery disease. C1 [Li, Qizhai; Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100080, Peoples R China. [Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Zheng, Gang] NHLBI, Off Biostat Res, Off Director, Bethesda, MD 20892 USA. [Li, Zhaohai] NICHHD, Biomet & Math Stat Branch, Bethesda, MD 20892 USA. RP Yu, K (reprint author), 6120 Execut Blvd,Room 8050, Rockville, MD 20852 USA. EM yuka@mail.nih.gov FU Intramural NIH HHS; NEI NIH HHS [EY014478] NR 27 TC 43 Z9 44 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD MAY PY 2008 VL 72 BP 397 EP 406 DI 10.1111/j.1469-1809.2008.00437.x PN 3 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 287OT UT WOS:000254927100012 PM 18318785 ER PT J AU Ingle, JN Tu, D Pater, JL Muss, HB Martino, S Robert, NJ Piccart, MJ Castiglione, M Shepherd, LE Pritchard, KI Livingston, RB Davidson, NE Norton, L Perez, EA Abrams, JS Cameron, DA Palmer, MJ Goss, PE AF Ingle, J. N. Tu, D. Pater, J. L. Muss, H. B. Martino, S. Robert, N. J. Piccart, M. J. Castiglione, M. Shepherd, L. E. Pritchard, K. I. Livingston, R. B. Davidson, N. E. Norton, L. Perez, E. A. Abrams, J. S. Cameron, D. A. Palmer, M. J. Goss, P. E. TI Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCICCTG MA.17 SO ANNALS OF ONCOLOGY LA English DT Article DE extended adjuvant therapy; intent-to-treat; letrozole ID POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; TAMOXIFEN; RECEPTOR AB Background: MA. 17 evaluated letrozole or placebo after 5 years of tamoxifen and showed significant improvement in disease- free survival ( DFS) for letrozole [ hazard ratio ( HR) 0.57, P = 0.00008]. The trial was unblinded and placebo patients were offered letrozole. Patients and methods: An intent- to- treat analysis of all outcomes, before and after unblinding, on the basis of the original randomization was carried out. Results: In all, 5187 patients were randomly allocated to the study at baseline and, at unblinding, 1579 ( 66%) of 2383 placebo patients accepted letrozole. At median follow- up of 64 months ( range 16 - 95), 399 recurrences or contralateral breast cancers ( CLBCs) ( 164 letrozole and 235 placebo) occurred. Four- year DFS was 94.3% ( letrozole) and 91.4% ( placebo) [ HR 0.68, 95% confidence interval ( CI) 0.55 - 0.83, P = 0.0001] and showed superiority for letrozole in both node- positive and - negative patients. Corresponding 4- year distant DFS was 96.3% and 94.9% ( HR 0.80, 95% CI 0.62 - 1.03, P = 0.082). Four- year overall survival was 95.1% for both groups. The annual rate of CLBC was 0.28% for letrozole and 0.46% for placebo patients ( HR 0.61, 95% CI 0.39 - 0.97, P = 0.033). Conclusions: Patients originally randomly assigned to receive letrozole within 3 months of stopping tamoxifen did better than placebo patients in DFS and CLBC, despite 66% of placebo patients taking letrozole after unblinding. C1 [Ingle, J. N.] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA. [Tu, D.; Pater, J. L.; Shepherd, L. E.; Palmer, M. J.] Natl Canc Inst, Canada Trials Grp, Kingston, ON, Canada. [Muss, H. B.] Univ Vermont, Div Hematol Oncol, Burlington, VT USA. [Martino, S.] Angeles Clin & Res Inst, Santa Monica, CA USA. [Robert, N. J.] Inova Fairfax Hosp, Falls Church, VA USA. [Piccart, M. J.] Inst Jules Bordet, Dept Chemotherapy, B-1000 Brussels, Belgium. [Castiglione, M.] Int Breast Canc Study Grp Coordinating Ctr, Bern, Switzerland. [Pritchard, K. I.] Toronto Sunnybrook Reg Canc Ctr, Dept Med, Toronto, ON, Canada. [Livingston, R. B.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Davidson, N. E.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Med, Baltimore, MD USA. [Norton, L.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Perez, E. A.] Mayo Clin, Div Hematol Oncol, Jacksonville, FL USA. [Abrams, J. S.] NCI, Clin Invest Branch, Rockville, MD USA. [Cameron, D. A.] Univ Leeds, Natl Canc Res Network, Leeds, W Yorkshire, England. [Goss, P. E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Ingle, JN (reprint author), Mayo Clin, Div Med Oncol, 200 1st St SW, Rochester, MN 55905 USA. EM ingle.james@mayo.edu OI Norton, Larry/0000-0003-3701-9250 FU NCI NIH HHS [CA25224, CA31946, CA32102, CA21115, CA38926] NR 11 TC 42 Z9 44 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAY PY 2008 VL 19 IS 5 BP 877 EP 882 DI 10.1093/annonc/mdm566 PG 6 WC Oncology SC Oncology GA 296DU UT WOS:000255524500008 PM 18332043 ER PT J AU Guijarro, A Osei-Hyiaman, D Harvey-White, J Kunos, G Suzuki, S Nadtochiy, S Brookes, PS Meguid, MM AF Guijarro, Ana Osei-Hyiaman, Douglas Harvey-White, Judith Kunos, George Suzuki, Susumu Nadtochiy, Sergiy Brookes, Paul S. Meguid, Michael M. TI Sustained weight loss after roux-en-y gastric bypass is characterized by down regulation of endocannabinoids and mitochondrial function SO ANNALS OF SURGERY LA English DT Article ID RECEPTOR ANTAGONIST SR141716; CANNABINOID CB1 RECEPTORS; ACTIVATED PROTEIN-KINASE; VAGAL AFFERENT NEURONS; DIET-INDUCED OBESITY; FOOD-INTAKE; BARIATRIC SURGERY; ENERGY-EXPENDITURE; RAT MODEL; CALORIC RESTRICTION AB Objective: To determine the physiologic importance of endocannabinoids and mitochondrial function in the long-term outcome using a rat model of Roux-en-Y gastric bypass (RYGB) surgery. Background: Sixteen million people are morbidly obese and RYGB surgery is the most effective treatment. Endocannabinoids are implicated in appetite stimulation and regulation of peripheral energy metabolism. We hypothesize that down-regulation of endocannabinoids and alterations in mitochondrial function and hormones favoring catabolism contribute to sustained RYGB-induced weight loss. Methods: Diet-.induced obese Sprague-Dawley rats were randomized to sham-operated obese controls, RYGB, and sham-operated obese pair-fed rats. Body weight and food intake were recorded, and food efficiency was calculated. Endocannabinoid levels in skeletal muscle and liver, muscle mitochondrial respiratory complex I-V content, and hormones concentrations were determined 14 and 28 days postsurgery, reflecting rapid and sustained weight loss periods after RYGB, respectively. Results: Compared with pair-fed controls, RYGB rats had significant reduction in body weight and food efficiency (P < 0.001). Increased cholecystokinin, reduced insulin, leptin, adiponectin, T3, and down-regulation of mitochondrial complex I were evident on day 14 postsurgery. On day 28, leptin, insulin, and T3 remained low, whereas adiponectin and cholecystokinin were normal. Along with complex 1, the endocannabinoids anandamide in muscle (P = 0.003) and 2-arachidonoylglycerol in liver were significantly down-regulated (P < 0.001). Conclusions: The attenuated caloric intake, reduced food efficiency, and normalization of hormonal levels on day 28 post-RYGB were associated with significant down-regulation of endocannabinoids anandamide and 2-arachidonoylglycerol in muscle and liver, respectively. These results suggest a role for endocannabinoids in the mechanism of sustained weight loss and RYGB success, and may have implications for treatment of morbid obesity. C1 [Guijarro, Ana; Suzuki, Susumu; Meguid, Michael M.] SUNY Upstate Med Univ, Univ Hosp, Dept Surg, Neurosci Program,Surg Metab & Nutr Lab, Syracuse, NY 13210 USA. [Osei-Hyiaman, Douglas; Harvey-White, Judith; Kunos, George] NIAAA, Sect Neuroendocrinol, Lab Physiol Studies, NIH, Bethesda, MD USA. [Nadtochiy, Sergiy; Brookes, Paul S.] Univ Rochester, Med Ctr, Dept Anesthesiol, Rochester, NY 14642 USA. [Nadtochiy, Sergiy; Brookes, Paul S.] Univ Rochester, Med Ctr, Mitochondrial Res Interest Grp, Rochester, NY 14642 USA. RP Meguid, MM (reprint author), SUNY Upstate Med Univ, Univ Hosp, Dept Surg, Neurosci Program,Surg Metab & Nutr Lab, 750 E Adams St, Syracuse, NY 13210 USA. EM meguidm@upstate.edu FU Intramural NIH HHS [Z01 AA000350-07]; NHLBI NIH HHS [R01 HL071158, HL071158] NR 75 TC 29 Z9 29 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAY PY 2008 VL 247 IS 5 BP 779 EP 790 DI 10.1097/SLA.0b013e318166fd5f PG 12 WC Surgery SC Surgery GA 294RD UT WOS:000255422300010 PM 18438115 ER PT J AU Isenberg, JS Romeo, MJ Maxhimer, JB Smedley, J Frazier, WA Roberts, DD AF Isenberg, Jeff S. Romeo, Martin J. Maxhimer, Justin B. Smedley, Jeremy Frazier, William A. Roberts, David D. TI Gene silencing of CD47 and antibody ligation of thrombospondin-1 enhance ischemic tissue survival in a porcine model - Implications for human disease SO ANNALS OF SURGERY LA English DT Article ID SMOOTH-MUSCLE-CELLS; PERIPHERAL ARTERIAL-DISEASE; CYSTEINE-GLYCINE RECEPTOR; CRITICAL LIMB ISCHEMIA; SKIN FLAP SURVIVAL; NITRIC-OXIDE; MONOCLONAL-ANTIBODIES; ENDOTHELIAL-CELLS; RESPONSES; EXPRESSION AB Background: Insufficient tissue perfusion underlies many acute and chronic diseases. Tissue perfusion in turn requires adequate blood flow, determined in large part by the relative state of relaxation or constriction of arterial vessels. Nitric oxide (NO) produced by vascular cells modulates blood flow and tissue perfusion by relaxing and dilating arteries. Recently, we reported that the secreted protein thrombospondin-1 (TSPI), through its cell surface receptor CD47, limits the ability of NO to relax and dilate blood vessels and thus decreases tissue perfusion. In the present study, we tested the hypothesis that blocking TSP1-CD47 signaling increases ischemic tissue survival in random cutaneous porcine flaps. Methods: Random cutaneous flaps 2 X 10 cm(2) were raised in white hairless Yucatan miniature pigs and were treated with a monoclonal antibody to TSP1, an antisense morpholino oligonucleotide to CD47 or control agents and tissue survival assessed. Primary vascular smooth muscle cell cultured from Yucatan pigs were also treated with the same agents +/- and an NO donor (DEA/NO) and cGMP quantified. Results: Antibody blockade of TSPI or morpholino suppression of CD47 dramatically enhanced survival of random tissue flaps. These responses correlated with increased blood vessel patency and tissue blood flow on vessel injection studies. NO-stimulated cGMP flux in Yucatan vascular smooth muscle cell was abrogated after antibody or morpholino treatment. Conclusion: Antibody ligation of TSPI or antisense morpholino knock down of CD47 greatly increased tissue survival to ischemia. Given the similarity between porcine and human soft tissues these results suggest significant therapeutic potential for people. C1 [Isenberg, Jeff S.; Romeo, Martin J.; Maxhimer, Justin B.; Roberts, David D.] NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Maxhimer, Justin B.; Smedley, Jeremy] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. [Frazier, William A.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Isenberg, JS (reprint author), NCI, Pathol Lab, Canc Res Ctr, NIH, Bldg 10,2A33, Bethesda, MD 20892 USA. EM isenberj@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS [Z01 SC009172-04, Z01 SC009174-04]; NHLBI NIH HHS [HL54390, R01 HL054390, R56 HL054390]; NIGMS NIH HHS [GM57573, R01 GM057573] NR 50 TC 33 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAY PY 2008 VL 247 IS 5 BP 860 EP 868 DI 10.1097/SLA.0b013e311816c4006 PG 9 WC Surgery SC Surgery GA 294RD UT WOS:000255422300020 PM 18438125 ER PT J AU Brosh, RM AF Brosh, Robert M., Jr. TI DNA repair as a target for anti-cancer therapy SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Editorial Material C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM broshr@grc.nia.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD MAY PY 2008 VL 8 IS 4 BP 350 EP 350 PG 1 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 300FV UT WOS:000255810600001 PM 18473719 ER PT J AU Dexheimer, TS Antony, S Marchand, C Pommier, Y AF Dexheimer, Thomas S. Antony, Smitha Marchand, Christophe Pommier, Yves TI Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article ID STRAND BREAK REPAIR; PHOSPHOLIPASE-D SUPERFAMILY; TOPOISOMERASE-I INHIBITORS; CRYSTAL-STRUCTURE; SPINOCEREBELLAR ATAXIA; COVALENT COMPLEXES; CATALYTIC MECHANISM; CLEAVAGE COMPLEXES; DAMAGED DNA; HUMAN-CELLS AB Tyrosyl-DNA phosphodiesterase 1 ( Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3'-end DNA alterations including 3'-phosphoglycolates and 3'-abasic sites indicating it may function as a general 3'-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy ( SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy. C1 [Dexheimer, Thomas S.; Antony, Smitha; Marchand, Christophe; Pommier, Yves] NIH, Mol Pharmacol Lab, Ctr Canc Res, Natl Canc Inst, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NIH, Mol Pharmacol Lab, Ctr Canc Res, Natl Canc Inst, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Perez , Claudio Alejandro/F-8310-2010; Marchand, Christophe/D-8559-2016 OI Perez , Claudio Alejandro/0000-0001-9688-184X; FU Intramural NIH HHS [Z99 HG999999] NR 77 TC 68 Z9 70 U1 0 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD MAY PY 2008 VL 8 IS 4 BP 381 EP 389 PG 9 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 300FV UT WOS:000255810600005 PM 18473723 ER PT J AU Gupta, R Brosh, RM AF Gupta, Rigu Brosh, Robert M., Jr. TI Helicases as prospective targets for anti-cancer therapy SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Review DE helicase; chemotherapy; anti-cancer drug; DNA repair; genomic instability; cancer; RecQ; Fanconi anemia; Werner syndrome ID WERNER-SYNDROME PROTEIN; INTERSTRAND CROSS-LINKS; SISTER-CHROMATID COHESION; REPAIR GENE POLYMORPHISMS; ROTHMUND-THOMSON-SYNDROME; SQUAMOUS-CELL CARCINOMA; SINGLE-STRANDED-DNA; ATP-BINDING-SITE; S-PHASE ARREST; FANCONI-ANEMIA AB It has been proposed that selective inactivation of a DNA repair pathway may enhance anti-cancer therapies that eliminate cancerous cells through the cytotoxic effects of DNA damaging agents or radiation. Given the unique and critically important roles of DNA helicases in the DNA damage response, DNA repair, and maintenance of genomic stability, a number of strategies currently being explored or in use to combat cancer may be either mediated or enhanced through the modulation of helicase function. The focus of this review will be to examine the roles of helicases in DNA repair that might be suitably targeted by cancer therapeutic approaches. Treatment of cancers with anti-cancer drugs such as small molecule compounds that modulate helicase expression or function is a viable approach to selectively kill cancer cells through the inactivation of helicase-dependent DNA repair pathways, particularly those associated with DNA recombination, replication restart, and cell cycle checkpoint. C1 [Gupta, Rigu; Brosh, Robert M., Jr.] NIA, Lab mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM broshr@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000741-07] NR 112 TC 12 Z9 12 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD MAY PY 2008 VL 8 IS 4 BP 390 EP 401 PG 12 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 300FV UT WOS:000255810600006 PM 18473724 ER PT J AU Litman, R Gupta, R Brosh, RM Cantor, SB AF Litman, Rachel Gupta, Rigu Brosh, Robert M., Jr. Cantor, Sharon B. TI BRCA-FA pathway as a target for anti-tumor drugs SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Fanconi anemia; DNA repair; anti; tumor drug; BRCA ID STRAND BREAK REPAIR; FANCONI-ANEMIA/BRCA PATHWAY; DIRECTED DNA-REPAIR; HOMOLOGOUS RECOMBINATION; GENETIC INSTABILITY; ANTICANCER AGENT; FANCD2 FUNCTIONS; HELICASE BRIP1; S-PHASE; CELLS AB Promising research on DNA repair signaling pathways predicts a new age of anti-tumor drugs. This research was initiated through the discovery and characterization of proteins that functioned together in signaling pathways to sense, respond, and repair DNA damage. It was realized that tumor cells often lacked distinct DNA repair pathways, but simultaneously relied heavily on compensating pathways. More recently, researchers have begun to manipulate these compensating pathways to reign in and kill tumor cells. In a striking example it was shown that tumors derived from mutations in the DNA repair genes, of BRCA-FA pathway, were selectively sensitive to inhibition of the base excision repair pathway. These findings suggest that tumors derived from defects in DNA repair genes will be easier to treat clinically, providing a streamlined and targeted therapy that spares healthy cells. In the future, identifying patients with susceptible tumors and discovering additional DNA repair targets amenable to anti-tumor drugs will have a major impact on the course of cancer treatment. C1 [Litman, Rachel; Cantor, Sharon B.] Univ Massachusetts, Sch Med, Dept Canc Biol, Womens Canc Program,UMASS Mem Canc Ctr, Worcester, MA 01605 USA. [Gupta, Rigu; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Cantor, SB (reprint author), Univ Massachusetts, Sch Med, Dept Canc Biol, Womens Canc Program,UMASS Mem Canc Ctr, 364 Plantat St, Worcester, MA 01605 USA. EM Sharon.Cantor@umassmed.edu FU Intramural NIH HHS [Z01 AG000741-07] NR 47 TC 14 Z9 14 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD MAY PY 2008 VL 8 IS 4 BP 426 EP 430 PG 5 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 300FV UT WOS:000255810600009 PM 18473727 ER PT J AU Cao, YJ Flexner, CW Dunaway, S Park, JG Klingman, K Wiggins, I Conley, J Radebaugh, C Kashuba, AD MacFarland, R Becker, S Hendrix, CW AF Cao, Ying Jun Flexner, Charles W. Dunaway, Shelia Park, Jeong-Gun Klingman, Karin Wiggins, Ilene Conley, Jeanne Radebaugh, Christine Kashuba, Angela D. MacFarland, Ron Becker, Stephen Hendrix, Craig W. TI Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CHEMOKINE RECEPTOR; P-GLYCOPROTEIN; INHIBITOR; CELLS; AMD3100; SAFETY; BLOCKADE AB AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C-max), 934 h . ng/ml (313 to 2,127 h . ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C-max of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers. C1 [Cao, Ying Jun; Flexner, Charles W.; Wiggins, Ilene; Radebaugh, Christine; Hendrix, Craig W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Dunaway, Shelia; Conley, Jeanne] Univ Washington, Seattle, WA 98195 USA. Univ Washington, Seattle, WA 98195 USA. [Dunaway, Shelia; Conley, Jeanne] Harborview Med Ctr, Baltimore, MD USA. [Park, Jeong-Gun] Harvard Univ, Sch Publ Hlth, Frontier Sci & Technol Res Fdn, Boston, MA 02115 USA. [Klingman, Karin] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Kashuba, Angela D.] Univ N Carolina, Chapel Hill, NC USA. [MacFarland, Ron; Becker, Stephen] AnorMED Inc, Langley, BC, Canada. RP Cao, YJ (reprint author), Osler 501,600 N Wolfe St, Baltimore, MD 21287 USA. EM ycao3@jhmi.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU NCRR NIH HHS [M01RR000052, M01RR00037, M01 RR000052, M01 RR000037]; NIAID NIH HHS [AI038855, U01 AI027664, U01 AI027668, U01 AI038855, U01AI027668, U01AI27664] NR 18 TC 8 Z9 8 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2008 VL 52 IS 5 BP 1630 EP 1634 DI 10.1128/AAC.01460-07 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 294RA UT WOS:000255422000007 PM 18285477 ER PT J AU Moore, MD Fu, W Ptak, RG Hu, WS AF Moore, Michael D. Fu, William Ptak, Roger G. Hu, Wei-Shau TI Sub-optimal protease inhibition of HIV-1: Effects on virion morphogenesis and RNA maturation SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 21st International Conference on Antiviral Research CY APR 13-17, 2008 CL Montreal, CANADA SP Int Soc Antiviral Res C1 [Moore, Michael D.; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Fu, William; Ptak, Roger G.] So Res Inst, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2008 VL 78 IS 2 MA 74 BP A45 EP A45 DI 10.1016/j.antiviral.2008.01.088 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 295PN UT WOS:000255486500066 ER PT J AU Viswanathan, P Mueller, N Pattabiraman, N Lee, K Cuny, G Takhampunyal, R Ansarah-Sabrino, C Pierson, T Padmanabhan, R AF Viswanathan, Prasanth Mueller, Niklaus Pattabiraman, Nagarajan Lee, Kyungae Cuny, Gregory Takhampunyal, Ratree Ansarah-Sabrino, Camilo Pierson, Theodore Padmanabhan, R. TI Characterization of small molecule inhibitors of West Nile Virus NS3 Serine Protease SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 21st International Conference on Antiviral Research CY APR 13-17, 2008 CL Montreal, CANADA SP Int Soc Antiviral Res C1 [Viswanathan, Prasanth; Mueller, Niklaus; Takhampunyal, Ratree; Padmanabhan, R.] Georgetown Univ, Dept Microbiol & Immunol, Washington, DC USA. [Pattabiraman, Nagarajan] Georgetown Univ, Dept Oncol, Washington, DC USA. [Lee, Kyungae; Cuny, Gregory] Harvard Univ, Sch Med, New England Reg Ctr Excellence Biodef & Emerging, Boston, MA USA. [Cuny, Gregory] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Boston, MA 02115 USA. [Cuny, Gregory] Harvard Univ, Sch Med, Boston, MA USA. [Ansarah-Sabrino, Camilo; Pierson, Theodore] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RI Pattabiraman, Nagarjan /A-9347-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2008 VL 78 IS 2 MA 88 BP A50 EP A50 DI 10.1016/j.antiviral.2008.01.102 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 295PN UT WOS:000255486500080 ER EF